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{'attachments': [{'url': 'https://downloads.regulations.gov/ATSDR-2026-0133-0003/attachment_1.pdf', 'body': {'text': "## Toxicological Profile for Hexachlorocyclopentadiene (HCCPD)\nDraft for Public Comment\nOctober 2026\n\nU.S. Department of Health and Human Services\nAgency for Toxic Substances and Disease Registry\n\n---\n\n## DISCLAIMER\n\nUse of trade names is for identification only and does not imply endorsement by the Agency for Toxic \nSubstances and Disease Registry, the Public Health Service, or the U.S. Department of Health and Human \nServices.\n\nThis information is distributed solely for the purpose of pre-dissemination for public comment under \napplicable information quality guidelines.  It has not been formally disseminated by the Agency for Toxic \nSubstances and Disease Registry.  It does not represent and should not be construed to represent any \nagency determination or policy.\n\n---\n\n## FOREWORD\n\nThis toxicological profile is prepared in accordance with guidelines developed by the Agency for Toxic \nSubstances and Disease Registry (ATSDR) and the Environmental Protection Agency (EPA).  The \noriginal guidelines were published in the *Federal Register* on April 17, 1987.  Each profile will be revised \nand republished as necessary.\n\nThe ATSDR toxicological profile succinctly characterizes the toxicologic and adverse health effects \ninformation for these toxic substances described therein.  Each peer-reviewed profile identifies and \nreviews the key literature that describes a substance's toxicologic properties.  Other pertinent literature is \nalso presented but is described in less detail than the key studies.  The profile is not intended to be an \nexhaustive document; however, more comprehensive sources of specialty information are referenced.\n\nThe focus of the profiles is on health and toxicologic information; therefore, each toxicological profile \nbegins with a relevance to public health discussion which would allow a public health professional to \nmake a real-time determination of whether the presence of a particular substance in the environment \nposes a potential threat to human health.  The adequacy of information to determine a substance's health \neffects is described in a health effects summary.  Data needs that are of significance to the protection of \npublic health are identified by ATSDR.\n\nEach profile includes the following:\n\n(A) The examination, summary, and interpretation of available toxicologic information and \nepidemiologic evaluations on a toxic substance to ascertain the levels of significant \nhuman exposure for the substance due to associated acute-, intermediate-, and chronicduration exposures;\n\n(B) A determination of whether adequate information on the health effects of each substance \nis available or in the process of development to determine the levels of exposure that \npresent a significant risk to human health due to acute-, intermediate-, and chronicduration exposures; and\n\n(C) Where appropriate, identification of toxicologic testing needed to identify the types or \nlevels of exposure that may present significant risk of adverse health effects in humans.\n\nThe principal audiences for the toxicological profiles are health professionals at the Federal, State, and \nlocal levels; interested private sector organizations and groups; and members of the public.  ATSDR plans \nto revise these documents in response to public comments and as additional data become available.  \nTherefore, we encourage comments that will make the toxicological profile series of the greatest use.\n\nElectronic comments may be submitted via: www.regulations.gov. Follow the on-line instructions for \nsubmitting comments.\n\nWritten comments may also be sent to:\n\nAgency for Toxic Substances and Disease Registry\n\nOffice of Innovation and Analytics\n\nToxicology Section\n\n1600 Clifton Road, N.E.\n\nMail Stop S106-5\n\nAtlanta, Georgia 30329-4027\n\n---\n\nThe toxicological profiles are developed under the Comprehensive Environmental Response, \nCompensation, and Liability Act of 1980, as amended (CERCLA or Superfund).  CERCLA \nSection 104(i)(1) directs the Administrator of ATSDR to “…effectuate and implement the health-related \nauthorities” of the statute.  This includes the preparation of toxicological profiles for hazardous \nsubstances most commonly found at facilities on the CERCLA National Priorities List (NPL) and that \npose the most significant potential threat to human health, as determined by ATSDR and the EPA.  \nSection 104(i)(3) of CERCLA, as amended, directs the Administrator of ATSDR to prepare a \ntoxicological profile for each substance on the list.  In addition, ATSDR has the authority to prepare \ntoxicological profiles for substances not found at sites on the NPL, in an effort to “…establish and \nmaintain inventory of literature, research, and studies on the health effects of toxic substances” under \nCERCLA Section 104(i)(1)(B), to respond to requests for consultation under Section 104(i)(4), and as \notherwise necessary to support the site-specific response actions conducted by ATSDR.\n\nThis profile reflects ATSDR’s assessment of all relevant toxicologic testing and information that has been \npeer-reviewed.  Staffs of the Centers for Disease Control and Prevention and other Federal scientists have \nalso reviewed the profile.  In addition, this profile has been peer-reviewed by a nongovernmental panel \nand is being made available for public review.  Final responsibility for the contents and views expressed \nin this toxicological profile resides with ATSDR.\n\nChristopher M. Reh, Ph.D. \nAssociate Director, \nAgency for Toxic Substances and Disease Registry \nCenters for Disease Control and Prevention\n\n---\n\n**VERSION HISTORY**\n\n| Date | Description |\n| --- | --- |\n| October 2026 | Draft for public comment toxicological profile released |\n| July 1999 | Final toxicological profile released |\n\n---\n\n# CONTRIBUTORS & REVIEWERS\n\n# CHEMICAL MANAGER TEAM\n\nGaston Casillas, Ph.D. (Lead)\nFahim Atif, Ph.D.\nJennifer Przybyla, Ph.D.\nNickolette Roney, M.P.H.\nBrittany Szafran, D.V.M., Ph.D., D.A.B.T.\n\nZach Guerrette, Ph.D., D.A.B.T.\nChristina Coley, M.S.\nLisa Ingerman, Ph.D., D.A.B.T.\nKimberly Zaccaria, Ph.D., D.A.B.T.\nMario Citra, Ph.D.\n\nATSDR, Office of Innovation and Analytics, \nToxicology Section, Atlanta, GA\n\nSRC, Inc., North Syracuse, NY\n\n### REVIEWERS\n\n#### Interagency Minimal Risk Level Workgroup:\n\nIncludes ATSDR; National Center for Environmental Health (NCEH); U.S. Environmental Protection \nAgency (EPA); National Toxicology Program (NTP).\n\n#### Additional reviews for science and/or policy:\n\nATSDR, Office of Community Health Hazard Assessment; ATSDR, Office of Capacity Development \nand Applied Prevention Science; ATSDR, Office of Science; NCEH, Division of Laboratory Sciences; \nNCEH, Division of Environmental Health Science and Practice; EPA, Office of Research and \nDevelopment; EPA, Office of Water.\n\n### PEER REVIEWERS\n\n1. David Dorman, D.V.M., Ph.D., D.A.B.V.T., D.A.B.T.; Professor of Toxicology; North Carolina \nState University; College of Veterinary Medicine; Department of Molecular Biomedical \nSciences; Raleigh, North Carolina\n\n2. Slawo Lomnicki, Ph.D.; Assistant Professor of Environmental Sciences; Louisiana State \nUniversity, Chemistry Department; LSU Superfund Research Materials Core leader; Baton \nRouge, Louisiana\n\n3. Deborah A. Slechta, Ph.D., M.A.; University of Rochester; Professor - Department of \nEnvironmental Medicine (SMD); Professor - Department of Neuroscience (SMD) -– Joint; \nProfessor - Department of Public Health Sciences (SMD) - Joint; Rochester, New York\n\nThese experts collectively have knowledge of toxicology, chemistry, and/or health effects.  All reviewers \nwere selected in conformity with Section 104(I)(13) of the Comprehensive Environmental Response, \nCompensation, and Liability Act, as amended.\n\nATSDR scientists review peer reviewers’ comments and determine whether changes will be made to the \nprofile based on comments.  The peer reviewers’ comments and responses to these comments are part of \nthe administrative record for this compound.\n\nThe listing of peer reviewers should not be understood to imply their approval of the profile's final \ncontent.  The responsibility for the content of this profile lies with ATSDR.\n\n---\n\n## CONTENTS\n\nDISCLAIMER .............................................................................................................................................. ii\nFOREWORD ............................................................................................................................................... iii\nVERSION HISTORY ................................................................................................................................... v\nCONTRIBUTORS & REVIEWERS ........................................................................................................... vi\nCONTENTS ................................................................................................................................................ vii\nLIST OF FIGURES ..................................................................................................................................... ix\nLIST OF TABLES ........................................................................................................................................ x\nCHAPTER 1. RELEVANCE TO PUBLIC HEALTH ................................................................................. 1\n1.1 OVERVIEW AND U.S. EXPOSURES ......................................................................................... 1\n1.2 SUMMARY OF HEALTH EFFECTS........................................................................................... 1\n1.3 MINIMAL RISK LEVELS (MRLs) .............................................................................................. 6\nCHAPTER 2. HEALTH EFFECTS ............................................................................................................ 10\n2.1 INTRODUCTION ........................................................................................................................ 10\n2.2 DEATH ........................................................................................................................................ 55\n2.3 BODY WEIGHT .......................................................................................................................... 57\n2.4 RESPIRATORY .......................................................................................................................... 58\n2.5 CARDIOVASCULAR ................................................................................................................. 63\n2.6 GASTROINTESTINAL ............................................................................................................... 63\n2.7 HEMATOLOGICAL ................................................................................................................... 65\n2.8 MUSCULOSKELETAL .............................................................................................................. 68\n2.9 HEPATIC ..................................................................................................................................... 68\n2.10 RENAL ........................................................................................................................................ 70\n2.11 DERMAL ..................................................................................................................................... 72\n2.12 OCULAR ..................................................................................................................................... 73\n2.13 ENDOCRINE ............................................................................................................................... 74\n2.14 IMMUNOLOGICAL ................................................................................................................... 75\n2.15 NEUROLOGICAL....................................................................................................................... 76\n2.16 REPRODUCTIVE ....................................................................................................................... 77\n2.17 DEVELOPMENTAL ................................................................................................................... 78\n2.18 OTHER NONCANCER ............................................................................................................... 79\n2.19 CANCER ...................................................................................................................................... 79\n2.20 GENOTOXICITY ........................................................................................................................ 80\n2.21 MECHANISM OF ACTION ....................................................................................................... 82\nCHAPTER 3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, \nCHEMICAL INTERACTIONS ........................................................................................... 84\n3.1 TOXICOKINETICS..................................................................................................................... 84\n3.1.1 Absorption ............................................................................................................................. 84\n3.1.2 Distribution ........................................................................................................................... 86\n3.1.3 Metabolism ............................................................................................................................ 88\n3.1.4 Excretion ............................................................................................................................... 90\n3.1.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models ............. 92\n3.1.6 Animal-to-Human Extrapolations ......................................................................................... 93\n3.2 CHILDREN AND OTHER POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE ..... 93\n3.3 BIOMARKERS OF EXPOSURE AND EFFECT ....................................................................... 95\n\n---\n\n3.3.1 Biomarkers of Exposure ........................................................................................................ 95\n3.3.2 Biomarkers of Effect ............................................................................................................. 96\n3.4 INTERACTIONS WITH OTHER CHEMICALS ....................................................................... 97\nCHAPTER 4. CHEMICAL AND PHYSICAL INFORMATION ............................................................. 98\n4.1 CHEMICAL IDENTITY ............................................................................................................. 98\n4.2 PHYSICAL AND CHEMICAL PROPERTIES .......................................................................... 98\nCHAPTER 5. POTENTIAL FOR HUMAN EXPOSURE ....................................................................... 100\n5.1 OVERVIEW .............................................................................................................................. 100\n5.2 PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL ................................................ 101\n5.2.1 Production ........................................................................................................................... 101\n5.2.2 Import/Export ...................................................................................................................... 103\n5.2.3 Use ...................................................................................................................................... 103\n5.2.4 Disposal ............................................................................................................................... 104\n5.3 RELEASES TO THE ENVIRONMENT ................................................................................... 104\n5.3.1 Air ....................................................................................................................................... 105\n5.3.2 Water ................................................................................................................................... 107\n5.3.3 Soil ...................................................................................................................................... 108\n5.4 ENVIRONMENTAL FATE ...................................................................................................... 109\n5.4.1 Transport and Partitioning ................................................................................................... 109\n5.4.2 Transformation and Degradation ........................................................................................ 112\n5.5 LEVELS IN THE ENVIRONMENT ......................................................................................... 116\n5.5.1 Air ....................................................................................................................................... 117\n5.5.2 Water ................................................................................................................................... 118\n5.5.3 Sediment and Soil ............................................................................................................... 122\n5.5.4 Other Media ........................................................................................................................ 123\n5.6 GENERAL POPULATION EXPOSURE.................................................................................. 124\n5.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES .............................................. 125\nCHAPTER 6. ADEQUACY OF THE DATABASE ................................................................................ 126\n6.1 EXISTING INFORMATION ON HEALTH EFFECTS ........................................................... 126\n6.2 IDENTIFICATION OF DATA NEEDS .................................................................................... 126\n6.3 ONGOING STUDIES ................................................................................................................ 135\nCHAPTER 7. REGULATIONS AND GUIDELINES ............................................................................. 136\nCHAPTER 8. REFERENCES .................................................................................................................. 138\nAPPENDICES\nAPPENDIX A.  ATSDR MINIMAL RISK LEVEL WORKSHEETS .................................................... A-1 \nAPPENDIX B. LITERATURE SEARCH FRAMEWORK FOR HCCPD ............................................. B-1 \nAPPENDIX C. FRAMEWORK FOR ATSDR’S SYSTEMATIC REVIEW OF HEALTH EFFECTS \nDATA FOR HCCPD ...................................................................................................... C-1 \nAPPENDIX D.  USER’S GUIDE ............................................................................................................. D-1 \nAPPENDIX E.  QUICK REFERENCE FOR HEALTH CARE PROVIDERS ....................................... E-1 \nAPPENDIX F.  GLOSSARY .................................................................................................................... F-1 \nAPPENDIX G.  ACRONYMS, ABBREVIATIONS, AND SYMBOLS................................................. G-1\n\n---\n\n## LIST OF FIGURES\n\n1-1.  Health Effects Found in Animals Following Inhalation Exposure to HCCPD .................................... 3\n1-2.  Health Effects Found in Animals Following Oral Exposure to HCCPD .............................................. 4\n1-3.  Summary of Sensitive Targets of HCCPD – Inhalation ....................................................................... 7\n1-4.  Summary of Sensitive Targets of HCCPD – Oral ................................................................................ 8\n2-1.  Overview of the Number of Studies Examining HCCPD Health Effects .......................................... 14\n2-2.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation ..................................... 28\n2-3.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Oral .............................................. 44\n5-1.  Number of NPL Sites with Hexachlorocyclopentadiene Contamination ......................................... 100\n5-2.  Transformation of Hexachlorocyclopentadiene ................................................................................ 113\n6-1.  Summary of Existing Health Effects Studies on HCCPD by Route and Endpoint .......................... 127\n\n---\n\n## LIST OF TABLES\n\n1-1.  Provisional Minimal Risk Levels (MRLs) for HCCPD ........................................................................ 9\n2-1.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation ..................................... 15\n2-2.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Oral .............................................. 39\n2-3.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Dermal ......................................... 49\n2-4.  LOAEL Values for Red Blood Cell Hematological Effects of Rats Exposed to HCCPD \nVapor in Acute- and Intermediate-Duration Inhalation  Studies ........................................................ 65\n2-5.  Genotoxicity of Hexachlorocyclopentadiene *In Vivo* ......................................................................... 81\n2-6.  Genotoxicity of Hexachlorocyclopentadiene *In Vitro* ........................................................................ 81\n4-1.  Chemical Identity of Hexachlorocyclopentadiene .............................................................................. 98\n4-2.  Physical and Chemical Properties of Hexachlorocyclopentadiene ..................................................... 98\n5-1.  Facilities that Produce, Process, or Use Hexachlorocyclopentadiene .............................................. 102\n5-2.  Summary of National Aggregate Volumes Reported to U.S. Environmental Protection \nAgency (EPA) Chemical Data  Reporting (CDR) ............................................................................ 103\n5-3.  Releases to the Environment from Facilities that Produce, Process, or Use \nHexachlorocyclopentadiene .............................................................................................................. 105\n5-4.  Summary of Releases to the Environment from the Emissions Inventory System (EIS) \nGateway Emission Sectors in 2020 .................................................................................................. 106\n5-5.  Summary of Releases to the Environment from the Emissions Inventory System (EIS) \nGateway Emission Sectors in 2021 .................................................................................................. 107\n5-6.  Lowest Limit of Detection Based on Standards ............................................................................... 117\n5-7.  Summary of Environmental Levels of HCCPD ............................................................................... 117\n5-*8.*  Summary of Water Monitoring Data for Hexachlorocyclopentadiene Across the \nUnited States ..................................................................................................................................... 119\n7-1.  Regulations and Guidelines Applicable to Hexachlorocyclopentadiene .......................................... 136\n\n---\n\n# CHAPTER 1. RELEVANCE TO PUBLIC HEALTH\n\n###### 1.1 OVERVIEW AND U.S. EXPOSURES\n\nHexachlorocyclopentadiene (HCCPD) is a highly volatile, reactive liquid.  HCCPD is an anthropogenic \nchemical that has entered the environment primarily because of its use in the production of chlorinated \npesticides and flame-retardant chemicals.  Restriction of pesticides synthesized from HCCPD has \ndecreased the possibility of exposure to HCCPD and pesticide residues among most members of the \ngeneral population.  Exposure to materials containing HCCPD at hazardous waste sites is still possible.\n\nThe potential for persistence of HCCPD in the environment is low.  Due to its high vapor pressure, \nHCCPD is most likely released to the environment through volatilization, especially from surface waters \nand soils.  The main degradation processes expected include photolysis and photooxidation, hydrolysis, \nand, to a lesser extent, biodegradation.  HCCPD in the air is expected to degrade with estimated half-lives \nranging from 5 hours to <1 day, which limits its potential for long-range transport. HCCPD in water is \nexpected to degrade rapidly, with half-lives for photolysis of ~2–4 minutes and half-lives for hydrolysis \nof ~3–5.45 days.\n\nOccupational exposure to HCCPD is most likely to occur via inhalation and dermal routes.  The general \npopulation may be exposed to HCCPD through inhalation of air contaminated with this chemical and \ningestion of drinking water contaminated with this chemical.\n\n###### 1.2 SUMMARY OF HEALTH EFFECTS\n\nInformation on the noncancer toxicity of HCCPD in humans is limited to reports by wastewater treatment \nplant (WWTP) workers and cleanup crew members exposed after an inadvertent industrial release.  No \noccupational studies evaluating health effects in workers exposed during regular manufacture or use of \nHCCPD are available.  Additionally, no observational epidemiological studies of workers or the public \nare available for HCCPD.  Further information on the noncancer toxicity of HCCPD comes from \ninhalation and oral studies in animals.  Data following dermal exposure are very limited in humans and \nanimals.\n\nIn laboratory animals, evaluation of available dose-response data by route and duration indicates that \nsensitive noncancer targets of HCCPD toxicity are respiratory and hematological effects following inhalation exposure (Figure 1-1).  Ovarian inflammation was noted in mice following chronic-duration \ninhalation exposure; however, the causal relationship between the effect and HCCPD exposure could not \nbe determined due to apparent association with stress-induced susceptibility to an infection in the mouse \ncolony (see Section 2.16).  Due to this, female reproductive (ovarian) effects were not considered as \npotential sensitive effects or included in Figure 1-1.  The oral database is very limited; the only potential \ntargets identified below doses associated with lethality include the gastrointestinal tract and kidney \n(Figure 1-2). General toxicity (decreased body weight) was also observed at similar doses.  A systematic \nreview of sensitive target organs/systems by exposure route resulted in the following hazard identification \nconclusions:\n\n• Respiratory effects are a presumed health effect for humans following inhalation exposure.\n\n• Gastrointestinal effects are a presumed health effect for humans following oral exposure.\n\n• Hematological (red blood cell) effects are suspected health effects for humans following \ninhalation exposure; white blood cell effects are not classifiable as to the hazard to humans.\n\n• Renal effects are a presumed health effect for humans following oral exposure.\n\n**_Respiratory Effects (Inhalation Route)._**  The respiratory tract is sensitive to HCCPD toxicity after \ninhalation exposure; findings are attributed to compound reactivity upon contact with respiratory tissues \nat the portal of entry.  WWTP workers and cleanup crew members reported respiratory symptoms \nincluding coughing, nose and throat irritation, and difficulty breathing following inhalation of HCCPD \nvapors from an inadvertent industrial discharge (Kominsky et al. 1980; Morse et al. 1979).  Acuteduration inhalation exposure studies in animals identified increased or labored respiration or abnormal \nrespiratory patterns at concentrations ≥0.5 ppm (Alexander et al. 1980a; Jackson and Hardy 1986, 1987; \nRand et al. 1982a).  Sneezing and altered respiratory rates/patterns were observed in rodents at \nintermediate-duration exposures of ≥0.56 ppm (Clark 1981; NTP 1994).  Histopathological evaluation \nidentified changes to the nasal, tracheobronchial, and/or pulmonary epithelium in rats and mice at \n≥0.385 and ≥0.2 ppm, respectively; these changes consisted of inflammation (suppurative or necrotizing) \nor metaplasia at nonlethal concentrations (Clark 1981; NTP 1994) and hemorrhaging or necrosis at lethal \nconcentrations (NTP 1994).  Nasal and pulmonary lesions were observed in mice exposed to 0.2 ppm \nHCCPD for 2 years, while no lesions were observed in rats under the same exposure conditions (NTP \n1994).\n\n$$\n\\geq0.385and\\geq0.2\n$$\n\n---\n\n**Figure 1-1.  Health Effects Found in Animals Following Inhalation Exposure to** \n**HCCPD**\n\n**Concentration (ppm)**\n\n**≥1.4**\n\n**Effects in Animals**\n\n**Acute:**  Neurobehavioral effects\n\n**Intermediate:**  Hepatic effects\n\n**0.5**\n\n**Acute:**  Death, respiratory lesions, altered hematology parameters, \ndecreased body weight, decreased food and water intake\n\n**Intermediate:**  Decreased body weight\n\n**0.389**\n\n**Intermediate:**  Death\n\n**0.2**\n\n**0.039**\n\n**Intermediate:**  Respiratory lesions\n\n**Chronic:**  Death, respiratory lesions\n\n**Intermediate:**  Altered red blood cell parameters\n\n1x10<sup>-4</sup> ppm\n6x10<sup>-5</sup> ppm\n\n**Provisional Intermediate MRL**\n**Provisional Chronic MRL**\n\n---\n\n**Figure 1-2.  Health Effects Found in Animals Following Oral Exposure to HCCPD**\n\nDose (mg/kg/day) Effects in Animals\n≥464 Acute:  Gastrointestinal, neurological, respiratory, and musculoskeletal  \neffects \n150 Intermediate:  Death\n75 Acute:  Death, developmental effects\n38 Intermediate:  Gastrointestinal and renal lesions, decreased body \nweight\n0.06 mg/kg/day Provisional Intermediate MRL\n\n**_Gastrointestinal Effects (Oral Route)._** The gastrointestinal tract is sensitive to HCCPD after oral \nexposure; findings are attributed to compound reactivity upon contact with gastrointestinal tissues at the \nportal of entry.  No human data are available evaluating potential gastrointestinal effects of HCCPD \nfollowing oral exposure.  Diarrhea was reported in rodents administered single oral doses of ≥464 mg/kg \n(Dean 1977; Gardner 1986a); this effect was not reported at lower doses in intermediate-duration studies \nup to 150 mg/kg/day in rats or 300 mg/kg/day in mice (Abdo et al. 1984).  In the only available \nintermediate-duration oral study in animals, focal inflammation and epithelial hyperplasia of the \nforestomach were observed in rats and mice exposed to ≥38 and ≥75 mg/kg/day, respectively (Abdo et al.\n1984).  While humans lack a forestomach, analogous lesions could occur in the proximate portions of the \nhuman gastrointestinal tract, including oral, pharyngeal, and/or esophageal tissues, due to portal-of-entry \nreactivity following oral exposure to HCCPD.\n\n**_Hematological Effects (Inhalation Route)._**  No changes in blood counts were observed in workers \nexposed to HCCPD at a WWTP following an inadvertent industrial discharge (Kominsky et al. 1980).  \nAlterations in red blood cell parameters, primarily elevated red blood cell counts and hemoglobin levels, were reported in rats following acute- and intermediate-duration inhalation exposure to HCCPD at \nconcentrations of 0.5 and ≥0.14 ppm, respectively (Clark 1981; NTP 1994; Rand et al. 1982a); similar \nfindings were observed in mice at intermediate-duration inhalation concentrations ≥0.039 ppm (NTP \n1994).  Based on the absence of histopathological changes to bone marrow, observed red blood cell \neffects have been hypothesized to be a compensatory response to hemorrhagic damage to the lungs \nfollowing inhalation exposure rather than direct effects on hematopoiesis (Rand et al. 1982a).  However,\nrats showed sex-specific findings (females were less sensitive), and there were inconsistencies between \nthe main 13-week (comprehensive) study and the 13-week specialized hematological study conducted by \nNTP (1994).  In mice, findings were limited and inconsistent with respect to alterations in red blood cell \nparameters after exposure for 13–42 weeks (NTP 1994).  Additionally, no hematological effects were \nobserved in the 2-year inhalation studies in rats or mice at concentrations up to 2 ppm (NTP 1994).  No \nconsistent effects on white blood cell parameters were observed with inhalation exposures in animal \nstudies (Clark 1981; NTP 1994; Rand et al. 1982a).\n\n**_Renal Effects (Oral Route)._** No human data are available to assess the potential for HCCPD to cause \nrenal toxicity.  In the only available oral study in animals evaluating the kidney, HCCPD produced toxic \nnephrosis in male and female rats at ≥38 mg/kg/day and in female mice at ≥75 mg/kg/day (Abdo et al. \n1984).  Toxic nephrosis was not identified in male mice, but acute tubular necrosis was identified in male \nmice exposed to 300 mg/kg/day. Available toxicokinetic data indicate that HCCPD and/or its metabolites \ndistribute to the kidneys in both rats and mice after oral dosing; however, the highest distribution is to the \nkidney in the rat and to the liver in the mouse (Dorough and Ranieri 1984).  This observed difference in \ndistribution may explain the observed species sensitivity.\n\n**_Cancer Effects._**  There were no data from studies in humans pertaining to the carcinogenicity of HCCPD.  \nThe National Toxicology Program (NTP) conducted 2-year bioassays of HCCPD in mice and rats and \nconcluded that it is not a carcinogen in either species (NTP 1994).  Although the incidence of \nalveolar/bronchiolar carcinomas was significantly increased in male mice exposed to 0.5 ppm for 26 or \n42 weeks and evaluated at 2 years, the incidence was within the historical range for the laboratory and \nwas not elevated in animals exposed to 0.2 ppm for 2 years. There was also a slight increase in the \nincidence of adenomas of the pituitary pars distalis in male rats and thyroid follicle cell adenomas in \nfemale mice, but these tumors were not considered to be exposure-related since the incidences were \nsimilar to the historical control means, were within the historical control range, or did not exhibit a dosedependency.  Based on these results, the U.S. Environmental Protection Agency (EPA) determined that \nHCCPD is not likely to be a human carcinogen by the inhalation route (IRIS 2003).  The International\n\n---\n\nAgency for Research on Cancer (IARC) has not evaluated the carcinogenicity of HCCPD (IARC 2025).  \nThe U.S. Department of Health and Human Services (HHS) has not evaluated a cancer classification \ncategory for HCCPD (NTP 2021).\n\n###### 1.3 MINIMAL RISK LEVELS (MRLs)\n\nAs illustrated in Figure 1-3, available inhalation data for HCCPD suggest that the respiratory and \nhematological systems are the most sensitive targets for toxicity. The inhalation database was considered \nadequate for derivation of provisional intermediate- and chronic-duration MRLs.  As discussed in \nSection 1.2, ovarian effects observed in the chronic-duration mouse study were not considered as \npotential sensitive effects due to potential confounding by a utero-ovarian infection (see Appendix A for \ndetails).  Therefore, female reproductive effects are not included in Figure 1-3.\n\nAs illustrated in Figure 1-4, gastrointestinal, renal, and body weight effects appear to be the most \nsensitive targets of HCCPD toxicity following oral exposure. The oral database was considered adequate \nfor derivation of a provisional intermediate-duration MRL for HCCPD.  The acute- and chronic-duration \noral data were insufficient for deriving MRLs.\n\nThe provisional MRL values are summarized in Table 1-1 and discussed in greater detail in Appendix A.\n\n---\n\n**Figure 1-3.  Summary of Sensitive Targets of HCCPD – Inhalation**\n\n**Available data indicate that the hematological and respiratory systems are the most sensitive \ntargets of HCCPD inhalation exposure.**\n\nNumbers in circles are the lowest LOAELs for all health effects in animals. No reliable dose response \ndata were available for humans.\n\n**Acute (ppm)**\n\n| Category | Acute (ppm) | Intermediate (ppm) | Chronic (ppm) |\n| --- | --- | --- | --- |\n| Death | 0.5 | 0.389 | 0.2 |\n| Body weight | 0.5 |  |  |\n| Respiratory | 0.5 | 0.2 | 0.2 |\n| Hematological | 0.5 | 0.039 |  |\n| Other noncancer | 0.5 |  |  |\n\n---\n\n**Figure 1-4. Summary of Sensitive Targets of HCCPD – Oral**\n\n**Available data indicate that the gastrointestinal tract, renal system, and body weight are the most\nsensitive targets of HCCPD oral exposure.**\nNumbers in circles are the lowest LOAELs for all health effects in animals. \nNo reliable dose response data were available for humans.\n\n## Acute (mg/kg/day)\n\n| Category | Lowest LOAEL (mg/kg/day) |\n| --- | --- |\n| Death (Acute) | 75 |\n| Developmental (Acute) | 75 |\n| Gastrointestinal (Acute) | 464 |\n| Neuological (Acute) | 464 |\n| Body weight (Intermediate) | 38 |\n| Gastrointestinal (Intermediate) | 38 |\n| Renal (Intermediate) | 38 |\n| Death (Intermediate) | 150 |\n\n---\n\nTable 1-1. Provisional Minimal Risk Levels (MRLs) for HCCPD<sup>a</sup>\n\n| Exposure route | Exposure duration | Provisional MRL | Critical effect | POD type | POD value | Uncertainty/modifying factor | Reference |\n| --- | --- | --- | --- | --- | --- | --- | --- |\n| Inhalation | Acute | None | - | - | - | - | - |\n| Inhalation | Intermediate | 1 × 10-4 ppm (1 × 10-3 mg/m3) | Nasal suppurative inflammation in rats | NOAELHEC | 0.00344 ppm | UF: 30 | NTP 1994 |\n| Inhalation | Chronic | 6 × 10-5 ppm (7 × 10-4 mg/m3) | Nasal suppurative inflammation in mice | BMCLHEC | 0.0019 ppm | UF: 30 | NTP 1994 |\n| Oral | Acute | None | - | - | - | - | - |\n| Oral | Intermediate | 0.06 mg/kg/day | Combined incidence of forestomach epithelial hyperplasia and focal inflammation in rats | BMDLADJ | 5.5 mg/kg/day | UF: 100 | Abdo et al. 1984: Velsicol 1981b |\n| Oral | Chronic | None | - | - | - | - | - |\n\n$$\n1\\times10^{-4}ppm\n$$\n\n$$\n(1\\times10^{-3}mg/m^3)\n$$\n\n$$\n6\\times10^{-5}ppm\n$$\n\n$$\n(7\\times10^{-4}mg/m^3)\n$$\n\n<sup>a</sup>See Appendix A for additional information.\n\nADJ = adjusted for intermittent exposure; BMCL = benchmark concentration lower confidence limit; BMDL = benchmark dose lower confidence limit;\n\nHEC = human equivalent concentration; NOAEL = no-observed-adverse-effect level; POD = point of departure; UF = uncertainty factor\n\n---\n\n# CHAPTER 2. HEALTH EFFECTS\n\n###### 2.1 INTRODUCTION\n\nThe primary purpose of this chapter is to provide public health officials, physicians, toxicologists, and \nother interested individuals and groups with an overall perspective on the toxicology of HCCPD.  It \ncontains descriptions and evaluations of toxicological studies and epidemiological investigations and \nprovides conclusions, where possible, on the relevance of toxicity and toxicokinetic data to public health.  \nWhen available, mechanisms of action are discussed along with the health effects data; toxicokinetic \nmechanistic data are discussed in Section 3.1.\n\nA glossary and list of acronyms, abbreviations, and symbols can be found at the end of this profile.\n\nTo help public health professionals and others address the needs of persons living or working near hazardous \nwaste sites, the information in this section is organized by health effects.  These data are discussed in terms \nof route of exposure (inhalation, oral, and dermal) and three exposure periods:  acute (≤14 days), \nintermediate (15–364 days), and chronic (≥365 days).\n\nAs discussed in Appendix B, a literature search was conducted to identify relevant studies examining health \neffect endpoints.  Figure 2-1 provides an overview of the database of studies in humans or experimental \nanimals included in this chapter of the profile.  These studies evaluate the potential health effects associated \nwith inhalation, oral, or dermal exposure to HCCPD, but may not be inclusive of the entire body of literature.  \nA systematic review of the scientific evidence of the health effects associated with exposure to HCCPD was \nalso conducted; the results of this review are presented in Appendix C.\n\nHuman and animal inhalation studies are presented in Table 2-1 and Figure 2-2, animal oral studies are \npresented in Table 2-2 and Figure 2-3, and human and animal dermal studies are presented in Table 2-3.  \nDue to the limited nature of the database, several older studies lacking quantitative data reporting are \nincluded in Chapter 2 to provide data potentially relevant for hazard identification; however, data that are \nonly reported qualitatively (i.e., histopathological data lacking incidence data) are not included in \nTables 2-1, 2-2, or 2-3.\n\nLevels of significant exposure (LSEs) for each route and duration are presented in tables and illustrated in \nfigures.  The points in the figures showing no-observed-adverse-effect levels (NOAELs) or lowest- observed-adverse-effect levels (LOAELs) reflect the actual doses (levels of exposure) used in the studies.  \nEffects have been classified into “less serious LOAELs” or “serious LOAELs (SLOAELs).”  “Serious” \neffects are those that evoke failure in a biological system and can lead to morbidity or mortality (e.g., \nacute respiratory distress or death).  “Less serious” effects are those that are not expected to cause \nsignificant dysfunction or death, or those whose significance to the organism is not entirely clear.  \nATSDR acknowledges that a considerable amount of judgment may be required in establishing whether \nan endpoint should be classified as a NOAEL, “less serious” LOAEL, or “serious” LOAEL, and that in \nsome cases, there will be insufficient data to decide whether the effect is indicative of significant \ndysfunction.  However, the Agency has established guidelines and policies that are used to classify these \nendpoints.  ATSDR believes that there is sufficient merit in this approach to warrant an attempt at \ndistinguishing between “less serious” and “serious” effects.  The distinction between “less serious” effects \nand “serious” effects is considered to be important because it helps the users of the profiles to identify \nlevels of exposure at which major health effects start to appear.  LOAELs or NOAELs should also help in \ndetermining whether or not the effects vary with dose and/or duration, and place into perspective the \npossible significance of these effects to human health.\n\nA User's Guide has been provided at the end of this profile (see Appendix C).  This guide should aid in \nthe interpretation of the tables and figures for LSEs and MRLs.\n\nThe health effects of HCCPD have been evaluated in 2 human studies and 68 animal studies.  As \nillustrated in Figure 2-1, most of the health effect data come from dermal and inhalation studies in \nanimals.  In both human and animal studies, the ocular effects observed in HCCPD inhalation studies are \nlikely attributable to direct contact with HCCPD vapors.  Therefore, ocular effects from inhalation studies \nare counted as dermal exposure in Figure 2-1 and are listed in the dermal LSE table.\n\nThe available human studies were predominantly focused on evaluation of dermal, ocular, and respiratory \neffects in WWTP workers and cleanup crew members following an inadvertent industrial release of \nHCCPD.  For these studies, exposure was evaluated as HCCPD vapor levels in air.\n\nFor animal data, inhalation and oral studies are available for most health effects.  Acute-, intermediate-, \nand chronic-duration studies are available for the inhalation route, while only acute- and intermediateduration studies are available for the oral route.  The dermal animal database is mostly limited to ocular \nand dermal effects, largely following exposure to HCCPD vapor.  The most examined endpoints in \nanimal studies were death, respiratory, hepatic, renal, and ocular.\n\n---\n\nA systematic review was conducted on potential targets of HCCPD exposure, which included respiratory \nand hematological effects for inhalation exposure and gastrointestinal and renal effects following oral \nexposure (see Appendix C for details).\n\n• **Respiratory Effects.** Respiratory effects are a presumed health effect associated with HCCPD \nexposure via inhalation based on inadequate evidence in humans and a high level of evidence in \nanimals.  WWTP workers and cleanup crew members reported respiratory symptoms including \ncoughing and respiratory tract irritation after exposure to HCCPD vapors following an \ninadvertent industrial release.  Several animal studies have reported altered respiratory patterns \nfollowing single or repeated exposures to HCCPD.  Upon histopathological examination, \nnonneoplastic lesions of the nasal, tracheobronchial, and pulmonary regions were consistently \nobserved in mice and rats exposed for intermediate durations to concentrations ≥0.2 or \n≥0.385 ppm, respectively.  Chronic-duration exposure to 0.2 ppm resulted in similar lesions in \nmice, but not rats.  Observed lesions (suppurative, serous, or necrotizing inflammation; epithelial \nhyperplasia) are consistent with chronic irritation at the portal of entry.\n\n• **Gastrointestinal Effects.** Gastrointestinal effects are a presumed health effect associated with \nHCCPD exposure via oral exposure based on no human data and a high level of evidence in \nanimal studies.  Diarrhea was reported in rodents following exposure to high acute doses \n≥464 mg/kg.  Forestomach lesions (epithelial hyperplasia and focal inflammation) were observed \nin rats and mice following intermediate-duration exposures of ≥38 and ≥75 mg/kg/day, \nrespectively.  Although humans lack a forestomach, effects associated with HCCPD are \nconsistent with chronic irritation at the portal of entry.  Thus, the upper gastrointestinal tract is\npresumably vulnerable to toxicity following oral exposure to HCCPD.\n\n• **Hematological Effects.** Hematological effects, specifically red blood cell parameters, are a \nsuspected health effect associated with HCCPD exposure via inhalation based on inadequate data \nin humans and a moderate level of evidence in animals.  No changes in blood counts were \nobserved in WWTP workers after exposure to HCCPD vapors following an inadvertent industrial \nrelease.  Several acute- and intermediate-duration inhalation studies reported altered red blood \ncell parameters (e.g., increased hemoglobin, red blood cell counts, and packed cell volume) at \nconcentrations as low as 0.14 and 0.039 ppm in rats and mice, respectively; however, these \nfindings were not consistent across sexes or species nor were they reproducible in targeted \nanalyses by the same researchers.  Observed red blood cell effects may be attributable to\ncompromised gas exchange following tissue damage to the respiratory tract, as no evidence of \nbone marrow hyperplasia was observed in rodents following repeated inhalation exposure to \nHCCPD. White blood cell effects are not classifiable as to the hazard to humans based on no data \nin humans and inadequate evidence in animals.  Available studies did not find consistent evidence \nof alterations in white blood cell parameters in rats or mice following intermediate- or chronicduration inhalation exposure to HCCPD.\n\n• **Renal Effects.** Renal effects are a presumed health effect associated with oral exposure to\nHCCPD based on no human data and a high level of evidence in animal studies.  Renal lesions, \nspecifically toxic nephrosis, were observed in rats and mice following intermediate-duration \nexposures to ≥38 and ≥75 mg/kg/day, respectively. Acute tubular necrosis was observed in male \nmice at a higher dose (300 mg/kg/day).  Available toxicokinetic data indicate that HCCPD and/or\n\n---\n\n###### 2. HEALTH EFFECTS\n\nits metabolites distribute to the kidneys of both rats and mice after oral dosing; however, it will \naccumulate to a higher degree in rats.\n\n---\n\n**Figure 2-1.  Overview of the Number of Studies Examining HCCPD Health Effects***\n\n**Most studies examined the potential death, respiratory, neurological, renal, hepatic, and ocular effects of HCCPD**\nFewer studies evaluated health effects in **humans** than **animals** (counts represent studies examining endpoint)\n\n| Category | Number of studies |\n| --- | --- |\n| Death | 57 |\n| Body weight | 18 |\n| Respiratory | 44 |\n| Cardiovascular | 35 |\n| Gastrointestinal | 16 |\n| Hematological | 13 |\n| Musculoskeletal | 10 |\n| Hepatic | 39 |\n| Renal | 39 |\n| Dermal | 16 |\n| Ocular | 39 |\n| Endocrine | 35 |\n| Immunological | 12 |\n| Neurolgical | 41 |\n| Reproductive | 11 |\n| Developmental | 3 |\n| Other Noncancer | 7 |\n| Cancer | 5 |\n\n**Exposure Route**\n\n| Category | Share of studies (%) |\n| --- | --- |\n| Inhalation | 40 |\n| Oral | 13 |\n| Dermal | 47 |\n\n**Exposure Duration**\n\n| Category | Share of studies (%) |\n| --- | --- |\n| Chronic | 2 |\n| Acute | 78 |\n| Intermediate | 20 |\n\n*Includes studies discussed in Chapter 2.  A total of 70 studies (including those finding no effect) have examined toxicity; most studies examined multiple \nendpoints.\n\n---\n\n**Table 2-1. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation\n(ppm)**\n\n| Species (strain) keya | No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| ACUTE EXPOSURE |  |  |  |  |  |  |  |  |  |\n| Alexander et al. 1980a; Rand et al. 1982a |  |  |  |  |  |  |  |  |  |\n| 1 | Rat (Sprague-Dawley) 10 M, 10 F | 1–2 weeks 5 days/week 6 hours/day (WB) | 0, 0.022, 0.11, 0.5 | LE, CS, BW, FI, HE, BC, GN, OW, HP | Death Bd wt | 0.11 |  | 0.5 M | 10/10 died or were sacrificed in moribund condition Decreased terminal body weight in females (29%) and males (32%) Labored respiration; increased absolute lung weight; bronchiole inflammation, hyperplasia, and epithelial erosion |\n| 1 | Rat (Sprague-Dawley) 10 M, 10 F | 1–2 weeks 5 days/week 6 hours/day (WB) | 0, 0.022, 0.11, 0.5 | LE, CS, BW, FI, HE, BC, GN, OW, HP | Resp | 0.11 |  | 0.5 | 10/10 died or were sacrificed in moribund condition Decreased terminal body weight in females (29%) and males (32%) Labored respiration; increased absolute lung weight; bronchiole inflammation, hyperplasia, and epithelial erosion |\n| 1 | Rat (Sprague-Dawley) 10 M, 10 F | 1–2 weeks 5 days/week 6 hours/day (WB) | 0, 0.022, 0.11, 0.5 | LE, CS, BW, FI, HE, BC, GN, OW, HP | Cardio Hematoc | 0.5 0.11 | 0.5 | 0.5 | Males: total white blood cell and lymphocyte counts reduced Females: neutrophils increased Both: red blood cell count, packed cell volume, and hemoglobin increased |\n| 1 | Rat (Sprague-Dawley) 10 M, 10 F | 1–2 weeks 5 days/week 6 hours/day (WB) | 0, 0.022, 0.11, 0.5 | LE, CS, BW, FI, HE, BC, GN, OW, HP | Hepatic Renal Immuno Neuro | 0.5 0.5 0.5 Other noncancer | 0.5 |  | Decreased food and water intake |\n| Jackson and Hardy 1986 |  |  |  |  |  |  |  |  |  |\n| 2 | Rat (Wistar) 5 M, 5 F | 1 hour (WB) | 0, 1.67, 2.38, 3.53, 6.25, 8.30 | LE, CS, BW, FI, WI, OW, GN | Death Bd wt | 1.67 |  | 3.69 | LC50 Decreased body weight at death or scheduled sacrifice (3-weeks post exposure) in males (41%) and females (26%) Abnormal respiratory pattern Decreased food consumption |\n| 2 | Rat (Wistar) 5 M, 5 F | 1 hour (WB) | 0, 1.67, 2.38, 3.53, 6.25, 8.30 | LE, CS, BW, FI, WI, OW, GN | Resp Other noncancer | 1.67 1.67 |  |  | LC50 Decreased body weight at death or scheduled sacrifice (3-weeks post exposure) in males (41%) and females (26%) Abnormal respiratory pattern Decreased food consumption |\n\n---\n\n**Table 2-1. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation\n(ppm)**\n\nAbnormal respiratory pattern\nDecreased food consumption\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Jackson and Hardy 1987 |  |  |  |  |  |  |  |  |  |\n| 3 | Rat (Wistar) 5 M, 5 F | 4 hours (WB) | 0, 1.68, 1.83, 3.31, 3.47 | LE, CS, BW, FI, WI, GN, OW | Death Bd wt |  |  | 2.9 1.68 M | LC50 23% decreased body weight at scheduled sacrifice (4 weeks post exposure) |\n| 3 | Rat (Wistar) 5 M, 5 F | 4 hours (WB) | 0, 1.68, 1.83, 3.31, 3.47 | LE, CS, BW, FI, WI, GN, OW | Resp Other noncancer | 1.68 F | 1.68 1.68 | 1.83 F | 24% decreased body weight at death or scheduled sacrifice (4 weeks post exposure) |\n| OxyChem 1972 |  |  |  |  |  |  |  |  |  |\n| 4 | Rat (Carworth CFE) 10 M | 4 hours (WB) | 176, 1,760 | LE, CS, GN | Death |  |  | 176 | 10/10 died within 48 hours |\n| Rand et al. 1982a |  |  |  |  |  |  |  |  |  |\n| 5 | Rat (Sprague-Dawley) 10 M, 10 F | 4 hours (WB) | 0.28, 1.4, 2.5, 3.1, 3.3, 3.4, 4, 5.8 | LE, CS, BW | Death |  |  | 3.5 F 1.6 M | LC50 LC50 |\n| 5 | Rat (Sprague-Dawley) 10 M, 10 F | 4 hours (WB) | 0.28, 1.4, 2.5, 3.1, 3.3, 3.4, 4, 5.8 | LE, CS, BW | Bd wt | 0.28 | 1.4 F | 1.4 M | 17% body weight loss 25% body weight loss |\n| 5 | Rat (Sprague-Dawley) 10 M, 10 F | 4 hours (WB) | 0.28, 1.4, 2.5, 3.1, 3.3, 3.4, 4, 5.8 | LE, CS, BW | Neuro | 0.28 | 1.4 | 5.8 | LOAEL: Sedation SLOAEL: Ataxia |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 6 | Rat 4 NS | 2 days 7 hours/day (WB) | 3.2 | LE, CS, GN | Death |  |  | 3.2 | 4/4 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 7 | Rat 4 NS | 3 days 7 hours/day (WB) | 1.4 | LE, CS, GN | Death |  |  | 1.4 | 3/4 died |\n\n---\n\n**Table 2-1. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation\n(ppm)**\n\n| Species |  |  |  |  |  |  |  |  |  |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Figure keya | No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 8 | Rat 4 NS | 2.6–3.6 hours (WB) | 1.4, 3.1, 7.1, 12.4, 12.7, 46.5, 56.9, 70.4 | LE, CS, GN | Death |  |  | 3.1 | 2/4 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 9 | Rat 4 NS | 7 hours (WB) | 1.5, 3.2, 6.7 | LE, CS, GN | Death |  |  | 3.2 | 3/4 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 10 | Rat 4 NS | 5 days 7 hours/day (WB) | 0.33, 1.0, 1.6 | LE, CS, GN | Death |  |  | 1 | 4/4 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 11 | Rat 4 NS | 0.25–1.25 hours (WB) | 1.4, 1.5, 3.1, 7.2, 13.0, 13.8, 19.4, 20.0, 20.2, 69.1, 69.2 | LE, CS, GN | Death |  |  | 7.2 | 2/4 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 12 | Rat 4 NS | 4 hours (WB) | 73.6 | LE, CS, GN | Death |  |  | 73.6 | 4/4 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 13 | Mouse 5 NS | 0.25–1.25 hours (WB) | 1.4, 1.5, 3.1, 7.2, 13.0, 13.8, 19.4, 20.0, 20.2, 69.1, 69.2 | LE, CS, GN | Death |  |  | 7.2 | 5/5 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 14 | Mouse 5 NS | 4 hours (WB) | 73.6 | LE, CS, GN | Death |  |  | 73.6 | 5/5 died |\n\n---\n\n**Table 2-1. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation\n(ppm)**\n\n| Species (strain) keya | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| 15 Mouse 5 NS | 2 days 7 hours/day (WB) | 3.2 | LE, CS, GN | Death |  |  | 3.2 | 4/5 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| 16 Mouse 5 NS | 3 days 7 hours/day (WB) | 1.4 | LE, CS, GN | Death |  |  | 1.4 | 5/5 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| 17 Mouse 5 NS | 7 hours (WB) | 1.5, 3.2, 6.7 | LE, CS, GN | Death |  |  | 1.5 | 4/5 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| 18 Mouse 5 NS | 2.6– 3.6 hours (WB) | 1.4, 3.1, 7.1, 12.4, 12.7, 46.5, 56.9, 70.4 | LE, CS, GN | Death |  |  | 3.1 | 4/5 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| 19 Mouse 5 NS | 5 days 7 hours/day (WB) | 0.33, 1.0, 1.6 | LE, CS, GN | Death |  |  | 1 | 4/5 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| 20 Rabbit 3 NS | 4 hours (WB) | 73.6 | LE, CS, GN | Death |  |  | 73.6 | 3/3 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| 21 Rabbit 3 NS | 3 days 7 hours/day (WB) | 1.4 | LE, CS, GN | Death |  |  | 1.4 | 3/3 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| 22 Rabbit 3 NS | 5 days 7 hours/day (WB) | 1, 1.6 | LE, CS, GN | Death |  |  | 1 | 3/3 died |\n\n---\n\n**Table 2-1. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation\n(ppm)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 23 | Rabbit 3 NS | 2.6–3.6 hours (WB) | 1.4, 3.1, 7.1, 12.4, 12.7, 46.5, 56.9, 70.4 | LE, CS, GN | Death |  |  | 1.4 | 2/3 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 24 | Rabbit 3 NS | 7 hours (WB) | 1.5, 3.2, 6.7 | LE, CS, GN | Death |  |  | 1.5 | 3/3 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 25 | Rabbit 3 NS | 0.25–1.25 hours (WB) | 1.4, 1.5, 3.1, 7.2, 13.0, 13.8, 19.4, 20.0, 20.2, 69.1, 69.2 | LE, CS, GN | Death |  |  | 3.1 | 2/3 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 26 | Rabbit 3 NS | 2 days 7 hours/day (WB) | 3.2 | LE, CS, GN | Death |  |  | 3.2 | 3/3 died |\n| INTERMEDIATE EXPOSURE |  |  |  |  |  |  |  |  |  |\n| Alexander et al. 1980b; Rand et al. 1982a, 1982b |  |  |  |  |  |  |  |  |  |\n| 27 | Monkey (Cynomolgus) 6 M, 6 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, HE, BC, UR, OP, GN, OW, HP, OF | Bd wt Resp Cardio Gastro Hemato Musc/skel Hepatic Renal Ocular Endocr Immuno | 0.2 0.2 0.2 0.2 0.2 0.2 |  |  |  |\n\n---\n\n**Table 2-1. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation\n(ppm)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n|  |  |  |  |  | Neuro | 0.2 |  |  |  |\n|  |  |  |  |  | Repro | 0.2 |  |  |  |\n|  |  |  |  |  | Other |  |  |  |  |\n|  |  |  |  |  | noncancer |  |  |  |  |\n| Alexander et al. 1980b; Huntingdon Research Centre 1980; Rand et al. 1982a, 1982b |  |  |  |  |  |  |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Bd wt | 0.2 |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Resp | 0.2 |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Cardio | 0.2 |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Gastro | 0.2 |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Hemat | 0.2 |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Musc/skel | 0.2 |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Hepatic | 0.2 |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Renal | 0.2 |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Ocular | 0.2 |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Endocr | 0.2 |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Immuno | 0.2 |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Neuro | 0.2 |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Repro | 0.2 |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Other |  |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | noncancer |  |  |  |  |\n\n---\n\n**Table 2-1. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation\n(ppm)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Clark 1981 |  |  |  |  |  |  |  |  |  |\n| 29 | Rat (Wistar) 18 M, 18 F | 30 weeks 5 days/week 6 hours/day (WB) | 0, 0.06, 0.14, 0.56 | LE, CS, BW, FI, WI, HE, BC, UR, GN, OW, HP | Death Bd wt Resp | 0.56 | 0.56 F | 0.56 M | 4/18 males and 2/18 females died |\n| 29 | Rat (Wistar) 18 M, 18 F | 30 weeks 5 days/week 6 hours/day (WB) | 0, 0.06, 0.14, 0.56 | LE, CS, BW, FI, WI, HE, BC, UR, GN, OW, HP | Resp | 0.14 | 0.56 F | 0.56 M | Females: perivascular/peribronchiolar inflammatory cell infiltration; sneezing Males: bronchiolar epithelial ulceration/thinning and perivascular/peribronchiolar inflammatory cell infiltration; sneezing |\n| 29 | Rat (Wistar) 18 M, 18 F | 30 weeks 5 days/week 6 hours/day (WB) | 0, 0.06, 0.14, 0.56 | LE, CS, BW, FI, WI, HE, BC, UR, GN, OW, HP | Cardio Gastro Hematoma | 0.56 0.56 F 0.06 M | 0.56 F 0.14 M |  | Decreased lymphocyte counts Increased red blood cell counts, hemoglobin, hematocrit, and neutrophil counts; decreased lymphocyte percentage |\n| 29 | Rat (Wistar) 18 M, 18 F | 30 weeks 5 days/week 6 hours/day (WB) | 0, 0.06, 0.14, 0.56 | LE, CS, BW, FI, WI, HE, BC, UR, GN, OW, HP | Musc/skel Hepatic Renal Dermal Ocular Endocr Immuno Neuro Repro | 0.56 0.56 0.56 0.56 0.56 0.56 |  |  |  |\n\n---\n\n**Table 2-1. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation\n(ppm)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n|  |  |  |  |  | Other noncancer | 0.56 |  |  |  |\n| NTP 1994 |  |  |  |  |  |  |  |  |  |\n| 30 | Rat (Fischer-344) 10 M, 10 F | 13 weeks 5 days/week 6 hours/day (WB) | 0, 0.039, 0.146, 0.385, 0.941, 2.065 | LE, CS, BW, HE, BC, GN, OW, HP | Death Bd wt Resp | 0.385 0.385 F 0.146b M | 0.385 M | 0.941 | 100% mortality during first 4 weeks |\n|  |  |  |  |  |  |  |  |  | Nasal squamous metaplasia and suppurative inflammation; suppurative and necrotizing inflammation of the bronchus/bronchiole; increased absolute and relative lung weights |\n|  |  |  |  |  |  |  |  | 0.941 | Increased respiration rate and mouth breathing; suppurative inflammation and hemorrhaging in the alveolus; necrotizing inflammation of the nose, larynx, trachea, and bronchus/bronchiole |\n|  |  |  |  |  | Cardio Gastro Hemato | 0.385 0.385 0.146 | 0.385 |  |  |\n|  |  |  |  |  | Musc/skel | 0.385 |  |  | Males: increased packed cell volume, hemoglobin, red blood cell count, and MCHC |\n|  |  |  |  |  | Hepatic | 0.385 |  |  |  |\n|  |  |  |  |  | Renal | 0.385 |  |  |  |\n|  |  |  |  |  | Endocr | 0.385 |  |  |  |\n|  |  |  |  |  | Immuno | 0.385 |  |  |  |\n|  |  |  |  |  | Neuro | 0.385 |  |  |  |\n|  |  |  |  |  | Repro | 0.385 |  |  |  |\n\n***DRAFT FOR PUBLIC COMMENT***\n\n---\n\n**Table 2-1. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation\n(ppm)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| NTP 1994 |  |  |  |  |  |  |  |  |  |\n| 31 | Rat (Fischer-344) 20 M, 20 F | 13 weeks 5 days/week 6 hours/day (WB) | 0, 0.039, 0.385, 2.065 | LE, HE, BC, UR | Death Hemato | 0.039 | 0.385 | 2.065 | 100% mortality Males: increased MCV; Females: increased MCV, packed cell volume, hemoglobin, and red blood cell count Increased AST |\n| 31 | Rat (Fischer-344) 20 M, 20 F | 13 weeks 5 days/week 6 hours/day (WB) | 0, 0.039, 0.385, 2.065 | LE, HE, BC, UR | Hepatic Renal | 0.385 2.065 | 2.065 | 2.065 | 100% mortality Males: increased MCV; Females: increased MCV, packed cell volume, hemoglobin, and red blood cell count Increased AST |\n| NTP 1994 |  |  |  |  |  |  |  |  |  |\n| 32 | Mouse (B6C3F1) 10 M | 42 weeks 5 days/week 6 hours/day (WB) | 0, 0.5 | LE, CS, BW, GN, OW, HP | Death Bd wt |  |  | 0.5 | 14% decreased survival at 45 weeks Decreased body weight (19%) and body weight gain (42%) at the end of the exposure period Suppurative inflammation of the nose, trachea, and lungs |\n| 32 | Mouse (B6C3F1) 10 M | 42 weeks 5 days/week 6 hours/day (WB) | 0, 0.5 | LE, CS, BW, GN, OW, HP | Resp |  | 0.5 | 0.5 | 14% decreased survival at 45 weeks Decreased body weight (19%) and body weight gain (42%) at the end of the exposure period Suppurative inflammation of the nose, trachea, and lungs |\n| 32 | Mouse (B6C3F1) 10 M | 42 weeks 5 days/week 6 hours/day (WB) | 0, 0.5 | LE, CS, BW, GN, OW, HP | Gastro Hepatic | 0.5 |  | 0.5 | 14% decreased survival at 45 weeks Decreased body weight (19%) and body weight gain (42%) at the end of the exposure period Suppurative inflammation of the nose, trachea, and lungs |\n| 32 | Mouse (B6C3F1) 10 M | 42 weeks 5 days/week 6 hours/day (WB) | 0, 0.5 | LE, CS, BW, GN, OW, HP | Renal | 0.5 |  | 0.5 | 14% decreased survival at 45 weeks Decreased body weight (19%) and body weight gain (42%) at the end of the exposure period Suppurative inflammation of the nose, trachea, and lungs |\n| 32 | Mouse (B6C3F1) 10 M | 42 weeks 5 days/week 6 hours/day (WB) | 0, 0.5 | LE, CS, BW, GN, OW, HP | Endocr Immuno | 0.5 |  | 0.5 | 14% decreased survival at 45 weeks Decreased body weight (19%) and body weight gain (42%) at the end of the exposure period Suppurative inflammation of the nose, trachea, and lungs |\n| 32 | Mouse (B6C3F1) 10 M | 42 weeks 5 days/week 6 hours/day (WB) | 0, 0.5 | LE, CS, BW, GN, OW, HP | Repro | 0.5 |  | 0.5 | 14% decreased survival at 45 weeks Decreased body weight (19%) and body weight gain (42%) at the end of the exposure period Suppurative inflammation of the nose, trachea, and lungs |\n| NTP 1994 |  |  |  |  |  |  |  |  |  |\n| 33 | Mouse (B6C3F1) 20 M, 20 F | 13 weeks 5 days/week 6 hours/day (WB) | 0, 0.039, 0.389, 2.142 | LE, HE, BC, UR | Death Hemato |  | 0.039 F 0.389 M | 2.142 | 100% mortality Increased MCHC Increased MCHC |\n| 33 | Mouse (B6C3F1) 20 M, 20 F | 13 weeks 5 days/week 6 hours/day (WB) | 0, 0.039, 0.389, 2.142 | LE, HE, BC, UR | Hepatic Renal | 0.039 M 2.142 2.142 | 0.039 F 0.389 M | 2.142 | 100% mortality Increased MCHC Increased MCHC |\n\n---\n\n**Table 2-1. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation\n(ppm)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| NTP 1994 |  |  |  |  |  |  |  |  |  |\n| 34 | Mouse (B6C3F1) 10 M | 26 weeks 5 days/week 6 hours/day (WB) | 0, 0.5 | LE, CS, BW, GN, OW, HP | Bd wt Resp | 0.5 | 0.5 |  | Nasal suppurative inflammation |\n| NTP 1994 |  |  |  |  |  |  |  |  |  |\n| 35 | Mouse (B6C3F1) 10 M | 33 weeks 5 days/week 6 hours/day (WB) | 0, 0.2 | LE, CS, BW, GN, OW, HP | Bd wt Resp Gastro Hepatic Renal Immuno Neuro Repro | 0.2 | 0.2 |  | Nasal suppurative inflammation |\n| NTP 1994 |  |  |  |  |  |  |  |  |  |\n| 36 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week 6 hours/day (WB) | 0, 0.039, 0.146, 0.389, 0.949, 2.142 | LE, CS, BW, HE, BC, OW, HP | Death |  |  | 0.949 F 0.389 M | 10/10 died 5/10 died |\n| 36 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week 6 hours/day (WB) | 0, 0.039, 0.146, 0.389, 0.949, 2.142 | LE, CS, BW, HE, BC, OW, HP | Bd wt Resp | 0.389 |  |  | Females: focal serous or suppurative inflammation of the nose Males: squamous metaplasia in the trachea, focal serous or suppurative inflammation of the nose |\n| 36 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week 6 hours/day (WB) | 0, 0.039, 0.146, 0.389, 0.949, 2.142 | LE, CS, BW, HE, BC, OW, HP | Cardio Gastro Hemato | 0.389 |  |  | Decreased MCV |\n| 36 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week 6 hours/day (WB) | 0, 0.039, 0.146, 0.389, 0.949, 2.142 | LE, CS, BW, HE, BC, OW, HP | Musc/skel | 0.389 |  |  |  |\n\n***DRAFT FOR PUBLIC COMMENT***\n\n---\n\n**Table 2-1. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation\n(ppm)**\n\n| Species Figure keya | Species (strain) No./group | Species Exposure parameters | Species Doses | Species Parameters monitored | Species Endpoint | Species NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n|  |  |  |  |  | Hepatic | 0.389 |  |  |  |\n|  |  |  |  |  | Renal | 0.389 |  |  |  |\n|  |  |  |  |  | Endocr | 0.389 |  |  |  |\n|  |  |  |  |  | Immuno | 0.389 |  |  |  |\n|  |  |  |  |  | Neuro | 0.389 |  |  |  |\n|  |  |  |  |  | Repro | 0.389 |  |  |  |\n| CHRONIC EXPOSURE |  |  |  |  |  |  |  |  |  |\n| NTP 1994 |  |  |  |  |  |  |  |  |  |\n| 37 | Rat (Fischer-344) 50 M, 50 F | 104 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, UR, GN, OW, HP | Bd wt | 0.2 |  |  |  |\n| 37 | Rat (Fischer-344) 50 M, 50 F | 104 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, UR, GN, OW, HP | Resp | 0.2 |  |  |  |\n| 37 | Rat (Fischer-344) 50 M, 50 F | 104 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, UR, GN, OW, HP | Cardio | 0.2 |  |  |  |\n| 37 | Rat (Fischer-344) 50 M, 50 F | 104 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, UR, GN, OW, HP | Gastro | 0.2 |  |  |  |\n| 37 | Rat (Fischer-344) 50 M, 50 F | 104 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, UR, GN, OW, HP | Hemat | 0.2 |  |  |  |\n| 37 | Rat (Fischer-344) 50 M, 50 F | 104 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, UR, GN, OW, HP | Musc/skel | 0.2 |  |  |  |\n| 37 | Rat (Fischer-344) 50 M, 50 F | 104 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, UR, GN, OW, HP | Hepatic | 0.2 |  |  |  |\n| 37 | Rat (Fischer-344) 50 M, 50 F | 104 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, UR, GN, OW, HP | Renal | 0.2 |  |  |  |\n| 37 | Rat (Fischer-344) 50 M, 50 F | 104 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, UR, GN, OW, HP | Dermal | 0.2 |  |  |  |\n| 37 | Rat (Fischer-344) 50 M, 50 F | 104 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, UR, GN, OW, HP | Endocr | 0.2 |  |  |  |\n| 37 | Rat (Fischer-344) 50 M, 50 F | 104 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, UR, GN, OW, HP | Immuno | 0.2 |  |  |  |\n| 37 | Rat (Fischer-344) 50 M, 50 F | 104 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, UR, GN, OW, HP | Neuro | 0.2 |  |  |  |\n| 37 | Rat (Fischer-344) 50 M, 50 F | 104 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, UR, GN, OW, HP | Repro | 0.2 |  |  |  |\n\n---\n\n**Table 2-1. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation\n(ppm)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| NTP 1994 |  |  |  |  |  |  |  |  |  |\n| 38 | Mouse (B6C3F1) 50 M, 50 F | 103 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, BW, GN, OW, HP | Death Bd wt Resp | 0.2 0.05c | 0.2 | 0.2 F | 57% mortality |\n| 38 | Mouse (B6C3F1) 50 M, 50 F | 103 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, BW, GN, OW, HP | Death Bd wt Resp | 0.2 0.05c | 0.2 | 0.2 F | Males: nasal suppurative inflammation, alveolar epithelium hyperplasia, and suppurative inflammation of the lung Females: nasal suppurative inflammation (BMCL10 for nasal suppurative inflammation in females = 0.0052 ppm)c |\n| 38 | Mouse (B6C3F1) 50 M, 50 F | 103 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, BW, GN, OW, HP | Cardio Gastro Hemat Muc/skel Hepatic Renal Dermal Endocr Immuno Neuro | 0.2 0.2 0.2 0.2 0.2 0.2 | 0.2 | 0.2 F | Males: nasal suppurative inflammation, alveolar epithelium hyperplasia, and suppurative inflammation of the lung Females: nasal suppurative inflammation (BMCL10 for nasal suppurative inflammation in females = 0.0052 ppm)c |\n\n---\n\n**Table 2-1. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation\n(ppm)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n|  |  |  |  |  | Repro | 0.01 F | 0.05 F | 0.2 F | LOAEL: Suppurative inflammation of the ovaries SLOAEL: Severe ovarian suppurative inflammation (associated with increased lethality) |\n|  |  |  |  |  |  | 0.2 M |  |  |  |\n\n<sup>a</sup>The number corresponds to entries in Figure 2-2; differences in levels of health effects and cancer effects between male and females are not indicated in \nFigure 2-2. Where such differences exist, only the levels of effect for the most sensitive sex are presented.\n\n$$\n1\\times10^{-4}\n$$\n\n<sup>b</sup>Used to derive a provisional intermediate-duration inhalation MRL of 1x10<sup>-4</sup> ppm based on a NOAEL of 0.146 ppm, which was converted into a NOAELHEC of \n0.00344 ppm and divided by an uncertainty factor of 30 (10 for human variability and 3 for animal to human extrapolation after dosimetric adjustment).\n<sup>c</sup>Used to derive a provisional chronic-duration inhalation MRL of 6x10<sup>-5</sup> ppm based on a BMCL10 of 0.052 ppm, which was converted into a BMCLHEC of \n0.0019 ppm and divided by an uncertainty factor of 30 (10 for human variability and 3 for animal to human extrapolation after dosimetric adjustment).\n\nGreen shading indicates the study selected for derivation of provisional inhalation MRLs.\n\nAST = aspartate aminotransferase; BC = blood chemistry; Bd wt or BW = body weight; BMCL = benchmark concentration lower confidence limit; BMCL10 = 95% \nlower confidence limit on the benchmark concentration (subscripts denote benchmark response: i.e., 10 = concentration associated with 10% extra risk); \nCardio = cardiovascular; CS = clinical signs; Endocr = endocrine; F = female(s); FI = food intake; Gastro = gastrointestinal; GN = gross necropsy; \nHE = hematology; HEC = human equivalent concentration; Hemato = hematological; HP = histopathology; Immuno = immunological; LC50 = median lethal \nconcentration; LE = lethality; LOAEL = lowest-observed-adverse-effect level; M = male(s); MCHC = mean corpuscular hemoglobin concentration; MCV = mean \ncorpuscular volume; MRL = Minimal Risk Level; Musc/skeletal = muscular/skeletal; Neuro = neurological; NOAEL = no-observed-adverse-effect level; NS = not \nspecified; OF = organ function; OP = ophthalmology; OW = organ weight; Repro = reproductive; Resp = respiratory; SLOAEL = serious lowest-observed-adverseeffect level; UR = urinalysis; (WB) = whole body; WI = water intake\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation**\nAcute (≤14 days)\n\n**Figure 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation Acute (≤14 days) - Death**\n\n| Category | Animal - LD50/LC50 (ppm) | Animal - NOAEL (ppm) | Animal - LOAEL (ppm) | Animal - SLOAEL (ppm) |\n| --- | --- | --- | --- | --- |\n| 1R |  |  |  | 0.45 |\n| 2R | 3.4 |  |  |  |\n| 3R | 2.6 |  |  |  |\n| 4R |  |  |  | 170 |\n| 5R | 1.6 |  |  |  |\n| 6R |  |  |  | 2.8 |\n| 7R |  |  | 1.4 |  |\n| 8R |  |  |  | 3.2 |\n| 9R |  |  |  | 2.8 |\n| 10R |  |  |  | 1.0 |\n| 11R |  |  |  | 7.0 |\n| 12R |  |  |  | 75 |\n| 13M |  |  |  | 7.5 |\n| 14M |  |  |  | 75 |\n| 15M |  |  |  | 3.2 |\n| 16M |  |  |  | 1.4 |\n| 17M |  |  |  | 1.5 |\n| 18M |  |  |  | 3.2 |\n| 19M |  |  |  | 1.0 |\n| 20H |  |  |  | 75 |\n| 21H |  |  |  | 1.4 |\n| 22H |  |  |  | 1.0 |\n| 23H |  |  |  | 1.4 |\n| 24H |  |  |  | 1.5 |\n| 25H |  |  |  | 3.2 |\n| 26H |  |  |  | 3.2 |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation**\nAcute (≤14 days)\n\n| Category | Body Weight Animal - LD50/LC50 (ppm) | Body Weight Animal - NOAEL (ppm) | Body Weight Animal - LOAEL (ppm) | Body Weight Animal - SLOAEL (ppm) | Respiratory Animal - LD50/LC50 (ppm) | Respiratory Animal - NOAEL (ppm) | Respiratory Animal - LOAEL (ppm) | Respiratory Animal - SLOAEL (ppm) | Cardiovascular Animal - LD50/LC50 (ppm) | Cardiovascular Animal - NOAEL (ppm) | Cardiovascular Animal - LOAEL (ppm) | Cardiovascular Animal - SLOAEL (ppm) | Hematological Animal - LD50/LC50 (ppm) | Hematological Animal - NOAEL (ppm) | Hematological Animal - LOAEL (ppm) | Hematological Animal - SLOAEL (ppm) |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| 1R |  | 0.12 |  | 0.5 |  | 0.12 |  | 0.5 |  | 0.5 |  |  |  | 0.12 |  | 0.5 |\n| 2R |  | 1.8 |  | 2.6 |  |  |  | 1.8 |  |  |  |  |  |  |  |  |\n| 3R |  |  |  | 1.8 |  |  |  | 1.8 |  |  |  |  |  |  |  |  |\n| 5R |  | 0.26 |  | 1.4 |  |  |  |  |  |  |  |  |  |  |  |  |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation**\nAcute (≤14 days)\n\n**Figure 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation Acute (≤14 days)**\n\n| Category | Animal - NOAEL (ppm) | Animal - LOAEL (ppm) | Animal - SLOAEL (ppm) |\n| --- | --- | --- | --- |\n| Hepatic | 0.5 |  |  |\n| Renal | 0.45 |  |  |\n| Immunological | 0.5 |  |  |\n| Neuological | 0.4 | 1.4 | 5.5 |\n| Other Noncancer | 0.12 | 0.45 | 1.7 |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation**\nIntermediate (15–364 days)\n\n**Figure 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation Intermediate (15–364 days)**\n\n| Category | Death Animal - NOAEL (ppm) | Death Animal - LOAEL (ppm) | Death Animal - SLOAEL (ppm) | Body Weight Animal - NOAEL (ppm) | Body Weight Animal - LOAEL (ppm) | Body Weight Animal - SLOAEL (ppm) | Respiratory Animal - NOAEL (ppm) | Respiratory Animal - LOAEL (ppm) | Respiratory Animal - SLOAEL (ppm) |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| 29R |  |  | 0.6 | 0.5 |  |  | 0.15 |  | 0.6 |\n| 30R |  |  | 1.0 | 0.4 |  |  | 0.15 | 0.45 | 1.0 |\n| 31R |  |  | 2.3 |  |  |  |  |  |  |\n| 32M |  |  | 0.55 |  | 0.5 |  |  | 0.5 |  |\n| 33M |  |  | 2.6 |  |  |  |  |  |  |\n| 36M |  |  | 0.4 | 0.45 |  |  | 0.15 | 0.45 |  |\n| 27K |  |  |  | 0.2 |  |  | 0.2 |  |  |\n| 28R |  |  |  | 0.2 |  |  | 0.2 |  |  |\n| 34M |  |  |  | 0.55 |  |  |  | 0.5 |  |\n| 35M |  |  |  | 0.2 |  |  |  | 0.2 |  |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation**\nIntermediate (15–364 days)\n\n**Figure 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation Intermediate (15–364 days)**\n\n| Category | Cardiovascular Animal - NOAEL (ppm) | Cardiovascular Animal - LOAEL (ppm) | Cardiovascular Animal - SLOAEL (ppm) | Gastrointestinal Animal - NOAEL (ppm) | Gastrointestinal Animal - LOAEL (ppm) | Gastrointestinal Animal - SLOAEL (ppm) | Hematological Animal - NOAEL (ppm) | Hematological Animal - LOAEL (ppm) | Hematological Animal - SLOAEL (ppm) |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| 27K | 0.22 |  |  | 0.22 |  |  | 0.22 |  |  |\n| 28R | 0.22 |  |  | 0.22 |  |  | 0.22 |  |  |\n| 29R | 0.55 |  |  | 0.55 |  |  | 0.060 | 0.15 |  |\n| 30R | 0.44 |  |  | 0.44 |  |  | 0.17 | 0.44 |  |\n| 36M | 0.44 |  |  | 0.44 |  |  | 0.17 | 0.44 |  |\n| 32M |  |  |  | 0.50 |  |  |  |  |  |\n| 35M |  |  |  | 0.22 |  |  |  |  |  |\n| 31R |  |  |  |  |  |  | 0.040 | 0.44 |  |\n| 33M |  |  |  |  |  |  |  | 0.044 |  |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation**\nIntermediate (15–364 days)\n\n**Figure 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation Intermediate (15–364 days)**\n\n| Category | Musculoskeletal Animal - NOAEL (ppm) | Musculoskeletal Animal - LOAEL (ppm) | Musculoskeletal Animal - SLOAEL (ppm) | Hepatic Animal - NOAEL (ppm) | Hepatic Animal - LOAEL (ppm) | Hepatic Animal - SLOAEL (ppm) | Renal Animal - NOAEL (ppm) | Renal Animal - LOAEL (ppm) | Renal Animal - SLOAEL (ppm) |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| 27K | 0.22 |  |  | 0.20 |  |  | 0.20 |  |  |\n| 28R | 0.20 |  |  | 0.22 |  |  | 0.20 |  |  |\n| 29R | 0.55 |  |  | 0.60 |  |  | 0.55 |  |  |\n| 30R | 0.44 |  |  | 0.40 |  |  | 0.40 |  |  |\n| 36M | 0.44 |  |  | 0.44 |  |  | 0.44 |  |  |\n| 31R |  |  |  | 0.44 |  |  | 2.2 |  |  |\n| 31R |  |  |  |  |  | 2.4 |  |  |  |\n| 32M |  |  |  | 0.55 |  |  | 0.60 |  |  |\n| 33M |  |  |  | 2.4 |  |  | 2.4 |  |  |\n| 35M |  |  |  | 0.20 |  |  | 0.20 |  |  |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation**\nIntermediate (15–364 days)\n\n**Figure 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation Intermediate (15–364 days)**\n\n| Category | Animal - NOAEL (ppm) | Animal - LOAEL (ppm) | Animal - SLOAEL (ppm) |\n| --- | --- | --- | --- |\n| Dermal 29R | 0.55 |  |  |\n| Ocular 27K | 0.20 |  |  |\n| Ocular 28R | 0.20 |  |  |\n| Ocular 29R | 0.55 |  |  |\n| Endocrine 27K | 0.20 |  |  |\n| Endocrine 28R | 0.20 |  |  |\n| Endocrine 29R | 0.60 |  |  |\n| Endocrine 30R | 0.40 |  |  |\n| Endocrine 32M | 0.50 |  |  |\n| Endocrine 36M | 0.40 |  |  |\n| Immunological 27K | 0.20 |  |  |\n| Immunological 28R | 0.20 |  |  |\n| Immunological 29R | 0.60 |  |  |\n| Immunological 30R | 0.40 |  |  |\n| Immunological 32M | 0.55 |  |  |\n| Immunological 35M | 0.20 |  |  |\n| Immunological 36M | 0.40 |  |  |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation**\nIntermediate (15–364 days)\n\n**Figure 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation Intermediate (15–364 days)**\n\n| Category | Neuropsychological Animal - NOAEL (ppm) | Neuropsychological Animal - LOAEL (ppm) | Neuropsychological Animal - SLOAEL (ppm) | Reproductive Animal - NOAEL (ppm) | Reproductive Animal - LOAEL (ppm) | Reproductive Animal - SLOAEL (ppm) | Other Noncancer Animal - NOAEL (ppm) | Other Noncancer Animal - LOAEL (ppm) | Other Noncancer Animal - SLOAEL (ppm) |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| 27K | 0.22 |  |  | 0.22 |  |  | 0.22 |  |  |\n| 28R | 0.22 |  |  | 0.22 |  |  | 0.22 |  |  |\n| 29R | 0.55 |  |  | 0.55 |  |  | 0.55 |  |  |\n| 30R | 0.44 |  |  | 0.44 |  |  |  |  |  |\n| 35M | 0.22 |  |  | 0.22 |  |  |  |  |  |\n| 36M | 0.44 |  |  | 0.44 |  |  |  |  |  |\n| 32M |  |  |  | 0.55 |  |  |  |  |  |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation**\nChronic (≥365 days)\n\n**Figure 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation Chronic (≥365 days)**\n\n| Category | R-Rat Animal - NOAEL (ppm) | R-Rat Animal - LOAEL (ppm) | R-Rat Animal - SLOAEL (ppm) | M-Mouse Animal - NOAEL (ppm) | M-Mouse Animal - LOAEL (ppm) | M-Mouse Animal - SLOAEL (ppm) | M-Mouse MRL for effect other than cancer (ppm) |\n| --- | --- | --- | --- | --- | --- | --- | --- |\n| Death |  |  |  |  |  | 0.22 |  |\n| Body Weight |  |  |  | 0.22 |  |  |  |\n| Respiratory | 0.22 |  |  |  | 0.055 | 0.22 | 0.006 |\n| Cardiovascular | 0.22 |  |  | 0.22 |  |  |  |\n| Gastrointestinal |  |  |  | 0.22 |  |  |  |\n| unlabelled 1 |  |  |  | 0.22 |  |  |  |\n\n---\n\n2.  HEALTH EFFECTS\n\n**Figure 2-2.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation**\nChronic (≥365 days)\n\n| Category | R-Rat (ppm) | M-Mouse (ppm) |\n| --- | --- | --- |\n| Hematological | 0.22 | 0.22 |\n| Musculoskeletal | 0.22 | 0.22 |\n| Hepatic | 0.22 | 0.22 |\n| Renal | 0.22 | 0.22 |\n| Dermal | 0.22 | 0.22 |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation**\nChronic (≥365 days)\n\n**Figure 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation Chronic (≥365 days)**\n\n| Category | Endocrine Animal - NOAEL (ppm) | Endocrine Animal - LOAEL (ppm) | Endocrine Animal - SLOAEL (ppm) | Immunological Animal - NOAEL (ppm) | Immunological Animal - LOAEL (ppm) | Immunological Animal - SLOAEL (ppm) | Neuological Animal - NOAEL (ppm) | Neuological Animal - LOAEL (ppm) | Neuological Animal - SLOAEL (ppm) | Reproductive Animal - NOAEL (ppm) | Reproductive Animal - LOAEL (ppm) | Reproductive Animal - SLOAEL (ppm) |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| 37R | 0.23 |  |  | 0.23 |  |  | 0.23 |  |  | 0.23 |  |  |\n| 38M | 0.23 |  |  | 0.23 |  |  | 0.23 |  |  | 0.011 | 0.055 | 0.23 |\n\n---\n\n**Table 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Oral\n(mg/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| ACUTE EXPOSURE |  |  |  |  |  |  |  |  |  |\n| Gardner 1986a |  |  |  |  |  |  |  |  |  |\n| 1 | Rat (CFY) 5 M, 5 F | Once (GO) | 1,260, 1,600, 2,000 | LE, CS, BW, GN | Death |  |  | 1,300 F 1,500 M | LD50 LD50 |\n| 1 | Rat (CFY) 5 M, 5 F | Once (GO) | 1,260, 1,600, 2,000 | LE, CS, BW, GN | Resp Gastro Neuro |  | 1,260 | 1,260 | Decreased respiratory rate Diarrhea Abnormal gait, lethargy |\n| OxyChem 1972 |  |  |  |  |  |  |  |  |  |\n| 2 | Rat (Spartan) 25 M, 25 F | Once (GO) | 315, 500, 794, 1,250, 1,984 | LE | Death |  |  | 530 F 630 M | LD50 LD50 |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 3 | Rat 9–11 M | Once (GO) | 280, 340, 420, 520, 620, 940, 1,400 | LE, CS, GN | Death |  |  | 505 | LD50 |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 4 | Rat 10 F | Once (GO) | 280, 940, 1,400, 2,100 | LE, CS, GN | Death |  |  | 940 | 9/10 died |\n| Chernoff and Kavlock 1982, 1983; Gray and Kavlock 1984; Gray et al. 1986 |  |  |  |  |  |  |  |  |  |\n| 5 | Mouse (CD-1) 16 F | 5 days GDs 8–12 (GO) | 0, 45 | BW, DX | Bd wt Develop | 45 |  |  |  |\n\n$$\n\\mathsf{L}\\mathsf{D}_{50}\n$$\n\nOffspring evaluated through PND 250 for postnatal viability, growth, locomotor activity, female sexual development, and reproductive function\n\n---\n\n**Table 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Oral\n(mg/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Dean 1977 |  |  |  |  |  |  |  |  |  |\n| 6 | Mouse (CD-1) 5 M, 5 F | Once (GO) | 21.5, 46.4, 100, 215, 464, 1,000, 2,150 | LE, CS, BW | Death Resp Gastro | 1,000 215 F 464 M 464 | 464 F 1,000 M 1,000 | 679 2,150 | LD50 Decreased respiratory rate Diarrhea Diarrhea Decreased limb tone in animals that died LOAEL: Hypoactivity SLOAEL: Ataxia |\n| 6 | Mouse (CD-1) 5 M, 5 F | Once (GO) | 21.5, 46.4, 100, 215, 464, 1,000, 2,150 | LE, CS, BW | Musc/skel | 215 | 464 | 1,000 | LOAEL: Hypoactivity SLOAEL: Ataxia |\n| Murray et al. 1980 |  |  |  |  |  |  |  |  |  |\n| 7 | Mouse (CF-1) NS F | 10 days GDs 6–15 (GO) | 0, 5, 25, 75 | LE, CS, BW, FI, WI, RX, DX | Bd wt Develop Other noncancer | 75 75 75 |  |  |  |\n| Murray et al. 1980 |  |  |  |  |  |  |  |  |  |\n| 8 | Mouse (CF-1) 5 F | 10 days GDs 6–15 (GO) | 0, 25, 75, 250, 500 | LE, CS, BW | Death |  |  | 250 | 3/5 dams died |\n| Murray et al. 1980 |  |  |  |  |  |  |  |  |  |\n| 9 | Rabbit (New Zealand) NS F | 13 days GDs 6–18 (GO) | 0, 5, 25, 75 | LE, CS, BW, RX, DX | Death Develop | 25 | 75 | 75 | Unspecified increased maternal death during pregnancy Increased proportion of fetuses with 13 ribs |\n| Murray et al. 1980 |  |  |  |  |  |  |  |  |  |\n| 10 | Rabbit (New Zealand) 5 F | 13 days GDs 6–18 (GO) | 0, 25, 75, 250, 500 | LE, CS, BW | Death |  |  | 250 | 4/5 does die |\n\n---\n\n**Table 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Oral\n(mg/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 11 | Rabbit 3 F | Once (GO) | 180, 280, 420, 620, 940 | LE, CS, GN | Death |  |  | 940 | 3/3 died |\n| INTERMEDIATE EXPOSURE |  |  |  |  |  |  |  |  |  |\n| Abdo et al. 1984; Velsicol 1981b |  |  |  |  |  |  |  |  |  |\n| 12 | Rat (Fischer-344) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 10, 19, 38, 75, 150 | LE, BW, GN, OW, HP | Death Bd wt | 38 F | 75 F | 150 M | 60% treatment-related mortality 15% decreased terminal body weight LOAEL: 13% decreased terminal body weight SLOAEL: 30% decreased terminal body weight Forestomach epithelial hyperplasia and focal inflammation (BMDL10 for combined incidence of forestomach lesions = 7.7 mg/kg/day)b |\n| 12 | Rat (Fischer-344) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 10, 19, 38, 75, 150 | LE, BW, GN, OW, HP | Resp Cardio Gastro | 150 150 19b | 38 |  |  |\n| 12 | Rat (Fischer-344) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 10, 19, 38, 75, 150 | LE, BW, GN, OW, HP | Hemato Musc/skel | 150 150 150 Renal | 38 |  | Toxic nephrosis |\n| 12 | Rat (Fischer-344) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 10, 19, 38, 75, 150 | LE, BW, GN, OW, HP | Dermal | 150 |  |  |  |\n| 12 | Rat (Fischer-344) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 10, 19, 38, 75, 150 | LE, BW, GN, OW, HP | Endocr | 150 |  |  |  |\n| 12 | Rat (Fischer-344) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 10, 19, 38, 75, 150 | LE, BW, GN, OW, HP | Immuno | 150 |  |  |  |\n| 12 | Rat (Fischer-344) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 10, 19, 38, 75, 150 | LE, BW, GN, OW, HP | Neuro | 150 |  |  |  |\n| 12 | Rat (Fischer-344) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 10, 19, 38, 75, 150 | LE, BW, GN, OW, HP | Repro | 150 |  |  |  |\n\n---\n\n**Table 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Oral\n(mg/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Abdo et al. 1984; Velsicol 1981a |  |  |  |  |  |  |  |  |  |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP | Death |  |  | 300 | 10/10 males died, 3/10 females died 11% decreased terminal body weight 13% decreased terminal body weight |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP | Bd wt | 75 M | 150 F | 300 | 10/10 males died, 3/10 females died 11% decreased terminal body weight 13% decreased terminal body weight |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP |  | 150 F | 300 F | 300 | 10/10 males died, 3/10 females died 11% decreased terminal body weight 13% decreased terminal body weight |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP | Resp | 300 |  |  |  |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP | Cardio | 300 |  |  |  |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP | Gastro | 38 | 75 |  | Focal inflammation and epithelial hyperplasia of the forestomach |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP | Hemato | 300 |  |  |  |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP | Musc/skel | 300 |  |  |  |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP | Hepatic | 300 |  |  |  |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP | Renal | 38 F | 75 F |  | Toxic nephrosis |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP |  | 150 M | 300 M |  | Acute tubular necrosis |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP | Dermal | 300 |  |  |  |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP | Endocr | 300 |  |  |  |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP | Immuno | 300 |  |  |  |\n\n---\n\n**Table 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Oral\n(mg/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n|  |  |  |  |  | Neuro Repro | 300 300 |  |  |  |\n\n<sup>a</sup>The number corresponds to entries in Figure 2-3; differences in levels of health effects between male and females are not indicated in Figure 2-3.  Where such \ndifferences exist, only the levels of effect for the most sensitive sex are presented.\n\n<sup>b</sup>Used to derive a provisional intermediate-duration oral MRL of 0.06 mg/kg/day based on a BMDL10 of 7.7 mg/kg/day, which was adjusted to continuous duration \nexposure to a BMDLADJ of 5.5 mg/kg/day and divided by an uncertainty factor of 100 (10 for human variability and 10 for animal to human extrapolation).  See \nAppendix A for more detailed information regarding the MRL.\n\nGreen shading indicates the study selected for derivation of the provisional oral MRL.\n\nADJ = adjusted; Bd wt or BW = body weight; BMDL = benchmark dose lower confidence limit; BMDL10 = 95% benchmark dose lower confidence limit (subscript \ndenotes benchmark response: i.e., 10 = dose associated with 10% extra risk); Cardio = cardiovascular; CS = clinical signs; Develop = developmental; \nDX = developmental toxicity; Endocr = endocrine; F = female(s); FI = food intake; Gastro = gastrointestinal; GD = gestation day; GN = gross necropsy; \n(GO) = gavage in oil; Hemato = hematological; HP = histopathology; Immuno = immunological; LD50 = median lethal dose; LE = lethality; LOAEL = lowestobserved-adverse-effect level; M = male(s); MRL = Minimal Risk Level; Musc/skeletal = muscular/skeletal; Neuro = neurological; NOAEL = no-observed-adverseeffect level; NS = not specified; OW = organ weight; PND = postnatal day; Repro = reproductive; Resp = respiratory; RX = reproductive function; \nSLOAEL = serious lowest-observed-adverse-effect level; WI = water intake\n\n---\n\n**Figure 2-3.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Oral**\nAcute (≤14 days)\n\n| Category | Animal - LD50/LC50 (mg/kg/day) | Animal - NOAEL (mg/kg/day) | Animal - LOAEL (mg/kg/day) | Animal - SLOAEL (mg/kg/day) |\n| --- | --- | --- | --- | --- |\n| 1R | 1300 |  |  |  |\n| 2R | 530 |  |  |  |\n| 3R | 500 |  |  |  |\n| 4R |  |  |  | 950 |\n| 6M | 660 |  |  |  |\n| 8M |  |  |  | 300 |\n| 9H |  |  |  | 75 |\n| 10H |  |  |  | 280 |\n| 11H |  |  |  | 950 |\n| 5M |  | 50 |  |  |\n| 7M |  | 80 |  |  |\n| 1R |  |  |  | 1200 |\n| 6M |  | 1000 |  | 2400 |\n\n---\n\n**Figure 2-3.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Oral**\nAcute (≤14 days)\n\n| Category | R-Rat (mg/kg/day) | M-Mouse (mg/kg/day) | H-Rabbit (mg/kg/day) |\n| --- | --- | --- | --- |\n| Animal - LD50/LC50 |  |  |  |\n| Animal - NOAEL |  | 130 |  |\n| Animal - LOAEL |  |  | 1300 |\n| Animal - SLOAEL |  |  | 1000 |\n\n---\n\n**Figure 2-3.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Oral**\nIntermediate (15–364 days)\n\n| Category | R-Rat Animal - NOAEL (mg/kg/day) | R-Rat Animal - LOAEL (mg/kg/day) | R-Rat Animal - SLOAEL (mg/kg/day) | M-Mouse Animal - NOAEL (mg/kg/day) | M-Mouse Animal - LOAEL (mg/kg/day) | M-Mouse Animal - SLOAEL (mg/kg/day) |\n| --- | --- | --- | --- | --- | --- | --- |\n| Death |  |  |  |  |  |  |\n| 12R |  |  | 150 |  |  |  |\n| 13M |  |  | 330 |  |  |  |\n| Body Weight |  |  |  |  |  |  |\n| 12R | 20 |  |  |  |  |  |\n| 12R |  | 40 |  |  |  |  |\n| 12R |  |  | 75 |  |  |  |\n| 13M |  | 80 |  |  |  |  |\n| 13M |  |  | 150 |  |  |  |\n| 13M |  |  | 160 |  |  |  |\n| Respiratory |  |  |  |  |  |  |\n| 12R | 160 |  |  |  |  |  |\n| 13M | 330 |  |  |  |  |  |\n| Cardiovascular |  |  |  |  |  |  |\n| 12R | 150 |  |  |  |  |  |\n| 13M | 330 |  |  |  |  |  |\n| Gastrointestinal |  |  |  |  |  |  |\n| 12R BMDL | 8.0 |  |  |  |  |  |\n| 12R | 20 |  |  |  |  |  |\n| 12R |  | 44 |  |  |  |  |\n| 13M | 40 |  |  |  |  |  |\n| 13M |  |  | 80 |  |  |  |\n\n---\n\n**Figure 2-3.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Oral**\nIntermediate (15–364 days)\n\n| Category | R-Rat Animal - NOAEL (mg/kg/day) | R-Rat Animal - LOAEL (mg/kg/day) | R-Rat Animal - SLOAEL (mg/kg/day) | M-Mouse Animal - NOAEL (mg/kg/day) | M-Mouse Animal - LOAEL (mg/kg/day) | M-Mouse Animal - SLOAEL (mg/kg/day) |\n| --- | --- | --- | --- | --- | --- | --- |\n| Hematological | 150 |  |  | 330 |  |  |\n| Musculoskeletal |  |  |  | 150 |  |  |\n| Hepatic |  |  |  | 150 |  |  |\n| Renal | 20 | 44 |  | 36 |  | 80 |\n| Dermal |  |  |  | 150 |  | 330 |\n\n---\n\n**Figure 2-3.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Oral**\nIntermediate (15–364 days)\n\n**Figure 2-3. Levels of Significant Exposure to Hexachlorocyclopentadiene – Oral Intermediate (15–364 days)**\n\n| Category | Animal - NOAEL (mg/kg/day) | Animal - LOAEL (mg/kg/day) | Animal - SLOAEL (mg/kg/day) |\n| --- | --- | --- | --- |\n| Endocrine 12R | 160 |  |  |\n| Endocrine 13M | 330 |  |  |\n| Immunological 12R | 160 |  |  |\n| Immunological 13M | 330 |  |  |\n| Neuological 12R | 160 |  |  |\n| Neuological 13M | 330 |  |  |\n| Reproductive 12R | 160 |  |  |\n| Reproductive 13M | 330 |  |  |\n\n---\n\n**Table 2-3. Levels of Significant Exposure to Hexachlorocyclopentadiene – Dermal**\n\n| Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| ACUTE EXPOSURE |  |  |  |  |  |  |  |  |\n| Kominsky et al. 1980 |  |  |  |  |  |  |  |  |\n| Human 154 M, 23 F | 3–15 days | ≤0.97 ppm | CS, BC | Dermal Ocular |  | 0.97 0.97 |  | Skin irritation Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Monkey 1 NS | Once | 0.001, 0.01, 0.1, 1, 10% (0.01 mL); 20, 40, 60, 90% (0.05 mL) | CS | Dermal | 10 | 20 |  | Skin discoloration and swelling |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Monkey 1 NS | 3 days Once/day | 10% | CS | Dermal |  |  | 10 | Skin irritation, necrosis, hemorrhaging |\n| Alexander et al. 1980a; Rand et al. 1982a |  |  |  |  |  |  |  |  |\n| Rat (Sprague-Dawley) 10 M, 10 F | 1–2 weeks 5 days/week 6 hours/day | 0, 0.022, 0.11, 0.5 ppm | CS | Ocular | 0.11 | 0.5 |  | Dark red eyes |\n| Gardner 1986b |  |  |  |  |  |  |  |  |\n| Rat (CFY) 5 M, 5 F | 24 hours | 1,600, 2,000, 3,200 mg/kg | LE, CS, BW, GN | Death |  |  | 3,100 F 2,600 M | LD50 LD50 |\n| Rat (CFY) 5 M, 5 F | 24 hours | 1,600, 2,000, 3,200 mg/kg | LE, CS, BW, GN | Dermal |  | 1,600 |  | Moderate to severe edema |\n| Jackson and Hardy 1986 |  |  |  |  |  |  |  |  |\n| Rat (Wistar) 5 M, 5 F | 1 hour | 0, 1.67, 2.38, 3.53, 6.25, 8.30 ppm | CS | Ocular |  | 1.67 |  | Total or partial closing of the eyes |\n| Jackson and Hardy 1987 |  |  |  |  |  |  |  |  |\n| Rat (Wistar) 5 M, 5 F | 4 hours | 0, 1.68, 1.83, 3.31, 3.47 ppm | CS | Ocular |  | 1.68 |  | Total or partial closing of the eyes |\n| Rand et al. 1982a |  |  |  |  |  |  |  |  |\n| Rat (Sprague-Dawley) 10 M, 10 F | 4 hours | 0.28, 1.4, 2.5, 3.1, 3.3, 3.4, 4, 5.8 ppm | CS | Ocular | 4 | 5.8 |  | Lacrimation |\n\n$$\n\\mathsf{L}\\mathsf{D}_{50}\n$$\n\n$$\n\\mathsf{L}\\mathsf{D}_{50}\n$$\n\n---\n\n**Table 2-3. Levels of Significant Exposure to Hexachlorocyclopentadiene – Dermal**\n\n| Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rat 4 NS | 5 days 7 hours/day | 0.33, 1, 1.6 ppm | CS | Ocular |  | 0.33 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rat 4 NS | 3 days 7 hours/day | 1.4 ppm | CS | Ocular |  | 1.4 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rat 4 NS | 4 hours | 73.6 ppm | CS | Ocular |  | 73.6 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rat 4 NS | 7 hours | 1.5, 3.2, 6.7 ppm | CS | Ocular |  | 1.5 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rat 4 NS | 2.6–3.6 hours | 1.4, 3.1, 7.1, 11.1, 12.7, 46.5, 56.9, 70.4 ppm | CS | Ocular |  | 1.4 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rat 3–4 NS | 0.25–1.25 hours | 1.4, 1.5, 3.1, 7.2, 13.0, 13.8, 19.4, 20.0, 20.2, 69.1, 69.2 ppm | CS | Ocular |  | 1.4 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rat 4 NS | 2 days 7 hours/day | 3.2 ppm | CS | Ocular |  | 3.2 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Mouse 4–5 NS | 0.25–1.25 hours | 1.4, 1.5, 3.1, 7.2, 13.0, 13.8, 19.4, 20.0, 20.2, 69.1, 69.2 ppm | CS | Ocular |  | 1.4 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Mouse 5 NS | 7 hours | 1.5, 3.2, 6.7 ppm | CS | Ocular |  | 1.5 |  | Eye irritation |\n\n---\n\n**Table 2-3. Levels of Significant Exposure to Hexachlorocyclopentadiene – Dermal**\n\n| Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Mouse 5 NS | 2.6–3.6 hours | 1.4, 3.1, 7.1, 12.4, 12.7, 46.5, 56.9, 70.4 ppm | CS | Ocular |  | 1.4 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Mouse 5 NS | 4 hours | 73.6 ppm | CS | Ocular |  | 73.6 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Mouse 5 NS | 2 days 7 hours/day | 3.2 ppm | CS | Ocular |  | 3.2 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Mouse 5 NS | 3 days 7 hours/day | 1.4 ppm | CS | Ocular |  | 1.4 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Mouse 5 NS | 5 days 7 hours/day | 0.33, 1.0, 1.6 ppm | CS | Ocular |  | 0.33 |  | Eye irritation |\n| OxyChem 1972 |  |  |  |  |  |  |  |  |\n| Rabbit (New Zealand) 3 M, 3 F | 4 hours | 0.5 mL | LE, CS | Death Dermal Neuro | 0.5 | 0.5 | 0.5 | 3/6 died Moderate to severe edema Ataxia and hypoactivity |\n| OxyChem 1972 |  |  |  |  |  |  |  |  |\n| Rabbit (New Zealand) 5 NS | 5 minutes | 0.1 mL | LE, CS | Death |  | 0.1 | 5/5 died within 9 days |  |\n| OxyChem 1972 |  |  |  |  |  |  |  |  |\n| Rabbit (New Zealand) 2 M, 2 F | Once | 200, 2,000 mg/kg | LE, CS, BW | Death |  | 200 M 2,000 F | 2/2 died within 14 days 2/2 died within 24 hours Dermal irritation and discoloration Hypoactivity |  |\n|  |  |  |  | Dermal Neuro | 200 200 M |  |  |  |\n\n---\n\n**Table 2-3. Levels of Significant Exposure to Hexachlorocyclopentadiene – Dermal**\n\n| Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| OxyChem 1972 |  |  |  |  |  |  |  |  |\n| Rabbit (New Zealand) 3 NS | 24 hours | 0.1 mL | LE, CS | Death Ocular |  |  | 0.1 0.1 | 3/3 died within 6 days Severe eye irritation and corrosion |\n| OxyChem 1992 |  |  |  |  |  |  |  |  |\n| Rabbit (New Zealand) 12 NS | 24 hours | 200 mg/kg | LE, CS | Death Dermal |  |  | 200 200 | 8/12 died Eschar formation |\n| OxyChem 1992 |  |  |  |  |  |  |  |  |\n| Rabbit (New Zealand) 6 NS | 4 hours | 0.5 mL | LE, CS | Dermal |  |  | 0.5 | Erythema, edema, necrosis |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rabbit 1–3 F | 24 hours | 430, 610, 1,020, 2,130, 6,130 mg/kg | LE, CS, GN | Death Dermal |  | 430 | 1020 | 2/3 died Skin irritation, discoloration, subcutaneous edema, acanthosis, epiulation, hyperkeratosis, chronic inflammation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rabbit 3 NS | 4 hours | 73.6 ppm | CS | Ocular |  | 73.6 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rabbit 3 NS | 2.6–3.6 hours | 1.4, 3.1, 7.1, 12.4, 12.7, 46.5, 56.9, 70.4 ppm | CS | Ocular |  | 1.4 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rabbit 3 NS | 7 hours | 1.5, 3.2, 6.7 ppm | CS | Ocular |  | 1.5 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rabbit 3 NS | 0.25–1.25 hours | 1.4, 1.5, 3.1, 7.2, 13.0, 13.8, 19.4, 20.0, 20.2, 69.1, 69.2 ppm | CS | Ocular |  | 1.4 |  | Eye irritation |\n\n---\n\n**Table 2-3. Levels of Significant Exposure to Hexachlorocyclopentadiene – Dermal**\n\n| Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rabbit 3 NS | 2 days 7 hours/day | 3.2 ppm | CS | Ocular |  | 3.2 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rabbit 3 NS | 3 days 7 hours/day | 1.4 ppm | CS | Ocular |  | 1.4 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rabbit 3 NS | 5 days 7 hours/day | 1, 1.6 ppm | CS | Ocular |  | 1 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Guinea pig 2 NS | Once | 0.01, 0.1, 1, 40, 60, 90% | CS | Dermal | 1 | 40 |  | Skin discoloration and irritation |\n| INTERMEDIATE EXPOSURE |  |  |  |  |  |  |  |  |\n| Alexander et al. 1980b; Rand et al. 1982a |  |  |  |  |  |  |  |  |\n| Monkey (Cynomolgus) 6 M, 6 F | 14 weeks 5 days/week 6 hours/day | 0, 0.01, 0.05, 0.2 ppm | CS | Ocular | 0.2 |  |  |  |\n| Alexander et al. 1980b; Rand et al. 1982a |  |  |  |  |  |  |  |  |\n| Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day | 0, 0.01, 0.05, 0.2 ppm | CS | Ocular | 0.01 | 0.05 |  | Dark red eyes |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rat 4 NS | 30 weeks 5 days/week 7 hours/day | 0.15 ppm | CS | Ocular | 0.15 |  |  |  |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rat 4 NS | 6 weeks 5 days/week 7 hours/day | 0.34 ppm | CS | Ocular |  | 0.34 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Mouse 5 NS | 30 weeks 5 days/week 7 hours/day | 0.15 ppm | CS | Ocular | 0.15 |  |  |  |\n\n***DRAFT FOR PUBLIC COMMENT***\n\n---\n\n**Table 2-3. Levels of Significant Exposure to Hexachlorocyclopentadiene – Dermal**\n\n| Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Mouse 5 NS | 6 weeks 5 days/week 7 hours/day (WB) | 0.34 ppm | CS | Ocular |  | 0.34 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rabbit 6 NS | 6 weeks 5 days/week 7 hours/day | 0.34 ppm | CS | Ocular |  | 0.34 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rabbit 2 NS | 30 weeks 5 days/week 7 hours/day | 0.15 ppm | CS | Ocular | 0.15 |  |  |  |\n\nBC = serum (blood) chemistry; BW = body weight; CS = clinical signs; F = female(s); GN = gross necropsy; LD50 = median lethal dose; LE = lethality; \nLOAEL = lowest-observed-adverse-effect level; M = male(s); Neuro = neurological; NOAEL = no-observed-adverse-effect level; NS = not specified; (WB) = wholebody exposure\n\n---\n\n###### 2.2 DEATH\n\nNo studies were located regarding mortality in humans after exposure to HCCPD.\n\nHCCPD induced death in experimental animals via the inhalation, oral, and dermal routes.  The lethality \nof HCCPD following inhalation exposures has been evaluated for acute-, intermediate-, and chronicduration studies.  Acute-duration inhalation exposures to HCCPD at 1.0–73.6 ppm were lethal to rats, \nmice, guinea pigs, and rabbits in a concentration- and exposure duration-related manner (Treon et al. \n1955).  For example, the concentrations that produced 50% fatalities in mice after 1-, 3.5-, and 7-hour \nexposures were 7.2, <3.1, and <1.5 ppm, respectively.  Species-specific differences were observed in the \nmortality data; the concentrations that produced 50% fatalities after 3.5-hour exposures were 7.1 ppm for \nguinea pigs, 3.1 ppm for rats, <3.1 ppm for mice, and <1.4 ppm for rabbits.  All 10 rats exposed to \n176 ppm HCCPD for 4 hours died within 48 hours of the exposure period (OxyChem 1972).  The 1- and \n4-hour inhalation LC50 values for rats are 3.69 ppm (Jackson and Hardy 1986) and 2.9 ppm (Jackson and \nHardy 1987), respectively.  Male rats appear to be more susceptible to HCCPD lethality than female rats; \nthe sex-specific 4-hour inhalation median lethal concentration (LC50) values are 1.6 ppm for males and \n3.5 ppm for females (Rand et al. 1982a).  With 2-week exposures to 0.5 ppm HCCPD, one rat of each sex \ndied, and nine male rats and one female rat were sacrificed in moribund condition by the end of the \nexposure period.  When the exposure duration was reduced to 5 days, three of five males and none of five\nfemales died at 0.5 ppm.  All animals exposed to ≤0.11 ppm survived until the scheduled sacrifice\n(Alexander et al. 1980a; Rand et al. 1982a).\n\n$$\n\\mathrm{LC}_{50}\n$$\n\n$$\n\\left(LC_{50}\\right)\n$$\n\nIn 13-week studies, all rats and mice exposed to ≥0.941 ppm HCCPD died during the exposure periods \n(NTP 1994).  As was observed after acute-duration inhalation exposures, mice appeared to be more \nsensitive to HCCPD-induced lethality; all mice exposed to 2.142 ppm died during the first week while \nrats exposed to 2.065 ppm survived for up to 3 weeks.  Additionally, no rat mortalities were observed at \n≤0.385 ppm, while 5 of 10 male mice died at 0.389 ppm.  NTP (1994) hypothesized that the sensitivity of \nmice to inhalation exposure was the result of HCCPD-induced inflammation of the breathing passages \nand the narrower diameter of the mouse air passages.  No treatment-related deaths were reported for rats \nor monkeys exposed to ≤0.2 ppm for 14 weeks (Alexander et al. 1980b; Rand et al. 1982a) and overall \nsurvival was not statistically significantly affected by HCCPD treatment in male mice exposed to 0.2 ppm \nfor 33 weeks or 0.5 ppm for 26 weeks (NTP 1994).  Although overall survival of male rats was not \naffected after exposure to 0.5 ppm for 42 weeks, survival in this group decreased 14% 3 weeks after \nexposure cessation (NTP 1994).  In a 30-week study, 22% of male rats exposed to 0.56 ppm died during\n\n$$\n\\leq0.385ppm\n$$ the exposure period (Clark 1981).  No mortality attributed to HCCPD was observed in rats exposed to \n0.06 or 0.14 ppm.\n\nSurvival of male and female rats and male mice chronically exposed to 0.01–0.2 ppm HCCPD for 2 years \nwas similar to controls.  Decreased survival was observed for female mice exposed to 0.2 ppm, but not at \nlower concentrations (NTP 1994).  Ovarian inflammation, possibly resulting from an infection, appeared \nto be the cause of premature deaths in female mice exposed to 0.2 ppm HCCPD.\n\nThe lethality of HCCPD in laboratory animals has been evaluated for acute- and intermediate-duration \noral exposures.  The oral median lethal dose (LD50) values were 505 mg/kg in male rats of an unspecified \nstrain (Treon et al. 1955), 630 and 530 mg/kg in male and female Spartan rats, respectively (OxyChem\n1972), and 1,500 and 1,300 mg/kg in male and female CFY rats, respectively (Gardner 1986a).  An oral\ndose of 940 mg/kg was lethal to ≥90% of the male and female rats (Treon et al. 1955).  Acute-duration \noral lethality data for species other than rats are more limited.  The oral LD50 value for male and female \nmice is 679 mg/kg (Dean 1977).  In rabbits, doses of 420, 620, and 940 mg/kg killed 0/3, 1/3, and \n3/3 animals, respectively (Treon et al. 1955).  In pregnant animals, several rabbits (exact number not \nidentified) did not survive 13 days of treatment with 75 mg/kg/day HCCPD on gestational days (GDs) 6–\n18 (Murray et al. 1980).  With intermediate-duration oral exposure, rats appeared to be more sensitive to \nHCCPD lethality than mice, a reverse of the sensitivity observed for inhalation exposures.  There were no \nmouse deaths following 13-week exposures to ≤150 mg/kg/day, but 6 of 10 male rat deaths at \n150 mg/kg/day were attributed to HCCPD treatment following 13 weeks of exposure (Abdo et al. 1984: \nVelsicol 1981a, 1981b).  All 10 male mice and 3 of 10 female mice died during the first 2 weeks of \nexposure to 300 mg/kg/day (Abdo et al. 1984; Velsicol 1981a).\n\n$$\n\\left(\\mathrm{LD}_{50}\\right)\n$$\n\n$$\n\\mathrm{LD}_{50}\n$$\n\n$$\n\\leqq150\n$$\n\nFor the dermal route, lethality of HCCPD in laboratory animals has only been evaluated for acuteduration exposures.  In rabbits administered topical applications of 200 mg/kg for 24 hours, deaths were \nreported in 2/2 males and 0/2 females (OxyChem 1972) and 8/12 rabbits of unspecified sex (OxyChem \n1992).  Dermal exposure to 2,000 mg/kg resulted in 100% mortality in male and female rabbits within \n24 hours (OxyChem 1972).  At lower doses, single dermal doses applied for 24 hours caused mortality in \n0/3, 1/3, and 2/3 rabbits at 430, 610, and 1,020 mg/kg, respectively (Treon et al. 1955).  In the multi-dose \nstudy by Treon et al. (1955), survival time was inversely proportional to the dose; rabbits survived 72, \n24–48, 20, and 17 hours after dermal dosing with 610, 1,020, 2,130, and 6,130 mg/kg, respectively.  None \nof the animals died with a dermal application of 430 mg/kg, although one rabbit was in poor condition \nand likely would have died had it not been sacrificed at 21 days.  In rats, the dermal LD50 values were\n\n$$\n\\mathrm{LD}_{50}\n$$\n\n---\n\n2,600 mg/kg in males and 3,100 mg/kg in females (Gardner 1986b).  These results suggest that rabbits are \nmore sensitive to HCCPD toxicity via the dermal route relative to rats.\n\nWhen 0.1 mL of HCCPD was instilled into the conjunctival sac of five rabbits for 5 minutes and then \nrinsed with water, the quantity of material absorbed was lethal to all the animals within 9 days (OxyChem\n1972).  When ocular rinsing was delayed until 24 hours post-instillation, all three rabbits administered\n0.1 mL of HCCPD died within 6 days.\n\n###### 2.3 BODY WEIGHT\n\nNo reports of body weight effects in humans after exposure to HCCPD were found.  The available data in \nlaboratory animals indicate that HCCPD produces body weight effects at sufficiently high inhalation and \noral exposure levels; no body weight data are available via the dermal route. In several of these studies, \nbody weight changes were associated with decreased food and/or water intake (see Section 2.18, Other \nNoncancer, for additional details).\n\nBody weight effects resulting from inhalation exposures to HCCPD have been assessed in acute-, \nintermediate-, and chronic-duration studies.  Inhalation exposures to sufficient HCCPD concentrations \nover acute and intermediate periods decrease body weights and/or suppress body weight gains.  A single \n1-hour exposure to HCCPD resulted in decreased body weights in rats during the 3-week post-exposure \nobservation period at concentrations ≥2.38 ppm; when animals that died prematurely and those sacrificed \nat the end of the observation period are combined, body weight decreases compared to control were 41% \nin males and 26% in females (Jackson and Hardy 1986).  A 4-hour exposure resulted in >20% decreases \nin body weight in male and female rats at ≥1.68 and 1.83 ppm, respectively, during the 4-week \nobservation period (Jackson and Hardy 1987).  In both studies by Jackson and Hardy (1986, 1987), body \nweight effects were associated with decreased food intake.  Similarly, after a 4-hour exposure to HCCPD, \nbody weight decreases of at least 25 and 17% relative to pre-exposure weights were observed for male \nand female rats, respectively, after exposures to 1.4–5.8 ppm; no food intake data were provided (Rand et \nal. 1982a).  With significantly decreased food intake, male and female rats exposed to 0.5 ppm HCCPD \nfor 1–2 weeks lost body weight; male body weights decreased 32% on day 10 and terminal female body \nweight decreased 29% (Alexander et al. 1980a; Rand et al. 1982a).\n\n$$\nt\\geqq1.68\n$$\n\nIn 13-week inhalation studies, terminal body weights remained within 10% of control values following \nexposure to HCCPD at concentrations up to 0.385 ppm in rats and 0.389 ppm in mice (NTP 1994).\n\n---\n\nSimilarly, no effects on body weight were observed in rats and monkeys exposed to ≤0.2 ppm HCCPD \nfor 14 weeks (Alexander et al. 1980b; Rand et al. 1982a).  Body weight decreased 19% and body weight \ngain decreased 42% in male mice exposed to 0.5 ppm for 42 weeks (NTP 1994).  No body weight deficits \nwere identified after exposure of male mice to 0.2 ppm for 33 weeks or to 0.5 ppm for 26 weeks (NTP \n1994).  Body weights remained within 10% of control values for male and female rats exposed to \n≤0.56 ppm for 30 weeks (Clark 1981), and in male and female mice and rats exposed to ≤0.2 ppm for \n2 years (NTP 1994).\n\nBody weight effects after oral exposure to HCCPD in experimental animals have been evaluated in acuteand intermediate-duration studies.  In intermediate-duration studies, sufficient oral dosing with HCCPD \ndecreased body weights and suppressed body weight gains.  Male and female rats and mice experienced \ndose-related decreased body weights and body weight gains when compared to controls after oral \nexposure to HCCPD for 13 weeks (Abdo et al. 1984; Velsicol 1981a, 1981b).  Male rats were affected \nmore than females, and rats were affected more than mice.  Terminal body weights in male rats decreased \n13–35% and overall body weight gains were reduced 21–58% at dose levels of ≥38 mg/kg/day. In female\nrats exposed to 75–150 mg/kg/day, terminal body weights were reduced 15–17% and overall body weight \ngains decreased 28–36%.  Terminal body weights in male mice were reduced 11% and overall body \nweight gains decreased 39% at 150 mg/kg/day.  In female mice, terminal body weights decreased 13% at \n300 mg/kg/day and overall body weight gains were reduced 22–44% at ≥150 mg/kg/day. Differences in \nterminal body weights and overall body weight gains were within 10% of control values for male rats at \n≤19 mg/kg/day, female rats at ≤38 mg/kg/day, and male and female mice at ≤75 mg/kg/day.  Maternal \nweight loss was observed in rabbits administered 75 mg/kg/day on GDs 6–18; the magnitude of weight \nloss was not reported (Murray et al. 1980).  No body weight effects were reported for rabbits dosed with \n≤25 mg/kg/day on GDs 6–18 or for mice dosed with ≤75 mg/kg/day on GDs 6–15.\n\n###### 2.4 RESPIRATORY\n\nThe data provide strong evidence that HCCPD produces portal-of-entry effects in the respiratory system \nfollowing inhalation exposures; no effects on the respiratory tract were observed following oral or dermal \nexposures to HCCPD.  Based upon systematic review (Appendix C), the respiratory system is a presumed \nhazard of HCCPD toxicity following inhalation exposure based on inadequate evidence in humans and a \nhigh level of evidence from laboratory animal studies.\n\n---\n\nThe available data on respiratory effects of HCCPD in humans are limited to reports of WWTP workers \nand cleanup crew members exposed to HCCPD for 3–15 days after an inadvertent industrial release of \nthis material into the sewage system (Kominsky et al. 1980; Morse et al. 1979).  Maximum atmospheric \nconcentrations for the treatment plant workers were unknown but were most likely >0.97 ppm, the \nmaximum concentration measured 4 days after compound identification (Morse et al. 1979).  The \nmaximum concentration recorded during cleanup was 19.2 ppm (Kominsky et al. 1980).  Symptoms of \ntracheobronchial irritation were reported by the treatment plant workers early in the exposure period.  \nThese symptoms were recounted by 39 of 145 (27%) employees who responded to a questionnaire shortly \nafter the exposure incident and by 16 of 177 (9%) employees who responded to a follow-up questionnaire \n6 weeks later (Morse et al. 1979).  Chest x-rays of 28 exposed workers were normal and tests of \npulmonary function were normal in a subset of 22 workers from this group (Kominsky et al. 1980).  \nMinor respiratory complaints included sore throat, cough, chest discomfort, and difficulty breathing.  \nThese effects were likely a consequence of the direct action of the HCCPD vapor on the mucous \nmembranes of the respiratory tract, rather than systemic effects due to exposure to HCCPD through the \nlungs.  One cleanup crew worker also reported respiratory difficulty when exposed for a few seconds to \n19.2 ppm HCCPD without protective equipment (Kominsky et al. 1980).  Chest discomfort persisted for \nseveral days in this individual.\n\nRespiratory effects induced by HCCPD in laboratory animals have been evaluated in acute-, \nintermediate-, and chronic-duration inhalation exposure studies.  Inhalation exposures to HCCPD \nproduced clinical signs of respiratory toxicity and/or irritation including abnormal respiratory pattern \n(irregular or exaggerated respiratory movements, fast or irregular respiration rate or pattern, rales and/or \nnoisy respiration, and/or gasping), labored respiration, sneezing, increased respiration rate, and/or mouth \nbreathing in rats exposed to 1.67 ppm for 1 hour (Jackson and Hardy 1986), 1.68 ppm for 4 hours \n(Jackson and Hardy 1987), 0.5 ppm for 1–2 weeks (Alexander et al. 1980a; Rand et al. 1982a), 0.56 ppm \nfor 30 weeks (Clark 1981), and ≥0.941 ppm for 13 weeks (NTP 1994).  No respiratory clinical signs were \nobserved in rats or monkeys exposed to 0.2 ppm for 14 weeks (Alexander et al. 1980b; Rand et al. \n1982a), mice exposed to ≤2.142 ppm for 13 weeks (NTP 1994), male mice exposed to 0.2 ppm for \n33 weeks or 0.5 ppm for 26 or 42 weeks (NTP 1994), or rats and mice exposed to ≤0.2 ppm for 2 years \n(NTP 1994).  Based on these data, it appears that rats are more susceptible to HCCPD-induced respiratory \nirritation effects than mice. Blood gas analysis, pulmonary ventilation, and lung mechanics were within \nnormal ranges in pulmonary function tests of monkeys exposed to ≤0.2 ppm HCCPD for 7 and 13 weeks \n(Alexander et al. 1980b; Rand et al. 1982a).\n\n---\n\nInhalation exposures to HCCPD vapor caused histopathological changes in the respiratory tracts of \nexperimental animals.  At nonlethal concentrations, these alterations were largely inflammatory or \nhyperplastic in nature, consistent with repetitive irritation at the portal of entry.  Inflammation of the \ntissues was followed by necrosis, exfoliation, and/or hemorrhage.  No histopathological examination was \nconducted, but gross necropsy of the lungs showed pale and swollen lungs in rats exposed to ≥1.68 ppm \nfor 4 hours; findings were associated with increased absolute and relative lung weights at ≥3.31 and \n1.83 ppm in male and female rats, respectively (Jackson and Hardy 1987).  Inflammation, hyperplasia, \nand epithelial erosion were identified in the lungs of rats exposed to HCCPD vapor at 0.5 ppm for 1–\n2 weeks; recovery was apparent 2 weeks after exposure ceased in surviving animals (Alexander et al. \n1980a; Rand et al. 1982a).  No histopathological changes were identified in respiratory tissues of rats\nexposed to ≤0.11 ppm in the same manner (Alexander et al. 1980a; Rand et al. 1982a) or in rats and \nmonkeys exposed to ≤0.2 ppm for 14 weeks (Alexander et al. 1980b; Rand et al. 1982a). Using electron \nmicroscopy, exposure-related increases in electron-lucent inclusions in club cells, formerly called Clara \ncells, were observed in rats exposed to 0.01–0.2 ppm for 14 weeks (Huntingdon Research Centre 1980; \nRand et al. 1982b); however, this findings is considered a biomarker of exposure rather than evidence of \ntoxicity due to the absence of histopathological findings or any other ultrastructural changes.  No \nexposure-related ultrastructural changes were observed in monkeys exposed to ≤0.2 ppm for 14 weeks\n(Rand et al. 1982b).  In a 30-week inhalation exposure study in rats, increased incidences of \nperivascular/peribronchiolar inflammatory cell infiltration were observed in males and females exposed to \n0.56 ppm; males exposed to this concentration also exhibited an increased incidence of bronchiolar \nepithelial thinning/ulceration (Clark 1981).  The incidences of bronchiolar epithelial hyperplasia, \nsloughing/loss, and edema also increased in male and female rats exposed to 0.56 ppm but did not reach \nstatistical significance.  Following a 14-week recovery period, no histopathological differences were \nidentified in the lungs of control and treated rats, indicating reversibility of these lesions.\n\n$$\nt_{0}\\geqq1.68\n$$\n\nIn 13-week studies, microscopic effects in the respiratory system produced by lethal HCCPD \nconcentrations included necrotizing inflammation of the nose, larynx, trachea, and bronchus/bronchiole \nand hemorrhaging of the alveolus in male and female rats exposed to 0.941–2.065 ppm; suppurative \ninflammation of the alveolus in male and female rats at 0.941 ppm; acute necrosis of the nose, larynx, \ntrachea, and lung epithelium and lung congestion in male and female mice at 2.142 ppm; tracheal \nsquamous metaplasia in male and female mice at 0.949 ppm; and suppurative inflammation of the nasal \nepithelium of male and female mice exposed to 0.949–2.142 ppm (NTP 1994).  Increased incidences of \nsuppurative inflammation and squamous metaplasia in the nose and necrotizing and suppurative \ninflammation of the bronchus/bronchiole were identified in male rats exposed to 0.385 ppm, increased incidences of nasal suppurative inflammation and tracheal squamous metaplasia were observed in male \nmice exposed to 0.389 ppm, and an increased incidence of nasal serous inflammation was present in \nfemale mice exposed to 0.389 ppm.  No statistically significant increases were identified for nonneoplastic lesions in the respiratory tract tissues of female rats exposed to ≤0.385 ppm, male rats exposed \nto 0.146 ppm, or male or female mice exposed to ≤0.146 ppm (NTP 1994).\n\nHistopathological findings in male and female mice exposed to 0.2 ppm for 2 years included nasal \nsuppurative inflammation characterized by accumulation of cellular debris, mucus, neutrophils, and fibrin \nin the nasal lumen and infiltration of mononuclear cells and neutrophils into the lamina propria (NTP \n1994).  After 2-year exposures, an increased incidence of squamous metaplasia of the larynx (minimal \nseverity) was identified in female rats at 0.01 and 0.2 ppm; the incidence at 0.05 ppm was also elevated \nbut was not statistically significantly different from the concurrent control incidence.  No treatmentrelated respiratory tract lesions were identified in male rats.  The toxicological relevance of the squamous \nmetaplasia was not clear to the NTP (1994) authors due to difficulties in obtaining consistent sections for \nanalysis and determination of the boundary between squamous and columnar epithelium.  Due to this, as \nwell as the lack of clear dose-response, a LOAEL determination for squamous metaplasia was not \nincluded in Table 2-1.\n\nTo examine the progression and permanence of non-neoplastic lesions in the respiratory tract, NTP \n(1994) conducted additional studies in male mice with the intent of evaluating the relative effects of \nconcentration and duration on development of these lesions.  In these studies, concentrations were 0 or \n0.2 ppm for 33 weeks and 0 or 0.5 ppm for 26 or 42 weeks.  Animals were sacrificed at interim \nevaluations after 27, 34, or 43 weeks or 15 months of exposure or were sacrificed after 2 years.  At the \nend of the exposure periods, the incidence of nasal suppurative inflammation increased in all treatment \ngroups and suppurative inflammation of the trachea and lungs and alveolar epithelial hyperplasia \nincreased in animals exposed to 0.5 ppm for 42 weeks.  The incidence of alveolar epithelial hyperplasia \nalso increased in male mice exposed to 0.5 ppm for 42 weeks.  An evaluation of the data indicated that \nboth concentration and duration of exposure influenced the development of these respiratory tract lesions; \nthe inflammation of the trachea and lungs was not observed unless the product of the concentration and \nduration was >20 or 21 ppm-weeks.\n\nIn the chronic-duration studies of rats and mice exposed to HCCPD for 2 years, accumulation of a \ngranular yellow-brown pigment was observed in the nasal epithelium in male and female rats and mice at \n≥0.01 ppm, tracheal epithelium of male and female mice at ≥0.01 ppm, bronchiole epithelium of female\n\n$$\n\\geqq0.01\n$$ rats at ≥0.01 ppm, and lung epithelium of male and female mice ≥0.05 ppm (NTP 1994).  At 0.2 ppm, \nminimal-to-mild tracheal, bronchiole, and peribronchiole pigmentation was observed in male rats and \nperibronchiole pigmentation was identified in female rats (NTP 1994).  The pigmentation incidence and \nseverity generally increased with concentration for each sex-species combination.  In male mice exposed \nto 0.2 ppm for 33 weeks or 0.5 ppm for 26 or 42 weeks and then maintained for up to 2 years, \npigmentation of the respiratory tract (nose, trachea, and/or lungs) was seen in the majority of exposed \nanimals and did not disappear following exposure cessation and evaluation at 2 years, indicating a lack of \nrecovery and physiological turnover of the pigment material.  The incidence and severity were similar \nafter 33, 66, and 104 weeks of exposure to 0.2 ppm HCCPD.  In the chronic-duration and additional \nstudies in male mice exposed to 0.2 ppm for 33 weeks and 0.5 ppm for 26 or 42 weeks, the pigmentation \ndid not co-occur with respiratory lesions and did not appear to be a precursor to more significant effects \n(i.e., did not indicate an initial phase in the progression of a disease state).  Results of several staining \nprocedures applied to the pigmented lung sections of rats and mice indicated the presence of reducing \nsubstances, but no further analytical identification was performed.  NTP (1994) indicated that the \npigmentation may be a unique response to HCCPD and could be due to lipid peroxidation.  Based on \nthese data, ATSDR concludes that it is more appropriate to characterize the pigmentation as a marker of \nexposure to HCCPD rather than an adverse effect attributable to HCCPD exposure.\n\nThe potential for oral exposure to HCCPD to induce respiratory effects has been evaluated in acute- and \nintermediate-duration studies.  In rats and mice administered lethal gavage doses of HCCPD, decreased \nrespiratory rates were observed prior to death (Dean 1977; Gardner 1986a); this clinical sign was likely a \nconsequence of significant morbidity prior to death rather than an effect of HCCPD on the respiratory \nsystem.  No gross or histopathological changes were identified in the nasal cavity, trachea, larynx, \nbronchi, or lungs of rats at doses ≤150 mg/kg/day or in mice at doses ≤300 mg/kg/day for 13 weeks \n(Abdo et al. 1984; Velsicol 1981a, 1981b).\n\nThe potential toxicological effects of HCCPD on the respiratory tract following dermal exposure were \nevaluated in one acute-duration dermal toxicity study.  A decreased rate of respiration was observed in \nrats administered topical doses ≥2,000 mg/kg for 24 hours (Gardner 1986b).  The animals appeared \nnormal 5–9 days after dosing and no gross pathological changes were identified in the lungs of animals \nthat survived to the scheduled sacrifice.\n\n---\n\n###### 2.5 CARDIOVASCULAR\n\nNo studies were located regarding cardiovascular effects in humans after exposure to HCCPD. Available\ndata from laboratory animals indicate that the cardiovascular system is not a sensitive toxicity target \nfollowing inhalation or oral exposure to HCCPD.\n\nThe cardiovascular system has been evaluated in experimental animals exposed to HCCPD via inhalation \nin acute-, intermediate-, and chronic-duration studies.  Diffuse degenerative changes were observed in the \nhearts of rats, mice, and rabbits that died following acute exposure to lethal concentrations of HCCPD \nranging from 0.3 to 66 ppm for 15 minutes to 2 weeks; incidence data were not provided, and findings \nwere potentially attributable to autolysis (Treon et al. 1955).  In another acute-duration study, there were \nno histopathological changes in the heart in rats exposed to concentrations up to 0.5 ppm after either 1 or \n2 weeks (Alexander et al. 1980a; Rand et al. 1982a).  In longer-term inhalation studies, there was no \nevidence for histopathological changes in the heart at intermediate-duration concentrations up to \n0.56 ppm in rats, 0.389 ppm in mice, or 0.2 ppm in monkeys (Alexander et al. 1980b; Clark 1981; NTP \n1994; Rand et al. 1982a) or chronic-duration concentrations up to 0.2 ppm in rats or mice (NTP 1994).\n\nPotential cardiovascular effects of HCCPD oral exposures in experimental animals were evaluated in \nacute- and intermediate-duration studies.  Single oral doses of 280–2,100 mg/kg caused degenerative \nchanges in the hearts of rats and rabbits, possibly due to tissue autolysis; incidence data were not provided\n(Treon et al. 1955).  In contrast, there were no gross or histopathological changes in the hearts of rats \nexposed to doses ≤150 mg/kg/day or mice exposed to doses ≤300 mg/kg/day for 13 weeks (Abdo et al. \n1984; Velsicol 1981a, 1981b).\n\nRabbits that died following single dermal doses of 610–6,130 mg/kg displayed degenerative changes in \nthe heart, possibly because of tissue autolysis; incidence data were not provided (Treon et al. 1955).\n\n###### 2.6 GASTROINTESTINAL\n\nThe data provide evidence that HCCPD produces portal-of-entry effects in the gastrointestinal system, \nspecifically the stomach, following oral exposures.  Data on adverse gastrointestinal effects following \ninhalation exposure are limited to clinical signs following accidental occupational exposure; no effects on \nthe gastrointestinal system were observed following dermal exposure to HCCPD.  Based upon systematic \nreview (Appendix C), the gastrointestinal system is a presumed hazard of HCCPD toxicity following oral exposure based on no route-specific data in humans and a high level of evidence from laboratory animal \nstudies.\n\nWWTP workers exposed to HCCPD for 3–15 days due to an inadvertent industrial release complained of \nnausea (22% of 177 workers) and abdominal cramps (prevalence not specified) (Kominsky et al. 1980; \nMorse et al. 1979).  One member of the cleanup crew who was exposed to 19.2 ppm for several seconds \nwithout protective equipment experienced nausea several minutes after the exposure (Kominsky et al. \n1980).  While classified as gastrointestinal in this profile, it is possible that nausea may be neurological in \norigin.\n\nGastrointestinal effects of HCCPD have been evaluated in laboratory animals following intermediate- and \nchronic-duration inhalation exposures.  No microscopic changes were seen in the stomach, esophagus, or \nintestines of monkeys, rats, or mice exposed to concentrations up to 0.2, 0.56, or 0.5 ppm, respectively, in\nintermediate-duration studies (Alexander et al. 1980b; Clark 1981; NTP 1994; Rand et al. 1982a), or rats \nor mice following chronic-duration exposure to concentrations up to 0.2 ppm (NTP 1994).  The \ngastrointestinal tract does not appear to be a sensitive target for HCCPD in animals following inhalation \nexposures.\n\nThe potential impact of HCCPD exposure on gastrointestinal tissues has been evaluated in acute- and \nintermediate-duration oral exposure studies in experimental animals.  Increased incidences of diarrhea \nwere observed in rats dosed with ≥1,260 mg/kg (Gardner 1986a) and female and male mice dosed with \n464 and 1,000 mg/kg, respectively (Dean 1977).  Acute necrotic lesions of the forestomach were noted in \nsome rats administered an oral dose of 280–2,100 mg/kg; incidence data were not provided (Treon et al. \n1955).  After 13-week exposures to HCCPD, increased incidences of forestomach epithelial hyperplasia \nwere observed in male and female rats at 38 mg/kg/day and male and female mice at 75 mg/kg/day (Abdo \net al. 1984; Velsicol 1981a, 1981b).  Increased incidences of focal inflammation in the forestomach were \nidentified in male and female rats at 38 mg/kg/day and male and female mice at 75 mg/kg/day.  The \nincidences and ranges of lesion severities were directly related to the dose.  No histopathological changes \nwere identified in the esophagus, duodenum, jejunum, ileum, or colon of males and females of either \nspecies.  These data suggest that rats are more sensitive to HCCPD-induced effects to the forestomach \nthan mice.  The presence of the forestomach lesions and lack of histopathological changes in other \nregions of the gastrointestinal tract suggests that the forestomach effects result from direct contact of \nthese tissues with HCCPD.\n\n---\n\n###### 2.7 HEMATOLOGICAL\n\nThe data indicate HCCPD may alter red blood cell hematology parameters following inhalation exposure \nwithout causing histopathological changes to bone marrow; no consistent effects were noted in white \nblood cell parameters following inhalation exposure and no effects on the hematological system were \nobserved in animals following oral exposures to HCCPD.  Data are not available via the dermal route.  \nBased upon systematic review (Appendix C), the hematological system, specifically red blood cell \nparameters, is a suspected hazard of HCCPD toxicity following inhalation exposure based on inadequate \ndata in humans and a moderate level of evidence from laboratory animal studies.  White blood cell effects \nare not classifiable as to the hazard to humans based on inadequate data in humans and animals.\n\nNo changes in blood counts were observed in workers exposed to HCCPD at a WWTP after an industrial \ndischarge of the material into the sewage system (Kominsky et al. 1980).\n\nThe potential hematological effects of HCCPD were evaluated in experimental animals exposed via \ninhalation after acute-, intermediate-, and chronic-duration exposures.  No effects on bone marrow \nhistopathology were reported in rats exposed to 0.5 ppm for 1–2 weeks (Alexander et al. 1980a; Rand et \nal. 1982a), rats and mice exposed to ≤0.385 and ≤0.389 ppm, respectively, for 13 weeks, or rats and mice \nexposed to ≤0.2 ppm for 2 years (Alexander et al. 1980b; NTP 1994; Rand et al. 1982a).  Across acuteand intermediate-duration multiple exposure studies, altered red blood cell hematology parameters were \nidentified in rats, particularly males, as seen in Table 2-4.\n\n**Table 2-4. LOAEL Values for Red Blood Cell Hematological Effects of Rats** \n**Exposed to HCCPD Vapor in Acute- and Intermediate-Duration Inhalation**\n**Studies**\n\n| Hematology parameter | Rand et al. 1982aa: 1–2 weeks | Rand et al. 1982aa: 1–2 weeks (recovery group) | NTP 1994: 13 weeks | NTP 1994: 13-week special hematology study | Clark 1981: 30 weeks |\n| --- | --- | --- | --- | --- | --- |\n| Males |  |  |  |  |  |\n| PCV | \\(\\uparrow (0.5^{{b}})\\) | ↔ | \\(\\uparrow (0.385)\\) | ↔ | - |\n| Hb | \\(\\uparrow (0.5)\\) | \\(\\uparrow (0.5)\\) | \\(\\uparrow (0.385)\\) | ↔ | \\(\\uparrow (0.14)\\) |\n| RBC | \\(\\uparrow (0.5)\\) | ↔ | \\(\\uparrow (0.385)\\) | ↔ | \\(\\uparrow (0.14)\\) |\n| MCV | ↔ | ↔ | ↔ | \\(\\uparrow (0.385)\\) | ↔ |\n| MCH | - | - | \\(\\uparrow (0.385)\\) | ↔ | ↔ |\n| MCHC | ↔ | \\(\\uparrow (0.5)\\) | ↔ | ↔ | ↔ |\n\n---\n\n**Table 2-4. LOAEL Values for Red Blood Cell Hematological Effects of Rats** \n**Exposed to HCCPD Vapor in Acute- and Intermediate-Duration Inhalation**\n**Studies**\n\n| Hematology parameter | Rand et al. 1982aa: 1–2 weeks | Rand et al. 1982aa: 1–2 weeks (recovery group) | NTP 1994: 13 weeks | NTP 1994: 13-week special hematology study | Clark 1981: 30 weeks |\n| --- | --- | --- | --- | --- | --- |\n| HCT | - | - | - | - | \\(\\uparrow\\) (0.14) |\n| Females |  |  |  |  |  |\n| PCV | \\(\\uparrow\\) (0.5) | ↔ | ↔ | \\(\\uparrow\\) (0.385) | - |\n| Hb | \\(\\uparrow\\) (0.5) | ↔ | ↔ | \\(\\uparrow\\) (0.385) | ↔ |\n| RBC | \\(\\uparrow\\) (0.5) | ↔ | \\(\\downarrow\\) (0.385) | \\(\\uparrow\\) (0.385) | ↔ |\n| MCV | ↔ | ↔ | \\(\\uparrow\\) (0.385) | \\(\\uparrow\\) (0.385) | ↔ |\n| MCH | - | - | ↔ | \\(\\uparrow\\) (0.385) | ↔ |\n| MCHC | ↔ | ↔ | ↔ | ↔ | ↔ |\n| HCT | - | - | - | - | ↔ |\n\n<sup>a</sup>Data are also available in the unpublished industry report by Alexander et al. (1980a).\n\n<sup>b</sup>LOAEL concentrations are in ppm.\n\n↑ = increased mean value; ↓ = decreased mean value; ↔ = no significant, dose-related change in mean value;\n\n– = not assessed; Hb = hemoglobin; HCT =hematocrit; MCH = mean cell hemoglobin; MCHC = mean cell\n\nhemoglobin concentration; MCV = mean cell volume; PCV = packed cell volume; RBC = red blood cell count\n\nThe most consistently observed effects were increased hemoglobin levels in male and female rats and \nincreased red blood cell counts in male rats.  Generally, effects were observed at concentrations \n≥0.14 ppm and had magnitudes of effect that were <10% of control values.  The exceptions are for the 1–\n2-week range-finding study (Alexander et al. 1980a; Rand et al. 1982a), where 20–30% increases in red \nblood cell parameters were identified at 0.5 ppm, a concentration that co-occurred with significantly \ndecreased water intake and produced significant mortality and morbidity (see Section 2.2).  Drinking \nwater intakes were not assessed in the NTP (1994) studies and were not affected by HCCPD exposure in \nthe Clark (1981) study (see Section 2.18).  While statistically significant altered hemoglobin, mean cell \nvolume (MCV), and mean cell hemoglobin concentration (MCHC) values were reported in rats following \na 14-week exposure at concentrations as low as 0.01 ppm, these changes were sporadically observed and\nwere not dose-responsive, and the magnitudes of effect were generally low (≤5%) (Alexander et al. \n1980b; Rand et al. 1982a).  Therefore, they were not considered to be biologically significant in this \nassessment and are not presented in Table 2-4.  For intermediate-duration exposures in rats, the NOAEL \nvalues were 0.039–0.146 ppm for the NTP (1994) 13-week studies and 0.06 ppm for the Clark (1981) \n30-week study.\n\n---\n\nRand et al. (1982a) postulated that these minor variances in hematological parameters were a \nconsequence of hemorrhagic lesions in the lungs and not a direct influence of HCCPD on hematopoiesis \nor red cell turnover.  Since the red blood cell hematology parameters were more consistently altered in \nmale rats than in female rats, this hypothesis correlates with the increased absolute and relative lung \nweights and more severe histopathological effects observed in the lungs of male rats in the 1–2-week\nRand et al. (1982a) study.  NTP (1994) suggested that the red blood cell hematology alterations were not \nattributable to HCCPD treatment due to the inconsistent dose-response and lack of correlation in the \nresults across sexes and between the core and special 13-week hematology studies.  While there are \ninconsistencies in the red blood cell parameter results obtained from the NTP (1994) studies, common \nalterations in hemoglobin levels and red blood cell counts across repeated inhalation exposure studies \nsuggest a consistent biological response to HCCPD.  In the absence of additional data and based on the \nlack of histopathological effects to bone marrow, ATSDR considers the altered red blood cell parameters \nto be plausibly related to respiratory tract damage resulting in compromised gas exchange.\n\nIn mice, the only consistent HCCPD treatment-related effect on red blood cell hematology parameters \nacross studies was decreased MCV in female mice after exposure to 0.389 ppm for 13 weeks in the core\nand special hematology studies (NTP 1994).  Other red blood cell effects were limited to increased \nMCHC in male mice at 0.389 ppm and in female mice at 0.039–0.389 ppm in the special 13-week \nhematology study.  The magnitudes of effect were within 5% of control values.  HCCPD treatmentrelated effects on other hematological parameters following inhalation exposures were limited to \ndecreased reticulocytes (40%) in female rats exposed to 0.385 ppm in the special hematology study (NTP \n1994); decreased total white blood cells (46%) and lymphocyte count (53%) in male rats, and increased \nneutrophil count (114%) in female rats exposed to 0.5 ppm for 1–2 weeks (Alexander et al. 1980a; Rand \net al. 1982a); and decreased percent lymphocytes (8–10%) and increased neutrophil count (27–36%) in \nmale rats exposed to ≥0.14 ppm and decreased lymphocyte count (16%) in female rats exposed to \n0.56 ppm for 30 weeks (Clark 1981).  No clear biological basis can be identified for these effects based \non the lack of consistency across studies.\n\nIn intermediate-duration oral exposure studies, no histopathological changes were identified in the bone \nmarrow of rats dosed with ≤150 mg/kg/day or mice dosed with ≤300 mg/kg/day for 13 weeks (Abdo et al. \n1984; Velsicol 1981a, 1981b).  Hematology parameters were not evaluated in this study.\n\n---\n\n###### 2.8 MUSCULOSKELETAL\n\nNo studies were located regarding musculoskeletal effects in humans after exposure to HCCPD.  \nAvailable inhalation and oral data in laboratory animals indicate the musculoskeletal system is not a \nsensitive target of toxicity following exposure to HCCPD; no dermal studies were identified.\n\nThe potential effect of HCCPD on musculoskeletal tissues has been evaluated in laboratory animals \nfollowing intermediate- and chronic-duration inhalation exposures and acute- and intermediate-duration \noral exposures.  HCCPD did not affect skeletal muscle of rats or monkeys exposed to up to 0.2 ppm for \n14 weeks (Alexander et al. 1980b; Rand et al. 1982a); femoral muscle, knee joint, or femur of male and \nfemale rats exposed to ≤0.56 ppm for 30 weeks (Clark 1981); bone histopathology of mice or rats \nexposed to ≤0.389 ppm for 13 weeks or ≤0.2 ppm for 2 years (NTP 1994).  Similarly, no \nhistopathological changes were identified in thigh muscle, rib (costochondral junction), or femur of rats \nexposed to ≤150 mg/kg/day or mice exposed to ≤300 mg/kg/day via gavage for 13 weeks (Abdo et al. \n1984; Velsicol 1981a, 1981b). In animals that died, decreased limb tone was observed in mice (prior to \ndeath) after a single exposure to 1,000 mg/kg via gavage (Dean 1977).\n\n###### 2.9 HEPATIC\n\nThe data indicate that the hepatic system is not a sensitive target of HCCPD toxicity.\n\nSerum markers of hepatotoxicity were evaluated in 97 cleanup workers exposed to HCCPD vapors at a \nWWTP because of an inadvertent industrial release (Kominsky et al. 1980).  Abnormal serum marker \nranges were identified for 18 of the 97 workers (19%); aspartate aminotransferase (AST) values were \nelevated for 12 workers, alkaline phosphatase (ALP) was elevated for 5 workers, and total bilirubin was \nelevated for 1 worker (Kominsky et al. 1980).  For 8 of the 97 cleanup crew members, these biochemical \nparameters were abnormal on more than one occasion, and 7 workers had values that were temporallyrelated to exposure conditions.  It should be noted that evaluations were not performed on unexposed \nworkers, and it is not known if the abnormal values observed in exposed workers differ from the \nunexposed local general population.\n\nRelative to a group of 35 controls, 73 male operators employed for an average of 8.2 years (range 0.5–\n23 years) in a plant producing chlorinated hydrocarbons, including HCCPD, showed no evidence of \nhepatotoxicity (Boogaard et al. 1993).  Clinical tests included measurement of alanine aminotransferase\n\n---\n\n(ALT), AST, ALP, total bilirubin, γ-glutamyltransferase (GGT), lactate dehydrogenase (LDH), and total \nbile acids.  Personal air sampling for HCCPD was performed on a subset of study participants but was not \nused to evaluate associations between HCCPD exposure and liver function values.\n\nThe hepatotoxic potential of HCCPD has been evaluated in laboratory animals following acute-, \nintermediate-, and chronic-duration inhalation exposures.  Mild-to-moderate hepatic tissue degeneration \nwas observed following acute-duration inhalation exposures to 0.34–73.6 ppm for 15 minutes to 5 days, \nand to intermediate-duration exposures to 0.34 ppm for 6 weeks or 0.15 ppm for 30 weeks; incidence data \nwere not provided (Treon et al. 1955).  Hepatic damage was more pronounced in the animals that died \nthan in those that survived and, thus, may have been, at least partially, the result of autolysis in moribund \nor dying animals.  An apparent dose-related increase in perivascular/peribiliary inflammatory cell \ninfiltrates in the liver was observed in female rats exposed to 0.06–0.56 ppm; however, incidences did not \ndiffer significantly from control and no hepatic lesions were observed in similarly exposed male rats \n(Clark 1981).  In other inhalation studies, no exposure-related hepatic lesions were seen following acuteduration exposure in rats to concentrations up to 0.5 ppm (Alexander et al. 1980a; Rand et al. 1982a); \nintermediate-duration exposure in monkeys, rats, or mice to concentrations up to 0.2, 0.385, or 0.5 ppm, \nrespectively (Alexander et al. 1980b; NTP 1994; Rand et al. 1982a); or chronic-duration exposure in rats \nor mice to concentrations up to 0.2 ppm (NTP 1994).\n\nNo consistent evidence of exposure-related changes in hepatic serum biochemistry or liver weight was \nobserved following inhalation exposure to HCCPD.  Serum concentrations of the biochemical parameters\nLDH, AST, ALP, and ALT in rats and mice were not influenced by inhalation exposure to HCCPD \nconcentrations ≤0.389 ppm for 13–14 weeks (Alexander et al. 1980b; NTP 1994; Rand et al. 1982a).  \nDuring the 13-week special hematology, clinical chemistry, and urinalysis study conducted in rats by \nNTP (1994), the highest concentration of 2.065 ppm caused elevated serum AST concentrations (1.7–\n7.6-fold) in male and female rats on days 4–16; however, this concentration was lethal to all the animals \nprior to the day 46 clinical evaluation, and a comparable increase was not observed in mice (NTP 1994).  \nRelative liver weights of rats were significantly reduced by 3–15% in males and females exposed to 0.01–\n0.2 ppm for 13 weeks, but the decreases were not dose-related (Alexander et al. 1980b; Rand et al. \n1982a).  No changes in liver weights were observed in rats or mice exposed to concentrations ≤0.389 ppm \nfor 13 weeks or ≤0.2 ppm for 2 years (NTP 1994).\n\nAcute- and intermediate-duration oral toxicity studies have evaluated the potential effects of HCCPD\nexposure on the liver.  High, acute-duration oral doses of HCCPD were associated with liver necrosis and tissue degeneration in rats (261–1,959 mg/kg) and rabbits (579–877 mg/kg); incidence data were not \nprovided (Treon et al. 1955).  HCCPD did not induce histopathological changes in hepatic tissues of rats \nand mice exposed to doses up to 150 and 300 mg/kg/day, respectively, via gavage for 13 weeks (Abdo et \nal. 1984; Velsicol 1981a, 1981b).\n\nThe potential for HCCPD to cause hepatotoxicity following dermal exposure was evaluated only for \nacute-duration exposures.  Rabbits exposed to single dermal doses of 401–5,719 mg/kg displayed necrosis \nof the liver; incidence data were not provided (Treon et al. 1955).  The study authors stated that \ndegenerative changes persisted even 21 days after the exposure period in surviving animals.\n\n###### 2.10 RENAL\n\nThe data indicate that the renal system is a potential target for HCCPD via the oral route; it does not \nappear to be a sensitive target for HCCPD via the inhalation or dermal routes.  Based upon systematic \nreview (Appendix C), the kidney is a presumed hazard of HCCPD toxicity following oral exposure based \non no data in humans and a high level of evidence from laboratory animal studies.\n\nUrine samples were collected from 41 workers exposed for 3–15 days to HCCPD at a WWTP as the \nresult of an inadvertent industrial release into the sewage system (Morse et al. 1979).  Proteinuria was \nidentified in 6 of 41 workers immediately after exposure but no abnormalities were detected 3 weeks \nlater.  Urinalysis parameters were normal in all 97 cleanup crew workers evaluated (Kominsky et al. \n1980).  It should be noted that urinalysis was not performed on unexposed workers, and it is not known if \nproteinuria values observed in exposed workers differ from the local general population.\n\nRelative to a group of 35 controls, 73 male operators employed for an average of 8.2 years in a plant \nproducing chlorinated hydrocarbons, including HCCPD, showed no evidence of damage to the renal \ntubules (Boogaard et al. 1993).  The investigations included measurement of urinary alanine \naminopeptidase, N-acetyl-β-D-glucosaminidase, and retinol binding protein.  Although total urinary \nprotein concentrations did not differ between the two groups, urinary albumin was significantly higher in \nthe exposed group.  The difference, however, was not related to time of employment, and there was no \ndifference in urinary albumin concentration in workers involved in the manufacture of HCCPD and those \ninvolved in the preparation of other chlorinated hydrocarbon.  Thus, the effect was not considered to be \ndue to the damage to the glomerulus caused by exposure to HCCPD.  Personal air sampling for HCCPD\n\n---\n\n2.  HEALTH EFFECTS\n\nwas performed on a subset of study participants but was not used to evaluate associations with renal \nfunction values.\n\nThe potential renal effects following inhalation exposure to HCCPD have been evaluated in laboratory \nanimals following acute, intermediate, and chronic durations.  Inhalation exposure of HCCPD caused \nrenal tubular necrosis in rats, mice, guinea pigs, and rabbits at 0.34–73.6 ppm for 15 minutes to 7 days, \n0.34 ppm for 6 weeks, and 0.15 ppm for 30 weeks; incidence data were not provided (Treon et al. 1955).  \nIn other inhalation studies, no significant, exposure-related renal lesions were seen following acuteduration exposure in rats to concentrations up to 0.5 ppm (Alexander et al. 1980a; Rand et al. 1982a); \nintermediate-duration exposure in monkeys, rats, or mice to concentrations up to 0.2, 0.56, or 0.5 ppm, \nrespectively (Alexander et al. 1980b; Clark 1981; NTP 1994; Rand et al. 1982a); or chronic-duration \nexposure in rats or mice to concentrations up to 0.2 ppm (NTP 1994).\n\nThe potential toxicological effects of HCCPD on the kidneys have been evaluated in laboratory animals \nin acute-and intermediate-duration oral studies.  Degenerative lesions in the kidney tubules resulted from \nsingle gavage doses of 261–1,959 mg/kg in rats and 579–877 mg/kg in rabbits; incidence data were not \nprovided (Treon et al. 1955).  Toxic nephrosis was observed in male and female rats exposed to \n≥38 mg/kg/day and female mice exposed to ≥75 mg/kg/day via gavage for 13 weeks (Abdo et al. 1984; \nVelsicol 1981a, 1981b). These lesions were located in the terminal sections of the proximal tubules of the \nrenal cortex and were characterized by mild dilation of the tubules and karyomegaly, cytomegaly, and \nanisokaryosis accompanied by cytoplasmic and nuclear vacuolization.  Additionally, brown granular \npigment debris protruded into the lumen.  In male mice, tubular necrosis was present in 70% of the male \nmice receiving the 300 mg/kg/day dose but not at lower doses; this lesion was morphologically distinct \nfrom the toxic nephrosis seen in the other animals and may have contributed to the early deaths observed \nat this dose level.  No renal histopathological effects were identified in male and female rats at\n≤19 mg/kg/day, female mice at ≤38 mg/kg/day, or male mice at ≤150 mg/kg/day (Abdo et al. 1984; \nVelsicol 1981a, 1981b).\n\nRabbits exposed to single dermal doses of 401–5,719 mg/kg displayed degeneration and necrosis of the \nkidney tubules; incidence data were not provided (Treon et al. 1955). The study authors stated that renal \neffects were still apparent 21 days after dosing in surviving animals.\n\n---\n\n2.  HEALTH EFFECTS\n\n###### 2.11 DERMAL\n\nHuman and animal data indicate HCCPD causes skin irritation following direct dermal contact with \nHCCPD liquid or vapor.\n\nAn unspecified percentage of 145 workers exposed to HCCPD vapors for 3–15 days at a WWTP as a \nresult of an inadvertent industrial release reported skin irritation, with five employees verified to exhibit\nvisible signs of skin irritation (Morse et al. 1979).  In a subsequent publication, 21% of 177 employees \nwith usable medical questionnaire responses reported skin irritation following HCCPD release and prior \nto plant closure; 10% of the 177 employees reported experiencing skin irritation approximately 6 weeks \nlater (Kominsky et al. 1980).\n\nIn acute-duration dermal toxicity studies, topical application of HCCPD in either its pure form or in \nsolution appears to have a pronounced effect upon the epidermis of experimental animals.  Generally, \nHCCPD initially causes edema that progressed to hardening or encrustation at the application site \n(Gardner 1986b; OxyChem 1972; Treon et al. 1955).  In a series of studies, severe irritation and skin \nnecrosis were observed in a monkey administered 0.05 mL of a 10% (v/v) solution for 3 days; necrotic, \nhardened, encrusted, and discolored skin was identified following application of Ultrasene solutions \ncontaining ≥40% HCCPD to guinea pigs; and subcutaneous edema and local discoloration that progressed \nto encrustation and fissuring were observed after a dermal dose of ≥430 mg/kg was applied to rabbit skin; \nincidence data were not provided (Treon et al. 1955).  The lesions generally healed with time in the \nsurviving animals.  Thirteen months after exposure, the monkey’s treated skin was scarred and hairless.  \nNo evidence of dermal effects was identified in a monkey administered 0.01 mL of Ultrasene solutions \ncontaining up to 10% HCCPD, but application of 0.05 mL of solutions containing ≥20% HCCPD caused \nthe skin to become discolored and swell.  No evidence of skin irritation was observed in guinea pigs after \ndermal doses of 0.05 mL of Ultrasene solutions containing ≤1% HCCPD (Treon et al. 1955).  Eschar \nformation was noted after dermal application of 200 mg/kg HCCPD to rabbits (OxyChem 1992).  Results \nof standard dermal irritation tests indicated that 0.5 mL HCCPD produced slight to severe edema and \nnecrosis at the application sites (OxyChem 1972, 1992).\n\nThe potential effects of systemic HCCPD exposure on skin histopathology of laboratory animals were \nevaluated in intermediate- and chronic-duration inhalation studies and intermediate-duration oral studies.  \nNo histopathological changes were identified in the skin (specific location not identified) of male or \nfemale rats exposed to concentrations ≤0.56 ppm for 30 weeks (Clark 1981) or in male or female rats and mice exposed to concentrations ≤0.2 ppm for 2 years (NTP 1994).  Additionally, no histopathological \nchanges were identified in skin (specific location not identified) of rats and mice at gavage doses up to \n150 or 300 mg/kg/day, respectively, for 13 weeks (Abdo et al. 1984; Velsicol 1981a, 1981b).\n\n###### 2.12 OCULAR\n\nHuman and animal data indicate that direct ocular contact with HCCPD vapor may produce ocular \nirritation at sufficiently high concentrations.\n\nEye irritation was one of the major symptoms reported by sewage treatment plant workers exposed to \nHCCPD vapors for 3–15 days at a WWTP because of an inadvertent industrial release (Kominsky et al. \n1980; Morse et al. 1979).  From the 145 individuals who responded to a questionnaire immediately after \nexposure occurred, 85 (59%) complained of eye irritation (Morse et al. 1979).  In a follow-up \nquestionnaire 6 weeks later, 9% of 177 respondents were still experiencing ocular irritation (Kominsky et \nal. 1980; Morse et al. 1979).  Tearing and redness of the eyes were present in five individuals on the day \nof exposure.\n\nEye irritation, as evidenced by lacrimation, was also observed in animals exposed to HCCPD vapors for \nup to 7 hours (Jackson and Hardy 1986, 1987; OxyChem 1972; Rand et al. 1982a; Treon et al. 1955).  \nPartially or completely closed eyes were identified in rats exposed to ≥1.67 ppm for 1 hour (Jackson and \nHardy 1986) and ≥1.68 ppm for 4 hours (Jackson and Hardy 1987).  Direct ocular exposure to HCCPD\nvapors most likely contributed to these effects.  Irritation of the eyes or eyelids was observed for rats, \nmice, guinea pigs, and rabbits following single exposures to HCCPD concentrations as low as 1.0 ppm \nand multiple exposures to concentrations as low as 0.33 ppm for up to 6 weeks; ocular irritation was not \nobserved in any species exposed to 0.15 ppm for up to 30 weeks (Treon et al. 1955).  Lacrimation was \nevident in rats exposed to 5.8 ppm HCCPD for 4 hours and dark red eyes were observed in rats exposed \nto 0.5 ppm for 5–10 days and ≥0.05 ppm for 14 weeks (Alexander et al. 1980a, 1980b; Rand et al. 1982a).  \nNo clinical signs of eye irritation were noted in monkeys exposed to HCCPD vapor at concentrations up \nto 0.2 ppm for 14 weeks (Alexander et al. 1980b; Rand et al. 1982a).  No ophthalmological or\nhistopathological changes were identified in the ocular tissues of rats or monkeys exposed to \nconcentrations up to 0.2 ppm for 14 weeks (Alexander et al. 1980b; Rand et al. 1982a).  HCCPD \nexposure did not cause histopathological changes in the eyes of rats exposed to concentrations up to \n0.56 ppm for 30 weeks (Clark 1981).\n\n---\n\nSevere eye irritation was produced when 0.1 mL of HCCPD was placed in the conjunctival eye sac for \n5 minutes and then rinsed with water (OxyChem 1972).  Corrosion of the ocular tissues occurred when \nthe material was left in place for 24 hours prior to rinsing (OxyChem 1972).\n\n###### 2.13 ENDOCRINE\n\n2.13  ENDOCRINE\n\nNo reports of changes in human endocrine parameters or organs after exposure to HCCPD were found. \nBased on available data in laboratory animals, HCCPD does not produce histopathological changes to \nendocrine organs.  Insufficient data are available to assess the potential effects of HCCPD exposure on \nendocrine function, including endocrine hormone levels.\n\nPotential histopathological and organ weight effects in endocrine organs have been evaluated in \nlaboratory animals following acute-, intermediate-, and chronic-duration inhalation exposure to HCCPD.  \nDegenerative changes in the adrenal glands of rats, mice, guinea pigs, and rabbits were observed after \nexposures to concentrations of 0.34–73.6 ppm for periods of 15 minutes to 1 week, 0.34 ppm for 6 weeks, \nand 0.15 ppm for 30 weeks; incidence data were not provided (Treon et al. 1955).  Due to the high \nmortality observed at these concentrations, these changes may have been the result of tissue autolysis in \nmoribund or dying animals.  Effects on the adrenal, thyroid, parathyroid, pancreas, and pituitary glands \nfollowing inhalation exposure of male mice to 0.039–0.389 ppm HCCPD for 13 weeks were limited to \nincreased relative adrenal weights; no histopathological changes were noted in these organs in treated \nmale mice and no effects on adrenal, thyroid, parathyroid, pancreas, or pituitary gland weights or\nhistopathology were observed in female mice exposed to ≤0.389 and male and female rats exposed to \n≤0.385 ppm for 13 weeks (NTP 1994).  The biological significance of these adrenal weight changes\ncannot be assessed quantitatively in the absence of hormone product measurements or concurrent \nhistopathological findings.  There were no organ weight or histopathological changes in the adrenal \nglands, pancreas, thyroid, parathyroid gland, and/or pituitary gland identified in male and female rats and \nmonkeys exposed for 14 weeks at ≤0.2 ppm (Alexander et al. 1980b; Rand et al. 1982a), in male and \nfemale rats after 30-week exposures to ≤0.56 ppm (Clark 1981), or in rats and mice following 2-year \nexposures to ≤0.2 ppm (NTP 1994).  Additionally, no effects on the adrenal glands were identified in \nmale mice exposed to 0.5 ppm for 26–42 weeks (NTP 1994).\n\n$$\n\\leq0.385ppm\n$$\n\nPotential effects of HCCPD on endocrine organ weight and histology have also been evaluated in \nlaboratory animals following acute- and intermediate-duration oral exposures and acute-duration dermal \nexposures.  Degenerative changes in the adrenal tissues resulted from exposure to single oral doses of\n\n---\n\n280–2,100 mg/kg in rats and 620–940 mg/kg in rabbits; these changes may have resulted from tissue \nautolysis in moribund or dying animals, but no incidence data were reported (Treon et al. 1955).  There \nwere no histopathological changes in the adrenals, thyroid, parathyroid, or pituitary glands in 13-week \nstudies at gavage doses up to 150 mg/kg/day in rats and 300 mg/kg/day in mice (Abdo et al. 1984; \nVelsicol 1981a, 1981b).  Rabbits that were dermally exposed to HCCPD (430–6,130 mg/kg) had \ndegenerative changes of the adrenal glands that were still apparent in survivors 21 days after exposure; \nincidence data were not provided (Treon et al. 1955).\n\nNo data were identified evaluating endocrine function following *in vivo* exposure to HCCPD; however, \nlimited *in vitro* screening data are available.  HCCPD exhibited statistically significant radioactive iodide \nuptake inhibition in a ToxCast high-throughput screening assay (Wang et al. 2019).  Iodide uptake is the \nfirst step in thyroid hormone biosynthesis.\n\n###### 2.14 IMMUNOLOGICAL\n\n2.14  IMMUNOLOGICAL\n\nNo studies were located regarding immunological effects in humans after exposure to HCCPD. Based on \navailable data in laboratory animals, HCCPD does not cause histopathological alterations to \nimmunological organs.  However, no studies evaluating immune function following exposure to HCCPD \nwere identified.\n\nPotential effects of HCCPD on immune organ weight and histology have also been evaluated in acute-, \nintermediate-, and chronic-duration inhalation exposure studies and intermediate-duration oral exposure \nstudies in laboratory animals.  No exposure-related changes were identified in these studies.  There were \nno histopathological changes in the spleen of rats exposed to ≤0.5 ppm for 1–2 weeks (Alexander et al. \n1980a; Rand et al. 1982a).  In intermediate-duration studies, no histopathological changes were identified \nin immune organs (spleen, thymus, and/or lymph nodes) of monkeys, rats, or mice to concentrations up to \n0.2, 0.56, or 0.5 ppm, respectively (Alexander et al. 1980b; Clark 1981; NTP 1994; Rand et al. 1982a).  \nSimilarly, no histopathological effects were observed in immune organs of rats or mice exposed to \n≤0.2 ppm for 2 years (NTP 1994).  In a 13-week oral study, no treatment-related histopathological \nfindings were identified in the mandibular and mesenteric lymph nodes, thymus, or spleen at gavage \ndoses up to 150 mg/kg/day in rats or 300 mg/kg/day in mice (Abdo et al. 1984; Velsicol 1981a, 1981b).\n\n---\n\n2.  HEALTH EFFECTS\n\n###### 2.15 NEUROLOGICAL\n\n2.15  NEUROLOGICAL\n\nBased on available data, HCCPD does not cause histopathological alterations in the nervous system.  \nEvaluation of neurological function is limited to clinical signs of toxicity; therefore, insufficient data are \navailable to assess the potential effect of HCCPD exposure on neurological function, including behavior.\n\nAmong sewage treatment plant workers exposed to HCCPD at a WWTP because of an inadvertent \nindustrial release, headaches were self-reported by 65 of 145 workers (45%) after exposure for 3–15 days \n(Morse et al. 1979).  Six weeks later, 32 of 177 workers (18%) responding to a questionnaire were still \nexperiencing headaches (Kominsky et al. 1980). No studies were located regarding neurological effects \nin humans after oral or dermal exposure to HCCPD.\n\nNeurological clinical signs of toxicity and nervous system histopathology were evaluated in acute-, \nintermediate-, and chronic-duration inhalation exposure studies.  Rats and mice exposed to concentrations \nof 0.385–2.142 ppm HCCPD were described as listless after 1–3 weeks of exposure (NTP 1994).  \nIncidence data for clinical signs were not provided, so it is unclear how many animals exhibited this effect \nor how frequently; however, the study authors did note that listlessness was observed earlier during the \nexposure period with higher HCCPD concentrations.  Some rats, mice, guinea pigs, and rabbits exposed \nto high lethal concentrations of HCCPD (≥46.5 ppm) by acute-duration inhalation experienced tremors; \nincidence data were not provided (Treon et al. 1955).  At necropsy, diffuse degenerative changes in the \nbrain were observed in all rats, mice, guinea pigs, and rabbits after exposures to 0.34–73.6 ppm for \nperiods of 15 minutes to 1 week, 0.34 ppm for 6 weeks, and 0.15 ppm for 30 weeks; incidence data were \nnot provided (Treon et al. 1955).  These degenerative changes may have been the result of tissue \nautolysis.  In contrast, there were no histopathological changes in the brains of rats exposed to 0.5 ppm \nfor 1–2 weeks (Alexander et al. 1980a; Rand et al. 1982a), male mice exposed to 0.2 ppm for 33 weeks \n(NTP 1994), or rats and mice exposed to ≤0.389 ppm for 13 weeks or ≤0.2 ppm for 2 years (NTP 1994).  \nSimilarly, no histopathological changes were observed in the brains or sciatic nerve of rats or monkeys \nexposed to ≤0.2 ppm for 14 weeks (Alexander et al. 1980b; Rand et al. 1982a) or in brain, spinal cord, or \nsciatic or posterior tibial nerves of rats exposed to ≤0.56 ppm for 30 weeks (Clark 1981).\n\nThe potential neurotoxicity of HCCPD has been evaluated in acute- and intermediate-duration oral \nexposure studies.  Clinical signs of neurotoxicity were observed following acute-duration gavage \nexposure in mice, including hypoactivity at 464 mg/kg and ataxia at 1,000 mg/kg, a dose associated with \nlethality (Dean 1977).  Similarly, all rats exposed once to ≥1,260 mg/kg via gavage exhibited abnormal gait (high stepping, waddling) and lethargy (Gardner 1986a).  Single oral doses ≥180 mg/kg caused \nlethargy in rats and rabbits in the period “immediately after exposure” (Treon et al. 1955).  During \npostmortem examination of tissues, degenerative lesions of the brain were observed in the rats and rabbits \nthat succumbed to exposure and in the rats that survived to the scheduled sacrifice; incidence data were \nnot provided.  No histopathological lesions of the brain, sciatic nerve, or spinal cord were noted in rats or \nmice exposed to gavage doses up to 150 or 300 mg/kg/day, respectively, for 13 weeks (Abdo et al. 1984; \nVelsicol 1981a, 1981b). These data suggest that brain lesions occur only with exposures to high oral \ndoses of HCCPD.\n\nRabbits exposed to single dermal doses of HCCPD (430–6,130 mg/kg) displayed degenerative changes in \nthe brain at necropsy; incidence data were not provided (Treon et al. 1955).  These changes were still \napparent 21 days after exposure in surviving animals.  Ataxia, hypoactivity, and a depressed breathing \npattern have been observed in rabbits at lethal dermal doses of HCCPD (OxyChem 1972).\n\n###### 2.16 REPRODUCTIVE\n\n2.16  REPRODUCTIVE\n\nNo studies were located regarding reproductive effects in humans after exposure to HCCPD.  The \navailable animal data do not indicate that HCCPD causes histopathological alterations to reproductive \norgans.  However, insufficient data are available to thoroughly assess the potential for toxicity to the \nreproductive system, as no studies evaluating reproductive function following inhalation, oral, or dermal \nexposure to HCCPD were identified.\n\nThe potential effects of HCCPD on reproductive organ weight and histology have been evaluated in \nexperimental animals exposed by inhalation for intermediate and chronic durations.  The sole effect on \nreproductive organs identified with HCCPD treatment is an increased incidence of ovarian suppurative \ninflammation in female mice exposed to HCCPD at 0.05–0.2 ppm for 2 years; no histopathological \nchanges were identified in the uterus (NTP 1994).  While this lesion is clearly adverse, as it was the \nsuspected cause of increased mortality at 0.2 ppm, the causal relationship between HCCPD exposure and \nlesion development is unclear.  The study authors noted that lesions were similar to those observed in \nother NTP studies attributed to stress-related susceptibility to utero-ovarian infection by *Klebsiella* \nspecies (NTP 1994).  In contrast, no treatment-related histopathological lesions of the female (ovaries and \nuterus) or male (testes, prostate, and/or seminal vesicle) reproductive organs were identified in monkeys, \nrats, or mice exposed to concentrations up to 0.2, 0.385, or 0.389 ppm for 13–14 weeks (Alexander et al. \n1980b; NTP 1994; Rand et al. 1982a); male mice exposed to 0.2 ppm for 33 weeks or 0.5 ppm for\n\n---\n\n42 weeks (NTP 1994); rats exposed to ≤0.56 ppm for 30 weeks (Clark 1981); or rats or male mice \nexposed to ≤0.2 ppm for 2 years (NTP 1994).\n\n$$\n\\leqq0.56\n$$\n\nThe potential effects of HCCPD on reproductive organ weight and histology have also been evaluated in \nlaboratory animals following intermediate-duration oral exposure.  HCCPD did not cause treatmentrelated effects on the testes, seminal vesicles, prostate, ovaries, or uterus in rats or mice exposed to doses \nup to 150 or 300 mg/kg/day, respectively, via gavage for 13 weeks (Abdo et al. 1984; Velsicol 1981a, \n1981b).\n\nNo data were identified evaluating reproductive function following inhalation, oral, or dermal exposure to \nHCCPD; however, limited screening data are available.  Although it exhibited some estrogen receptor \nbinding affinity in a recombinant human estrogen receptor α (hERα) binding assay, HCCPD did not \nexhibit estrogenic or anti-estrogenic activity in an immature uterotrophic assay in female rats following \nsubcutaneous injection (Akahori et al. 2008).  No anti-androgenic activity was detected for HCCPD in \nChinese hamster ovary (CHO) cells transfected with human androgen receptor (hAR) in an androgenresponsive luciferase reporter assay (Roy et al. 2004).\n\n###### 2.17 DEVELOPMENTAL\n\n2.17  DEVELOPMENTAL\n\nNo studies were located regarding developmental effects in humans after exposure to HCCPD.  Animal \ndata are available only via the oral route and are too limited to assess whether or not the developing \norganism is a target of HCCPD toxicity at doses below those associated with maternal toxicity.\n\nHCCPD was not embryotoxic, fetotoxic, or teratogenic in mice following maternal exposure to gavage \ndoses up to 75 mg/kg/day during GDs 6–15 (Murray et al. 1980).  In rabbits, a dose-dependent increase in \nthe incidence of 13 ribs was identified in the offspring of does exposed to 75 mg/kg/day via gavage \nduring GDs 6–18; nonstatistically significant increases were also identified at 5 and 25 mg/kg/day.  No \nother evidence of embryotoxicity, fetotoxicity, or teratogenicity was identified in rabbits (Murray et al. \n1980).  The natural variation in the number of ribs for rabbits is 12–13.  It should be noted that the \ncompound was not maternally toxic in mice, but maternal mortalities and weight loss were observed in \nrabbits at 75 mg/kg/day (numbers affected and magnitude of effect not specified).\n\nA screening study was performed to evaluate prenatal and postnatal development of mice exposed to \nHCCPD during gestation.  Mice born to dams administered 45 mg/kg/day HCCPD via gavage during\n\n---\n\nGDs 8–12 did not exhibit evidence of developmental toxicity when evaluated on postnatal days (PNDs) 1 \nand 3 (Chernoff and Kavlock 1982, 1983).  When the offspring were evaluated over a 250-day postnatal \nperiod (including through puberty and breeding), there were no adverse effects on postnatal viability, \ngrowth, locomotor activity, sexual development (percent vaginal patency at day 30), or reproductive \nfunction (Gray and Kavlock 1984; Gray et al. 1986).\n\n###### 2.18 OTHER NONCANCER\n\n2.18  OTHER NONCANCER\n\nNo studies were located regarding other noncancer effects in humans after exposure to HCCPD.\n\nOther noncancer effects of HCCPD identified in experimental animals are limited to food and water \nintake.  During the first few days of the post-exposure observation periods, decreased food and water \nintake were observed in rats exposed for 1 hour to ≥1.67 ppm (Jackson and Hardy 1986) and rats exposed \nfor 4 hours to ≥1.68 ppm (Jackson and Hardy 1987); these concentrations were associated with overt \nsigns of toxicity during exposure (e.g., abnormal respiratory pattern).  After a 1–2-week exposure to \nHCCPD, male and female rats exposed to 0.5 ppm had decreased food and water intake (Alexander et al. \n1980a; Rand et al. 1982a).  All males exposed to 0.5 ppm died or were sacrificed in moribund condition \nby the end of the exposure period.  Minor decreases in food intake were also observed for male rats \nexposed to 0.11 ppm without meaningful changes to body weight; the biological significance of this \nfinding is uncertain.  Food intake was not affected in rats or monkeys and water intake was not affected in \nrats exposed to ≤0.2 ppm for 14 weeks (Alexander et al. 1980b; Rand et al. 1982a).  In a 30-week study, \nno treatment-related deficits were identified for male or female rats regarding food or water intake\nfollowing exposure to ≤0.56 ppm (Clark 1981). No treatment-related effects were observed for food and \nwater intake of pregnant mice administered gavage doses of HCCPD at ≤75 mg/kg/day on GDs 6–15 \n(Murray et al. 1980).  Where deficits in food and/or water intake were observed after exposure to \nHCCPD, these effects were likely the result of nonspecific toxicity following exposures to high \nconcentrations of an irritating/corrosive chemical.\n\n$$\n\\mathrm{to}\\geq1.67\\mathrm{ppm}\n$$\n\n$$\nt0\\geq1.68\n$$\n\n$$\nt o\\leqq0.2\n$$\n\n$$\n0.56ppm\n$$\n\n###### 2.19 CANCER\n\nNo studies were located regarding cancer in humans following exposure to HCCPD.\n\nThe carcinogenicity of HCCPD has been evaluated in 2-year rodent bioassays in which male and female \nrats and mice were exposed to concentrations up to 0.2 ppm for 104 weeks (NTP 1994).  There were no statistically significant increases in tumor incidence in rats or mice.  There was a slight increase in the \nincidence of adenomas of the pituitary pars distalis in male rats at 0.2 ppm and in thyroid follicle cell \nadenomas in female mice at 0.05 ppm, but, since the incidences were similar to the historical control \nmeans, were within the historical control range, or did not exhibit a dose-dependency, NTP (1994) did not \nconsider these tumors to be related to HCCPD exposure.  In male mice exposed to 0.5 ppm for 26 or \n42 weeks, then evaluated at 105 weeks, the incidence of alveolar/bronchiolar carcinomas was \nsignificantly increased but was within the historical range for the laboratory (NTP 1994).  Thus, \nalveolar/bronchiolar carcinomas may n", 'pages': None, 'truncated': True, 'extraction': 'firecrawl-public-document-markdown', 'request_id': 'f55ece8d-03a0-45b7-b220-29efe5d1d238', 'source_url': 'https://downloads.regulations.gov/ATSDR-2026-0133-0003/attachment_1.pdf', 'observed_at': '2026-10-04T00:40:37.145404+00:00', 'content_hash': '063c002435b7a13b9144e8da7119795794d56ee2e0ab2fe90a88e51b9525c505'}, 'title': 'Draft Tox Profile for Hexachlorocyclopentadiene', 'check_failed': False}, {'url': 'https://downloads.regulations.gov/ATSDR-2026-0133-0003/content.pdf', 'body': {'text': "## Toxicological Profile for Hexachlorocyclopentadiene (HCCPD)\nDraft for Public Comment\nOctober 2026\n\nU.S. Department of Health and Human Services\nAgency for Toxic Substances and Disease Registry\n\n---\n\n## DISCLAIMER\n\nUse of trade names is for identification only and does not imply endorsement by the Agency for Toxic \nSubstances and Disease Registry, the Public Health Service, or the U.S. Department of Health and Human \nServices.\n\nThis information is distributed solely for the purpose of pre-dissemination for public comment under \napplicable information quality guidelines.  It has not been formally disseminated by the Agency for Toxic \nSubstances and Disease Registry.  It does not represent and should not be construed to represent any \nagency determination or policy.\n\n---\n\n## FOREWORD\n\nThis toxicological profile is prepared in accordance with guidelines developed by the Agency for Toxic \nSubstances and Disease Registry (ATSDR) and the Environmental Protection Agency (EPA).  The \noriginal guidelines were published in the *Federal Register* on April 17, 1987.  Each profile will be revised \nand republished as necessary.\n\nThe ATSDR toxicological profile succinctly characterizes the toxicologic and adverse health effects \ninformation for these toxic substances described therein.  Each peer-reviewed profile identifies and \nreviews the key literature that describes a substance's toxicologic properties.  Other pertinent literature is \nalso presented but is described in less detail than the key studies.  The profile is not intended to be an \nexhaustive document; however, more comprehensive sources of specialty information are referenced.\n\nThe focus of the profiles is on health and toxicologic information; therefore, each toxicological profile \nbegins with a relevance to public health discussion which would allow a public health professional to \nmake a real-time determination of whether the presence of a particular substance in the environment \nposes a potential threat to human health.  The adequacy of information to determine a substance's health \neffects is described in a health effects summary.  Data needs that are of significance to the protection of \npublic health are identified by ATSDR.\n\nEach profile includes the following:\n\n(A) The examination, summary, and interpretation of available toxicologic information and \nepidemiologic evaluations on a toxic substance to ascertain the levels of significant \nhuman exposure for the substance due to associated acute-, intermediate-, and chronicduration exposures;\n\n(B) A determination of whether adequate information on the health effects of each substance \nis available or in the process of development to determine the levels of exposure that \npresent a significant risk to human health due to acute-, intermediate-, and chronicduration exposures; and\n\n(C) Where appropriate, identification of toxicologic testing needed to identify the types or \nlevels of exposure that may present significant risk of adverse health effects in humans.\n\nThe principal audiences for the toxicological profiles are health professionals at the Federal, State, and \nlocal levels; interested private sector organizations and groups; and members of the public.  ATSDR plans \nto revise these documents in response to public comments and as additional data become available.  \nTherefore, we encourage comments that will make the toxicological profile series of the greatest use.\n\nElectronic comments may be submitted via: www.regulations.gov. Follow the on-line instructions for \nsubmitting comments.\n\nWritten comments may also be sent to:\n\nAgency for Toxic Substances and Disease Registry\n\nOffice of Innovation and Analytics\n\nToxicology Section\n\n1600 Clifton Road, N.E.\n\nMail Stop S106-5\n\nAtlanta, Georgia 30329-4027\n\n---\n\nThe toxicological profiles are developed under the Comprehensive Environmental Response, \nCompensation, and Liability Act of 1980, as amended (CERCLA or Superfund).  CERCLA \nSection 104(i)(1) directs the Administrator of ATSDR to “…effectuate and implement the health-related \nauthorities” of the statute.  This includes the preparation of toxicological profiles for hazardous \nsubstances most commonly found at facilities on the CERCLA National Priorities List (NPL) and that \npose the most significant potential threat to human health, as determined by ATSDR and the EPA.  \nSection 104(i)(3) of CERCLA, as amended, directs the Administrator of ATSDR to prepare a \ntoxicological profile for each substance on the list.  In addition, ATSDR has the authority to prepare \ntoxicological profiles for substances not found at sites on the NPL, in an effort to “…establish and \nmaintain inventory of literature, research, and studies on the health effects of toxic substances” under \nCERCLA Section 104(i)(1)(B), to respond to requests for consultation under Section 104(i)(4), and as \notherwise necessary to support the site-specific response actions conducted by ATSDR.\n\nThis profile reflects ATSDR’s assessment of all relevant toxicologic testing and information that has been \npeer-reviewed.  Staffs of the Centers for Disease Control and Prevention and other Federal scientists have \nalso reviewed the profile.  In addition, this profile has been peer-reviewed by a nongovernmental panel \nand is being made available for public review.  Final responsibility for the contents and views expressed \nin this toxicological profile resides with ATSDR.\n\nChristopher M. Reh, Ph.D. \nAssociate Director, \nAgency for Toxic Substances and Disease Registry \nCenters for Disease Control and Prevention\n\n---\n\n**VERSION HISTORY**\n\n| Date | Description |\n| --- | --- |\n| October 2026 | Draft for public comment toxicological profile released |\n| July 1999 | Final toxicological profile released |\n\n---\n\n# CONTRIBUTORS & REVIEWERS\n\n# CHEMICAL MANAGER TEAM\n\nGaston Casillas, Ph.D. (Lead)\nFahim Atif, Ph.D.\nJennifer Przybyla, Ph.D.\nNickolette Roney, M.P.H.\nBrittany Szafran, D.V.M., Ph.D., D.A.B.T.\n\nZach Guerrette, Ph.D., D.A.B.T.\nChristina Coley, M.S.\nLisa Ingerman, Ph.D., D.A.B.T.\nKimberly Zaccaria, Ph.D., D.A.B.T.\nMario Citra, Ph.D.\n\nATSDR, Office of Innovation and Analytics, \nToxicology Section, Atlanta, GA\n\nSRC, Inc., North Syracuse, NY\n\n### REVIEWERS\n\n#### Interagency Minimal Risk Level Workgroup:\n\nIncludes ATSDR; National Center for Environmental Health (NCEH); U.S. Environmental Protection \nAgency (EPA); National Toxicology Program (NTP).\n\n#### Additional reviews for science and/or policy:\n\nATSDR, Office of Community Health Hazard Assessment; ATSDR, Office of Capacity Development \nand Applied Prevention Science; ATSDR, Office of Science; NCEH, Division of Laboratory Sciences; \nNCEH, Division of Environmental Health Science and Practice; EPA, Office of Research and \nDevelopment; EPA, Office of Water.\n\n### PEER REVIEWERS\n\n1. David Dorman, D.V.M., Ph.D., D.A.B.V.T., D.A.B.T.; Professor of Toxicology; North Carolina \nState University; College of Veterinary Medicine; Department of Molecular Biomedical \nSciences; Raleigh, North Carolina\n\n2. Slawo Lomnicki, Ph.D.; Assistant Professor of Environmental Sciences; Louisiana State \nUniversity, Chemistry Department; LSU Superfund Research Materials Core leader; Baton \nRouge, Louisiana\n\n3. Deborah A. Slechta, Ph.D., M.A.; University of Rochester; Professor - Department of \nEnvironmental Medicine (SMD); Professor - Department of Neuroscience (SMD) -– Joint; \nProfessor - Department of Public Health Sciences (SMD) - Joint; Rochester, New York\n\nThese experts collectively have knowledge of toxicology, chemistry, and/or health effects.  All reviewers \nwere selected in conformity with Section 104(I)(13) of the Comprehensive Environmental Response, \nCompensation, and Liability Act, as amended.\n\nATSDR scientists review peer reviewers’ comments and determine whether changes will be made to the \nprofile based on comments.  The peer reviewers’ comments and responses to these comments are part of \nthe administrative record for this compound.\n\nThe listing of peer reviewers should not be understood to imply their approval of the profile's final \ncontent.  The responsibility for the content of this profile lies with ATSDR.\n\n---\n\n## CONTENTS\n\nDISCLAIMER .............................................................................................................................................. ii\nFOREWORD ............................................................................................................................................... iii\nVERSION HISTORY ................................................................................................................................... v\nCONTRIBUTORS & REVIEWERS ........................................................................................................... vi\nCONTENTS ................................................................................................................................................ vii\nLIST OF FIGURES ..................................................................................................................................... ix\nLIST OF TABLES ........................................................................................................................................ x\nCHAPTER 1. RELEVANCE TO PUBLIC HEALTH ................................................................................. 1\n1.1 OVERVIEW AND U.S. EXPOSURES ......................................................................................... 1\n1.2 SUMMARY OF HEALTH EFFECTS........................................................................................... 1\n1.3 MINIMAL RISK LEVELS (MRLs) .............................................................................................. 6\nCHAPTER 2. HEALTH EFFECTS ............................................................................................................ 10\n2.1 INTRODUCTION ........................................................................................................................ 10\n2.2 DEATH ........................................................................................................................................ 55\n2.3 BODY WEIGHT .......................................................................................................................... 57\n2.4 RESPIRATORY .......................................................................................................................... 58\n2.5 CARDIOVASCULAR ................................................................................................................. 63\n2.6 GASTROINTESTINAL ............................................................................................................... 63\n2.7 HEMATOLOGICAL ................................................................................................................... 65\n2.8 MUSCULOSKELETAL .............................................................................................................. 68\n2.9 HEPATIC ..................................................................................................................................... 68\n2.10 RENAL ........................................................................................................................................ 70\n2.11 DERMAL ..................................................................................................................................... 72\n2.12 OCULAR ..................................................................................................................................... 73\n2.13 ENDOCRINE ............................................................................................................................... 74\n2.14 IMMUNOLOGICAL ................................................................................................................... 75\n2.15 NEUROLOGICAL....................................................................................................................... 76\n2.16 REPRODUCTIVE ....................................................................................................................... 77\n2.17 DEVELOPMENTAL ................................................................................................................... 78\n2.18 OTHER NONCANCER ............................................................................................................... 79\n2.19 CANCER ...................................................................................................................................... 79\n2.20 GENOTOXICITY ........................................................................................................................ 80\n2.21 MECHANISM OF ACTION ....................................................................................................... 82\nCHAPTER 3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, \nCHEMICAL INTERACTIONS ........................................................................................... 84\n3.1 TOXICOKINETICS..................................................................................................................... 84\n3.1.1 Absorption ............................................................................................................................. 84\n3.1.2 Distribution ........................................................................................................................... 86\n3.1.3 Metabolism ............................................................................................................................ 88\n3.1.4 Excretion ............................................................................................................................... 90\n3.1.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models ............. 92\n3.1.6 Animal-to-Human Extrapolations ......................................................................................... 93\n3.2 CHILDREN AND OTHER POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE ..... 93\n3.3 BIOMARKERS OF EXPOSURE AND EFFECT ....................................................................... 95\n\n---\n\n3.3.1 Biomarkers of Exposure ........................................................................................................ 95\n3.3.2 Biomarkers of Effect ............................................................................................................. 96\n3.4 INTERACTIONS WITH OTHER CHEMICALS ....................................................................... 97\nCHAPTER 4. CHEMICAL AND PHYSICAL INFORMATION ............................................................. 98\n4.1 CHEMICAL IDENTITY ............................................................................................................. 98\n4.2 PHYSICAL AND CHEMICAL PROPERTIES .......................................................................... 98\nCHAPTER 5. POTENTIAL FOR HUMAN EXPOSURE ....................................................................... 100\n5.1 OVERVIEW .............................................................................................................................. 100\n5.2 PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL ................................................ 101\n5.2.1 Production ........................................................................................................................... 101\n5.2.2 Import/Export ...................................................................................................................... 103\n5.2.3 Use ...................................................................................................................................... 103\n5.2.4 Disposal ............................................................................................................................... 104\n5.3 RELEASES TO THE ENVIRONMENT ................................................................................... 104\n5.3.1 Air ....................................................................................................................................... 105\n5.3.2 Water ................................................................................................................................... 107\n5.3.3 Soil ...................................................................................................................................... 108\n5.4 ENVIRONMENTAL FATE ...................................................................................................... 109\n5.4.1 Transport and Partitioning ................................................................................................... 109\n5.4.2 Transformation and Degradation ........................................................................................ 112\n5.5 LEVELS IN THE ENVIRONMENT ......................................................................................... 116\n5.5.1 Air ....................................................................................................................................... 117\n5.5.2 Water ................................................................................................................................... 118\n5.5.3 Sediment and Soil ............................................................................................................... 122\n5.5.4 Other Media ........................................................................................................................ 123\n5.6 GENERAL POPULATION EXPOSURE.................................................................................. 124\n5.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES .............................................. 125\nCHAPTER 6. ADEQUACY OF THE DATABASE ................................................................................ 126\n6.1 EXISTING INFORMATION ON HEALTH EFFECTS ........................................................... 126\n6.2 IDENTIFICATION OF DATA NEEDS .................................................................................... 126\n6.3 ONGOING STUDIES ................................................................................................................ 135\nCHAPTER 7. REGULATIONS AND GUIDELINES ............................................................................. 136\nCHAPTER 8. REFERENCES .................................................................................................................. 138\nAPPENDICES\nAPPENDIX A.  ATSDR MINIMAL RISK LEVEL WORKSHEETS .................................................... A-1 \nAPPENDIX B. LITERATURE SEARCH FRAMEWORK FOR HCCPD ............................................. B-1 \nAPPENDIX C. FRAMEWORK FOR ATSDR’S SYSTEMATIC REVIEW OF HEALTH EFFECTS \nDATA FOR HCCPD ...................................................................................................... C-1 \nAPPENDIX D.  USER’S GUIDE ............................................................................................................. D-1 \nAPPENDIX E.  QUICK REFERENCE FOR HEALTH CARE PROVIDERS ....................................... E-1 \nAPPENDIX F.  GLOSSARY .................................................................................................................... F-1 \nAPPENDIX G.  ACRONYMS, ABBREVIATIONS, AND SYMBOLS................................................. G-1\n\n---\n\n## LIST OF FIGURES\n\n1-1.  Health Effects Found in Animals Following Inhalation Exposure to HCCPD .................................... 3\n1-2.  Health Effects Found in Animals Following Oral Exposure to HCCPD .............................................. 4\n1-3.  Summary of Sensitive Targets of HCCPD – Inhalation ....................................................................... 7\n1-4.  Summary of Sensitive Targets of HCCPD – Oral ................................................................................ 8\n2-1.  Overview of the Number of Studies Examining HCCPD Health Effects .......................................... 14\n2-2.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation ..................................... 28\n2-3.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Oral .............................................. 44\n5-1.  Number of NPL Sites with Hexachlorocyclopentadiene Contamination ......................................... 100\n5-2.  Transformation of Hexachlorocyclopentadiene ................................................................................ 113\n6-1.  Summary of Existing Health Effects Studies on HCCPD by Route and Endpoint .......................... 127\n\n---\n\n## LIST OF TABLES\n\n1-1.  Provisional Minimal Risk Levels (MRLs) for HCCPD ........................................................................ 9\n2-1.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation ..................................... 15\n2-2.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Oral .............................................. 39\n2-3.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Dermal ......................................... 49\n2-4.  LOAEL Values for Red Blood Cell Hematological Effects of Rats Exposed to HCCPD \nVapor in Acute- and Intermediate-Duration Inhalation  Studies ........................................................ 65\n2-5.  Genotoxicity of Hexachlorocyclopentadiene *In Vivo* ......................................................................... 81\n2-6.  Genotoxicity of Hexachlorocyclopentadiene *In Vitro* ........................................................................ 81\n4-1.  Chemical Identity of Hexachlorocyclopentadiene .............................................................................. 98\n4-2.  Physical and Chemical Properties of Hexachlorocyclopentadiene ..................................................... 98\n5-1.  Facilities that Produce, Process, or Use Hexachlorocyclopentadiene .............................................. 102\n5-2.  Summary of National Aggregate Volumes Reported to U.S. Environmental Protection \nAgency (EPA) Chemical Data  Reporting (CDR) ............................................................................ 103\n5-3.  Releases to the Environment from Facilities that Produce, Process, or Use \nHexachlorocyclopentadiene .............................................................................................................. 105\n5-4.  Summary of Releases to the Environment from the Emissions Inventory System (EIS) \nGateway Emission Sectors in 2020 .................................................................................................. 106\n5-5.  Summary of Releases to the Environment from the Emissions Inventory System (EIS) \nGateway Emission Sectors in 2021 .................................................................................................. 107\n5-6.  Lowest Limit of Detection Based on Standards ............................................................................... 117\n5-7.  Summary of Environmental Levels of HCCPD ............................................................................... 117\n5-*8.*  Summary of Water Monitoring Data for Hexachlorocyclopentadiene Across the \nUnited States ..................................................................................................................................... 119\n7-1.  Regulations and Guidelines Applicable to Hexachlorocyclopentadiene .......................................... 136\n\n---\n\n# CHAPTER 1. RELEVANCE TO PUBLIC HEALTH\n\n###### 1.1 OVERVIEW AND U.S. EXPOSURES\n\nHexachlorocyclopentadiene (HCCPD) is a highly volatile, reactive liquid.  HCCPD is an anthropogenic \nchemical that has entered the environment primarily because of its use in the production of chlorinated \npesticides and flame-retardant chemicals.  Restriction of pesticides synthesized from HCCPD has \ndecreased the possibility of exposure to HCCPD and pesticide residues among most members of the \ngeneral population.  Exposure to materials containing HCCPD at hazardous waste sites is still possible.\n\nThe potential for persistence of HCCPD in the environment is low.  Due to its high vapor pressure, \nHCCPD is most likely released to the environment through volatilization, especially from surface waters \nand soils.  The main degradation processes expected include photolysis and photooxidation, hydrolysis, \nand, to a lesser extent, biodegradation.  HCCPD in the air is expected to degrade with estimated half-lives \nranging from 5 hours to <1 day, which limits its potential for long-range transport. HCCPD in water is \nexpected to degrade rapidly, with half-lives for photolysis of ~2–4 minutes and half-lives for hydrolysis \nof ~3–5.45 days.\n\nOccupational exposure to HCCPD is most likely to occur via inhalation and dermal routes.  The general \npopulation may be exposed to HCCPD through inhalation of air contaminated with this chemical and \ningestion of drinking water contaminated with this chemical.\n\n###### 1.2 SUMMARY OF HEALTH EFFECTS\n\nInformation on the noncancer toxicity of HCCPD in humans is limited to reports by wastewater treatment \nplant (WWTP) workers and cleanup crew members exposed after an inadvertent industrial release.  No \noccupational studies evaluating health effects in workers exposed during regular manufacture or use of \nHCCPD are available.  Additionally, no observational epidemiological studies of workers or the public \nare available for HCCPD.  Further information on the noncancer toxicity of HCCPD comes from \ninhalation and oral studies in animals.  Data following dermal exposure are very limited in humans and \nanimals.\n\nIn laboratory animals, evaluation of available dose-response data by route and duration indicates that \nsensitive noncancer targets of HCCPD toxicity are respiratory and hematological effects following inhalation exposure (Figure 1-1).  Ovarian inflammation was noted in mice following chronic-duration \ninhalation exposure; however, the causal relationship between the effect and HCCPD exposure could not \nbe determined due to apparent association with stress-induced susceptibility to an infection in the mouse \ncolony (see Section 2.16).  Due to this, female reproductive (ovarian) effects were not considered as \npotential sensitive effects or included in Figure 1-1.  The oral database is very limited; the only potential \ntargets identified below doses associated with lethality include the gastrointestinal tract and kidney \n(Figure 1-2). General toxicity (decreased body weight) was also observed at similar doses.  A systematic \nreview of sensitive target organs/systems by exposure route resulted in the following hazard identification \nconclusions:\n\n• Respiratory effects are a presumed health effect for humans following inhalation exposure.\n\n• Gastrointestinal effects are a presumed health effect for humans following oral exposure.\n\n• Hematological (red blood cell) effects are suspected health effects for humans following \ninhalation exposure; white blood cell effects are not classifiable as to the hazard to humans.\n\n• Renal effects are a presumed health effect for humans following oral exposure.\n\n**_Respiratory Effects (Inhalation Route)._**  The respiratory tract is sensitive to HCCPD toxicity after \ninhalation exposure; findings are attributed to compound reactivity upon contact with respiratory tissues \nat the portal of entry.  WWTP workers and cleanup crew members reported respiratory symptoms \nincluding coughing, nose and throat irritation, and difficulty breathing following inhalation of HCCPD \nvapors from an inadvertent industrial discharge (Kominsky et al. 1980; Morse et al. 1979).  Acuteduration inhalation exposure studies in animals identified increased or labored respiration or abnormal \nrespiratory patterns at concentrations ≥0.5 ppm (Alexander et al. 1980a; Jackson and Hardy 1986, 1987; \nRand et al. 1982a).  Sneezing and altered respiratory rates/patterns were observed in rodents at \nintermediate-duration exposures of ≥0.56 ppm (Clark 1981; NTP 1994).  Histopathological evaluation \nidentified changes to the nasal, tracheobronchial, and/or pulmonary epithelium in rats and mice at \n≥0.385 and ≥0.2 ppm, respectively; these changes consisted of inflammation (suppurative or necrotizing) \nor metaplasia at nonlethal concentrations (Clark 1981; NTP 1994) and hemorrhaging or necrosis at lethal \nconcentrations (NTP 1994).  Nasal and pulmonary lesions were observed in mice exposed to 0.2 ppm \nHCCPD for 2 years, while no lesions were observed in rats under the same exposure conditions (NTP \n1994).\n\n$$\n\\geq0.385and\\geq0.2\n$$\n\n---\n\n**Figure 1-1.  Health Effects Found in Animals Following Inhalation Exposure to** \n**HCCPD**\n\n**Concentration (ppm)**\n\n**≥1.4**\n\n**Effects in Animals**\n\n**Acute:**  Neurobehavioral effects\n\n**Intermediate:**  Hepatic effects\n\n**0.5**\n\n**Acute:**  Death, respiratory lesions, altered hematology parameters, \ndecreased body weight, decreased food and water intake\n\n**Intermediate:**  Decreased body weight\n\n**0.389**\n\n**Intermediate:**  Death\n\n**0.2**\n\n**0.039**\n\n**Intermediate:**  Respiratory lesions\n\n**Chronic:**  Death, respiratory lesions\n\n**Intermediate:**  Altered red blood cell parameters\n\n1x10<sup>-4</sup> ppm\n6x10<sup>-5</sup> ppm\n\n**Provisional Intermediate MRL**\n**Provisional Chronic MRL**\n\n---\n\n**Figure 1-2.  Health Effects Found in Animals Following Oral Exposure to HCCPD**\n\nDose (mg/kg/day) Effects in Animals\n≥464 Acute:  Gastrointestinal, neurological, respiratory, and musculoskeletal  \neffects \n150 Intermediate:  Death\n75 Acute:  Death, developmental effects\n38 Intermediate:  Gastrointestinal and renal lesions, decreased body \nweight\n0.06 mg/kg/day Provisional Intermediate MRL\n\n**_Gastrointestinal Effects (Oral Route)._** The gastrointestinal tract is sensitive to HCCPD after oral \nexposure; findings are attributed to compound reactivity upon contact with gastrointestinal tissues at the \nportal of entry.  No human data are available evaluating potential gastrointestinal effects of HCCPD \nfollowing oral exposure.  Diarrhea was reported in rodents administered single oral doses of ≥464 mg/kg \n(Dean 1977; Gardner 1986a); this effect was not reported at lower doses in intermediate-duration studies \nup to 150 mg/kg/day in rats or 300 mg/kg/day in mice (Abdo et al. 1984).  In the only available \nintermediate-duration oral study in animals, focal inflammation and epithelial hyperplasia of the \nforestomach were observed in rats and mice exposed to ≥38 and ≥75 mg/kg/day, respectively (Abdo et al.\n1984).  While humans lack a forestomach, analogous lesions could occur in the proximate portions of the \nhuman gastrointestinal tract, including oral, pharyngeal, and/or esophageal tissues, due to portal-of-entry \nreactivity following oral exposure to HCCPD.\n\n**_Hematological Effects (Inhalation Route)._**  No changes in blood counts were observed in workers \nexposed to HCCPD at a WWTP following an inadvertent industrial discharge (Kominsky et al. 1980).  \nAlterations in red blood cell parameters, primarily elevated red blood cell counts and hemoglobin levels, were reported in rats following acute- and intermediate-duration inhalation exposure to HCCPD at \nconcentrations of 0.5 and ≥0.14 ppm, respectively (Clark 1981; NTP 1994; Rand et al. 1982a); similar \nfindings were observed in mice at intermediate-duration inhalation concentrations ≥0.039 ppm (NTP \n1994).  Based on the absence of histopathological changes to bone marrow, observed red blood cell \neffects have been hypothesized to be a compensatory response to hemorrhagic damage to the lungs \nfollowing inhalation exposure rather than direct effects on hematopoiesis (Rand et al. 1982a).  However,\nrats showed sex-specific findings (females were less sensitive), and there were inconsistencies between \nthe main 13-week (comprehensive) study and the 13-week specialized hematological study conducted by \nNTP (1994).  In mice, findings were limited and inconsistent with respect to alterations in red blood cell \nparameters after exposure for 13–42 weeks (NTP 1994).  Additionally, no hematological effects were \nobserved in the 2-year inhalation studies in rats or mice at concentrations up to 2 ppm (NTP 1994).  No \nconsistent effects on white blood cell parameters were observed with inhalation exposures in animal \nstudies (Clark 1981; NTP 1994; Rand et al. 1982a).\n\n**_Renal Effects (Oral Route)._** No human data are available to assess the potential for HCCPD to cause \nrenal toxicity.  In the only available oral study in animals evaluating the kidney, HCCPD produced toxic \nnephrosis in male and female rats at ≥38 mg/kg/day and in female mice at ≥75 mg/kg/day (Abdo et al. \n1984).  Toxic nephrosis was not identified in male mice, but acute tubular necrosis was identified in male \nmice exposed to 300 mg/kg/day. Available toxicokinetic data indicate that HCCPD and/or its metabolites \ndistribute to the kidneys in both rats and mice after oral dosing; however, the highest distribution is to the \nkidney in the rat and to the liver in the mouse (Dorough and Ranieri 1984).  This observed difference in \ndistribution may explain the observed species sensitivity.\n\n**_Cancer Effects._**  There were no data from studies in humans pertaining to the carcinogenicity of HCCPD.  \nThe National Toxicology Program (NTP) conducted 2-year bioassays of HCCPD in mice and rats and \nconcluded that it is not a carcinogen in either species (NTP 1994).  Although the incidence of \nalveolar/bronchiolar carcinomas was significantly increased in male mice exposed to 0.5 ppm for 26 or \n42 weeks and evaluated at 2 years, the incidence was within the historical range for the laboratory and \nwas not elevated in animals exposed to 0.2 ppm for 2 years. There was also a slight increase in the \nincidence of adenomas of the pituitary pars distalis in male rats and thyroid follicle cell adenomas in \nfemale mice, but these tumors were not considered to be exposure-related since the incidences were \nsimilar to the historical control means, were within the historical control range, or did not exhibit a dosedependency.  Based on these results, the U.S. Environmental Protection Agency (EPA) determined that \nHCCPD is not likely to be a human carcinogen by the inhalation route (IRIS 2003).  The International\n\n---\n\nAgency for Research on Cancer (IARC) has not evaluated the carcinogenicity of HCCPD (IARC 2025).  \nThe U.S. Department of Health and Human Services (HHS) has not evaluated a cancer classification \ncategory for HCCPD (NTP 2021).\n\n###### 1.3 MINIMAL RISK LEVELS (MRLs)\n\nAs illustrated in Figure 1-3, available inhalation data for HCCPD suggest that the respiratory and \nhematological systems are the most sensitive targets for toxicity. The inhalation database was considered \nadequate for derivation of provisional intermediate- and chronic-duration MRLs.  As discussed in \nSection 1.2, ovarian effects observed in the chronic-duration mouse study were not considered as \npotential sensitive effects due to potential confounding by a utero-ovarian infection (see Appendix A for \ndetails).  Therefore, female reproductive effects are not included in Figure 1-3.\n\nAs illustrated in Figure 1-4, gastrointestinal, renal, and body weight effects appear to be the most \nsensitive targets of HCCPD toxicity following oral exposure. The oral database was considered adequate \nfor derivation of a provisional intermediate-duration MRL for HCCPD.  The acute- and chronic-duration \noral data were insufficient for deriving MRLs.\n\nThe provisional MRL values are summarized in Table 1-1 and discussed in greater detail in Appendix A.\n\n---\n\n**Figure 1-3.  Summary of Sensitive Targets of HCCPD – Inhalation**\n\n**Available data indicate that the hematological and respiratory systems are the most sensitive \ntargets of HCCPD inhalation exposure.**\n\nNumbers in circles are the lowest LOAELs for all health effects in animals. No reliable dose response \ndata were available for humans.\n\n**Acute (ppm)**\n\n| Category | Acute (ppm) | Intermediate (ppm) | Chronic (ppm) |\n| --- | --- | --- | --- |\n| Death | 0.5 | 0.389 | 0.2 |\n| Body weight | 0.5 |  |  |\n| Respiratory | 0.5 | 0.2 | 0.2 |\n| Hematological | 0.5 | 0.039 |  |\n| Other noncancer | 0.5 |  |  |\n\n---\n\n**Figure 1-4. Summary of Sensitive Targets of HCCPD – Oral**\n\n**Available data indicate that the gastrointestinal tract, renal system, and body weight are the most\nsensitive targets of HCCPD oral exposure.**\nNumbers in circles are the lowest LOAELs for all health effects in animals. \nNo reliable dose response data were available for humans.\n\n## Acute (mg/kg/day)\n\n| Category | Lowest LOAEL (mg/kg/day) |\n| --- | --- |\n| Death (Acute) | 75 |\n| Developmental (Acute) | 75 |\n| Gastrointestinal (Acute) | 464 |\n| Neuological (Acute) | 464 |\n| Body weight (Intermediate) | 38 |\n| Gastrointestinal (Intermediate) | 38 |\n| Renal (Intermediate) | 38 |\n| Death (Intermediate) | 150 |\n\n---\n\nTable 1-1. Provisional Minimal Risk Levels (MRLs) for HCCPD<sup>a</sup>\n\n| Exposure route | Exposure duration | Provisional MRL | Critical effect | POD type | POD value | Uncertainty/modifying factor | Reference |\n| --- | --- | --- | --- | --- | --- | --- | --- |\n| Inhalation | Acute | None | - | - | - | - | - |\n| Inhalation | Intermediate | 1 × 10-4 ppm (1 × 10-3 mg/m3) | Nasal suppurative inflammation in rats | NOAELHEC | 0.00344 ppm | UF: 30 | NTP 1994 |\n| Inhalation | Chronic | 6 × 10-5 ppm (7 × 10-4 mg/m3) | Nasal suppurative inflammation in mice | BMCLHEC | 0.0019 ppm | UF: 30 | NTP 1994 |\n| Oral | Acute | None | - | - | - | - | - |\n| Oral | Intermediate | 0.06 mg/kg/day | Combined incidence of forestomach epithelial hyperplasia and focal inflammation in rats | BMDLADJ | 5.5 mg/kg/day | UF: 100 | Abdo et al. 1984: Velsicol 1981b |\n| Oral | Chronic | None | - | - | - | - | - |\n\n$$\n1\\times10^{-4}ppm\n$$\n\n$$\n(1\\times10^{-3}mg/m^3)\n$$\n\n$$\n6\\times10^{-5}ppm\n$$\n\n$$\n(7\\times10^{-4}mg/m^3)\n$$\n\n<sup>a</sup>See Appendix A for additional information.\n\nADJ = adjusted for intermittent exposure; BMCL = benchmark concentration lower confidence limit; BMDL = benchmark dose lower confidence limit;\n\nHEC = human equivalent concentration; NOAEL = no-observed-adverse-effect level; POD = point of departure; UF = uncertainty factor\n\n---\n\n# CHAPTER 2. HEALTH EFFECTS\n\n###### 2.1 INTRODUCTION\n\nThe primary purpose of this chapter is to provide public health officials, physicians, toxicologists, and \nother interested individuals and groups with an overall perspective on the toxicology of HCCPD.  It \ncontains descriptions and evaluations of toxicological studies and epidemiological investigations and \nprovides conclusions, where possible, on the relevance of toxicity and toxicokinetic data to public health.  \nWhen available, mechanisms of action are discussed along with the health effects data; toxicokinetic \nmechanistic data are discussed in Section 3.1.\n\nA glossary and list of acronyms, abbreviations, and symbols can be found at the end of this profile.\n\nTo help public health professionals and others address the needs of persons living or working near hazardous \nwaste sites, the information in this section is organized by health effects.  These data are discussed in terms \nof route of exposure (inhalation, oral, and dermal) and three exposure periods:  acute (≤14 days), \nintermediate (15–364 days), and chronic (≥365 days).\n\nAs discussed in Appendix B, a literature search was conducted to identify relevant studies examining health \neffect endpoints.  Figure 2-1 provides an overview of the database of studies in humans or experimental \nanimals included in this chapter of the profile.  These studies evaluate the potential health effects associated \nwith inhalation, oral, or dermal exposure to HCCPD, but may not be inclusive of the entire body of literature.  \nA systematic review of the scientific evidence of the health effects associated with exposure to HCCPD was \nalso conducted; the results of this review are presented in Appendix C.\n\nHuman and animal inhalation studies are presented in Table 2-1 and Figure 2-2, animal oral studies are \npresented in Table 2-2 and Figure 2-3, and human and animal dermal studies are presented in Table 2-3.  \nDue to the limited nature of the database, several older studies lacking quantitative data reporting are \nincluded in Chapter 2 to provide data potentially relevant for hazard identification; however, data that are \nonly reported qualitatively (i.e., histopathological data lacking incidence data) are not included in \nTables 2-1, 2-2, or 2-3.\n\nLevels of significant exposure (LSEs) for each route and duration are presented in tables and illustrated in \nfigures.  The points in the figures showing no-observed-adverse-effect levels (NOAELs) or lowest- observed-adverse-effect levels (LOAELs) reflect the actual doses (levels of exposure) used in the studies.  \nEffects have been classified into “less serious LOAELs” or “serious LOAELs (SLOAELs).”  “Serious” \neffects are those that evoke failure in a biological system and can lead to morbidity or mortality (e.g., \nacute respiratory distress or death).  “Less serious” effects are those that are not expected to cause \nsignificant dysfunction or death, or those whose significance to the organism is not entirely clear.  \nATSDR acknowledges that a considerable amount of judgment may be required in establishing whether \nan endpoint should be classified as a NOAEL, “less serious” LOAEL, or “serious” LOAEL, and that in \nsome cases, there will be insufficient data to decide whether the effect is indicative of significant \ndysfunction.  However, the Agency has established guidelines and policies that are used to classify these \nendpoints.  ATSDR believes that there is sufficient merit in this approach to warrant an attempt at \ndistinguishing between “less serious” and “serious” effects.  The distinction between “less serious” effects \nand “serious” effects is considered to be important because it helps the users of the profiles to identify \nlevels of exposure at which major health effects start to appear.  LOAELs or NOAELs should also help in \ndetermining whether or not the effects vary with dose and/or duration, and place into perspective the \npossible significance of these effects to human health.\n\nA User's Guide has been provided at the end of this profile (see Appendix C).  This guide should aid in \nthe interpretation of the tables and figures for LSEs and MRLs.\n\nThe health effects of HCCPD have been evaluated in 2 human studies and 68 animal studies.  As \nillustrated in Figure 2-1, most of the health effect data come from dermal and inhalation studies in \nanimals.  In both human and animal studies, the ocular effects observed in HCCPD inhalation studies are \nlikely attributable to direct contact with HCCPD vapors.  Therefore, ocular effects from inhalation studies \nare counted as dermal exposure in Figure 2-1 and are listed in the dermal LSE table.\n\nThe available human studies were predominantly focused on evaluation of dermal, ocular, and respiratory \neffects in WWTP workers and cleanup crew members following an inadvertent industrial release of \nHCCPD.  For these studies, exposure was evaluated as HCCPD vapor levels in air.\n\nFor animal data, inhalation and oral studies are available for most health effects.  Acute-, intermediate-, \nand chronic-duration studies are available for the inhalation route, while only acute- and intermediateduration studies are available for the oral route.  The dermal animal database is mostly limited to ocular \nand dermal effects, largely following exposure to HCCPD vapor.  The most examined endpoints in \nanimal studies were death, respiratory, hepatic, renal, and ocular.\n\n---\n\nA systematic review was conducted on potential targets of HCCPD exposure, which included respiratory \nand hematological effects for inhalation exposure and gastrointestinal and renal effects following oral \nexposure (see Appendix C for details).\n\n• **Respiratory Effects.** Respiratory effects are a presumed health effect associated with HCCPD \nexposure via inhalation based on inadequate evidence in humans and a high level of evidence in \nanimals.  WWTP workers and cleanup crew members reported respiratory symptoms including \ncoughing and respiratory tract irritation after exposure to HCCPD vapors following an \ninadvertent industrial release.  Several animal studies have reported altered respiratory patterns \nfollowing single or repeated exposures to HCCPD.  Upon histopathological examination, \nnonneoplastic lesions of the nasal, tracheobronchial, and pulmonary regions were consistently \nobserved in mice and rats exposed for intermediate durations to concentrations ≥0.2 or \n≥0.385 ppm, respectively.  Chronic-duration exposure to 0.2 ppm resulted in similar lesions in \nmice, but not rats.  Observed lesions (suppurative, serous, or necrotizing inflammation; epithelial \nhyperplasia) are consistent with chronic irritation at the portal of entry.\n\n• **Gastrointestinal Effects.** Gastrointestinal effects are a presumed health effect associated with \nHCCPD exposure via oral exposure based on no human data and a high level of evidence in \nanimal studies.  Diarrhea was reported in rodents following exposure to high acute doses \n≥464 mg/kg.  Forestomach lesions (epithelial hyperplasia and focal inflammation) were observed \nin rats and mice following intermediate-duration exposures of ≥38 and ≥75 mg/kg/day, \nrespectively.  Although humans lack a forestomach, effects associated with HCCPD are \nconsistent with chronic irritation at the portal of entry.  Thus, the upper gastrointestinal tract is\npresumably vulnerable to toxicity following oral exposure to HCCPD.\n\n• **Hematological Effects.** Hematological effects, specifically red blood cell parameters, are a \nsuspected health effect associated with HCCPD exposure via inhalation based on inadequate data \nin humans and a moderate level of evidence in animals.  No changes in blood counts were \nobserved in WWTP workers after exposure to HCCPD vapors following an inadvertent industrial \nrelease.  Several acute- and intermediate-duration inhalation studies reported altered red blood \ncell parameters (e.g., increased hemoglobin, red blood cell counts, and packed cell volume) at \nconcentrations as low as 0.14 and 0.039 ppm in rats and mice, respectively; however, these \nfindings were not consistent across sexes or species nor were they reproducible in targeted \nanalyses by the same researchers.  Observed red blood cell effects may be attributable to\ncompromised gas exchange following tissue damage to the respiratory tract, as no evidence of \nbone marrow hyperplasia was observed in rodents following repeated inhalation exposure to \nHCCPD. White blood cell effects are not classifiable as to the hazard to humans based on no data \nin humans and inadequate evidence in animals.  Available studies did not find consistent evidence \nof alterations in white blood cell parameters in rats or mice following intermediate- or chronicduration inhalation exposure to HCCPD.\n\n• **Renal Effects.** Renal effects are a presumed health effect associated with oral exposure to\nHCCPD based on no human data and a high level of evidence in animal studies.  Renal lesions, \nspecifically toxic nephrosis, were observed in rats and mice following intermediate-duration \nexposures to ≥38 and ≥75 mg/kg/day, respectively. Acute tubular necrosis was observed in male \nmice at a higher dose (300 mg/kg/day).  Available toxicokinetic data indicate that HCCPD and/or\n\n---\n\n###### 2. HEALTH EFFECTS\n\nits metabolites distribute to the kidneys of both rats and mice after oral dosing; however, it will \naccumulate to a higher degree in rats.\n\n---\n\n**Figure 2-1.  Overview of the Number of Studies Examining HCCPD Health Effects***\n\n**Most studies examined the potential death, respiratory, neurological, renal, hepatic, and ocular effects of HCCPD**\nFewer studies evaluated health effects in **humans** than **animals** (counts represent studies examining endpoint)\n\n| Category | Number of studies |\n| --- | --- |\n| Death | 57 |\n| Body weight | 18 |\n| Respiratory | 44 |\n| Cardiovascular | 35 |\n| Gastrointestinal | 16 |\n| Hematological | 13 |\n| Musculoskeletal | 10 |\n| Hepatic | 39 |\n| Renal | 39 |\n| Dermal | 16 |\n| Ocular | 39 |\n| Endocrine | 35 |\n| Immunological | 12 |\n| Neurolgical | 41 |\n| Reproductive | 11 |\n| Developmental | 3 |\n| Other Noncancer | 7 |\n| Cancer | 5 |\n\n**Exposure Route**\n\n| Category | Share of studies (%) |\n| --- | --- |\n| Inhalation | 40 |\n| Oral | 13 |\n| Dermal | 47 |\n\n**Exposure Duration**\n\n| Category | Share of studies (%) |\n| --- | --- |\n| Chronic | 2 |\n| Acute | 78 |\n| Intermediate | 20 |\n\n*Includes studies discussed in Chapter 2.  A total of 70 studies (including those finding no effect) have examined toxicity; most studies examined multiple \nendpoints.\n\n---\n\n**Table 2-1. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation\n(ppm)**\n\n| Species (strain) keya | No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| ACUTE EXPOSURE |  |  |  |  |  |  |  |  |  |\n| Alexander et al. 1980a; Rand et al. 1982a |  |  |  |  |  |  |  |  |  |\n| 1 | Rat (Sprague-Dawley) 10 M, 10 F | 1–2 weeks 5 days/week 6 hours/day (WB) | 0, 0.022, 0.11, 0.5 | LE, CS, BW, FI, HE, BC, GN, OW, HP | Death Bd wt | 0.11 |  | 0.5 M | 10/10 died or were sacrificed in moribund condition Decreased terminal body weight in females (29%) and males (32%) Labored respiration; increased absolute lung weight; bronchiole inflammation, hyperplasia, and epithelial erosion |\n| 1 | Rat (Sprague-Dawley) 10 M, 10 F | 1–2 weeks 5 days/week 6 hours/day (WB) | 0, 0.022, 0.11, 0.5 | LE, CS, BW, FI, HE, BC, GN, OW, HP | Resp | 0.11 |  | 0.5 | 10/10 died or were sacrificed in moribund condition Decreased terminal body weight in females (29%) and males (32%) Labored respiration; increased absolute lung weight; bronchiole inflammation, hyperplasia, and epithelial erosion |\n| 1 | Rat (Sprague-Dawley) 10 M, 10 F | 1–2 weeks 5 days/week 6 hours/day (WB) | 0, 0.022, 0.11, 0.5 | LE, CS, BW, FI, HE, BC, GN, OW, HP | Cardio Hematoc | 0.5 0.11 | 0.5 | 0.5 | Males: total white blood cell and lymphocyte counts reduced Females: neutrophils increased Both: red blood cell count, packed cell volume, and hemoglobin increased |\n| 1 | Rat (Sprague-Dawley) 10 M, 10 F | 1–2 weeks 5 days/week 6 hours/day (WB) | 0, 0.022, 0.11, 0.5 | LE, CS, BW, FI, HE, BC, GN, OW, HP | Hepatic Renal Immuno Neuro | 0.5 0.5 0.5 Other noncancer | 0.5 |  | Decreased food and water intake |\n| Jackson and Hardy 1986 |  |  |  |  |  |  |  |  |  |\n| 2 | Rat (Wistar) 5 M, 5 F | 1 hour (WB) | 0, 1.67, 2.38, 3.53, 6.25, 8.30 | LE, CS, BW, FI, WI, OW, GN | Death Bd wt | 1.67 |  | 3.69 | LC50 Decreased body weight at death or scheduled sacrifice (3-weeks post exposure) in males (41%) and females (26%) Abnormal respiratory pattern Decreased food consumption |\n| 2 | Rat (Wistar) 5 M, 5 F | 1 hour (WB) | 0, 1.67, 2.38, 3.53, 6.25, 8.30 | LE, CS, BW, FI, WI, OW, GN | Resp Other noncancer | 1.67 1.67 |  |  | LC50 Decreased body weight at death or scheduled sacrifice (3-weeks post exposure) in males (41%) and females (26%) Abnormal respiratory pattern Decreased food consumption |\n\n---\n\n**Table 2-1. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation\n(ppm)**\n\nAbnormal respiratory pattern\nDecreased food consumption\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Jackson and Hardy 1987 |  |  |  |  |  |  |  |  |  |\n| 3 | Rat (Wistar) 5 M, 5 F | 4 hours (WB) | 0, 1.68, 1.83, 3.31, 3.47 | LE, CS, BW, FI, WI, GN, OW | Death Bd wt |  |  | 2.9 1.68 M | LC50 23% decreased body weight at scheduled sacrifice (4 weeks post exposure) |\n| 3 | Rat (Wistar) 5 M, 5 F | 4 hours (WB) | 0, 1.68, 1.83, 3.31, 3.47 | LE, CS, BW, FI, WI, GN, OW | Resp Other noncancer | 1.68 F | 1.68 1.68 | 1.83 F | 24% decreased body weight at death or scheduled sacrifice (4 weeks post exposure) |\n| OxyChem 1972 |  |  |  |  |  |  |  |  |  |\n| 4 | Rat (Carworth CFE) 10 M | 4 hours (WB) | 176, 1,760 | LE, CS, GN | Death |  |  | 176 | 10/10 died within 48 hours |\n| Rand et al. 1982a |  |  |  |  |  |  |  |  |  |\n| 5 | Rat (Sprague-Dawley) 10 M, 10 F | 4 hours (WB) | 0.28, 1.4, 2.5, 3.1, 3.3, 3.4, 4, 5.8 | LE, CS, BW | Death |  |  | 3.5 F 1.6 M | LC50 LC50 |\n| 5 | Rat (Sprague-Dawley) 10 M, 10 F | 4 hours (WB) | 0.28, 1.4, 2.5, 3.1, 3.3, 3.4, 4, 5.8 | LE, CS, BW | Bd wt | 0.28 | 1.4 F | 1.4 M | 17% body weight loss 25% body weight loss |\n| 5 | Rat (Sprague-Dawley) 10 M, 10 F | 4 hours (WB) | 0.28, 1.4, 2.5, 3.1, 3.3, 3.4, 4, 5.8 | LE, CS, BW | Neuro | 0.28 | 1.4 | 5.8 | LOAEL: Sedation SLOAEL: Ataxia |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 6 | Rat 4 NS | 2 days 7 hours/day (WB) | 3.2 | LE, CS, GN | Death |  |  | 3.2 | 4/4 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 7 | Rat 4 NS | 3 days 7 hours/day (WB) | 1.4 | LE, CS, GN | Death |  |  | 1.4 | 3/4 died |\n\n---\n\n**Table 2-1. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation\n(ppm)**\n\n| Species |  |  |  |  |  |  |  |  |  |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Figure keya | No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 8 | Rat 4 NS | 2.6–3.6 hours (WB) | 1.4, 3.1, 7.1, 12.4, 12.7, 46.5, 56.9, 70.4 | LE, CS, GN | Death |  |  | 3.1 | 2/4 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 9 | Rat 4 NS | 7 hours (WB) | 1.5, 3.2, 6.7 | LE, CS, GN | Death |  |  | 3.2 | 3/4 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 10 | Rat 4 NS | 5 days 7 hours/day (WB) | 0.33, 1.0, 1.6 | LE, CS, GN | Death |  |  | 1 | 4/4 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 11 | Rat 4 NS | 0.25–1.25 hours (WB) | 1.4, 1.5, 3.1, 7.2, 13.0, 13.8, 19.4, 20.0, 20.2, 69.1, 69.2 | LE, CS, GN | Death |  |  | 7.2 | 2/4 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 12 | Rat 4 NS | 4 hours (WB) | 73.6 | LE, CS, GN | Death |  |  | 73.6 | 4/4 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 13 | Mouse 5 NS | 0.25–1.25 hours (WB) | 1.4, 1.5, 3.1, 7.2, 13.0, 13.8, 19.4, 20.0, 20.2, 69.1, 69.2 | LE, CS, GN | Death |  |  | 7.2 | 5/5 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 14 | Mouse 5 NS | 4 hours (WB) | 73.6 | LE, CS, GN | Death |  |  | 73.6 | 5/5 died |\n\n---\n\n**Table 2-1. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation\n(ppm)**\n\n| Species (strain) keya | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| 15 Mouse 5 NS | 2 days 7 hours/day (WB) | 3.2 | LE, CS, GN | Death |  |  | 3.2 | 4/5 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| 16 Mouse 5 NS | 3 days 7 hours/day (WB) | 1.4 | LE, CS, GN | Death |  |  | 1.4 | 5/5 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| 17 Mouse 5 NS | 7 hours (WB) | 1.5, 3.2, 6.7 | LE, CS, GN | Death |  |  | 1.5 | 4/5 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| 18 Mouse 5 NS | 2.6– 3.6 hours (WB) | 1.4, 3.1, 7.1, 12.4, 12.7, 46.5, 56.9, 70.4 | LE, CS, GN | Death |  |  | 3.1 | 4/5 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| 19 Mouse 5 NS | 5 days 7 hours/day (WB) | 0.33, 1.0, 1.6 | LE, CS, GN | Death |  |  | 1 | 4/5 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| 20 Rabbit 3 NS | 4 hours (WB) | 73.6 | LE, CS, GN | Death |  |  | 73.6 | 3/3 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| 21 Rabbit 3 NS | 3 days 7 hours/day (WB) | 1.4 | LE, CS, GN | Death |  |  | 1.4 | 3/3 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| 22 Rabbit 3 NS | 5 days 7 hours/day (WB) | 1, 1.6 | LE, CS, GN | Death |  |  | 1 | 3/3 died |\n\n---\n\n**Table 2-1. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation\n(ppm)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 23 | Rabbit 3 NS | 2.6–3.6 hours (WB) | 1.4, 3.1, 7.1, 12.4, 12.7, 46.5, 56.9, 70.4 | LE, CS, GN | Death |  |  | 1.4 | 2/3 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 24 | Rabbit 3 NS | 7 hours (WB) | 1.5, 3.2, 6.7 | LE, CS, GN | Death |  |  | 1.5 | 3/3 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 25 | Rabbit 3 NS | 0.25–1.25 hours (WB) | 1.4, 1.5, 3.1, 7.2, 13.0, 13.8, 19.4, 20.0, 20.2, 69.1, 69.2 | LE, CS, GN | Death |  |  | 3.1 | 2/3 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 26 | Rabbit 3 NS | 2 days 7 hours/day (WB) | 3.2 | LE, CS, GN | Death |  |  | 3.2 | 3/3 died |\n| INTERMEDIATE EXPOSURE |  |  |  |  |  |  |  |  |  |\n| Alexander et al. 1980b; Rand et al. 1982a, 1982b |  |  |  |  |  |  |  |  |  |\n| 27 | Monkey (Cynomolgus) 6 M, 6 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, HE, BC, UR, OP, GN, OW, HP, OF | Bd wt Resp Cardio Gastro Hemato Musc/skel Hepatic Renal Ocular Endocr Immuno | 0.2 0.2 0.2 0.2 0.2 0.2 |  |  |  |\n\n---\n\n**Table 2-1. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation\n(ppm)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n|  |  |  |  |  | Neuro | 0.2 |  |  |  |\n|  |  |  |  |  | Repro | 0.2 |  |  |  |\n|  |  |  |  |  | Other |  |  |  |  |\n|  |  |  |  |  | noncancer |  |  |  |  |\n| Alexander et al. 1980b; Huntingdon Research Centre 1980; Rand et al. 1982a, 1982b |  |  |  |  |  |  |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Bd wt | 0.2 |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Resp | 0.2 |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Cardio | 0.2 |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Gastro | 0.2 |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Hemat | 0.2 |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Musc/skel | 0.2 |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Hepatic | 0.2 |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Renal | 0.2 |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Ocular | 0.2 |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Endocr | 0.2 |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Immuno | 0.2 |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Neuro | 0.2 |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Repro | 0.2 |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Other |  |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | noncancer |  |  |  |  |\n\n---\n\n**Table 2-1. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation\n(ppm)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Clark 1981 |  |  |  |  |  |  |  |  |  |\n| 29 | Rat (Wistar) 18 M, 18 F | 30 weeks 5 days/week 6 hours/day (WB) | 0, 0.06, 0.14, 0.56 | LE, CS, BW, FI, WI, HE, BC, UR, GN, OW, HP | Death Bd wt Resp | 0.56 | 0.56 F | 0.56 M | 4/18 males and 2/18 females died |\n| 29 | Rat (Wistar) 18 M, 18 F | 30 weeks 5 days/week 6 hours/day (WB) | 0, 0.06, 0.14, 0.56 | LE, CS, BW, FI, WI, HE, BC, UR, GN, OW, HP | Resp | 0.14 | 0.56 F | 0.56 M | Females: perivascular/peribronchiolar inflammatory cell infiltration; sneezing Males: bronchiolar epithelial ulceration/thinning and perivascular/peribronchiolar inflammatory cell infiltration; sneezing |\n| 29 | Rat (Wistar) 18 M, 18 F | 30 weeks 5 days/week 6 hours/day (WB) | 0, 0.06, 0.14, 0.56 | LE, CS, BW, FI, WI, HE, BC, UR, GN, OW, HP | Cardio Gastro Hematoma | 0.56 0.56 F 0.06 M | 0.56 F 0.14 M |  | Decreased lymphocyte counts Increased red blood cell counts, hemoglobin, hematocrit, and neutrophil counts; decreased lymphocyte percentage |\n| 29 | Rat (Wistar) 18 M, 18 F | 30 weeks 5 days/week 6 hours/day (WB) | 0, 0.06, 0.14, 0.56 | LE, CS, BW, FI, WI, HE, BC, UR, GN, OW, HP | Musc/skel Hepatic Renal Dermal Ocular Endocr Immuno Neuro Repro | 0.56 0.56 0.56 0.56 0.56 0.56 |  |  |  |\n\n---\n\n**Table 2-1. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation\n(ppm)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n|  |  |  |  |  | Other noncancer | 0.56 |  |  |  |\n| NTP 1994 |  |  |  |  |  |  |  |  |  |\n| 30 | Rat (Fischer-344) 10 M, 10 F | 13 weeks 5 days/week 6 hours/day (WB) | 0, 0.039, 0.146, 0.385, 0.941, 2.065 | LE, CS, BW, HE, BC, GN, OW, HP | Death Bd wt Resp | 0.385 0.385 F 0.146b M | 0.385 M | 0.941 | 100% mortality during first 4 weeks |\n|  |  |  |  |  |  |  |  |  | Nasal squamous metaplasia and suppurative inflammation; suppurative and necrotizing inflammation of the bronchus/bronchiole; increased absolute and relative lung weights |\n|  |  |  |  |  |  |  |  | 0.941 | Increased respiration rate and mouth breathing; suppurative inflammation and hemorrhaging in the alveolus; necrotizing inflammation of the nose, larynx, trachea, and bronchus/bronchiole |\n|  |  |  |  |  | Cardio Gastro Hemato | 0.385 0.385 0.146 | 0.385 |  |  |\n|  |  |  |  |  | Musc/skel | 0.385 |  |  | Males: increased packed cell volume, hemoglobin, red blood cell count, and MCHC |\n|  |  |  |  |  | Hepatic | 0.385 |  |  |  |\n|  |  |  |  |  | Renal | 0.385 |  |  |  |\n|  |  |  |  |  | Endocr | 0.385 |  |  |  |\n|  |  |  |  |  | Immuno | 0.385 |  |  |  |\n|  |  |  |  |  | Neuro | 0.385 |  |  |  |\n|  |  |  |  |  | Repro | 0.385 |  |  |  |\n\n***DRAFT FOR PUBLIC COMMENT***\n\n---\n\n**Table 2-1. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation\n(ppm)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| NTP 1994 |  |  |  |  |  |  |  |  |  |\n| 31 | Rat (Fischer-344) 20 M, 20 F | 13 weeks 5 days/week 6 hours/day (WB) | 0, 0.039, 0.385, 2.065 | LE, HE, BC, UR | Death Hemato | 0.039 | 0.385 | 2.065 | 100% mortality Males: increased MCV; Females: increased MCV, packed cell volume, hemoglobin, and red blood cell count Increased AST |\n| 31 | Rat (Fischer-344) 20 M, 20 F | 13 weeks 5 days/week 6 hours/day (WB) | 0, 0.039, 0.385, 2.065 | LE, HE, BC, UR | Hepatic Renal | 0.385 2.065 | 2.065 | 2.065 | 100% mortality Males: increased MCV; Females: increased MCV, packed cell volume, hemoglobin, and red blood cell count Increased AST |\n| NTP 1994 |  |  |  |  |  |  |  |  |  |\n| 32 | Mouse (B6C3F1) 10 M | 42 weeks 5 days/week 6 hours/day (WB) | 0, 0.5 | LE, CS, BW, GN, OW, HP | Death Bd wt |  |  | 0.5 | 14% decreased survival at 45 weeks Decreased body weight (19%) and body weight gain (42%) at the end of the exposure period Suppurative inflammation of the nose, trachea, and lungs |\n| 32 | Mouse (B6C3F1) 10 M | 42 weeks 5 days/week 6 hours/day (WB) | 0, 0.5 | LE, CS, BW, GN, OW, HP | Resp |  | 0.5 | 0.5 | 14% decreased survival at 45 weeks Decreased body weight (19%) and body weight gain (42%) at the end of the exposure period Suppurative inflammation of the nose, trachea, and lungs |\n| 32 | Mouse (B6C3F1) 10 M | 42 weeks 5 days/week 6 hours/day (WB) | 0, 0.5 | LE, CS, BW, GN, OW, HP | Gastro Hepatic | 0.5 |  | 0.5 | 14% decreased survival at 45 weeks Decreased body weight (19%) and body weight gain (42%) at the end of the exposure period Suppurative inflammation of the nose, trachea, and lungs |\n| 32 | Mouse (B6C3F1) 10 M | 42 weeks 5 days/week 6 hours/day (WB) | 0, 0.5 | LE, CS, BW, GN, OW, HP | Renal | 0.5 |  | 0.5 | 14% decreased survival at 45 weeks Decreased body weight (19%) and body weight gain (42%) at the end of the exposure period Suppurative inflammation of the nose, trachea, and lungs |\n| 32 | Mouse (B6C3F1) 10 M | 42 weeks 5 days/week 6 hours/day (WB) | 0, 0.5 | LE, CS, BW, GN, OW, HP | Endocr Immuno | 0.5 |  | 0.5 | 14% decreased survival at 45 weeks Decreased body weight (19%) and body weight gain (42%) at the end of the exposure period Suppurative inflammation of the nose, trachea, and lungs |\n| 32 | Mouse (B6C3F1) 10 M | 42 weeks 5 days/week 6 hours/day (WB) | 0, 0.5 | LE, CS, BW, GN, OW, HP | Repro | 0.5 |  | 0.5 | 14% decreased survival at 45 weeks Decreased body weight (19%) and body weight gain (42%) at the end of the exposure period Suppurative inflammation of the nose, trachea, and lungs |\n| NTP 1994 |  |  |  |  |  |  |  |  |  |\n| 33 | Mouse (B6C3F1) 20 M, 20 F | 13 weeks 5 days/week 6 hours/day (WB) | 0, 0.039, 0.389, 2.142 | LE, HE, BC, UR | Death Hemato |  | 0.039 F 0.389 M | 2.142 | 100% mortality Increased MCHC Increased MCHC |\n| 33 | Mouse (B6C3F1) 20 M, 20 F | 13 weeks 5 days/week 6 hours/day (WB) | 0, 0.039, 0.389, 2.142 | LE, HE, BC, UR | Hepatic Renal | 0.039 M 2.142 2.142 | 0.039 F 0.389 M | 2.142 | 100% mortality Increased MCHC Increased MCHC |\n\n---\n\n**Table 2-1. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation\n(ppm)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| NTP 1994 |  |  |  |  |  |  |  |  |  |\n| 34 | Mouse (B6C3F1) 10 M | 26 weeks 5 days/week 6 hours/day (WB) | 0, 0.5 | LE, CS, BW, GN, OW, HP | Bd wt Resp | 0.5 | 0.5 |  | Nasal suppurative inflammation |\n| NTP 1994 |  |  |  |  |  |  |  |  |  |\n| 35 | Mouse (B6C3F1) 10 M | 33 weeks 5 days/week 6 hours/day (WB) | 0, 0.2 | LE, CS, BW, GN, OW, HP | Bd wt Resp Gastro Hepatic Renal Immuno Neuro Repro | 0.2 | 0.2 |  | Nasal suppurative inflammation |\n| NTP 1994 |  |  |  |  |  |  |  |  |  |\n| 36 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week 6 hours/day (WB) | 0, 0.039, 0.146, 0.389, 0.949, 2.142 | LE, CS, BW, HE, BC, OW, HP | Death |  |  | 0.949 F 0.389 M | 10/10 died 5/10 died |\n| 36 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week 6 hours/day (WB) | 0, 0.039, 0.146, 0.389, 0.949, 2.142 | LE, CS, BW, HE, BC, OW, HP | Bd wt Resp | 0.389 |  |  | Females: focal serous or suppurative inflammation of the nose Males: squamous metaplasia in the trachea, focal serous or suppurative inflammation of the nose |\n| 36 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week 6 hours/day (WB) | 0, 0.039, 0.146, 0.389, 0.949, 2.142 | LE, CS, BW, HE, BC, OW, HP | Cardio Gastro Hemato | 0.389 |  |  | Decreased MCV |\n| 36 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week 6 hours/day (WB) | 0, 0.039, 0.146, 0.389, 0.949, 2.142 | LE, CS, BW, HE, BC, OW, HP | Musc/skel | 0.389 |  |  |  |\n\n***DRAFT FOR PUBLIC COMMENT***\n\n---\n\n**Table 2-1. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation\n(ppm)**\n\n| Species Figure keya | Species (strain) No./group | Species Exposure parameters | Species Doses | Species Parameters monitored | Species Endpoint | Species NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n|  |  |  |  |  | Hepatic | 0.389 |  |  |  |\n|  |  |  |  |  | Renal | 0.389 |  |  |  |\n|  |  |  |  |  | Endocr | 0.389 |  |  |  |\n|  |  |  |  |  | Immuno | 0.389 |  |  |  |\n|  |  |  |  |  | Neuro | 0.389 |  |  |  |\n|  |  |  |  |  | Repro | 0.389 |  |  |  |\n| CHRONIC EXPOSURE |  |  |  |  |  |  |  |  |  |\n| NTP 1994 |  |  |  |  |  |  |  |  |  |\n| 37 | Rat (Fischer-344) 50 M, 50 F | 104 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, UR, GN, OW, HP | Bd wt | 0.2 |  |  |  |\n| 37 | Rat (Fischer-344) 50 M, 50 F | 104 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, UR, GN, OW, HP | Resp | 0.2 |  |  |  |\n| 37 | Rat (Fischer-344) 50 M, 50 F | 104 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, UR, GN, OW, HP | Cardio | 0.2 |  |  |  |\n| 37 | Rat (Fischer-344) 50 M, 50 F | 104 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, UR, GN, OW, HP | Gastro | 0.2 |  |  |  |\n| 37 | Rat (Fischer-344) 50 M, 50 F | 104 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, UR, GN, OW, HP | Hemat | 0.2 |  |  |  |\n| 37 | Rat (Fischer-344) 50 M, 50 F | 104 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, UR, GN, OW, HP | Musc/skel | 0.2 |  |  |  |\n| 37 | Rat (Fischer-344) 50 M, 50 F | 104 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, UR, GN, OW, HP | Hepatic | 0.2 |  |  |  |\n| 37 | Rat (Fischer-344) 50 M, 50 F | 104 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, UR, GN, OW, HP | Renal | 0.2 |  |  |  |\n| 37 | Rat (Fischer-344) 50 M, 50 F | 104 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, UR, GN, OW, HP | Dermal | 0.2 |  |  |  |\n| 37 | Rat (Fischer-344) 50 M, 50 F | 104 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, UR, GN, OW, HP | Endocr | 0.2 |  |  |  |\n| 37 | Rat (Fischer-344) 50 M, 50 F | 104 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, UR, GN, OW, HP | Immuno | 0.2 |  |  |  |\n| 37 | Rat (Fischer-344) 50 M, 50 F | 104 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, UR, GN, OW, HP | Neuro | 0.2 |  |  |  |\n| 37 | Rat (Fischer-344) 50 M, 50 F | 104 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, UR, GN, OW, HP | Repro | 0.2 |  |  |  |\n\n---\n\n**Table 2-1. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation\n(ppm)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| NTP 1994 |  |  |  |  |  |  |  |  |  |\n| 38 | Mouse (B6C3F1) 50 M, 50 F | 103 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, BW, GN, OW, HP | Death Bd wt Resp | 0.2 0.05c | 0.2 | 0.2 F | 57% mortality |\n| 38 | Mouse (B6C3F1) 50 M, 50 F | 103 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, BW, GN, OW, HP | Death Bd wt Resp | 0.2 0.05c | 0.2 | 0.2 F | Males: nasal suppurative inflammation, alveolar epithelium hyperplasia, and suppurative inflammation of the lung Females: nasal suppurative inflammation (BMCL10 for nasal suppurative inflammation in females = 0.0052 ppm)c |\n| 38 | Mouse (B6C3F1) 50 M, 50 F | 103 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, BW, GN, OW, HP | Cardio Gastro Hemat Muc/skel Hepatic Renal Dermal Endocr Immuno Neuro | 0.2 0.2 0.2 0.2 0.2 0.2 | 0.2 | 0.2 F | Males: nasal suppurative inflammation, alveolar epithelium hyperplasia, and suppurative inflammation of the lung Females: nasal suppurative inflammation (BMCL10 for nasal suppurative inflammation in females = 0.0052 ppm)c |\n\n---\n\n**Table 2-1. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation\n(ppm)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n|  |  |  |  |  | Repro | 0.01 F | 0.05 F | 0.2 F | LOAEL: Suppurative inflammation of the ovaries SLOAEL: Severe ovarian suppurative inflammation (associated with increased lethality) |\n|  |  |  |  |  |  | 0.2 M |  |  |  |\n\n<sup>a</sup>The number corresponds to entries in Figure 2-2; differences in levels of health effects and cancer effects between male and females are not indicated in \nFigure 2-2. Where such differences exist, only the levels of effect for the most sensitive sex are presented.\n\n$$\n1\\times10^{-4}\n$$\n\n<sup>b</sup>Used to derive a provisional intermediate-duration inhalation MRL of 1x10<sup>-4</sup> ppm based on a NOAEL of 0.146 ppm, which was converted into a NOAELHEC of \n0.00344 ppm and divided by an uncertainty factor of 30 (10 for human variability and 3 for animal to human extrapolation after dosimetric adjustment).\n<sup>c</sup>Used to derive a provisional chronic-duration inhalation MRL of 6x10<sup>-5</sup> ppm based on a BMCL10 of 0.052 ppm, which was converted into a BMCLHEC of \n0.0019 ppm and divided by an uncertainty factor of 30 (10 for human variability and 3 for animal to human extrapolation after dosimetric adjustment).\n\nGreen shading indicates the study selected for derivation of provisional inhalation MRLs.\n\nAST = aspartate aminotransferase; BC = blood chemistry; Bd wt or BW = body weight; BMCL = benchmark concentration lower confidence limit; BMCL10 = 95% \nlower confidence limit on the benchmark concentration (subscripts denote benchmark response: i.e., 10 = concentration associated with 10% extra risk); \nCardio = cardiovascular; CS = clinical signs; Endocr = endocrine; F = female(s); FI = food intake; Gastro = gastrointestinal; GN = gross necropsy; \nHE = hematology; HEC = human equivalent concentration; Hemato = hematological; HP = histopathology; Immuno = immunological; LC50 = median lethal \nconcentration; LE = lethality; LOAEL = lowest-observed-adverse-effect level; M = male(s); MCHC = mean corpuscular hemoglobin concentration; MCV = mean \ncorpuscular volume; MRL = Minimal Risk Level; Musc/skeletal = muscular/skeletal; Neuro = neurological; NOAEL = no-observed-adverse-effect level; NS = not \nspecified; OF = organ function; OP = ophthalmology; OW = organ weight; Repro = reproductive; Resp = respiratory; SLOAEL = serious lowest-observed-adverseeffect level; UR = urinalysis; (WB) = whole body; WI = water intake\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation**\nAcute (≤14 days)\n\n**Figure 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation Acute (≤14 days) - Death**\n\n| Category | Animal - LD50/LC50 (ppm) | Animal - NOAEL (ppm) | Animal - LOAEL (ppm) | Animal - SLOAEL (ppm) |\n| --- | --- | --- | --- | --- |\n| 1R |  |  |  | 0.45 |\n| 2R | 3.4 |  |  |  |\n| 3R | 2.6 |  |  |  |\n| 4R |  |  |  | 170 |\n| 5R | 1.6 |  |  |  |\n| 6R |  |  |  | 2.8 |\n| 7R |  |  | 1.4 |  |\n| 8R |  |  |  | 3.2 |\n| 9R |  |  |  | 2.8 |\n| 10R |  |  |  | 1.0 |\n| 11R |  |  |  | 7.0 |\n| 12R |  |  |  | 75 |\n| 13M |  |  |  | 7.5 |\n| 14M |  |  |  | 75 |\n| 15M |  |  |  | 3.2 |\n| 16M |  |  |  | 1.4 |\n| 17M |  |  |  | 1.5 |\n| 18M |  |  |  | 3.2 |\n| 19M |  |  |  | 1.0 |\n| 20H |  |  |  | 75 |\n| 21H |  |  |  | 1.4 |\n| 22H |  |  |  | 1.0 |\n| 23H |  |  |  | 1.4 |\n| 24H |  |  |  | 1.5 |\n| 25H |  |  |  | 3.2 |\n| 26H |  |  |  | 3.2 |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation**\nAcute (≤14 days)\n\n| Category | Body Weight Animal - LD50/LC50 (ppm) | Body Weight Animal - NOAEL (ppm) | Body Weight Animal - LOAEL (ppm) | Body Weight Animal - SLOAEL (ppm) | Respiratory Animal - LD50/LC50 (ppm) | Respiratory Animal - NOAEL (ppm) | Respiratory Animal - LOAEL (ppm) | Respiratory Animal - SLOAEL (ppm) | Cardiovascular Animal - LD50/LC50 (ppm) | Cardiovascular Animal - NOAEL (ppm) | Cardiovascular Animal - LOAEL (ppm) | Cardiovascular Animal - SLOAEL (ppm) | Hematological Animal - LD50/LC50 (ppm) | Hematological Animal - NOAEL (ppm) | Hematological Animal - LOAEL (ppm) | Hematological Animal - SLOAEL (ppm) |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| 1R |  | 0.12 |  | 0.5 |  | 0.12 |  | 0.5 |  | 0.5 |  |  |  | 0.12 |  | 0.5 |\n| 2R |  | 1.8 |  | 2.6 |  |  |  | 1.8 |  |  |  |  |  |  |  |  |\n| 3R |  |  |  | 1.8 |  |  |  | 1.8 |  |  |  |  |  |  |  |  |\n| 5R |  | 0.26 |  | 1.4 |  |  |  |  |  |  |  |  |  |  |  |  |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation**\nAcute (≤14 days)\n\n**Figure 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation Acute (≤14 days)**\n\n| Category | Animal - NOAEL (ppm) | Animal - LOAEL (ppm) | Animal - SLOAEL (ppm) |\n| --- | --- | --- | --- |\n| Hepatic | 0.5 |  |  |\n| Renal | 0.45 |  |  |\n| Immunological | 0.5 |  |  |\n| Neuological | 0.4 | 1.4 | 5.5 |\n| Other Noncancer | 0.12 | 0.45 | 1.7 |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation**\nIntermediate (15–364 days)\n\n**Figure 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation Intermediate (15–364 days)**\n\n| Category | Death Animal - NOAEL (ppm) | Death Animal - LOAEL (ppm) | Death Animal - SLOAEL (ppm) | Body Weight Animal - NOAEL (ppm) | Body Weight Animal - LOAEL (ppm) | Body Weight Animal - SLOAEL (ppm) | Respiratory Animal - NOAEL (ppm) | Respiratory Animal - LOAEL (ppm) | Respiratory Animal - SLOAEL (ppm) |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| 29R |  |  | 0.6 | 0.5 |  |  | 0.15 |  | 0.6 |\n| 30R |  |  | 1.0 | 0.4 |  |  | 0.15 | 0.45 | 1.0 |\n| 31R |  |  | 2.3 |  |  |  |  |  |  |\n| 32M |  |  | 0.55 |  | 0.5 |  |  | 0.5 |  |\n| 33M |  |  | 2.6 |  |  |  |  |  |  |\n| 36M |  |  | 0.4 | 0.45 |  |  | 0.15 | 0.45 |  |\n| 27K |  |  |  | 0.2 |  |  | 0.2 |  |  |\n| 28R |  |  |  | 0.2 |  |  | 0.2 |  |  |\n| 34M |  |  |  | 0.55 |  |  |  | 0.5 |  |\n| 35M |  |  |  | 0.2 |  |  |  | 0.2 |  |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation**\nIntermediate (15–364 days)\n\n**Figure 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation Intermediate (15–364 days)**\n\n| Category | Cardiovascular Animal - NOAEL (ppm) | Cardiovascular Animal - LOAEL (ppm) | Cardiovascular Animal - SLOAEL (ppm) | Gastrointestinal Animal - NOAEL (ppm) | Gastrointestinal Animal - LOAEL (ppm) | Gastrointestinal Animal - SLOAEL (ppm) | Hematological Animal - NOAEL (ppm) | Hematological Animal - LOAEL (ppm) | Hematological Animal - SLOAEL (ppm) |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| 27K | 0.22 |  |  | 0.22 |  |  | 0.22 |  |  |\n| 28R | 0.22 |  |  | 0.22 |  |  | 0.22 |  |  |\n| 29R | 0.55 |  |  | 0.55 |  |  | 0.060 | 0.15 |  |\n| 30R | 0.44 |  |  | 0.44 |  |  | 0.17 | 0.44 |  |\n| 36M | 0.44 |  |  | 0.44 |  |  | 0.17 | 0.44 |  |\n| 32M |  |  |  | 0.50 |  |  |  |  |  |\n| 35M |  |  |  | 0.22 |  |  |  |  |  |\n| 31R |  |  |  |  |  |  | 0.040 | 0.44 |  |\n| 33M |  |  |  |  |  |  |  | 0.044 |  |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation**\nIntermediate (15–364 days)\n\n**Figure 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation Intermediate (15–364 days)**\n\n| Category | Musculoskeletal Animal - NOAEL (ppm) | Musculoskeletal Animal - LOAEL (ppm) | Musculoskeletal Animal - SLOAEL (ppm) | Hepatic Animal - NOAEL (ppm) | Hepatic Animal - LOAEL (ppm) | Hepatic Animal - SLOAEL (ppm) | Renal Animal - NOAEL (ppm) | Renal Animal - LOAEL (ppm) | Renal Animal - SLOAEL (ppm) |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| 27K | 0.22 |  |  | 0.20 |  |  | 0.20 |  |  |\n| 28R | 0.20 |  |  | 0.22 |  |  | 0.20 |  |  |\n| 29R | 0.55 |  |  | 0.60 |  |  | 0.55 |  |  |\n| 30R | 0.44 |  |  | 0.40 |  |  | 0.40 |  |  |\n| 36M | 0.44 |  |  | 0.44 |  |  | 0.44 |  |  |\n| 31R |  |  |  | 0.44 |  |  | 2.2 |  |  |\n| 31R |  |  |  |  |  | 2.4 |  |  |  |\n| 32M |  |  |  | 0.55 |  |  | 0.60 |  |  |\n| 33M |  |  |  | 2.4 |  |  | 2.4 |  |  |\n| 35M |  |  |  | 0.20 |  |  | 0.20 |  |  |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation**\nIntermediate (15–364 days)\n\n**Figure 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation Intermediate (15–364 days)**\n\n| Category | Animal - NOAEL (ppm) | Animal - LOAEL (ppm) | Animal - SLOAEL (ppm) |\n| --- | --- | --- | --- |\n| Dermal 29R | 0.55 |  |  |\n| Ocular 27K | 0.20 |  |  |\n| Ocular 28R | 0.20 |  |  |\n| Ocular 29R | 0.55 |  |  |\n| Endocrine 27K | 0.20 |  |  |\n| Endocrine 28R | 0.20 |  |  |\n| Endocrine 29R | 0.60 |  |  |\n| Endocrine 30R | 0.40 |  |  |\n| Endocrine 32M | 0.50 |  |  |\n| Endocrine 36M | 0.40 |  |  |\n| Immunological 27K | 0.20 |  |  |\n| Immunological 28R | 0.20 |  |  |\n| Immunological 29R | 0.60 |  |  |\n| Immunological 30R | 0.40 |  |  |\n| Immunological 32M | 0.55 |  |  |\n| Immunological 35M | 0.20 |  |  |\n| Immunological 36M | 0.40 |  |  |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation**\nIntermediate (15–364 days)\n\n**Figure 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation Intermediate (15–364 days)**\n\n| Category | Neuropsychological Animal - NOAEL (ppm) | Neuropsychological Animal - LOAEL (ppm) | Neuropsychological Animal - SLOAEL (ppm) | Reproductive Animal - NOAEL (ppm) | Reproductive Animal - LOAEL (ppm) | Reproductive Animal - SLOAEL (ppm) | Other Noncancer Animal - NOAEL (ppm) | Other Noncancer Animal - LOAEL (ppm) | Other Noncancer Animal - SLOAEL (ppm) |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| 27K | 0.22 |  |  | 0.22 |  |  | 0.22 |  |  |\n| 28R | 0.22 |  |  | 0.22 |  |  | 0.22 |  |  |\n| 29R | 0.55 |  |  | 0.55 |  |  | 0.55 |  |  |\n| 30R | 0.44 |  |  | 0.44 |  |  |  |  |  |\n| 35M | 0.22 |  |  | 0.22 |  |  |  |  |  |\n| 36M | 0.44 |  |  | 0.44 |  |  |  |  |  |\n| 32M |  |  |  | 0.55 |  |  |  |  |  |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation**\nChronic (≥365 days)\n\n**Figure 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation Chronic (≥365 days)**\n\n| Category | R-Rat Animal - NOAEL (ppm) | R-Rat Animal - LOAEL (ppm) | R-Rat Animal - SLOAEL (ppm) | M-Mouse Animal - NOAEL (ppm) | M-Mouse Animal - LOAEL (ppm) | M-Mouse Animal - SLOAEL (ppm) | M-Mouse MRL for effect other than cancer (ppm) |\n| --- | --- | --- | --- | --- | --- | --- | --- |\n| Death |  |  |  |  |  | 0.22 |  |\n| Body Weight |  |  |  | 0.22 |  |  |  |\n| Respiratory | 0.22 |  |  |  | 0.055 | 0.22 | 0.006 |\n| Cardiovascular | 0.22 |  |  | 0.22 |  |  |  |\n| Gastrointestinal |  |  |  | 0.22 |  |  |  |\n| unlabelled 1 |  |  |  | 0.22 |  |  |  |\n\n---\n\n2.  HEALTH EFFECTS\n\n**Figure 2-2.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation**\nChronic (≥365 days)\n\n| Category | R-Rat (ppm) | M-Mouse (ppm) |\n| --- | --- | --- |\n| Hematological | 0.22 | 0.22 |\n| Musculoskeletal | 0.22 | 0.22 |\n| Hepatic | 0.22 | 0.22 |\n| Renal | 0.22 | 0.22 |\n| Dermal | 0.22 | 0.22 |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation**\nChronic (≥365 days)\n\n**Figure 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation Chronic (≥365 days)**\n\n| Category | Endocrine Animal - NOAEL (ppm) | Endocrine Animal - LOAEL (ppm) | Endocrine Animal - SLOAEL (ppm) | Immunological Animal - NOAEL (ppm) | Immunological Animal - LOAEL (ppm) | Immunological Animal - SLOAEL (ppm) | Neuological Animal - NOAEL (ppm) | Neuological Animal - LOAEL (ppm) | Neuological Animal - SLOAEL (ppm) | Reproductive Animal - NOAEL (ppm) | Reproductive Animal - LOAEL (ppm) | Reproductive Animal - SLOAEL (ppm) |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| 37R | 0.23 |  |  | 0.23 |  |  | 0.23 |  |  | 0.23 |  |  |\n| 38M | 0.23 |  |  | 0.23 |  |  | 0.23 |  |  | 0.011 | 0.055 | 0.23 |\n\n---\n\n**Table 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Oral\n(mg/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| ACUTE EXPOSURE |  |  |  |  |  |  |  |  |  |\n| Gardner 1986a |  |  |  |  |  |  |  |  |  |\n| 1 | Rat (CFY) 5 M, 5 F | Once (GO) | 1,260, 1,600, 2,000 | LE, CS, BW, GN | Death |  |  | 1,300 F 1,500 M | LD50 LD50 |\n| 1 | Rat (CFY) 5 M, 5 F | Once (GO) | 1,260, 1,600, 2,000 | LE, CS, BW, GN | Resp Gastro Neuro |  | 1,260 | 1,260 | Decreased respiratory rate Diarrhea Abnormal gait, lethargy |\n| OxyChem 1972 |  |  |  |  |  |  |  |  |  |\n| 2 | Rat (Spartan) 25 M, 25 F | Once (GO) | 315, 500, 794, 1,250, 1,984 | LE | Death |  |  | 530 F 630 M | LD50 LD50 |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 3 | Rat 9–11 M | Once (GO) | 280, 340, 420, 520, 620, 940, 1,400 | LE, CS, GN | Death |  |  | 505 | LD50 |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 4 | Rat 10 F | Once (GO) | 280, 940, 1,400, 2,100 | LE, CS, GN | Death |  |  | 940 | 9/10 died |\n| Chernoff and Kavlock 1982, 1983; Gray and Kavlock 1984; Gray et al. 1986 |  |  |  |  |  |  |  |  |  |\n| 5 | Mouse (CD-1) 16 F | 5 days GDs 8–12 (GO) | 0, 45 | BW, DX | Bd wt Develop | 45 |  |  |  |\n\n$$\n\\mathsf{L}\\mathsf{D}_{50}\n$$\n\nOffspring evaluated through PND 250 for postnatal viability, growth, locomotor activity, female sexual development, and reproductive function\n\n---\n\n**Table 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Oral\n(mg/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Dean 1977 |  |  |  |  |  |  |  |  |  |\n| 6 | Mouse (CD-1) 5 M, 5 F | Once (GO) | 21.5, 46.4, 100, 215, 464, 1,000, 2,150 | LE, CS, BW | Death Resp Gastro | 1,000 215 F 464 M 464 | 464 F 1,000 M 1,000 | 679 2,150 | LD50 Decreased respiratory rate Diarrhea Diarrhea Decreased limb tone in animals that died LOAEL: Hypoactivity SLOAEL: Ataxia |\n| 6 | Mouse (CD-1) 5 M, 5 F | Once (GO) | 21.5, 46.4, 100, 215, 464, 1,000, 2,150 | LE, CS, BW | Musc/skel | 215 | 464 | 1,000 | LOAEL: Hypoactivity SLOAEL: Ataxia |\n| Murray et al. 1980 |  |  |  |  |  |  |  |  |  |\n| 7 | Mouse (CF-1) NS F | 10 days GDs 6–15 (GO) | 0, 5, 25, 75 | LE, CS, BW, FI, WI, RX, DX | Bd wt Develop Other noncancer | 75 75 75 |  |  |  |\n| Murray et al. 1980 |  |  |  |  |  |  |  |  |  |\n| 8 | Mouse (CF-1) 5 F | 10 days GDs 6–15 (GO) | 0, 25, 75, 250, 500 | LE, CS, BW | Death |  |  | 250 | 3/5 dams died |\n| Murray et al. 1980 |  |  |  |  |  |  |  |  |  |\n| 9 | Rabbit (New Zealand) NS F | 13 days GDs 6–18 (GO) | 0, 5, 25, 75 | LE, CS, BW, RX, DX | Death Develop | 25 | 75 | 75 | Unspecified increased maternal death during pregnancy Increased proportion of fetuses with 13 ribs |\n| Murray et al. 1980 |  |  |  |  |  |  |  |  |  |\n| 10 | Rabbit (New Zealand) 5 F | 13 days GDs 6–18 (GO) | 0, 25, 75, 250, 500 | LE, CS, BW | Death |  |  | 250 | 4/5 does die |\n\n---\n\n**Table 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Oral\n(mg/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 11 | Rabbit 3 F | Once (GO) | 180, 280, 420, 620, 940 | LE, CS, GN | Death |  |  | 940 | 3/3 died |\n| INTERMEDIATE EXPOSURE |  |  |  |  |  |  |  |  |  |\n| Abdo et al. 1984; Velsicol 1981b |  |  |  |  |  |  |  |  |  |\n| 12 | Rat (Fischer-344) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 10, 19, 38, 75, 150 | LE, BW, GN, OW, HP | Death Bd wt | 38 F | 75 F | 150 M | 60% treatment-related mortality 15% decreased terminal body weight LOAEL: 13% decreased terminal body weight SLOAEL: 30% decreased terminal body weight Forestomach epithelial hyperplasia and focal inflammation (BMDL10 for combined incidence of forestomach lesions = 7.7 mg/kg/day)b |\n| 12 | Rat (Fischer-344) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 10, 19, 38, 75, 150 | LE, BW, GN, OW, HP | Resp Cardio Gastro | 150 150 19b | 38 |  |  |\n| 12 | Rat (Fischer-344) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 10, 19, 38, 75, 150 | LE, BW, GN, OW, HP | Hemato Musc/skel | 150 150 150 Renal | 38 |  | Toxic nephrosis |\n| 12 | Rat (Fischer-344) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 10, 19, 38, 75, 150 | LE, BW, GN, OW, HP | Dermal | 150 |  |  |  |\n| 12 | Rat (Fischer-344) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 10, 19, 38, 75, 150 | LE, BW, GN, OW, HP | Endocr | 150 |  |  |  |\n| 12 | Rat (Fischer-344) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 10, 19, 38, 75, 150 | LE, BW, GN, OW, HP | Immuno | 150 |  |  |  |\n| 12 | Rat (Fischer-344) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 10, 19, 38, 75, 150 | LE, BW, GN, OW, HP | Neuro | 150 |  |  |  |\n| 12 | Rat (Fischer-344) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 10, 19, 38, 75, 150 | LE, BW, GN, OW, HP | Repro | 150 |  |  |  |\n\n---\n\n**Table 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Oral\n(mg/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Abdo et al. 1984; Velsicol 1981a |  |  |  |  |  |  |  |  |  |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP | Death |  |  | 300 | 10/10 males died, 3/10 females died 11% decreased terminal body weight 13% decreased terminal body weight |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP | Bd wt | 75 M | 150 F | 300 | 10/10 males died, 3/10 females died 11% decreased terminal body weight 13% decreased terminal body weight |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP |  | 150 F | 300 F | 300 | 10/10 males died, 3/10 females died 11% decreased terminal body weight 13% decreased terminal body weight |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP | Resp | 300 |  |  |  |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP | Cardio | 300 |  |  |  |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP | Gastro | 38 | 75 |  | Focal inflammation and epithelial hyperplasia of the forestomach |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP | Hemato | 300 |  |  |  |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP | Musc/skel | 300 |  |  |  |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP | Hepatic | 300 |  |  |  |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP | Renal | 38 F | 75 F |  | Toxic nephrosis |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP |  | 150 M | 300 M |  | Acute tubular necrosis |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP | Dermal | 300 |  |  |  |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP | Endocr | 300 |  |  |  |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP | Immuno | 300 |  |  |  |\n\n---\n\n**Table 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Oral\n(mg/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n|  |  |  |  |  | Neuro Repro | 300 300 |  |  |  |\n\n<sup>a</sup>The number corresponds to entries in Figure 2-3; differences in levels of health effects between male and females are not indicated in Figure 2-3.  Where such \ndifferences exist, only the levels of effect for the most sensitive sex are presented.\n\n<sup>b</sup>Used to derive a provisional intermediate-duration oral MRL of 0.06 mg/kg/day based on a BMDL10 of 7.7 mg/kg/day, which was adjusted to continuous duration \nexposure to a BMDLADJ of 5.5 mg/kg/day and divided by an uncertainty factor of 100 (10 for human variability and 10 for animal to human extrapolation).  See \nAppendix A for more detailed information regarding the MRL.\n\nGreen shading indicates the study selected for derivation of the provisional oral MRL.\n\nADJ = adjusted; Bd wt or BW = body weight; BMDL = benchmark dose lower confidence limit; BMDL10 = 95% benchmark dose lower confidence limit (subscript \ndenotes benchmark response: i.e., 10 = dose associated with 10% extra risk); Cardio = cardiovascular; CS = clinical signs; Develop = developmental; \nDX = developmental toxicity; Endocr = endocrine; F = female(s); FI = food intake; Gastro = gastrointestinal; GD = gestation day; GN = gross necropsy; \n(GO) = gavage in oil; Hemato = hematological; HP = histopathology; Immuno = immunological; LD50 = median lethal dose; LE = lethality; LOAEL = lowestobserved-adverse-effect level; M = male(s); MRL = Minimal Risk Level; Musc/skeletal = muscular/skeletal; Neuro = neurological; NOAEL = no-observed-adverseeffect level; NS = not specified; OW = organ weight; PND = postnatal day; Repro = reproductive; Resp = respiratory; RX = reproductive function; \nSLOAEL = serious lowest-observed-adverse-effect level; WI = water intake\n\n---\n\n**Figure 2-3.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Oral**\nAcute (≤14 days)\n\n| Category | Animal - LD50/LC50 (mg/kg/day) | Animal - NOAEL (mg/kg/day) | Animal - LOAEL (mg/kg/day) | Animal - SLOAEL (mg/kg/day) |\n| --- | --- | --- | --- | --- |\n| 1R | 1300 |  |  |  |\n| 2R | 530 |  |  |  |\n| 3R | 500 |  |  |  |\n| 4R |  |  |  | 950 |\n| 6M | 660 |  |  |  |\n| 8M |  |  |  | 300 |\n| 9H |  |  |  | 75 |\n| 10H |  |  |  | 280 |\n| 11H |  |  |  | 950 |\n| 5M |  | 50 |  |  |\n| 7M |  | 80 |  |  |\n| 1R |  |  |  | 1200 |\n| 6M |  | 1000 |  | 2400 |\n\n---\n\n**Figure 2-3.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Oral**\nAcute (≤14 days)\n\n| Category | R-Rat (mg/kg/day) | M-Mouse (mg/kg/day) | H-Rabbit (mg/kg/day) |\n| --- | --- | --- | --- |\n| Animal - LD50/LC50 |  |  |  |\n| Animal - NOAEL |  | 130 |  |\n| Animal - LOAEL |  |  | 1300 |\n| Animal - SLOAEL |  |  | 1000 |\n\n---\n\n**Figure 2-3.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Oral**\nIntermediate (15–364 days)\n\n| Category | R-Rat Animal - NOAEL (mg/kg/day) | R-Rat Animal - LOAEL (mg/kg/day) | R-Rat Animal - SLOAEL (mg/kg/day) | M-Mouse Animal - NOAEL (mg/kg/day) | M-Mouse Animal - LOAEL (mg/kg/day) | M-Mouse Animal - SLOAEL (mg/kg/day) |\n| --- | --- | --- | --- | --- | --- | --- |\n| Death |  |  |  |  |  |  |\n| 12R |  |  | 150 |  |  |  |\n| 13M |  |  | 330 |  |  |  |\n| Body Weight |  |  |  |  |  |  |\n| 12R | 20 |  |  |  |  |  |\n| 12R |  | 40 |  |  |  |  |\n| 12R |  |  | 75 |  |  |  |\n| 13M |  | 80 |  |  |  |  |\n| 13M |  |  | 150 |  |  |  |\n| 13M |  |  | 160 |  |  |  |\n| Respiratory |  |  |  |  |  |  |\n| 12R | 160 |  |  |  |  |  |\n| 13M | 330 |  |  |  |  |  |\n| Cardiovascular |  |  |  |  |  |  |\n| 12R | 150 |  |  |  |  |  |\n| 13M | 330 |  |  |  |  |  |\n| Gastrointestinal |  |  |  |  |  |  |\n| 12R BMDL | 8.0 |  |  |  |  |  |\n| 12R | 20 |  |  |  |  |  |\n| 12R |  | 44 |  |  |  |  |\n| 13M | 40 |  |  |  |  |  |\n| 13M |  |  | 80 |  |  |  |\n\n---\n\n**Figure 2-3.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Oral**\nIntermediate (15–364 days)\n\n| Category | R-Rat Animal - NOAEL (mg/kg/day) | R-Rat Animal - LOAEL (mg/kg/day) | R-Rat Animal - SLOAEL (mg/kg/day) | M-Mouse Animal - NOAEL (mg/kg/day) | M-Mouse Animal - LOAEL (mg/kg/day) | M-Mouse Animal - SLOAEL (mg/kg/day) |\n| --- | --- | --- | --- | --- | --- | --- |\n| Hematological | 150 |  |  | 330 |  |  |\n| Musculoskeletal |  |  |  | 150 |  |  |\n| Hepatic |  |  |  | 150 |  |  |\n| Renal | 20 | 44 |  | 36 |  | 80 |\n| Dermal |  |  |  | 150 |  | 330 |\n\n---\n\n**Figure 2-3.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Oral**\nIntermediate (15–364 days)\n\n**Figure 2-3. Levels of Significant Exposure to Hexachlorocyclopentadiene – Oral Intermediate (15–364 days)**\n\n| Category | Animal - NOAEL (mg/kg/day) | Animal - LOAEL (mg/kg/day) | Animal - SLOAEL (mg/kg/day) |\n| --- | --- | --- | --- |\n| Endocrine 12R | 160 |  |  |\n| Endocrine 13M | 330 |  |  |\n| Immunological 12R | 160 |  |  |\n| Immunological 13M | 330 |  |  |\n| Neuological 12R | 160 |  |  |\n| Neuological 13M | 330 |  |  |\n| Reproductive 12R | 160 |  |  |\n| Reproductive 13M | 330 |  |  |\n\n---\n\n**Table 2-3. Levels of Significant Exposure to Hexachlorocyclopentadiene – Dermal**\n\n| Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| ACUTE EXPOSURE |  |  |  |  |  |  |  |  |\n| Kominsky et al. 1980 |  |  |  |  |  |  |  |  |\n| Human 154 M, 23 F | 3–15 days | ≤0.97 ppm | CS, BC | Dermal Ocular |  | 0.97 0.97 |  | Skin irritation Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Monkey 1 NS | Once | 0.001, 0.01, 0.1, 1, 10% (0.01 mL); 20, 40, 60, 90% (0.05 mL) | CS | Dermal | 10 | 20 |  | Skin discoloration and swelling |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Monkey 1 NS | 3 days Once/day | 10% | CS | Dermal |  |  | 10 | Skin irritation, necrosis, hemorrhaging |\n| Alexander et al. 1980a; Rand et al. 1982a |  |  |  |  |  |  |  |  |\n| Rat (Sprague-Dawley) 10 M, 10 F | 1–2 weeks 5 days/week 6 hours/day | 0, 0.022, 0.11, 0.5 ppm | CS | Ocular | 0.11 | 0.5 |  | Dark red eyes |\n| Gardner 1986b |  |  |  |  |  |  |  |  |\n| Rat (CFY) 5 M, 5 F | 24 hours | 1,600, 2,000, 3,200 mg/kg | LE, CS, BW, GN | Death |  |  | 3,100 F 2,600 M | LD50 LD50 |\n| Rat (CFY) 5 M, 5 F | 24 hours | 1,600, 2,000, 3,200 mg/kg | LE, CS, BW, GN | Dermal |  | 1,600 |  | Moderate to severe edema |\n| Jackson and Hardy 1986 |  |  |  |  |  |  |  |  |\n| Rat (Wistar) 5 M, 5 F | 1 hour | 0, 1.67, 2.38, 3.53, 6.25, 8.30 ppm | CS | Ocular |  | 1.67 |  | Total or partial closing of the eyes |\n| Jackson and Hardy 1987 |  |  |  |  |  |  |  |  |\n| Rat (Wistar) 5 M, 5 F | 4 hours | 0, 1.68, 1.83, 3.31, 3.47 ppm | CS | Ocular |  | 1.68 |  | Total or partial closing of the eyes |\n| Rand et al. 1982a |  |  |  |  |  |  |  |  |\n| Rat (Sprague-Dawley) 10 M, 10 F | 4 hours | 0.28, 1.4, 2.5, 3.1, 3.3, 3.4, 4, 5.8 ppm | CS | Ocular | 4 | 5.8 |  | Lacrimation |\n\n$$\n\\mathsf{L}\\mathsf{D}_{50}\n$$\n\n$$\n\\mathsf{L}\\mathsf{D}_{50}\n$$\n\n---\n\n**Table 2-3. Levels of Significant Exposure to Hexachlorocyclopentadiene – Dermal**\n\n| Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rat 4 NS | 5 days 7 hours/day | 0.33, 1, 1.6 ppm | CS | Ocular |  | 0.33 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rat 4 NS | 3 days 7 hours/day | 1.4 ppm | CS | Ocular |  | 1.4 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rat 4 NS | 4 hours | 73.6 ppm | CS | Ocular |  | 73.6 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rat 4 NS | 7 hours | 1.5, 3.2, 6.7 ppm | CS | Ocular |  | 1.5 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rat 4 NS | 2.6–3.6 hours | 1.4, 3.1, 7.1, 11.1, 12.7, 46.5, 56.9, 70.4 ppm | CS | Ocular |  | 1.4 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rat 3–4 NS | 0.25–1.25 hours | 1.4, 1.5, 3.1, 7.2, 13.0, 13.8, 19.4, 20.0, 20.2, 69.1, 69.2 ppm | CS | Ocular |  | 1.4 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rat 4 NS | 2 days 7 hours/day | 3.2 ppm | CS | Ocular |  | 3.2 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Mouse 4–5 NS | 0.25–1.25 hours | 1.4, 1.5, 3.1, 7.2, 13.0, 13.8, 19.4, 20.0, 20.2, 69.1, 69.2 ppm | CS | Ocular |  | 1.4 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Mouse 5 NS | 7 hours | 1.5, 3.2, 6.7 ppm | CS | Ocular |  | 1.5 |  | Eye irritation |\n\n---\n\n**Table 2-3. Levels of Significant Exposure to Hexachlorocyclopentadiene – Dermal**\n\n| Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Mouse 5 NS | 2.6–3.6 hours | 1.4, 3.1, 7.1, 12.4, 12.7, 46.5, 56.9, 70.4 ppm | CS | Ocular |  | 1.4 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Mouse 5 NS | 4 hours | 73.6 ppm | CS | Ocular |  | 73.6 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Mouse 5 NS | 2 days 7 hours/day | 3.2 ppm | CS | Ocular |  | 3.2 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Mouse 5 NS | 3 days 7 hours/day | 1.4 ppm | CS | Ocular |  | 1.4 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Mouse 5 NS | 5 days 7 hours/day | 0.33, 1.0, 1.6 ppm | CS | Ocular |  | 0.33 |  | Eye irritation |\n| OxyChem 1972 |  |  |  |  |  |  |  |  |\n| Rabbit (New Zealand) 3 M, 3 F | 4 hours | 0.5 mL | LE, CS | Death Dermal Neuro | 0.5 | 0.5 | 0.5 | 3/6 died Moderate to severe edema Ataxia and hypoactivity |\n| OxyChem 1972 |  |  |  |  |  |  |  |  |\n| Rabbit (New Zealand) 5 NS | 5 minutes | 0.1 mL | LE, CS | Death |  | 0.1 | 5/5 died within 9 days |  |\n| OxyChem 1972 |  |  |  |  |  |  |  |  |\n| Rabbit (New Zealand) 2 M, 2 F | Once | 200, 2,000 mg/kg | LE, CS, BW | Death |  | 200 M 2,000 F | 2/2 died within 14 days 2/2 died within 24 hours Dermal irritation and discoloration Hypoactivity |  |\n|  |  |  |  | Dermal Neuro | 200 200 M |  |  |  |\n\n---\n\n**Table 2-3. Levels of Significant Exposure to Hexachlorocyclopentadiene – Dermal**\n\n| Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| OxyChem 1972 |  |  |  |  |  |  |  |  |\n| Rabbit (New Zealand) 3 NS | 24 hours | 0.1 mL | LE, CS | Death Ocular |  |  | 0.1 0.1 | 3/3 died within 6 days Severe eye irritation and corrosion |\n| OxyChem 1992 |  |  |  |  |  |  |  |  |\n| Rabbit (New Zealand) 12 NS | 24 hours | 200 mg/kg | LE, CS | Death Dermal |  |  | 200 200 | 8/12 died Eschar formation |\n| OxyChem 1992 |  |  |  |  |  |  |  |  |\n| Rabbit (New Zealand) 6 NS | 4 hours | 0.5 mL | LE, CS | Dermal |  |  | 0.5 | Erythema, edema, necrosis |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rabbit 1–3 F | 24 hours | 430, 610, 1,020, 2,130, 6,130 mg/kg | LE, CS, GN | Death Dermal |  | 430 | 1020 | 2/3 died Skin irritation, discoloration, subcutaneous edema, acanthosis, epiulation, hyperkeratosis, chronic inflammation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rabbit 3 NS | 4 hours | 73.6 ppm | CS | Ocular |  | 73.6 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rabbit 3 NS | 2.6–3.6 hours | 1.4, 3.1, 7.1, 12.4, 12.7, 46.5, 56.9, 70.4 ppm | CS | Ocular |  | 1.4 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rabbit 3 NS | 7 hours | 1.5, 3.2, 6.7 ppm | CS | Ocular |  | 1.5 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rabbit 3 NS | 0.25–1.25 hours | 1.4, 1.5, 3.1, 7.2, 13.0, 13.8, 19.4, 20.0, 20.2, 69.1, 69.2 ppm | CS | Ocular |  | 1.4 |  | Eye irritation |\n\n---\n\n**Table 2-3. Levels of Significant Exposure to Hexachlorocyclopentadiene – Dermal**\n\n| Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rabbit 3 NS | 2 days 7 hours/day | 3.2 ppm | CS | Ocular |  | 3.2 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rabbit 3 NS | 3 days 7 hours/day | 1.4 ppm | CS | Ocular |  | 1.4 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rabbit 3 NS | 5 days 7 hours/day | 1, 1.6 ppm | CS | Ocular |  | 1 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Guinea pig 2 NS | Once | 0.01, 0.1, 1, 40, 60, 90% | CS | Dermal | 1 | 40 |  | Skin discoloration and irritation |\n| INTERMEDIATE EXPOSURE |  |  |  |  |  |  |  |  |\n| Alexander et al. 1980b; Rand et al. 1982a |  |  |  |  |  |  |  |  |\n| Monkey (Cynomolgus) 6 M, 6 F | 14 weeks 5 days/week 6 hours/day | 0, 0.01, 0.05, 0.2 ppm | CS | Ocular | 0.2 |  |  |  |\n| Alexander et al. 1980b; Rand et al. 1982a |  |  |  |  |  |  |  |  |\n| Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day | 0, 0.01, 0.05, 0.2 ppm | CS | Ocular | 0.01 | 0.05 |  | Dark red eyes |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rat 4 NS | 30 weeks 5 days/week 7 hours/day | 0.15 ppm | CS | Ocular | 0.15 |  |  |  |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rat 4 NS | 6 weeks 5 days/week 7 hours/day | 0.34 ppm | CS | Ocular |  | 0.34 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Mouse 5 NS | 30 weeks 5 days/week 7 hours/day | 0.15 ppm | CS | Ocular | 0.15 |  |  |  |\n\n***DRAFT FOR PUBLIC COMMENT***\n\n---\n\n**Table 2-3. Levels of Significant Exposure to Hexachlorocyclopentadiene – Dermal**\n\n| Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Mouse 5 NS | 6 weeks 5 days/week 7 hours/day (WB) | 0.34 ppm | CS | Ocular |  | 0.34 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rabbit 6 NS | 6 weeks 5 days/week 7 hours/day | 0.34 ppm | CS | Ocular |  | 0.34 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rabbit 2 NS | 30 weeks 5 days/week 7 hours/day | 0.15 ppm | CS | Ocular | 0.15 |  |  |  |\n\nBC = serum (blood) chemistry; BW = body weight; CS = clinical signs; F = female(s); GN = gross necropsy; LD50 = median lethal dose; LE = lethality; \nLOAEL = lowest-observed-adverse-effect level; M = male(s); Neuro = neurological; NOAEL = no-observed-adverse-effect level; NS = not specified; (WB) = wholebody exposure\n\n---\n\n###### 2.2 DEATH\n\nNo studies were located regarding mortality in humans after exposure to HCCPD.\n\nHCCPD induced death in experimental animals via the inhalation, oral, and dermal routes.  The lethality \nof HCCPD following inhalation exposures has been evaluated for acute-, intermediate-, and chronicduration studies.  Acute-duration inhalation exposures to HCCPD at 1.0–73.6 ppm were lethal to rats, \nmice, guinea pigs, and rabbits in a concentration- and exposure duration-related manner (Treon et al. \n1955).  For example, the concentrations that produced 50% fatalities in mice after 1-, 3.5-, and 7-hour \nexposures were 7.2, <3.1, and <1.5 ppm, respectively.  Species-specific differences were observed in the \nmortality data; the concentrations that produced 50% fatalities after 3.5-hour exposures were 7.1 ppm for \nguinea pigs, 3.1 ppm for rats, <3.1 ppm for mice, and <1.4 ppm for rabbits.  All 10 rats exposed to \n176 ppm HCCPD for 4 hours died within 48 hours of the exposure period (OxyChem 1972).  The 1- and \n4-hour inhalation LC50 values for rats are 3.69 ppm (Jackson and Hardy 1986) and 2.9 ppm (Jackson and \nHardy 1987), respectively.  Male rats appear to be more susceptible to HCCPD lethality than female rats; \nthe sex-specific 4-hour inhalation median lethal concentration (LC50) values are 1.6 ppm for males and \n3.5 ppm for females (Rand et al. 1982a).  With 2-week exposures to 0.5 ppm HCCPD, one rat of each sex \ndied, and nine male rats and one female rat were sacrificed in moribund condition by the end of the \nexposure period.  When the exposure duration was reduced to 5 days, three of five males and none of five\nfemales died at 0.5 ppm.  All animals exposed to ≤0.11 ppm survived until the scheduled sacrifice\n(Alexander et al. 1980a; Rand et al. 1982a).\n\n$$\n\\mathrm{LC}_{50}\n$$\n\n$$\n\\left(LC_{50}\\right)\n$$\n\nIn 13-week studies, all rats and mice exposed to ≥0.941 ppm HCCPD died during the exposure periods \n(NTP 1994).  As was observed after acute-duration inhalation exposures, mice appeared to be more \nsensitive to HCCPD-induced lethality; all mice exposed to 2.142 ppm died during the first week while \nrats exposed to 2.065 ppm survived for up to 3 weeks.  Additionally, no rat mortalities were observed at \n≤0.385 ppm, while 5 of 10 male mice died at 0.389 ppm.  NTP (1994) hypothesized that the sensitivity of \nmice to inhalation exposure was the result of HCCPD-induced inflammation of the breathing passages \nand the narrower diameter of the mouse air passages.  No treatment-related deaths were reported for rats \nor monkeys exposed to ≤0.2 ppm for 14 weeks (Alexander et al. 1980b; Rand et al. 1982a) and overall \nsurvival was not statistically significantly affected by HCCPD treatment in male mice exposed to 0.2 ppm \nfor 33 weeks or 0.5 ppm for 26 weeks (NTP 1994).  Although overall survival of male rats was not \naffected after exposure to 0.5 ppm for 42 weeks, survival in this group decreased 14% 3 weeks after \nexposure cessation (NTP 1994).  In a 30-week study, 22% of male rats exposed to 0.56 ppm died during\n\n$$\n\\leq0.385ppm\n$$ the exposure period (Clark 1981).  No mortality attributed to HCCPD was observed in rats exposed to \n0.06 or 0.14 ppm.\n\nSurvival of male and female rats and male mice chronically exposed to 0.01–0.2 ppm HCCPD for 2 years \nwas similar to controls.  Decreased survival was observed for female mice exposed to 0.2 ppm, but not at \nlower concentrations (NTP 1994).  Ovarian inflammation, possibly resulting from an infection, appeared \nto be the cause of premature deaths in female mice exposed to 0.2 ppm HCCPD.\n\nThe lethality of HCCPD in laboratory animals has been evaluated for acute- and intermediate-duration \noral exposures.  The oral median lethal dose (LD50) values were 505 mg/kg in male rats of an unspecified \nstrain (Treon et al. 1955), 630 and 530 mg/kg in male and female Spartan rats, respectively (OxyChem\n1972), and 1,500 and 1,300 mg/kg in male and female CFY rats, respectively (Gardner 1986a).  An oral\ndose of 940 mg/kg was lethal to ≥90% of the male and female rats (Treon et al. 1955).  Acute-duration \noral lethality data for species other than rats are more limited.  The oral LD50 value for male and female \nmice is 679 mg/kg (Dean 1977).  In rabbits, doses of 420, 620, and 940 mg/kg killed 0/3, 1/3, and \n3/3 animals, respectively (Treon et al. 1955).  In pregnant animals, several rabbits (exact number not \nidentified) did not survive 13 days of treatment with 75 mg/kg/day HCCPD on gestational days (GDs) 6–\n18 (Murray et al. 1980).  With intermediate-duration oral exposure, rats appeared to be more sensitive to \nHCCPD lethality than mice, a reverse of the sensitivity observed for inhalation exposures.  There were no \nmouse deaths following 13-week exposures to ≤150 mg/kg/day, but 6 of 10 male rat deaths at \n150 mg/kg/day were attributed to HCCPD treatment following 13 weeks of exposure (Abdo et al. 1984: \nVelsicol 1981a, 1981b).  All 10 male mice and 3 of 10 female mice died during the first 2 weeks of \nexposure to 300 mg/kg/day (Abdo et al. 1984; Velsicol 1981a).\n\n$$\n\\left(\\mathrm{LD}_{50}\\right)\n$$\n\n$$\n\\mathrm{LD}_{50}\n$$\n\n$$\n\\leqq150\n$$\n\nFor the dermal route, lethality of HCCPD in laboratory animals has only been evaluated for acuteduration exposures.  In rabbits administered topical applications of 200 mg/kg for 24 hours, deaths were \nreported in 2/2 males and 0/2 females (OxyChem 1972) and 8/12 rabbits of unspecified sex (OxyChem \n1992).  Dermal exposure to 2,000 mg/kg resulted in 100% mortality in male and female rabbits within \n24 hours (OxyChem 1972).  At lower doses, single dermal doses applied for 24 hours caused mortality in \n0/3, 1/3, and 2/3 rabbits at 430, 610, and 1,020 mg/kg, respectively (Treon et al. 1955).  In the multi-dose \nstudy by Treon et al. (1955), survival time was inversely proportional to the dose; rabbits survived 72, \n24–48, 20, and 17 hours after dermal dosing with 610, 1,020, 2,130, and 6,130 mg/kg, respectively.  None \nof the animals died with a dermal application of 430 mg/kg, although one rabbit was in poor condition \nand likely would have died had it not been sacrificed at 21 days.  In rats, the dermal LD50 values were\n\n$$\n\\mathrm{LD}_{50}\n$$\n\n---\n\n2,600 mg/kg in males and 3,100 mg/kg in females (Gardner 1986b).  These results suggest that rabbits are \nmore sensitive to HCCPD toxicity via the dermal route relative to rats.\n\nWhen 0.1 mL of HCCPD was instilled into the conjunctival sac of five rabbits for 5 minutes and then \nrinsed with water, the quantity of material absorbed was lethal to all the animals within 9 days (OxyChem\n1972).  When ocular rinsing was delayed until 24 hours post-instillation, all three rabbits administered\n0.1 mL of HCCPD died within 6 days.\n\n###### 2.3 BODY WEIGHT\n\nNo reports of body weight effects in humans after exposure to HCCPD were found.  The available data in \nlaboratory animals indicate that HCCPD produces body weight effects at sufficiently high inhalation and \noral exposure levels; no body weight data are available via the dermal route. In several of these studies, \nbody weight changes were associated with decreased food and/or water intake (see Section 2.18, Other \nNoncancer, for additional details).\n\nBody weight effects resulting from inhalation exposures to HCCPD have been assessed in acute-, \nintermediate-, and chronic-duration studies.  Inhalation exposures to sufficient HCCPD concentrations \nover acute and intermediate periods decrease body weights and/or suppress body weight gains.  A single \n1-hour exposure to HCCPD resulted in decreased body weights in rats during the 3-week post-exposure \nobservation period at concentrations ≥2.38 ppm; when animals that died prematurely and those sacrificed \nat the end of the observation period are combined, body weight decreases compared to control were 41% \nin males and 26% in females (Jackson and Hardy 1986).  A 4-hour exposure resulted in >20% decreases \nin body weight in male and female rats at ≥1.68 and 1.83 ppm, respectively, during the 4-week \nobservation period (Jackson and Hardy 1987).  In both studies by Jackson and Hardy (1986, 1987), body \nweight effects were associated with decreased food intake.  Similarly, after a 4-hour exposure to HCCPD, \nbody weight decreases of at least 25 and 17% relative to pre-exposure weights were observed for male \nand female rats, respectively, after exposures to 1.4–5.8 ppm; no food intake data were provided (Rand et \nal. 1982a).  With significantly decreased food intake, male and female rats exposed to 0.5 ppm HCCPD \nfor 1–2 weeks lost body weight; male body weights decreased 32% on day 10 and terminal female body \nweight decreased 29% (Alexander et al. 1980a; Rand et al. 1982a).\n\n$$\nt\\geqq1.68\n$$\n\nIn 13-week inhalation studies, terminal body weights remained within 10% of control values following \nexposure to HCCPD at concentrations up to 0.385 ppm in rats and 0.389 ppm in mice (NTP 1994).\n\n---\n\nSimilarly, no effects on body weight were observed in rats and monkeys exposed to ≤0.2 ppm HCCPD \nfor 14 weeks (Alexander et al. 1980b; Rand et al. 1982a).  Body weight decreased 19% and body weight \ngain decreased 42% in male mice exposed to 0.5 ppm for 42 weeks (NTP 1994).  No body weight deficits \nwere identified after exposure of male mice to 0.2 ppm for 33 weeks or to 0.5 ppm for 26 weeks (NTP \n1994).  Body weights remained within 10% of control values for male and female rats exposed to \n≤0.56 ppm for 30 weeks (Clark 1981), and in male and female mice and rats exposed to ≤0.2 ppm for \n2 years (NTP 1994).\n\nBody weight effects after oral exposure to HCCPD in experimental animals have been evaluated in acuteand intermediate-duration studies.  In intermediate-duration studies, sufficient oral dosing with HCCPD \ndecreased body weights and suppressed body weight gains.  Male and female rats and mice experienced \ndose-related decreased body weights and body weight gains when compared to controls after oral \nexposure to HCCPD for 13 weeks (Abdo et al. 1984; Velsicol 1981a, 1981b).  Male rats were affected \nmore than females, and rats were affected more than mice.  Terminal body weights in male rats decreased \n13–35% and overall body weight gains were reduced 21–58% at dose levels of ≥38 mg/kg/day. In female\nrats exposed to 75–150 mg/kg/day, terminal body weights were reduced 15–17% and overall body weight \ngains decreased 28–36%.  Terminal body weights in male mice were reduced 11% and overall body \nweight gains decreased 39% at 150 mg/kg/day.  In female mice, terminal body weights decreased 13% at \n300 mg/kg/day and overall body weight gains were reduced 22–44% at ≥150 mg/kg/day. Differences in \nterminal body weights and overall body weight gains were within 10% of control values for male rats at \n≤19 mg/kg/day, female rats at ≤38 mg/kg/day, and male and female mice at ≤75 mg/kg/day.  Maternal \nweight loss was observed in rabbits administered 75 mg/kg/day on GDs 6–18; the magnitude of weight \nloss was not reported (Murray et al. 1980).  No body weight effects were reported for rabbits dosed with \n≤25 mg/kg/day on GDs 6–18 or for mice dosed with ≤75 mg/kg/day on GDs 6–15.\n\n###### 2.4 RESPIRATORY\n\nThe data provide strong evidence that HCCPD produces portal-of-entry effects in the respiratory system \nfollowing inhalation exposures; no effects on the respiratory tract were observed following oral or dermal \nexposures to HCCPD.  Based upon systematic review (Appendix C), the respiratory system is a presumed \nhazard of HCCPD toxicity following inhalation exposure based on inadequate evidence in humans and a \nhigh level of evidence from laboratory animal studies.\n\n---\n\nThe available data on respiratory effects of HCCPD in humans are limited to reports of WWTP workers \nand cleanup crew members exposed to HCCPD for 3–15 days after an inadvertent industrial release of \nthis material into the sewage system (Kominsky et al. 1980; Morse et al. 1979).  Maximum atmospheric \nconcentrations for the treatment plant workers were unknown but were most likely >0.97 ppm, the \nmaximum concentration measured 4 days after compound identification (Morse et al. 1979).  The \nmaximum concentration recorded during cleanup was 19.2 ppm (Kominsky et al. 1980).  Symptoms of \ntracheobronchial irritation were reported by the treatment plant workers early in the exposure period.  \nThese symptoms were recounted by 39 of 145 (27%) employees who responded to a questionnaire shortly \nafter the exposure incident and by 16 of 177 (9%) employees who responded to a follow-up questionnaire \n6 weeks later (Morse et al. 1979).  Chest x-rays of 28 exposed workers were normal and tests of \npulmonary function were normal in a subset of 22 workers from this group (Kominsky et al. 1980).  \nMinor respiratory complaints included sore throat, cough, chest discomfort, and difficulty breathing.  \nThese effects were likely a consequence of the direct action of the HCCPD vapor on the mucous \nmembranes of the respiratory tract, rather than systemic effects due to exposure to HCCPD through the \nlungs.  One cleanup crew worker also reported respiratory difficulty when exposed for a few seconds to \n19.2 ppm HCCPD without protective equipment (Kominsky et al. 1980).  Chest discomfort persisted for \nseveral days in this individual.\n\nRespiratory effects induced by HCCPD in laboratory animals have been evaluated in acute-, \nintermediate-, and chronic-duration inhalation exposure studies.  Inhalation exposures to HCCPD \nproduced clinical signs of respiratory toxicity and/or irritation including abnormal respiratory pattern \n(irregular or exaggerated respiratory movements, fast or irregular respiration rate or pattern, rales and/or \nnoisy respiration, and/or gasping), labored respiration, sneezing, increased respiration rate, and/or mouth \nbreathing in rats exposed to 1.67 ppm for 1 hour (Jackson and Hardy 1986), 1.68 ppm for 4 hours \n(Jackson and Hardy 1987), 0.5 ppm for 1–2 weeks (Alexander et al. 1980a; Rand et al. 1982a), 0.56 ppm \nfor 30 weeks (Clark 1981), and ≥0.941 ppm for 13 weeks (NTP 1994).  No respiratory clinical signs were \nobserved in rats or monkeys exposed to 0.2 ppm for 14 weeks (Alexander et al. 1980b; Rand et al. \n1982a), mice exposed to ≤2.142 ppm for 13 weeks (NTP 1994), male mice exposed to 0.2 ppm for \n33 weeks or 0.5 ppm for 26 or 42 weeks (NTP 1994), or rats and mice exposed to ≤0.2 ppm for 2 years \n(NTP 1994).  Based on these data, it appears that rats are more susceptible to HCCPD-induced respiratory \nirritation effects than mice. Blood gas analysis, pulmonary ventilation, and lung mechanics were within \nnormal ranges in pulmonary function tests of monkeys exposed to ≤0.2 ppm HCCPD for 7 and 13 weeks \n(Alexander et al. 1980b; Rand et al. 1982a).\n\n---\n\nInhalation exposures to HCCPD vapor caused histopathological changes in the respiratory tracts of \nexperimental animals.  At nonlethal concentrations, these alterations were largely inflammatory or \nhyperplastic in nature, consistent with repetitive irritation at the portal of entry.  Inflammation of the \ntissues was followed by necrosis, exfoliation, and/or hemorrhage.  No histopathological examination was \nconducted, but gross necropsy of the lungs showed pale and swollen lungs in rats exposed to ≥1.68 ppm \nfor 4 hours; findings were associated with increased absolute and relative lung weights at ≥3.31 and \n1.83 ppm in male and female rats, respectively (Jackson and Hardy 1987).  Inflammation, hyperplasia, \nand epithelial erosion were identified in the lungs of rats exposed to HCCPD vapor at 0.5 ppm for 1–\n2 weeks; recovery was apparent 2 weeks after exposure ceased in surviving animals (Alexander et al. \n1980a; Rand et al. 1982a).  No histopathological changes were identified in respiratory tissues of rats\nexposed to ≤0.11 ppm in the same manner (Alexander et al. 1980a; Rand et al. 1982a) or in rats and \nmonkeys exposed to ≤0.2 ppm for 14 weeks (Alexander et al. 1980b; Rand et al. 1982a). Using electron \nmicroscopy, exposure-related increases in electron-lucent inclusions in club cells, formerly called Clara \ncells, were observed in rats exposed to 0.01–0.2 ppm for 14 weeks (Huntingdon Research Centre 1980; \nRand et al. 1982b); however, this findings is considered a biomarker of exposure rather than evidence of \ntoxicity due to the absence of histopathological findings or any other ultrastructural changes.  No \nexposure-related ultrastructural changes were observed in monkeys exposed to ≤0.2 ppm for 14 weeks\n(Rand et al. 1982b).  In a 30-week inhalation exposure study in rats, increased incidences of \nperivascular/peribronchiolar inflammatory cell infiltration were observed in males and females exposed to \n0.56 ppm; males exposed to this concentration also exhibited an increased incidence of bronchiolar \nepithelial thinning/ulceration (Clark 1981).  The incidences of bronchiolar epithelial hyperplasia, \nsloughing/loss, and edema also increased in male and female rats exposed to 0.56 ppm but did not reach \nstatistical significance.  Following a 14-week recovery period, no histopathological differences were \nidentified in the lungs of control and treated rats, indicating reversibility of these lesions.\n\n$$\nt_{0}\\geqq1.68\n$$\n\nIn 13-week studies, microscopic effects in the respiratory system produced by lethal HCCPD \nconcentrations included necrotizing inflammation of the nose, larynx, trachea, and bronchus/bronchiole \nand hemorrhaging of the alveolus in male and female rats exposed to 0.941–2.065 ppm; suppurative \ninflammation of the alveolus in male and female rats at 0.941 ppm; acute necrosis of the nose, larynx, \ntrachea, and lung epithelium and lung congestion in male and female mice at 2.142 ppm; tracheal \nsquamous metaplasia in male and female mice at 0.949 ppm; and suppurative inflammation of the nasal \nepithelium of male and female mice exposed to 0.949–2.142 ppm (NTP 1994).  Increased incidences of \nsuppurative inflammation and squamous metaplasia in the nose and necrotizing and suppurative \ninflammation of the bronchus/bronchiole were identified in male rats exposed to 0.385 ppm, increased incidences of nasal suppurative inflammation and tracheal squamous metaplasia were observed in male \nmice exposed to 0.389 ppm, and an increased incidence of nasal serous inflammation was present in \nfemale mice exposed to 0.389 ppm.  No statistically significant increases were identified for nonneoplastic lesions in the respiratory tract tissues of female rats exposed to ≤0.385 ppm, male rats exposed \nto 0.146 ppm, or male or female mice exposed to ≤0.146 ppm (NTP 1994).\n\nHistopathological findings in male and female mice exposed to 0.2 ppm for 2 years included nasal \nsuppurative inflammation characterized by accumulation of cellular debris, mucus, neutrophils, and fibrin \nin the nasal lumen and infiltration of mononuclear cells and neutrophils into the lamina propria (NTP \n1994).  After 2-year exposures, an increased incidence of squamous metaplasia of the larynx (minimal \nseverity) was identified in female rats at 0.01 and 0.2 ppm; the incidence at 0.05 ppm was also elevated \nbut was not statistically significantly different from the concurrent control incidence.  No treatmentrelated respiratory tract lesions were identified in male rats.  The toxicological relevance of the squamous \nmetaplasia was not clear to the NTP (1994) authors due to difficulties in obtaining consistent sections for \nanalysis and determination of the boundary between squamous and columnar epithelium.  Due to this, as \nwell as the lack of clear dose-response, a LOAEL determination for squamous metaplasia was not \nincluded in Table 2-1.\n\nTo examine the progression and permanence of non-neoplastic lesions in the respiratory tract, NTP \n(1994) conducted additional studies in male mice with the intent of evaluating the relative effects of \nconcentration and duration on development of these lesions.  In these studies, concentrations were 0 or \n0.2 ppm for 33 weeks and 0 or 0.5 ppm for 26 or 42 weeks.  Animals were sacrificed at interim \nevaluations after 27, 34, or 43 weeks or 15 months of exposure or were sacrificed after 2 years.  At the \nend of the exposure periods, the incidence of nasal suppurative inflammation increased in all treatment \ngroups and suppurative inflammation of the trachea and lungs and alveolar epithelial hyperplasia \nincreased in animals exposed to 0.5 ppm for 42 weeks.  The incidence of alveolar epithelial hyperplasia \nalso increased in male mice exposed to 0.5 ppm for 42 weeks.  An evaluation of the data indicated that \nboth concentration and duration of exposure influenced the development of these respiratory tract lesions; \nthe inflammation of the trachea and lungs was not observed unless the product of the concentration and \nduration was >20 or 21 ppm-weeks.\n\nIn the chronic-duration studies of rats and mice exposed to HCCPD for 2 years, accumulation of a \ngranular yellow-brown pigment was observed in the nasal epithelium in male and female rats and mice at \n≥0.01 ppm, tracheal epithelium of male and female mice at ≥0.01 ppm, bronchiole epithelium of female\n\n$$\n\\geqq0.01\n$$ rats at ≥0.01 ppm, and lung epithelium of male and female mice ≥0.05 ppm (NTP 1994).  At 0.2 ppm, \nminimal-to-mild tracheal, bronchiole, and peribronchiole pigmentation was observed in male rats and \nperibronchiole pigmentation was identified in female rats (NTP 1994).  The pigmentation incidence and \nseverity generally increased with concentration for each sex-species combination.  In male mice exposed \nto 0.2 ppm for 33 weeks or 0.5 ppm for 26 or 42 weeks and then maintained for up to 2 years, \npigmentation of the respiratory tract (nose, trachea, and/or lungs) was seen in the majority of exposed \nanimals and did not disappear following exposure cessation and evaluation at 2 years, indicating a lack of \nrecovery and physiological turnover of the pigment material.  The incidence and severity were similar \nafter 33, 66, and 104 weeks of exposure to 0.2 ppm HCCPD.  In the chronic-duration and additional \nstudies in male mice exposed to 0.2 ppm for 33 weeks and 0.5 ppm for 26 or 42 weeks, the pigmentation \ndid not co-occur with respiratory lesions and did not appear to be a precursor to more significant effects \n(i.e., did not indicate an initial phase in the progression of a disease state).  Results of several staining \nprocedures applied to the pigmented lung sections of rats and mice indicated the presence of reducing \nsubstances, but no further analytical identification was performed.  NTP (1994) indicated that the \npigmentation may be a unique response to HCCPD and could be due to lipid peroxidation.  Based on \nthese data, ATSDR concludes that it is more appropriate to characterize the pigmentation as a marker of \nexposure to HCCPD rather than an adverse effect attributable to HCCPD exposure.\n\nThe potential for oral exposure to HCCPD to induce respiratory effects has been evaluated in acute- and \nintermediate-duration studies.  In rats and mice administered lethal gavage doses of HCCPD, decreased \nrespiratory rates were observed prior to death (Dean 1977; Gardner 1986a); this clinical sign was likely a \nconsequence of significant morbidity prior to death rather than an effect of HCCPD on the respiratory \nsystem.  No gross or histopathological changes were identified in the nasal cavity, trachea, larynx, \nbronchi, or lungs of rats at doses ≤150 mg/kg/day or in mice at doses ≤300 mg/kg/day for 13 weeks \n(Abdo et al. 1984; Velsicol 1981a, 1981b).\n\nThe potential toxicological effects of HCCPD on the respiratory tract following dermal exposure were \nevaluated in one acute-duration dermal toxicity study.  A decreased rate of respiration was observed in \nrats administered topical doses ≥2,000 mg/kg for 24 hours (Gardner 1986b).  The animals appeared \nnormal 5–9 days after dosing and no gross pathological changes were identified in the lungs of animals \nthat survived to the scheduled sacrifice.\n\n---\n\n###### 2.5 CARDIOVASCULAR\n\nNo studies were located regarding cardiovascular effects in humans after exposure to HCCPD. Available\ndata from laboratory animals indicate that the cardiovascular system is not a sensitive toxicity target \nfollowing inhalation or oral exposure to HCCPD.\n\nThe cardiovascular system has been evaluated in experimental animals exposed to HCCPD via inhalation \nin acute-, intermediate-, and chronic-duration studies.  Diffuse degenerative changes were observed in the \nhearts of rats, mice, and rabbits that died following acute exposure to lethal concentrations of HCCPD \nranging from 0.3 to 66 ppm for 15 minutes to 2 weeks; incidence data were not provided, and findings \nwere potentially attributable to autolysis (Treon et al. 1955).  In another acute-duration study, there were \nno histopathological changes in the heart in rats exposed to concentrations up to 0.5 ppm after either 1 or \n2 weeks (Alexander et al. 1980a; Rand et al. 1982a).  In longer-term inhalation studies, there was no \nevidence for histopathological changes in the heart at intermediate-duration concentrations up to \n0.56 ppm in rats, 0.389 ppm in mice, or 0.2 ppm in monkeys (Alexander et al. 1980b; Clark 1981; NTP \n1994; Rand et al. 1982a) or chronic-duration concentrations up to 0.2 ppm in rats or mice (NTP 1994).\n\nPotential cardiovascular effects of HCCPD oral exposures in experimental animals were evaluated in \nacute- and intermediate-duration studies.  Single oral doses of 280–2,100 mg/kg caused degenerative \nchanges in the hearts of rats and rabbits, possibly due to tissue autolysis; incidence data were not provided\n(Treon et al. 1955).  In contrast, there were no gross or histopathological changes in the hearts of rats \nexposed to doses ≤150 mg/kg/day or mice exposed to doses ≤300 mg/kg/day for 13 weeks (Abdo et al. \n1984; Velsicol 1981a, 1981b).\n\nRabbits that died following single dermal doses of 610–6,130 mg/kg displayed degenerative changes in \nthe heart, possibly because of tissue autolysis; incidence data were not provided (Treon et al. 1955).\n\n###### 2.6 GASTROINTESTINAL\n\nThe data provide evidence that HCCPD produces portal-of-entry effects in the gastrointestinal system, \nspecifically the stomach, following oral exposures.  Data on adverse gastrointestinal effects following \ninhalation exposure are limited to clinical signs following accidental occupational exposure; no effects on \nthe gastrointestinal system were observed following dermal exposure to HCCPD.  Based upon systematic \nreview (Appendix C), the gastrointestinal system is a presumed hazard of HCCPD toxicity following oral exposure based on no route-specific data in humans and a high level of evidence from laboratory animal \nstudies.\n\nWWTP workers exposed to HCCPD for 3–15 days due to an inadvertent industrial release complained of \nnausea (22% of 177 workers) and abdominal cramps (prevalence not specified) (Kominsky et al. 1980; \nMorse et al. 1979).  One member of the cleanup crew who was exposed to 19.2 ppm for several seconds \nwithout protective equipment experienced nausea several minutes after the exposure (Kominsky et al. \n1980).  While classified as gastrointestinal in this profile, it is possible that nausea may be neurological in \norigin.\n\nGastrointestinal effects of HCCPD have been evaluated in laboratory animals following intermediate- and \nchronic-duration inhalation exposures.  No microscopic changes were seen in the stomach, esophagus, or \nintestines of monkeys, rats, or mice exposed to concentrations up to 0.2, 0.56, or 0.5 ppm, respectively, in\nintermediate-duration studies (Alexander et al. 1980b; Clark 1981; NTP 1994; Rand et al. 1982a), or rats \nor mice following chronic-duration exposure to concentrations up to 0.2 ppm (NTP 1994).  The \ngastrointestinal tract does not appear to be a sensitive target for HCCPD in animals following inhalation \nexposures.\n\nThe potential impact of HCCPD exposure on gastrointestinal tissues has been evaluated in acute- and \nintermediate-duration oral exposure studies in experimental animals.  Increased incidences of diarrhea \nwere observed in rats dosed with ≥1,260 mg/kg (Gardner 1986a) and female and male mice dosed with \n464 and 1,000 mg/kg, respectively (Dean 1977).  Acute necrotic lesions of the forestomach were noted in \nsome rats administered an oral dose of 280–2,100 mg/kg; incidence data were not provided (Treon et al. \n1955).  After 13-week exposures to HCCPD, increased incidences of forestomach epithelial hyperplasia \nwere observed in male and female rats at 38 mg/kg/day and male and female mice at 75 mg/kg/day (Abdo \net al. 1984; Velsicol 1981a, 1981b).  Increased incidences of focal inflammation in the forestomach were \nidentified in male and female rats at 38 mg/kg/day and male and female mice at 75 mg/kg/day.  The \nincidences and ranges of lesion severities were directly related to the dose.  No histopathological changes \nwere identified in the esophagus, duodenum, jejunum, ileum, or colon of males and females of either \nspecies.  These data suggest that rats are more sensitive to HCCPD-induced effects to the forestomach \nthan mice.  The presence of the forestomach lesions and lack of histopathological changes in other \nregions of the gastrointestinal tract suggests that the forestomach effects result from direct contact of \nthese tissues with HCCPD.\n\n---\n\n###### 2.7 HEMATOLOGICAL\n\nThe data indicate HCCPD may alter red blood cell hematology parameters following inhalation exposure \nwithout causing histopathological changes to bone marrow; no consistent effects were noted in white \nblood cell parameters following inhalation exposure and no effects on the hematological system were \nobserved in animals following oral exposures to HCCPD.  Data are not available via the dermal route.  \nBased upon systematic review (Appendix C), the hematological system, specifically red blood cell \nparameters, is a suspected hazard of HCCPD toxicity following inhalation exposure based on inadequate \ndata in humans and a moderate level of evidence from laboratory animal studies.  White blood cell effects \nare not classifiable as to the hazard to humans based on inadequate data in humans and animals.\n\nNo changes in blood counts were observed in workers exposed to HCCPD at a WWTP after an industrial \ndischarge of the material into the sewage system (Kominsky et al. 1980).\n\nThe potential hematological effects of HCCPD were evaluated in experimental animals exposed via \ninhalation after acute-, intermediate-, and chronic-duration exposures.  No effects on bone marrow \nhistopathology were reported in rats exposed to 0.5 ppm for 1–2 weeks (Alexander et al. 1980a; Rand et \nal. 1982a), rats and mice exposed to ≤0.385 and ≤0.389 ppm, respectively, for 13 weeks, or rats and mice \nexposed to ≤0.2 ppm for 2 years (Alexander et al. 1980b; NTP 1994; Rand et al. 1982a).  Across acuteand intermediate-duration multiple exposure studies, altered red blood cell hematology parameters were \nidentified in rats, particularly males, as seen in Table 2-4.\n\n**Table 2-4. LOAEL Values for Red Blood Cell Hematological Effects of Rats** \n**Exposed to HCCPD Vapor in Acute- and Intermediate-Duration Inhalation**\n**Studies**\n\n| Hematology parameter | Rand et al. 1982aa: 1–2 weeks | Rand et al. 1982aa: 1–2 weeks (recovery group) | NTP 1994: 13 weeks | NTP 1994: 13-week special hematology study | Clark 1981: 30 weeks |\n| --- | --- | --- | --- | --- | --- |\n| Males |  |  |  |  |  |\n| PCV | \\(\\uparrow (0.5^{{b}})\\) | ↔ | \\(\\uparrow (0.385)\\) | ↔ | - |\n| Hb | \\(\\uparrow (0.5)\\) | \\(\\uparrow (0.5)\\) | \\(\\uparrow (0.385)\\) | ↔ | \\(\\uparrow (0.14)\\) |\n| RBC | \\(\\uparrow (0.5)\\) | ↔ | \\(\\uparrow (0.385)\\) | ↔ | \\(\\uparrow (0.14)\\) |\n| MCV | ↔ | ↔ | ↔ | \\(\\uparrow (0.385)\\) | ↔ |\n| MCH | - | - | \\(\\uparrow (0.385)\\) | ↔ | ↔ |\n| MCHC | ↔ | \\(\\uparrow (0.5)\\) | ↔ | ↔ | ↔ |\n\n---\n\n**Table 2-4. LOAEL Values for Red Blood Cell Hematological Effects of Rats** \n**Exposed to HCCPD Vapor in Acute- and Intermediate-Duration Inhalation**\n**Studies**\n\n| Hematology parameter | Rand et al. 1982aa: 1–2 weeks | Rand et al. 1982aa: 1–2 weeks (recovery group) | NTP 1994: 13 weeks | NTP 1994: 13-week special hematology study | Clark 1981: 30 weeks |\n| --- | --- | --- | --- | --- | --- |\n| HCT | - | - | - | - | \\(\\uparrow\\) (0.14) |\n| Females |  |  |  |  |  |\n| PCV | \\(\\uparrow\\) (0.5) | ↔ | ↔ | \\(\\uparrow\\) (0.385) | - |\n| Hb | \\(\\uparrow\\) (0.5) | ↔ | ↔ | \\(\\uparrow\\) (0.385) | ↔ |\n| RBC | \\(\\uparrow\\) (0.5) | ↔ | \\(\\downarrow\\) (0.385) | \\(\\uparrow\\) (0.385) | ↔ |\n| MCV | ↔ | ↔ | \\(\\uparrow\\) (0.385) | \\(\\uparrow\\) (0.385) | ↔ |\n| MCH | - | - | ↔ | \\(\\uparrow\\) (0.385) | ↔ |\n| MCHC | ↔ | ↔ | ↔ | ↔ | ↔ |\n| HCT | - | - | - | - | ↔ |\n\n<sup>a</sup>Data are also available in the unpublished industry report by Alexander et al. (1980a).\n\n<sup>b</sup>LOAEL concentrations are in ppm.\n\n↑ = increased mean value; ↓ = decreased mean value; ↔ = no significant, dose-related change in mean value;\n\n– = not assessed; Hb = hemoglobin; HCT =hematocrit; MCH = mean cell hemoglobin; MCHC = mean cell\n\nhemoglobin concentration; MCV = mean cell volume; PCV = packed cell volume; RBC = red blood cell count\n\nThe most consistently observed effects were increased hemoglobin levels in male and female rats and \nincreased red blood cell counts in male rats.  Generally, effects were observed at concentrations \n≥0.14 ppm and had magnitudes of effect that were <10% of control values.  The exceptions are for the 1–\n2-week range-finding study (Alexander et al. 1980a; Rand et al. 1982a), where 20–30% increases in red \nblood cell parameters were identified at 0.5 ppm, a concentration that co-occurred with significantly \ndecreased water intake and produced significant mortality and morbidity (see Section 2.2).  Drinking \nwater intakes were not assessed in the NTP (1994) studies and were not affected by HCCPD exposure in \nthe Clark (1981) study (see Section 2.18).  While statistically significant altered hemoglobin, mean cell \nvolume (MCV), and mean cell hemoglobin concentration (MCHC) values were reported in rats following \na 14-week exposure at concentrations as low as 0.01 ppm, these changes were sporadically observed and\nwere not dose-responsive, and the magnitudes of effect were generally low (≤5%) (Alexander et al. \n1980b; Rand et al. 1982a).  Therefore, they were not considered to be biologically significant in this \nassessment and are not presented in Table 2-4.  For intermediate-duration exposures in rats, the NOAEL \nvalues were 0.039–0.146 ppm for the NTP (1994) 13-week studies and 0.06 ppm for the Clark (1981) \n30-week study.\n\n---\n\nRand et al. (1982a) postulated that these minor variances in hematological parameters were a \nconsequence of hemorrhagic lesions in the lungs and not a direct influence of HCCPD on hematopoiesis \nor red cell turnover.  Since the red blood cell hematology parameters were more consistently altered in \nmale rats than in female rats, this hypothesis correlates with the increased absolute and relative lung \nweights and more severe histopathological effects observed in the lungs of male rats in the 1–2-week\nRand et al. (1982a) study.  NTP (1994) suggested that the red blood cell hematology alterations were not \nattributable to HCCPD treatment due to the inconsistent dose-response and lack of correlation in the \nresults across sexes and between the core and special 13-week hematology studies.  While there are \ninconsistencies in the red blood cell parameter results obtained from the NTP (1994) studies, common \nalterations in hemoglobin levels and red blood cell counts across repeated inhalation exposure studies \nsuggest a consistent biological response to HCCPD.  In the absence of additional data and based on the \nlack of histopathological effects to bone marrow, ATSDR considers the altered red blood cell parameters \nto be plausibly related to respiratory tract damage resulting in compromised gas exchange.\n\nIn mice, the only consistent HCCPD treatment-related effect on red blood cell hematology parameters \nacross studies was decreased MCV in female mice after exposure to 0.389 ppm for 13 weeks in the core\nand special hematology studies (NTP 1994).  Other red blood cell effects were limited to increased \nMCHC in male mice at 0.389 ppm and in female mice at 0.039–0.389 ppm in the special 13-week \nhematology study.  The magnitudes of effect were within 5% of control values.  HCCPD treatmentrelated effects on other hematological parameters following inhalation exposures were limited to \ndecreased reticulocytes (40%) in female rats exposed to 0.385 ppm in the special hematology study (NTP \n1994); decreased total white blood cells (46%) and lymphocyte count (53%) in male rats, and increased \nneutrophil count (114%) in female rats exposed to 0.5 ppm for 1–2 weeks (Alexander et al. 1980a; Rand \net al. 1982a); and decreased percent lymphocytes (8–10%) and increased neutrophil count (27–36%) in \nmale rats exposed to ≥0.14 ppm and decreased lymphocyte count (16%) in female rats exposed to \n0.56 ppm for 30 weeks (Clark 1981).  No clear biological basis can be identified for these effects based \non the lack of consistency across studies.\n\nIn intermediate-duration oral exposure studies, no histopathological changes were identified in the bone \nmarrow of rats dosed with ≤150 mg/kg/day or mice dosed with ≤300 mg/kg/day for 13 weeks (Abdo et al. \n1984; Velsicol 1981a, 1981b).  Hematology parameters were not evaluated in this study.\n\n---\n\n###### 2.8 MUSCULOSKELETAL\n\nNo studies were located regarding musculoskeletal effects in humans after exposure to HCCPD.  \nAvailable inhalation and oral data in laboratory animals indicate the musculoskeletal system is not a \nsensitive target of toxicity following exposure to HCCPD; no dermal studies were identified.\n\nThe potential effect of HCCPD on musculoskeletal tissues has been evaluated in laboratory animals \nfollowing intermediate- and chronic-duration inhalation exposures and acute- and intermediate-duration \noral exposures.  HCCPD did not affect skeletal muscle of rats or monkeys exposed to up to 0.2 ppm for \n14 weeks (Alexander et al. 1980b; Rand et al. 1982a); femoral muscle, knee joint, or femur of male and \nfemale rats exposed to ≤0.56 ppm for 30 weeks (Clark 1981); bone histopathology of mice or rats \nexposed to ≤0.389 ppm for 13 weeks or ≤0.2 ppm for 2 years (NTP 1994).  Similarly, no \nhistopathological changes were identified in thigh muscle, rib (costochondral junction), or femur of rats \nexposed to ≤150 mg/kg/day or mice exposed to ≤300 mg/kg/day via gavage for 13 weeks (Abdo et al. \n1984; Velsicol 1981a, 1981b). In animals that died, decreased limb tone was observed in mice (prior to \ndeath) after a single exposure to 1,000 mg/kg via gavage (Dean 1977).\n\n###### 2.9 HEPATIC\n\nThe data indicate that the hepatic system is not a sensitive target of HCCPD toxicity.\n\nSerum markers of hepatotoxicity were evaluated in 97 cleanup workers exposed to HCCPD vapors at a \nWWTP because of an inadvertent industrial release (Kominsky et al. 1980).  Abnormal serum marker \nranges were identified for 18 of the 97 workers (19%); aspartate aminotransferase (AST) values were \nelevated for 12 workers, alkaline phosphatase (ALP) was elevated for 5 workers, and total bilirubin was \nelevated for 1 worker (Kominsky et al. 1980).  For 8 of the 97 cleanup crew members, these biochemical \nparameters were abnormal on more than one occasion, and 7 workers had values that were temporallyrelated to exposure conditions.  It should be noted that evaluations were not performed on unexposed \nworkers, and it is not known if the abnormal values observed in exposed workers differ from the \nunexposed local general population.\n\nRelative to a group of 35 controls, 73 male operators employed for an average of 8.2 years (range 0.5–\n23 years) in a plant producing chlorinated hydrocarbons, including HCCPD, showed no evidence of \nhepatotoxicity (Boogaard et al. 1993).  Clinical tests included measurement of alanine aminotransferase\n\n---\n\n(ALT), AST, ALP, total bilirubin, γ-glutamyltransferase (GGT), lactate dehydrogenase (LDH), and total \nbile acids.  Personal air sampling for HCCPD was performed on a subset of study participants but was not \nused to evaluate associations between HCCPD exposure and liver function values.\n\nThe hepatotoxic potential of HCCPD has been evaluated in laboratory animals following acute-, \nintermediate-, and chronic-duration inhalation exposures.  Mild-to-moderate hepatic tissue degeneration \nwas observed following acute-duration inhalation exposures to 0.34–73.6 ppm for 15 minutes to 5 days, \nand to intermediate-duration exposures to 0.34 ppm for 6 weeks or 0.15 ppm for 30 weeks; incidence data \nwere not provided (Treon et al. 1955).  Hepatic damage was more pronounced in the animals that died \nthan in those that survived and, thus, may have been, at least partially, the result of autolysis in moribund \nor dying animals.  An apparent dose-related increase in perivascular/peribiliary inflammatory cell \ninfiltrates in the liver was observed in female rats exposed to 0.06–0.56 ppm; however, incidences did not \ndiffer significantly from control and no hepatic lesions were observed in similarly exposed male rats \n(Clark 1981).  In other inhalation studies, no exposure-related hepatic lesions were seen following acuteduration exposure in rats to concentrations up to 0.5 ppm (Alexander et al. 1980a; Rand et al. 1982a); \nintermediate-duration exposure in monkeys, rats, or mice to concentrations up to 0.2, 0.385, or 0.5 ppm, \nrespectively (Alexander et al. 1980b; NTP 1994; Rand et al. 1982a); or chronic-duration exposure in rats \nor mice to concentrations up to 0.2 ppm (NTP 1994).\n\nNo consistent evidence of exposure-related changes in hepatic serum biochemistry or liver weight was \nobserved following inhalation exposure to HCCPD.  Serum concentrations of the biochemical parameters\nLDH, AST, ALP, and ALT in rats and mice were not influenced by inhalation exposure to HCCPD \nconcentrations ≤0.389 ppm for 13–14 weeks (Alexander et al. 1980b; NTP 1994; Rand et al. 1982a).  \nDuring the 13-week special hematology, clinical chemistry, and urinalysis study conducted in rats by \nNTP (1994), the highest concentration of 2.065 ppm caused elevated serum AST concentrations (1.7–\n7.6-fold) in male and female rats on days 4–16; however, this concentration was lethal to all the animals \nprior to the day 46 clinical evaluation, and a comparable increase was not observed in mice (NTP 1994).  \nRelative liver weights of rats were significantly reduced by 3–15% in males and females exposed to 0.01–\n0.2 ppm for 13 weeks, but the decreases were not dose-related (Alexander et al. 1980b; Rand et al. \n1982a).  No changes in liver weights were observed in rats or mice exposed to concentrations ≤0.389 ppm \nfor 13 weeks or ≤0.2 ppm for 2 years (NTP 1994).\n\nAcute- and intermediate-duration oral toxicity studies have evaluated the potential effects of HCCPD\nexposure on the liver.  High, acute-duration oral doses of HCCPD were associated with liver necrosis and tissue degeneration in rats (261–1,959 mg/kg) and rabbits (579–877 mg/kg); incidence data were not \nprovided (Treon et al. 1955).  HCCPD did not induce histopathological changes in hepatic tissues of rats \nand mice exposed to doses up to 150 and 300 mg/kg/day, respectively, via gavage for 13 weeks (Abdo et \nal. 1984; Velsicol 1981a, 1981b).\n\nThe potential for HCCPD to cause hepatotoxicity following dermal exposure was evaluated only for \nacute-duration exposures.  Rabbits exposed to single dermal doses of 401–5,719 mg/kg displayed necrosis \nof the liver; incidence data were not provided (Treon et al. 1955).  The study authors stated that \ndegenerative changes persisted even 21 days after the exposure period in surviving animals.\n\n###### 2.10 RENAL\n\nThe data indicate that the renal system is a potential target for HCCPD via the oral route; it does not \nappear to be a sensitive target for HCCPD via the inhalation or dermal routes.  Based upon systematic \nreview (Appendix C), the kidney is a presumed hazard of HCCPD toxicity following oral exposure based \non no data in humans and a high level of evidence from laboratory animal studies.\n\nUrine samples were collected from 41 workers exposed for 3–15 days to HCCPD at a WWTP as the \nresult of an inadvertent industrial release into the sewage system (Morse et al. 1979).  Proteinuria was \nidentified in 6 of 41 workers immediately after exposure but no abnormalities were detected 3 weeks \nlater.  Urinalysis parameters were normal in all 97 cleanup crew workers evaluated (Kominsky et al. \n1980).  It should be noted that urinalysis was not performed on unexposed workers, and it is not known if \nproteinuria values observed in exposed workers differ from the local general population.\n\nRelative to a group of 35 controls, 73 male operators employed for an average of 8.2 years in a plant \nproducing chlorinated hydrocarbons, including HCCPD, showed no evidence of damage to the renal \ntubules (Boogaard et al. 1993).  The investigations included measurement of urinary alanine \naminopeptidase, N-acetyl-β-D-glucosaminidase, and retinol binding protein.  Although total urinary \nprotein concentrations did not differ between the two groups, urinary albumin was significantly higher in \nthe exposed group.  The difference, however, was not related to time of employment, and there was no \ndifference in urinary albumin concentration in workers involved in the manufacture of HCCPD and those \ninvolved in the preparation of other chlorinated hydrocarbon.  Thus, the effect was not considered to be \ndue to the damage to the glomerulus caused by exposure to HCCPD.  Personal air sampling for HCCPD\n\n---\n\n2.  HEALTH EFFECTS\n\nwas performed on a subset of study participants but was not used to evaluate associations with renal \nfunction values.\n\nThe potential renal effects following inhalation exposure to HCCPD have been evaluated in laboratory \nanimals following acute, intermediate, and chronic durations.  Inhalation exposure of HCCPD caused \nrenal tubular necrosis in rats, mice, guinea pigs, and rabbits at 0.34–73.6 ppm for 15 minutes to 7 days, \n0.34 ppm for 6 weeks, and 0.15 ppm for 30 weeks; incidence data were not provided (Treon et al. 1955).  \nIn other inhalation studies, no significant, exposure-related renal lesions were seen following acuteduration exposure in rats to concentrations up to 0.5 ppm (Alexander et al. 1980a; Rand et al. 1982a); \nintermediate-duration exposure in monkeys, rats, or mice to concentrations up to 0.2, 0.56, or 0.5 ppm, \nrespectively (Alexander et al. 1980b; Clark 1981; NTP 1994; Rand et al. 1982a); or chronic-duration \nexposure in rats or mice to concentrations up to 0.2 ppm (NTP 1994).\n\nThe potential toxicological effects of HCCPD on the kidneys have been evaluated in laboratory animals \nin acute-and intermediate-duration oral studies.  Degenerative lesions in the kidney tubules resulted from \nsingle gavage doses of 261–1,959 mg/kg in rats and 579–877 mg/kg in rabbits; incidence data were not \nprovided (Treon et al. 1955).  Toxic nephrosis was observed in male and female rats exposed to \n≥38 mg/kg/day and female mice exposed to ≥75 mg/kg/day via gavage for 13 weeks (Abdo et al. 1984; \nVelsicol 1981a, 1981b). These lesions were located in the terminal sections of the proximal tubules of the \nrenal cortex and were characterized by mild dilation of the tubules and karyomegaly, cytomegaly, and \nanisokaryosis accompanied by cytoplasmic and nuclear vacuolization.  Additionally, brown granular \npigment debris protruded into the lumen.  In male mice, tubular necrosis was present in 70% of the male \nmice receiving the 300 mg/kg/day dose but not at lower doses; this lesion was morphologically distinct \nfrom the toxic nephrosis seen in the other animals and may have contributed to the early deaths observed \nat this dose level.  No renal histopathological effects were identified in male and female rats at\n≤19 mg/kg/day, female mice at ≤38 mg/kg/day, or male mice at ≤150 mg/kg/day (Abdo et al. 1984; \nVelsicol 1981a, 1981b).\n\nRabbits exposed to single dermal doses of 401–5,719 mg/kg displayed degeneration and necrosis of the \nkidney tubules; incidence data were not provided (Treon et al. 1955). The study authors stated that renal \neffects were still apparent 21 days after dosing in surviving animals.\n\n---\n\n2.  HEALTH EFFECTS\n\n###### 2.11 DERMAL\n\nHuman and animal data indicate HCCPD causes skin irritation following direct dermal contact with \nHCCPD liquid or vapor.\n\nAn unspecified percentage of 145 workers exposed to HCCPD vapors for 3–15 days at a WWTP as a \nresult of an inadvertent industrial release reported skin irritation, with five employees verified to exhibit\nvisible signs of skin irritation (Morse et al. 1979).  In a subsequent publication, 21% of 177 employees \nwith usable medical questionnaire responses reported skin irritation following HCCPD release and prior \nto plant closure; 10% of the 177 employees reported experiencing skin irritation approximately 6 weeks \nlater (Kominsky et al. 1980).\n\nIn acute-duration dermal toxicity studies, topical application of HCCPD in either its pure form or in \nsolution appears to have a pronounced effect upon the epidermis of experimental animals.  Generally, \nHCCPD initially causes edema that progressed to hardening or encrustation at the application site \n(Gardner 1986b; OxyChem 1972; Treon et al. 1955).  In a series of studies, severe irritation and skin \nnecrosis were observed in a monkey administered 0.05 mL of a 10% (v/v) solution for 3 days; necrotic, \nhardened, encrusted, and discolored skin was identified following application of Ultrasene solutions \ncontaining ≥40% HCCPD to guinea pigs; and subcutaneous edema and local discoloration that progressed \nto encrustation and fissuring were observed after a dermal dose of ≥430 mg/kg was applied to rabbit skin; \nincidence data were not provided (Treon et al. 1955).  The lesions generally healed with time in the \nsurviving animals.  Thirteen months after exposure, the monkey’s treated skin was scarred and hairless.  \nNo evidence of dermal effects was identified in a monkey administered 0.01 mL of Ultrasene solutions \ncontaining up to 10% HCCPD, but application of 0.05 mL of solutions containing ≥20% HCCPD caused \nthe skin to become discolored and swell.  No evidence of skin irritation was observed in guinea pigs after \ndermal doses of 0.05 mL of Ultrasene solutions containing ≤1% HCCPD (Treon et al. 1955).  Eschar \nformation was noted after dermal application of 200 mg/kg HCCPD to rabbits (OxyChem 1992).  Results \nof standard dermal irritation tests indicated that 0.5 mL HCCPD produced slight to severe edema and \nnecrosis at the application sites (OxyChem 1972, 1992).\n\nThe potential effects of systemic HCCPD exposure on skin histopathology of laboratory animals were \nevaluated in intermediate- and chronic-duration inhalation studies and intermediate-duration oral studies.  \nNo histopathological changes were identified in the skin (specific location not identified) of male or \nfemale rats exposed to concentrations ≤0.56 ppm for 30 weeks (Clark 1981) or in male or female rats and mice exposed to concentrations ≤0.2 ppm for 2 years (NTP 1994).  Additionally, no histopathological \nchanges were identified in skin (specific location not identified) of rats and mice at gavage doses up to \n150 or 300 mg/kg/day, respectively, for 13 weeks (Abdo et al. 1984; Velsicol 1981a, 1981b).\n\n###### 2.12 OCULAR\n\nHuman and animal data indicate that direct ocular contact with HCCPD vapor may produce ocular \nirritation at sufficiently high concentrations.\n\nEye irritation was one of the major symptoms reported by sewage treatment plant workers exposed to \nHCCPD vapors for 3–15 days at a WWTP because of an inadvertent industrial release (Kominsky et al. \n1980; Morse et al. 1979).  From the 145 individuals who responded to a questionnaire immediately after \nexposure occurred, 85 (59%) complained of eye irritation (Morse et al. 1979).  In a follow-up \nquestionnaire 6 weeks later, 9% of 177 respondents were still experiencing ocular irritation (Kominsky et \nal. 1980; Morse et al. 1979).  Tearing and redness of the eyes were present in five individuals on the day \nof exposure.\n\nEye irritation, as evidenced by lacrimation, was also observed in animals exposed to HCCPD vapors for \nup to 7 hours (Jackson and Hardy 1986, 1987; OxyChem 1972; Rand et al. 1982a; Treon et al. 1955).  \nPartially or completely closed eyes were identified in rats exposed to ≥1.67 ppm for 1 hour (Jackson and \nHardy 1986) and ≥1.68 ppm for 4 hours (Jackson and Hardy 1987).  Direct ocular exposure to HCCPD\nvapors most likely contributed to these effects.  Irritation of the eyes or eyelids was observed for rats, \nmice, guinea pigs, and rabbits following single exposures to HCCPD concentrations as low as 1.0 ppm \nand multiple exposures to concentrations as low as 0.33 ppm for up to 6 weeks; ocular irritation was not \nobserved in any species exposed to 0.15 ppm for up to 30 weeks (Treon et al. 1955).  Lacrimation was \nevident in rats exposed to 5.8 ppm HCCPD for 4 hours and dark red eyes were observed in rats exposed \nto 0.5 ppm for 5–10 days and ≥0.05 ppm for 14 weeks (Alexander et al. 1980a, 1980b; Rand et al. 1982a).  \nNo clinical signs of eye irritation were noted in monkeys exposed to HCCPD vapor at concentrations up \nto 0.2 ppm for 14 weeks (Alexander et al. 1980b; Rand et al. 1982a).  No ophthalmological or\nhistopathological changes were identified in the ocular tissues of rats or monkeys exposed to \nconcentrations up to 0.2 ppm for 14 weeks (Alexander et al. 1980b; Rand et al. 1982a).  HCCPD \nexposure did not cause histopathological changes in the eyes of rats exposed to concentrations up to \n0.56 ppm for 30 weeks (Clark 1981).\n\n---\n\nSevere eye irritation was produced when 0.1 mL of HCCPD was placed in the conjunctival eye sac for \n5 minutes and then rinsed with water (OxyChem 1972).  Corrosion of the ocular tissues occurred when \nthe material was left in place for 24 hours prior to rinsing (OxyChem 1972).\n\n###### 2.13 ENDOCRINE\n\n2.13  ENDOCRINE\n\nNo reports of changes in human endocrine parameters or organs after exposure to HCCPD were found. \nBased on available data in laboratory animals, HCCPD does not produce histopathological changes to \nendocrine organs.  Insufficient data are available to assess the potential effects of HCCPD exposure on \nendocrine function, including endocrine hormone levels.\n\nPotential histopathological and organ weight effects in endocrine organs have been evaluated in \nlaboratory animals following acute-, intermediate-, and chronic-duration inhalation exposure to HCCPD.  \nDegenerative changes in the adrenal glands of rats, mice, guinea pigs, and rabbits were observed after \nexposures to concentrations of 0.34–73.6 ppm for periods of 15 minutes to 1 week, 0.34 ppm for 6 weeks, \nand 0.15 ppm for 30 weeks; incidence data were not provided (Treon et al. 1955).  Due to the high \nmortality observed at these concentrations, these changes may have been the result of tissue autolysis in \nmoribund or dying animals.  Effects on the adrenal, thyroid, parathyroid, pancreas, and pituitary glands \nfollowing inhalation exposure of male mice to 0.039–0.389 ppm HCCPD for 13 weeks were limited to \nincreased relative adrenal weights; no histopathological changes were noted in these organs in treated \nmale mice and no effects on adrenal, thyroid, parathyroid, pancreas, or pituitary gland weights or\nhistopathology were observed in female mice exposed to ≤0.389 and male and female rats exposed to \n≤0.385 ppm for 13 weeks (NTP 1994).  The biological significance of these adrenal weight changes\ncannot be assessed quantitatively in the absence of hormone product measurements or concurrent \nhistopathological findings.  There were no organ weight or histopathological changes in the adrenal \nglands, pancreas, thyroid, parathyroid gland, and/or pituitary gland identified in male and female rats and \nmonkeys exposed for 14 weeks at ≤0.2 ppm (Alexander et al. 1980b; Rand et al. 1982a), in male and \nfemale rats after 30-week exposures to ≤0.56 ppm (Clark 1981), or in rats and mice following 2-year \nexposures to ≤0.2 ppm (NTP 1994).  Additionally, no effects on the adrenal glands were identified in \nmale mice exposed to 0.5 ppm for 26–42 weeks (NTP 1994).\n\n$$\n\\leq0.385ppm\n$$\n\nPotential effects of HCCPD on endocrine organ weight and histology have also been evaluated in \nlaboratory animals following acute- and intermediate-duration oral exposures and acute-duration dermal \nexposures.  Degenerative changes in the adrenal tissues resulted from exposure to single oral doses of\n\n---\n\n280–2,100 mg/kg in rats and 620–940 mg/kg in rabbits; these changes may have resulted from tissue \nautolysis in moribund or dying animals, but no incidence data were reported (Treon et al. 1955).  There \nwere no histopathological changes in the adrenals, thyroid, parathyroid, or pituitary glands in 13-week \nstudies at gavage doses up to 150 mg/kg/day in rats and 300 mg/kg/day in mice (Abdo et al. 1984; \nVelsicol 1981a, 1981b).  Rabbits that were dermally exposed to HCCPD (430–6,130 mg/kg) had \ndegenerative changes of the adrenal glands that were still apparent in survivors 21 days after exposure; \nincidence data were not provided (Treon et al. 1955).\n\nNo data were identified evaluating endocrine function following *in vivo* exposure to HCCPD; however, \nlimited *in vitro* screening data are available.  HCCPD exhibited statistically significant radioactive iodide \nuptake inhibition in a ToxCast high-throughput screening assay (Wang et al. 2019).  Iodide uptake is the \nfirst step in thyroid hormone biosynthesis.\n\n###### 2.14 IMMUNOLOGICAL\n\n2.14  IMMUNOLOGICAL\n\nNo studies were located regarding immunological effects in humans after exposure to HCCPD. Based on \navailable data in laboratory animals, HCCPD does not cause histopathological alterations to \nimmunological organs.  However, no studies evaluating immune function following exposure to HCCPD \nwere identified.\n\nPotential effects of HCCPD on immune organ weight and histology have also been evaluated in acute-, \nintermediate-, and chronic-duration inhalation exposure studies and intermediate-duration oral exposure \nstudies in laboratory animals.  No exposure-related changes were identified in these studies.  There were \nno histopathological changes in the spleen of rats exposed to ≤0.5 ppm for 1–2 weeks (Alexander et al. \n1980a; Rand et al. 1982a).  In intermediate-duration studies, no histopathological changes were identified \nin immune organs (spleen, thymus, and/or lymph nodes) of monkeys, rats, or mice to concentrations up to \n0.2, 0.56, or 0.5 ppm, respectively (Alexander et al. 1980b; Clark 1981; NTP 1994; Rand et al. 1982a).  \nSimilarly, no histopathological effects were observed in immune organs of rats or mice exposed to \n≤0.2 ppm for 2 years (NTP 1994).  In a 13-week oral study, no treatment-related histopathological \nfindings were identified in the mandibular and mesenteric lymph nodes, thymus, or spleen at gavage \ndoses up to 150 mg/kg/day in rats or 300 mg/kg/day in mice (Abdo et al. 1984; Velsicol 1981a, 1981b).\n\n---\n\n2.  HEALTH EFFECTS\n\n###### 2.15 NEUROLOGICAL\n\n2.15  NEUROLOGICAL\n\nBased on available data, HCCPD does not cause histopathological alterations in the nervous system.  \nEvaluation of neurological function is limited to clinical signs of toxicity; therefore, insufficient data are \navailable to assess the potential effect of HCCPD exposure on neurological function, including behavior.\n\nAmong sewage treatment plant workers exposed to HCCPD at a WWTP because of an inadvertent \nindustrial release, headaches were self-reported by 65 of 145 workers (45%) after exposure for 3–15 days \n(Morse et al. 1979).  Six weeks later, 32 of 177 workers (18%) responding to a questionnaire were still \nexperiencing headaches (Kominsky et al. 1980). No studies were located regarding neurological effects \nin humans after oral or dermal exposure to HCCPD.\n\nNeurological clinical signs of toxicity and nervous system histopathology were evaluated in acute-, \nintermediate-, and chronic-duration inhalation exposure studies.  Rats and mice exposed to concentrations \nof 0.385–2.142 ppm HCCPD were described as listless after 1–3 weeks of exposure (NTP 1994).  \nIncidence data for clinical signs were not provided, so it is unclear how many animals exhibited this effect \nor how frequently; however, the study authors did note that listlessness was observed earlier during the \nexposure period with higher HCCPD concentrations.  Some rats, mice, guinea pigs, and rabbits exposed \nto high lethal concentrations of HCCPD (≥46.5 ppm) by acute-duration inhalation experienced tremors; \nincidence data were not provided (Treon et al. 1955).  At necropsy, diffuse degenerative changes in the \nbrain were observed in all rats, mice, guinea pigs, and rabbits after exposures to 0.34–73.6 ppm for \nperiods of 15 minutes to 1 week, 0.34 ppm for 6 weeks, and 0.15 ppm for 30 weeks; incidence data were \nnot provided (Treon et al. 1955).  These degenerative changes may have been the result of tissue \nautolysis.  In contrast, there were no histopathological changes in the brains of rats exposed to 0.5 ppm \nfor 1–2 weeks (Alexander et al. 1980a; Rand et al. 1982a), male mice exposed to 0.2 ppm for 33 weeks \n(NTP 1994), or rats and mice exposed to ≤0.389 ppm for 13 weeks or ≤0.2 ppm for 2 years (NTP 1994).  \nSimilarly, no histopathological changes were observed in the brains or sciatic nerve of rats or monkeys \nexposed to ≤0.2 ppm for 14 weeks (Alexander et al. 1980b; Rand et al. 1982a) or in brain, spinal cord, or \nsciatic or posterior tibial nerves of rats exposed to ≤0.56 ppm for 30 weeks (Clark 1981).\n\nThe potential neurotoxicity of HCCPD has been evaluated in acute- and intermediate-duration oral \nexposure studies.  Clinical signs of neurotoxicity were observed following acute-duration gavage \nexposure in mice, including hypoactivity at 464 mg/kg and ataxia at 1,000 mg/kg, a dose associated with \nlethality (Dean 1977).  Similarly, all rats exposed once to ≥1,260 mg/kg via gavage exhibited abnormal gait (high stepping, waddling) and lethargy (Gardner 1986a).  Single oral doses ≥180 mg/kg caused \nlethargy in rats and rabbits in the period “immediately after exposure” (Treon et al. 1955).  During \npostmortem examination of tissues, degenerative lesions of the brain were observed in the rats and rabbits \nthat succumbed to exposure and in the rats that survived to the scheduled sacrifice; incidence data were \nnot provided.  No histopathological lesions of the brain, sciatic nerve, or spinal cord were noted in rats or \nmice exposed to gavage doses up to 150 or 300 mg/kg/day, respectively, for 13 weeks (Abdo et al. 1984; \nVelsicol 1981a, 1981b). These data suggest that brain lesions occur only with exposures to high oral \ndoses of HCCPD.\n\nRabbits exposed to single dermal doses of HCCPD (430–6,130 mg/kg) displayed degenerative changes in \nthe brain at necropsy; incidence data were not provided (Treon et al. 1955).  These changes were still \napparent 21 days after exposure in surviving animals.  Ataxia, hypoactivity, and a depressed breathing \npattern have been observed in rabbits at lethal dermal doses of HCCPD (OxyChem 1972).\n\n###### 2.16 REPRODUCTIVE\n\n2.16  REPRODUCTIVE\n\nNo studies were located regarding reproductive effects in humans after exposure to HCCPD.  The \navailable animal data do not indicate that HCCPD causes histopathological alterations to reproductive \norgans.  However, insufficient data are available to thoroughly assess the potential for toxicity to the \nreproductive system, as no studies evaluating reproductive function following inhalation, oral, or dermal \nexposure to HCCPD were identified.\n\nThe potential effects of HCCPD on reproductive organ weight and histology have been evaluated in \nexperimental animals exposed by inhalation for intermediate and chronic durations.  The sole effect on \nreproductive organs identified with HCCPD treatment is an increased incidence of ovarian suppurative \ninflammation in female mice exposed to HCCPD at 0.05–0.2 ppm for 2 years; no histopathological \nchanges were identified in the uterus (NTP 1994).  While this lesion is clearly adverse, as it was the \nsuspected cause of increased mortality at 0.2 ppm, the causal relationship between HCCPD exposure and \nlesion development is unclear.  The study authors noted that lesions were similar to those observed in \nother NTP studies attributed to stress-related susceptibility to utero-ovarian infection by *Klebsiella* \nspecies (NTP 1994).  In contrast, no treatment-related histopathological lesions of the female (ovaries and \nuterus) or male (testes, prostate, and/or seminal vesicle) reproductive organs were identified in monkeys, \nrats, or mice exposed to concentrations up to 0.2, 0.385, or 0.389 ppm for 13–14 weeks (Alexander et al. \n1980b; NTP 1994; Rand et al. 1982a); male mice exposed to 0.2 ppm for 33 weeks or 0.5 ppm for\n\n---\n\n42 weeks (NTP 1994); rats exposed to ≤0.56 ppm for 30 weeks (Clark 1981); or rats or male mice \nexposed to ≤0.2 ppm for 2 years (NTP 1994).\n\n$$\n\\leqq0.56\n$$\n\nThe potential effects of HCCPD on reproductive organ weight and histology have also been evaluated in \nlaboratory animals following intermediate-duration oral exposure.  HCCPD did not cause treatmentrelated effects on the testes, seminal vesicles, prostate, ovaries, or uterus in rats or mice exposed to doses \nup to 150 or 300 mg/kg/day, respectively, via gavage for 13 weeks (Abdo et al. 1984; Velsicol 1981a, \n1981b).\n\nNo data were identified evaluating reproductive function following inhalation, oral, or dermal exposure to \nHCCPD; however, limited screening data are available.  Although it exhibited some estrogen receptor \nbinding affinity in a recombinant human estrogen receptor α (hERα) binding assay, HCCPD did not \nexhibit estrogenic or anti-estrogenic activity in an immature uterotrophic assay in female rats following \nsubcutaneous injection (Akahori et al. 2008).  No anti-androgenic activity was detected for HCCPD in \nChinese hamster ovary (CHO) cells transfected with human androgen receptor (hAR) in an androgenresponsive luciferase reporter assay (Roy et al. 2004).\n\n###### 2.17 DEVELOPMENTAL\n\n2.17  DEVELOPMENTAL\n\nNo studies were located regarding developmental effects in humans after exposure to HCCPD.  Animal \ndata are available only via the oral route and are too limited to assess whether or not the developing \norganism is a target of HCCPD toxicity at doses below those associated with maternal toxicity.\n\nHCCPD was not embryotoxic, fetotoxic, or teratogenic in mice following maternal exposure to gavage \ndoses up to 75 mg/kg/day during GDs 6–15 (Murray et al. 1980).  In rabbits, a dose-dependent increase in \nthe incidence of 13 ribs was identified in the offspring of does exposed to 75 mg/kg/day via gavage \nduring GDs 6–18; nonstatistically significant increases were also identified at 5 and 25 mg/kg/day.  No \nother evidence of embryotoxicity, fetotoxicity, or teratogenicity was identified in rabbits (Murray et al. \n1980).  The natural variation in the number of ribs for rabbits is 12–13.  It should be noted that the \ncompound was not maternally toxic in mice, but maternal mortalities and weight loss were observed in \nrabbits at 75 mg/kg/day (numbers affected and magnitude of effect not specified).\n\nA screening study was performed to evaluate prenatal and postnatal development of mice exposed to \nHCCPD during gestation.  Mice born to dams administered 45 mg/kg/day HCCPD via gavage during\n\n---\n\nGDs 8–12 did not exhibit evidence of developmental toxicity when evaluated on postnatal days (PNDs) 1 \nand 3 (Chernoff and Kavlock 1982, 1983).  When the offspring were evaluated over a 250-day postnatal \nperiod (including through puberty and breeding), there were no adverse effects on postnatal viability, \ngrowth, locomotor activity, sexual development (percent vaginal patency at day 30), or reproductive \nfunction (Gray and Kavlock 1984; Gray et al. 1986).\n\n###### 2.18 OTHER NONCANCER\n\n2.18  OTHER NONCANCER\n\nNo studies were located regarding other noncancer effects in humans after exposure to HCCPD.\n\nOther noncancer effects of HCCPD identified in experimental animals are limited to food and water \nintake.  During the first few days of the post-exposure observation periods, decreased food and water \nintake were observed in rats exposed for 1 hour to ≥1.67 ppm (Jackson and Hardy 1986) and rats exposed \nfor 4 hours to ≥1.68 ppm (Jackson and Hardy 1987); these concentrations were associated with overt \nsigns of toxicity during exposure (e.g., abnormal respiratory pattern).  After a 1–2-week exposure to \nHCCPD, male and female rats exposed to 0.5 ppm had decreased food and water intake (Alexander et al. \n1980a; Rand et al. 1982a).  All males exposed to 0.5 ppm died or were sacrificed in moribund condition \nby the end of the exposure period.  Minor decreases in food intake were also observed for male rats \nexposed to 0.11 ppm without meaningful changes to body weight; the biological significance of this \nfinding is uncertain.  Food intake was not affected in rats or monkeys and water intake was not affected in \nrats exposed to ≤0.2 ppm for 14 weeks (Alexander et al. 1980b; Rand et al. 1982a).  In a 30-week study, \nno treatment-related deficits were identified for male or female rats regarding food or water intake\nfollowing exposure to ≤0.56 ppm (Clark 1981). No treatment-related effects were observed for food and \nwater intake of pregnant mice administered gavage doses of HCCPD at ≤75 mg/kg/day on GDs 6–15 \n(Murray et al. 1980).  Where deficits in food and/or water intake were observed after exposure to \nHCCPD, these effects were likely the result of nonspecific toxicity following exposures to high \nconcentrations of an irritating/corrosive chemical.\n\n$$\n\\mathrm{to}\\geq1.67\\mathrm{ppm}\n$$\n\n$$\nt0\\geq1.68\n$$\n\n$$\nt o\\leqq0.2\n$$\n\n$$\n0.56ppm\n$$\n\n###### 2.19 CANCER\n\nNo studies were located regarding cancer in humans following exposure to HCCPD.\n\nThe carcinogenicity of HCCPD has been evaluated in 2-year rodent bioassays in which male and female \nrats and mice were exposed to concentrations up to 0.2 ppm for 104 weeks (NTP 1994).  There were no statistically significant increases in tumor incidence in rats or mice.  There was a slight increase in the \nincidence of adenomas of the pituitary pars distalis in male rats at 0.2 ppm and in thyroid follicle cell \nadenomas in female mice at 0.05 ppm, but, since the incidences were similar to the historical control \nmeans, were within the historical control range, or did not exhibit a dose-dependency, NTP (1994) did not \nconsider these tumors to be related to HCCPD exposure.  In male mice exposed to 0.5 ppm for 26 or \n42 weeks, then evaluated at 105 weeks, the incidence of alveolar/bronchiolar carcinomas was \nsignificantly increased but was within the historical range for the laboratory (NTP 1994).  Thus, \nalveolar/bronchiolar carcinomas may n", 'pages': None, 'truncated': True, 'extraction': 'firecrawl-public-document-markdown', 'request_id': '2f7ac126-1735-4f43-b7f0-10aa05b9cde7', 'source_url': 'https://downloads.regulations.gov/ATSDR-2026-0133-0003/content.pdf', 'observed_at': '2026-10-04T00:40:40.278109+00:00', 'content_hash': '063c002435b7a13b9144e8da7119795794d56ee2e0ab2fe90a88e51b9525c505'}, 'title': 'pdf', 'check_failed': False}]}

{'attachments': [{'url': 'https://downloads.regulations.gov/ATSDR-2026-0133-0003/attachment_1.pdf', 'body': {'text': "## Toxicological Profile for Hexachlorocyclopentadiene (HCCPD)\nDraft for Public Comment\nOctober 2026\n\nU.S. Department of Health and Human Services\nAgency for Toxic Substances and Disease Registry\n\n---\n\n## DISCLAIMER\n\nUse of trade names is for identification only and does not imply endorsement by the Agency for Toxic \nSubstances and Disease Registry, the Public Health Service, or the U.S. Department of Health and Human \nServices.\n\nThis information is distributed solely for the purpose of pre-dissemination for public comment under \napplicable information quality guidelines.  It has not been formally disseminated by the Agency for Toxic \nSubstances and Disease Registry.  It does not represent and should not be construed to represent any \nagency determination or policy.\n\n---\n\n## FOREWORD\n\nThis toxicological profile is prepared in accordance with guidelines developed by the Agency for Toxic \nSubstances and Disease Registry (ATSDR) and the Environmental Protection Agency (EPA).  The \noriginal guidelines were published in the *Federal Register* on April 17, 1987.  Each profile will be revised \nand republished as necessary.\n\nThe ATSDR toxicological profile succinctly characterizes the toxicologic and adverse health effects \ninformation for these toxic substances described therein.  Each peer-reviewed profile identifies and \nreviews the key literature that describes a substance's toxicologic properties.  Other pertinent literature is \nalso presented but is described in less detail than the key studies.  The profile is not intended to be an \nexhaustive document; however, more comprehensive sources of specialty information are referenced.\n\nThe focus of the profiles is on health and toxicologic information; therefore, each toxicological profile \nbegins with a relevance to public health discussion which would allow a public health professional to \nmake a real-time determination of whether the presence of a particular substance in the environment \nposes a potential threat to human health.  The adequacy of information to determine a substance's health \neffects is described in a health effects summary.  Data needs that are of significance to the protection of \npublic health are identified by ATSDR.\n\nEach profile includes the following:\n\n(A) The examination, summary, and interpretation of available toxicologic information and \nepidemiologic evaluations on a toxic substance to ascertain the levels of significant \nhuman exposure for the substance due to associated acute-, intermediate-, and chronicduration exposures;\n\n(B) A determination of whether adequate information on the health effects of each substance \nis available or in the process of development to determine the levels of exposure that \npresent a significant risk to human health due to acute-, intermediate-, and chronicduration exposures; and\n\n(C) Where appropriate, identification of toxicologic testing needed to identify the types or \nlevels of exposure that may present significant risk of adverse health effects in humans.\n\nThe principal audiences for the toxicological profiles are health professionals at the Federal, State, and \nlocal levels; interested private sector organizations and groups; and members of the public.  ATSDR plans \nto revise these documents in response to public comments and as additional data become available.  \nTherefore, we encourage comments that will make the toxicological profile series of the greatest use.\n\nElectronic comments may be submitted via: www.regulations.gov. Follow the on-line instructions for \nsubmitting comments.\n\nWritten comments may also be sent to:\n\nAgency for Toxic Substances and Disease Registry\n\nOffice of Innovation and Analytics\n\nToxicology Section\n\n1600 Clifton Road, N.E.\n\nMail Stop S106-5\n\nAtlanta, Georgia 30329-4027\n\n---\n\nThe toxicological profiles are developed under the Comprehensive Environmental Response, \nCompensation, and Liability Act of 1980, as amended (CERCLA or Superfund).  CERCLA \nSection 104(i)(1) directs the Administrator of ATSDR to “…effectuate and implement the health-related \nauthorities” of the statute.  This includes the preparation of toxicological profiles for hazardous \nsubstances most commonly found at facilities on the CERCLA National Priorities List (NPL) and that \npose the most significant potential threat to human health, as determined by ATSDR and the EPA.  \nSection 104(i)(3) of CERCLA, as amended, directs the Administrator of ATSDR to prepare a \ntoxicological profile for each substance on the list.  In addition, ATSDR has the authority to prepare \ntoxicological profiles for substances not found at sites on the NPL, in an effort to “…establish and \nmaintain inventory of literature, research, and studies on the health effects of toxic substances” under \nCERCLA Section 104(i)(1)(B), to respond to requests for consultation under Section 104(i)(4), and as \notherwise necessary to support the site-specific response actions conducted by ATSDR.\n\nThis profile reflects ATSDR’s assessment of all relevant toxicologic testing and information that has been \npeer-reviewed.  Staffs of the Centers for Disease Control and Prevention and other Federal scientists have \nalso reviewed the profile.  In addition, this profile has been peer-reviewed by a nongovernmental panel \nand is being made available for public review.  Final responsibility for the contents and views expressed \nin this toxicological profile resides with ATSDR.\n\nChristopher M. Reh, Ph.D. \nAssociate Director, \nAgency for Toxic Substances and Disease Registry \nCenters for Disease Control and Prevention\n\n---\n\n**VERSION HISTORY**\n\n| Date | Description |\n| --- | --- |\n| October 2026 | Draft for public comment toxicological profile released |\n| July 1999 | Final toxicological profile released |\n\n---\n\n# CONTRIBUTORS & REVIEWERS\n\n# CHEMICAL MANAGER TEAM\n\nGaston Casillas, Ph.D. (Lead)\nFahim Atif, Ph.D.\nJennifer Przybyla, Ph.D.\nNickolette Roney, M.P.H.\nBrittany Szafran, D.V.M., Ph.D., D.A.B.T.\n\nZach Guerrette, Ph.D., D.A.B.T.\nChristina Coley, M.S.\nLisa Ingerman, Ph.D., D.A.B.T.\nKimberly Zaccaria, Ph.D., D.A.B.T.\nMario Citra, Ph.D.\n\nATSDR, Office of Innovation and Analytics, \nToxicology Section, Atlanta, GA\n\nSRC, Inc., North Syracuse, NY\n\n### REVIEWERS\n\n#### Interagency Minimal Risk Level Workgroup:\n\nIncludes ATSDR; National Center for Environmental Health (NCEH); U.S. Environmental Protection \nAgency (EPA); National Toxicology Program (NTP).\n\n#### Additional reviews for science and/or policy:\n\nATSDR, Office of Community Health Hazard Assessment; ATSDR, Office of Capacity Development \nand Applied Prevention Science; ATSDR, Office of Science; NCEH, Division of Laboratory Sciences; \nNCEH, Division of Environmental Health Science and Practice; EPA, Office of Research and \nDevelopment; EPA, Office of Water.\n\n### PEER REVIEWERS\n\n1. David Dorman, D.V.M., Ph.D., D.A.B.V.T., D.A.B.T.; Professor of Toxicology; North Carolina \nState University; College of Veterinary Medicine; Department of Molecular Biomedical \nSciences; Raleigh, North Carolina\n\n2. Slawo Lomnicki, Ph.D.; Assistant Professor of Environmental Sciences; Louisiana State \nUniversity, Chemistry Department; LSU Superfund Research Materials Core leader; Baton \nRouge, Louisiana\n\n3. Deborah A. Slechta, Ph.D., M.A.; University of Rochester; Professor - Department of \nEnvironmental Medicine (SMD); Professor - Department of Neuroscience (SMD) -– Joint; \nProfessor - Department of Public Health Sciences (SMD) - Joint; Rochester, New York\n\nThese experts collectively have knowledge of toxicology, chemistry, and/or health effects.  All reviewers \nwere selected in conformity with Section 104(I)(13) of the Comprehensive Environmental Response, \nCompensation, and Liability Act, as amended.\n\nATSDR scientists review peer reviewers’ comments and determine whether changes will be made to the \nprofile based on comments.  The peer reviewers’ comments and responses to these comments are part of \nthe administrative record for this compound.\n\nThe listing of peer reviewers should not be understood to imply their approval of the profile's final \ncontent.  The responsibility for the content of this profile lies with ATSDR.\n\n---\n\n## CONTENTS\n\nDISCLAIMER .............................................................................................................................................. ii\nFOREWORD ............................................................................................................................................... iii\nVERSION HISTORY ................................................................................................................................... v\nCONTRIBUTORS & REVIEWERS ........................................................................................................... vi\nCONTENTS ................................................................................................................................................ vii\nLIST OF FIGURES ..................................................................................................................................... ix\nLIST OF TABLES ........................................................................................................................................ x\nCHAPTER 1. RELEVANCE TO PUBLIC HEALTH ................................................................................. 1\n1.1 OVERVIEW AND U.S. EXPOSURES ......................................................................................... 1\n1.2 SUMMARY OF HEALTH EFFECTS........................................................................................... 1\n1.3 MINIMAL RISK LEVELS (MRLs) .............................................................................................. 6\nCHAPTER 2. HEALTH EFFECTS ............................................................................................................ 10\n2.1 INTRODUCTION ........................................................................................................................ 10\n2.2 DEATH ........................................................................................................................................ 55\n2.3 BODY WEIGHT .......................................................................................................................... 57\n2.4 RESPIRATORY .......................................................................................................................... 58\n2.5 CARDIOVASCULAR ................................................................................................................. 63\n2.6 GASTROINTESTINAL ............................................................................................................... 63\n2.7 HEMATOLOGICAL ................................................................................................................... 65\n2.8 MUSCULOSKELETAL .............................................................................................................. 68\n2.9 HEPATIC ..................................................................................................................................... 68\n2.10 RENAL ........................................................................................................................................ 70\n2.11 DERMAL ..................................................................................................................................... 72\n2.12 OCULAR ..................................................................................................................................... 73\n2.13 ENDOCRINE ............................................................................................................................... 74\n2.14 IMMUNOLOGICAL ................................................................................................................... 75\n2.15 NEUROLOGICAL....................................................................................................................... 76\n2.16 REPRODUCTIVE ....................................................................................................................... 77\n2.17 DEVELOPMENTAL ................................................................................................................... 78\n2.18 OTHER NONCANCER ............................................................................................................... 79\n2.19 CANCER ...................................................................................................................................... 79\n2.20 GENOTOXICITY ........................................................................................................................ 80\n2.21 MECHANISM OF ACTION ....................................................................................................... 82\nCHAPTER 3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, \nCHEMICAL INTERACTIONS ........................................................................................... 84\n3.1 TOXICOKINETICS..................................................................................................................... 84\n3.1.1 Absorption ............................................................................................................................. 84\n3.1.2 Distribution ........................................................................................................................... 86\n3.1.3 Metabolism ............................................................................................................................ 88\n3.1.4 Excretion ............................................................................................................................... 90\n3.1.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models ............. 92\n3.1.6 Animal-to-Human Extrapolations ......................................................................................... 93\n3.2 CHILDREN AND OTHER POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE ..... 93\n3.3 BIOMARKERS OF EXPOSURE AND EFFECT ....................................................................... 95\n\n---\n\n3.3.1 Biomarkers of Exposure ........................................................................................................ 95\n3.3.2 Biomarkers of Effect ............................................................................................................. 96\n3.4 INTERACTIONS WITH OTHER CHEMICALS ....................................................................... 97\nCHAPTER 4. CHEMICAL AND PHYSICAL INFORMATION ............................................................. 98\n4.1 CHEMICAL IDENTITY ............................................................................................................. 98\n4.2 PHYSICAL AND CHEMICAL PROPERTIES .......................................................................... 98\nCHAPTER 5. POTENTIAL FOR HUMAN EXPOSURE ....................................................................... 100\n5.1 OVERVIEW .............................................................................................................................. 100\n5.2 PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL ................................................ 101\n5.2.1 Production ........................................................................................................................... 101\n5.2.2 Import/Export ...................................................................................................................... 103\n5.2.3 Use ...................................................................................................................................... 103\n5.2.4 Disposal ............................................................................................................................... 104\n5.3 RELEASES TO THE ENVIRONMENT ................................................................................... 104\n5.3.1 Air ....................................................................................................................................... 105\n5.3.2 Water ................................................................................................................................... 107\n5.3.3 Soil ...................................................................................................................................... 108\n5.4 ENVIRONMENTAL FATE ...................................................................................................... 109\n5.4.1 Transport and Partitioning ................................................................................................... 109\n5.4.2 Transformation and Degradation ........................................................................................ 112\n5.5 LEVELS IN THE ENVIRONMENT ......................................................................................... 116\n5.5.1 Air ....................................................................................................................................... 117\n5.5.2 Water ................................................................................................................................... 118\n5.5.3 Sediment and Soil ............................................................................................................... 122\n5.5.4 Other Media ........................................................................................................................ 123\n5.6 GENERAL POPULATION EXPOSURE.................................................................................. 124\n5.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES .............................................. 125\nCHAPTER 6. ADEQUACY OF THE DATABASE ................................................................................ 126\n6.1 EXISTING INFORMATION ON HEALTH EFFECTS ........................................................... 126\n6.2 IDENTIFICATION OF DATA NEEDS .................................................................................... 126\n6.3 ONGOING STUDIES ................................................................................................................ 135\nCHAPTER 7. REGULATIONS AND GUIDELINES ............................................................................. 136\nCHAPTER 8. REFERENCES .................................................................................................................. 138\nAPPENDICES\nAPPENDIX A.  ATSDR MINIMAL RISK LEVEL WORKSHEETS .................................................... A-1 \nAPPENDIX B. LITERATURE SEARCH FRAMEWORK FOR HCCPD ............................................. B-1 \nAPPENDIX C. FRAMEWORK FOR ATSDR’S SYSTEMATIC REVIEW OF HEALTH EFFECTS \nDATA FOR HCCPD ...................................................................................................... C-1 \nAPPENDIX D.  USER’S GUIDE ............................................................................................................. D-1 \nAPPENDIX E.  QUICK REFERENCE FOR HEALTH CARE PROVIDERS ....................................... E-1 \nAPPENDIX F.  GLOSSARY .................................................................................................................... F-1 \nAPPENDIX G.  ACRONYMS, ABBREVIATIONS, AND SYMBOLS................................................. G-1\n\n---\n\n## LIST OF FIGURES\n\n1-1.  Health Effects Found in Animals Following Inhalation Exposure to HCCPD .................................... 3\n1-2.  Health Effects Found in Animals Following Oral Exposure to HCCPD .............................................. 4\n1-3.  Summary of Sensitive Targets of HCCPD – Inhalation ....................................................................... 7\n1-4.  Summary of Sensitive Targets of HCCPD – Oral ................................................................................ 8\n2-1.  Overview of the Number of Studies Examining HCCPD Health Effects .......................................... 14\n2-2.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation ..................................... 28\n2-3.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Oral .............................................. 44\n5-1.  Number of NPL Sites with Hexachlorocyclopentadiene Contamination ......................................... 100\n5-2.  Transformation of Hexachlorocyclopentadiene ................................................................................ 113\n6-1.  Summary of Existing Health Effects Studies on HCCPD by Route and Endpoint .......................... 127\n\n---\n\n## LIST OF TABLES\n\n1-1.  Provisional Minimal Risk Levels (MRLs) for HCCPD ........................................................................ 9\n2-1.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation ..................................... 15\n2-2.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Oral .............................................. 39\n2-3.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Dermal ......................................... 49\n2-4.  LOAEL Values for Red Blood Cell Hematological Effects of Rats Exposed to HCCPD \nVapor in Acute- and Intermediate-Duration Inhalation  Studies ........................................................ 65\n2-5.  Genotoxicity of Hexachlorocyclopentadiene *In Vivo* ......................................................................... 81\n2-6.  Genotoxicity of Hexachlorocyclopentadiene *In Vitro* ........................................................................ 81\n4-1.  Chemical Identity of Hexachlorocyclopentadiene .............................................................................. 98\n4-2.  Physical and Chemical Properties of Hexachlorocyclopentadiene ..................................................... 98\n5-1.  Facilities that Produce, Process, or Use Hexachlorocyclopentadiene .............................................. 102\n5-2.  Summary of National Aggregate Volumes Reported to U.S. Environmental Protection \nAgency (EPA) Chemical Data  Reporting (CDR) ............................................................................ 103\n5-3.  Releases to the Environment from Facilities that Produce, Process, or Use \nHexachlorocyclopentadiene .............................................................................................................. 105\n5-4.  Summary of Releases to the Environment from the Emissions Inventory System (EIS) \nGateway Emission Sectors in 2020 .................................................................................................. 106\n5-5.  Summary of Releases to the Environment from the Emissions Inventory System (EIS) \nGateway Emission Sectors in 2021 .................................................................................................. 107\n5-6.  Lowest Limit of Detection Based on Standards ............................................................................... 117\n5-7.  Summary of Environmental Levels of HCCPD ............................................................................... 117\n5-*8.*  Summary of Water Monitoring Data for Hexachlorocyclopentadiene Across the \nUnited States ..................................................................................................................................... 119\n7-1.  Regulations and Guidelines Applicable to Hexachlorocyclopentadiene .......................................... 136\n\n---\n\n# CHAPTER 1. RELEVANCE TO PUBLIC HEALTH\n\n###### 1.1 OVERVIEW AND U.S. EXPOSURES\n\nHexachlorocyclopentadiene (HCCPD) is a highly volatile, reactive liquid.  HCCPD is an anthropogenic \nchemical that has entered the environment primarily because of its use in the production of chlorinated \npesticides and flame-retardant chemicals.  Restriction of pesticides synthesized from HCCPD has \ndecreased the possibility of exposure to HCCPD and pesticide residues among most members of the \ngeneral population.  Exposure to materials containing HCCPD at hazardous waste sites is still possible.\n\nThe potential for persistence of HCCPD in the environment is low.  Due to its high vapor pressure, \nHCCPD is most likely released to the environment through volatilization, especially from surface waters \nand soils.  The main degradation processes expected include photolysis and photooxidation, hydrolysis, \nand, to a lesser extent, biodegradation.  HCCPD in the air is expected to degrade with estimated half-lives \nranging from 5 hours to <1 day, which limits its potential for long-range transport. HCCPD in water is \nexpected to degrade rapidly, with half-lives for photolysis of ~2–4 minutes and half-lives for hydrolysis \nof ~3–5.45 days.\n\nOccupational exposure to HCCPD is most likely to occur via inhalation and dermal routes.  The general \npopulation may be exposed to HCCPD through inhalation of air contaminated with this chemical and \ningestion of drinking water contaminated with this chemical.\n\n###### 1.2 SUMMARY OF HEALTH EFFECTS\n\nInformation on the noncancer toxicity of HCCPD in humans is limited to reports by wastewater treatment \nplant (WWTP) workers and cleanup crew members exposed after an inadvertent industrial release.  No \noccupational studies evaluating health effects in workers exposed during regular manufacture or use of \nHCCPD are available.  Additionally, no observational epidemiological studies of workers or the public \nare available for HCCPD.  Further information on the noncancer toxicity of HCCPD comes from \ninhalation and oral studies in animals.  Data following dermal exposure are very limited in humans and \nanimals.\n\nIn laboratory animals, evaluation of available dose-response data by route and duration indicates that \nsensitive noncancer targets of HCCPD toxicity are respiratory and hematological effects following inhalation exposure (Figure 1-1).  Ovarian inflammation was noted in mice following chronic-duration \ninhalation exposure; however, the causal relationship between the effect and HCCPD exposure could not \nbe determined due to apparent association with stress-induced susceptibility to an infection in the mouse \ncolony (see Section 2.16).  Due to this, female reproductive (ovarian) effects were not considered as \npotential sensitive effects or included in Figure 1-1.  The oral database is very limited; the only potential \ntargets identified below doses associated with lethality include the gastrointestinal tract and kidney \n(Figure 1-2). General toxicity (decreased body weight) was also observed at similar doses.  A systematic \nreview of sensitive target organs/systems by exposure route resulted in the following hazard identification \nconclusions:\n\n• Respiratory effects are a presumed health effect for humans following inhalation exposure.\n\n• Gastrointestinal effects are a presumed health effect for humans following oral exposure.\n\n• Hematological (red blood cell) effects are suspected health effects for humans following \ninhalation exposure; white blood cell effects are not classifiable as to the hazard to humans.\n\n• Renal effects are a presumed health effect for humans following oral exposure.\n\n**_Respiratory Effects (Inhalation Route)._**  The respiratory tract is sensitive to HCCPD toxicity after \ninhalation exposure; findings are attributed to compound reactivity upon contact with respiratory tissues \nat the portal of entry.  WWTP workers and cleanup crew members reported respiratory symptoms \nincluding coughing, nose and throat irritation, and difficulty breathing following inhalation of HCCPD \nvapors from an inadvertent industrial discharge (Kominsky et al. 1980; Morse et al. 1979).  Acuteduration inhalation exposure studies in animals identified increased or labored respiration or abnormal \nrespiratory patterns at concentrations ≥0.5 ppm (Alexander et al. 1980a; Jackson and Hardy 1986, 1987; \nRand et al. 1982a).  Sneezing and altered respiratory rates/patterns were observed in rodents at \nintermediate-duration exposures of ≥0.56 ppm (Clark 1981; NTP 1994).  Histopathological evaluation \nidentified changes to the nasal, tracheobronchial, and/or pulmonary epithelium in rats and mice at \n≥0.385 and ≥0.2 ppm, respectively; these changes consisted of inflammation (suppurative or necrotizing) \nor metaplasia at nonlethal concentrations (Clark 1981; NTP 1994) and hemorrhaging or necrosis at lethal \nconcentrations (NTP 1994).  Nasal and pulmonary lesions were observed in mice exposed to 0.2 ppm \nHCCPD for 2 years, while no lesions were observed in rats under the same exposure conditions (NTP \n1994).\n\n$$\n\\geq0.385and\\geq0.2\n$$\n\n---\n\n**Figure 1-1.  Health Effects Found in Animals Following Inhalation Exposure to** \n**HCCPD**\n\n**Concentration (ppm)**\n\n**≥1.4**\n\n**Effects in Animals**\n\n**Acute:**  Neurobehavioral effects\n\n**Intermediate:**  Hepatic effects\n\n**0.5**\n\n**Acute:**  Death, respiratory lesions, altered hematology parameters, \ndecreased body weight, decreased food and water intake\n\n**Intermediate:**  Decreased body weight\n\n**0.389**\n\n**Intermediate:**  Death\n\n**0.2**\n\n**0.039**\n\n**Intermediate:**  Respiratory lesions\n\n**Chronic:**  Death, respiratory lesions\n\n**Intermediate:**  Altered red blood cell parameters\n\n1x10<sup>-4</sup> ppm\n6x10<sup>-5</sup> ppm\n\n**Provisional Intermediate MRL**\n**Provisional Chronic MRL**\n\n---\n\n**Figure 1-2.  Health Effects Found in Animals Following Oral Exposure to HCCPD**\n\nDose (mg/kg/day) Effects in Animals\n≥464 Acute:  Gastrointestinal, neurological, respiratory, and musculoskeletal  \neffects \n150 Intermediate:  Death\n75 Acute:  Death, developmental effects\n38 Intermediate:  Gastrointestinal and renal lesions, decreased body \nweight\n0.06 mg/kg/day Provisional Intermediate MRL\n\n**_Gastrointestinal Effects (Oral Route)._** The gastrointestinal tract is sensitive to HCCPD after oral \nexposure; findings are attributed to compound reactivity upon contact with gastrointestinal tissues at the \nportal of entry.  No human data are available evaluating potential gastrointestinal effects of HCCPD \nfollowing oral exposure.  Diarrhea was reported in rodents administered single oral doses of ≥464 mg/kg \n(Dean 1977; Gardner 1986a); this effect was not reported at lower doses in intermediate-duration studies \nup to 150 mg/kg/day in rats or 300 mg/kg/day in mice (Abdo et al. 1984).  In the only available \nintermediate-duration oral study in animals, focal inflammation and epithelial hyperplasia of the \nforestomach were observed in rats and mice exposed to ≥38 and ≥75 mg/kg/day, respectively (Abdo et al.\n1984).  While humans lack a forestomach, analogous lesions could occur in the proximate portions of the \nhuman gastrointestinal tract, including oral, pharyngeal, and/or esophageal tissues, due to portal-of-entry \nreactivity following oral exposure to HCCPD.\n\n**_Hematological Effects (Inhalation Route)._**  No changes in blood counts were observed in workers \nexposed to HCCPD at a WWTP following an inadvertent industrial discharge (Kominsky et al. 1980).  \nAlterations in red blood cell parameters, primarily elevated red blood cell counts and hemoglobin levels, were reported in rats following acute- and intermediate-duration inhalation exposure to HCCPD at \nconcentrations of 0.5 and ≥0.14 ppm, respectively (Clark 1981; NTP 1994; Rand et al. 1982a); similar \nfindings were observed in mice at intermediate-duration inhalation concentrations ≥0.039 ppm (NTP \n1994).  Based on the absence of histopathological changes to bone marrow, observed red blood cell \neffects have been hypothesized to be a compensatory response to hemorrhagic damage to the lungs \nfollowing inhalation exposure rather than direct effects on hematopoiesis (Rand et al. 1982a).  However,\nrats showed sex-specific findings (females were less sensitive), and there were inconsistencies between \nthe main 13-week (comprehensive) study and the 13-week specialized hematological study conducted by \nNTP (1994).  In mice, findings were limited and inconsistent with respect to alterations in red blood cell \nparameters after exposure for 13–42 weeks (NTP 1994).  Additionally, no hematological effects were \nobserved in the 2-year inhalation studies in rats or mice at concentrations up to 2 ppm (NTP 1994).  No \nconsistent effects on white blood cell parameters were observed with inhalation exposures in animal \nstudies (Clark 1981; NTP 1994; Rand et al. 1982a).\n\n**_Renal Effects (Oral Route)._** No human data are available to assess the potential for HCCPD to cause \nrenal toxicity.  In the only available oral study in animals evaluating the kidney, HCCPD produced toxic \nnephrosis in male and female rats at ≥38 mg/kg/day and in female mice at ≥75 mg/kg/day (Abdo et al. \n1984).  Toxic nephrosis was not identified in male mice, but acute tubular necrosis was identified in male \nmice exposed to 300 mg/kg/day. Available toxicokinetic data indicate that HCCPD and/or its metabolites \ndistribute to the kidneys in both rats and mice after oral dosing; however, the highest distribution is to the \nkidney in the rat and to the liver in the mouse (Dorough and Ranieri 1984).  This observed difference in \ndistribution may explain the observed species sensitivity.\n\n**_Cancer Effects._**  There were no data from studies in humans pertaining to the carcinogenicity of HCCPD.  \nThe National Toxicology Program (NTP) conducted 2-year bioassays of HCCPD in mice and rats and \nconcluded that it is not a carcinogen in either species (NTP 1994).  Although the incidence of \nalveolar/bronchiolar carcinomas was significantly increased in male mice exposed to 0.5 ppm for 26 or \n42 weeks and evaluated at 2 years, the incidence was within the historical range for the laboratory and \nwas not elevated in animals exposed to 0.2 ppm for 2 years. There was also a slight increase in the \nincidence of adenomas of the pituitary pars distalis in male rats and thyroid follicle cell adenomas in \nfemale mice, but these tumors were not considered to be exposure-related since the incidences were \nsimilar to the historical control means, were within the historical control range, or did not exhibit a dosedependency.  Based on these results, the U.S. Environmental Protection Agency (EPA) determined that \nHCCPD is not likely to be a human carcinogen by the inhalation route (IRIS 2003).  The International\n\n---\n\nAgency for Research on Cancer (IARC) has not evaluated the carcinogenicity of HCCPD (IARC 2025).  \nThe U.S. Department of Health and Human Services (HHS) has not evaluated a cancer classification \ncategory for HCCPD (NTP 2021).\n\n###### 1.3 MINIMAL RISK LEVELS (MRLs)\n\nAs illustrated in Figure 1-3, available inhalation data for HCCPD suggest that the respiratory and \nhematological systems are the most sensitive targets for toxicity. The inhalation database was considered \nadequate for derivation of provisional intermediate- and chronic-duration MRLs.  As discussed in \nSection 1.2, ovarian effects observed in the chronic-duration mouse study were not considered as \npotential sensitive effects due to potential confounding by a utero-ovarian infection (see Appendix A for \ndetails).  Therefore, female reproductive effects are not included in Figure 1-3.\n\nAs illustrated in Figure 1-4, gastrointestinal, renal, and body weight effects appear to be the most \nsensitive targets of HCCPD toxicity following oral exposure. The oral database was considered adequate \nfor derivation of a provisional intermediate-duration MRL for HCCPD.  The acute- and chronic-duration \noral data were insufficient for deriving MRLs.\n\nThe provisional MRL values are summarized in Table 1-1 and discussed in greater detail in Appendix A.\n\n---\n\n**Figure 1-3.  Summary of Sensitive Targets of HCCPD – Inhalation**\n\n**Available data indicate that the hematological and respiratory systems are the most sensitive \ntargets of HCCPD inhalation exposure.**\n\nNumbers in circles are the lowest LOAELs for all health effects in animals. No reliable dose response \ndata were available for humans.\n\n**Acute (ppm)**\n\n| Category | Acute (ppm) | Intermediate (ppm) | Chronic (ppm) |\n| --- | --- | --- | --- |\n| Death | 0.5 | 0.389 | 0.2 |\n| Body weight | 0.5 |  |  |\n| Respiratory | 0.5 | 0.2 | 0.2 |\n| Hematological | 0.5 | 0.039 |  |\n| Other noncancer | 0.5 |  |  |\n\n---\n\n**Figure 1-4. Summary of Sensitive Targets of HCCPD – Oral**\n\n**Available data indicate that the gastrointestinal tract, renal system, and body weight are the most\nsensitive targets of HCCPD oral exposure.**\nNumbers in circles are the lowest LOAELs for all health effects in animals. \nNo reliable dose response data were available for humans.\n\n## Acute (mg/kg/day)\n\n| Category | Lowest LOAEL (mg/kg/day) |\n| --- | --- |\n| Death (Acute) | 75 |\n| Developmental (Acute) | 75 |\n| Gastrointestinal (Acute) | 464 |\n| Neuological (Acute) | 464 |\n| Body weight (Intermediate) | 38 |\n| Gastrointestinal (Intermediate) | 38 |\n| Renal (Intermediate) | 38 |\n| Death (Intermediate) | 150 |\n\n---\n\nTable 1-1. Provisional Minimal Risk Levels (MRLs) for HCCPD<sup>a</sup>\n\n| Exposure route | Exposure duration | Provisional MRL | Critical effect | POD type | POD value | Uncertainty/modifying factor | Reference |\n| --- | --- | --- | --- | --- | --- | --- | --- |\n| Inhalation | Acute | None | - | - | - | - | - |\n| Inhalation | Intermediate | 1 × 10-4 ppm (1 × 10-3 mg/m3) | Nasal suppurative inflammation in rats | NOAELHEC | 0.00344 ppm | UF: 30 | NTP 1994 |\n| Inhalation | Chronic | 6 × 10-5 ppm (7 × 10-4 mg/m3) | Nasal suppurative inflammation in mice | BMCLHEC | 0.0019 ppm | UF: 30 | NTP 1994 |\n| Oral | Acute | None | - | - | - | - | - |\n| Oral | Intermediate | 0.06 mg/kg/day | Combined incidence of forestomach epithelial hyperplasia and focal inflammation in rats | BMDLADJ | 5.5 mg/kg/day | UF: 100 | Abdo et al. 1984: Velsicol 1981b |\n| Oral | Chronic | None | - | - | - | - | - |\n\n$$\n1\\times10^{-4}ppm\n$$\n\n$$\n(1\\times10^{-3}mg/m^3)\n$$\n\n$$\n6\\times10^{-5}ppm\n$$\n\n$$\n(7\\times10^{-4}mg/m^3)\n$$\n\n<sup>a</sup>See Appendix A for additional information.\n\nADJ = adjusted for intermittent exposure; BMCL = benchmark concentration lower confidence limit; BMDL = benchmark dose lower confidence limit;\n\nHEC = human equivalent concentration; NOAEL = no-observed-adverse-effect level; POD = point of departure; UF = uncertainty factor\n\n---\n\n# CHAPTER 2. HEALTH EFFECTS\n\n###### 2.1 INTRODUCTION\n\nThe primary purpose of this chapter is to provide public health officials, physicians, toxicologists, and \nother interested individuals and groups with an overall perspective on the toxicology of HCCPD.  It \ncontains descriptions and evaluations of toxicological studies and epidemiological investigations and \nprovides conclusions, where possible, on the relevance of toxicity and toxicokinetic data to public health.  \nWhen available, mechanisms of action are discussed along with the health effects data; toxicokinetic \nmechanistic data are discussed in Section 3.1.\n\nA glossary and list of acronyms, abbreviations, and symbols can be found at the end of this profile.\n\nTo help public health professionals and others address the needs of persons living or working near hazardous \nwaste sites, the information in this section is organized by health effects.  These data are discussed in terms \nof route of exposure (inhalation, oral, and dermal) and three exposure periods:  acute (≤14 days), \nintermediate (15–364 days), and chronic (≥365 days).\n\nAs discussed in Appendix B, a literature search was conducted to identify relevant studies examining health \neffect endpoints.  Figure 2-1 provides an overview of the database of studies in humans or experimental \nanimals included in this chapter of the profile.  These studies evaluate the potential health effects associated \nwith inhalation, oral, or dermal exposure to HCCPD, but may not be inclusive of the entire body of literature.  \nA systematic review of the scientific evidence of the health effects associated with exposure to HCCPD was \nalso conducted; the results of this review are presented in Appendix C.\n\nHuman and animal inhalation studies are presented in Table 2-1 and Figure 2-2, animal oral studies are \npresented in Table 2-2 and Figure 2-3, and human and animal dermal studies are presented in Table 2-3.  \nDue to the limited nature of the database, several older studies lacking quantitative data reporting are \nincluded in Chapter 2 to provide data potentially relevant for hazard identification; however, data that are \nonly reported qualitatively (i.e., histopathological data lacking incidence data) are not included in \nTables 2-1, 2-2, or 2-3.\n\nLevels of significant exposure (LSEs) for each route and duration are presented in tables and illustrated in \nfigures.  The points in the figures showing no-observed-adverse-effect levels (NOAELs) or lowest- observed-adverse-effect levels (LOAELs) reflect the actual doses (levels of exposure) used in the studies.  \nEffects have been classified into “less serious LOAELs” or “serious LOAELs (SLOAELs).”  “Serious” \neffects are those that evoke failure in a biological system and can lead to morbidity or mortality (e.g., \nacute respiratory distress or death).  “Less serious” effects are those that are not expected to cause \nsignificant dysfunction or death, or those whose significance to the organism is not entirely clear.  \nATSDR acknowledges that a considerable amount of judgment may be required in establishing whether \nan endpoint should be classified as a NOAEL, “less serious” LOAEL, or “serious” LOAEL, and that in \nsome cases, there will be insufficient data to decide whether the effect is indicative of significant \ndysfunction.  However, the Agency has established guidelines and policies that are used to classify these \nendpoints.  ATSDR believes that there is sufficient merit in this approach to warrant an attempt at \ndistinguishing between “less serious” and “serious” effects.  The distinction between “less serious” effects \nand “serious” effects is considered to be important because it helps the users of the profiles to identify \nlevels of exposure at which major health effects start to appear.  LOAELs or NOAELs should also help in \ndetermining whether or not the effects vary with dose and/or duration, and place into perspective the \npossible significance of these effects to human health.\n\nA User's Guide has been provided at the end of this profile (see Appendix C).  This guide should aid in \nthe interpretation of the tables and figures for LSEs and MRLs.\n\nThe health effects of HCCPD have been evaluated in 2 human studies and 68 animal studies.  As \nillustrated in Figure 2-1, most of the health effect data come from dermal and inhalation studies in \nanimals.  In both human and animal studies, the ocular effects observed in HCCPD inhalation studies are \nlikely attributable to direct contact with HCCPD vapors.  Therefore, ocular effects from inhalation studies \nare counted as dermal exposure in Figure 2-1 and are listed in the dermal LSE table.\n\nThe available human studies were predominantly focused on evaluation of dermal, ocular, and respiratory \neffects in WWTP workers and cleanup crew members following an inadvertent industrial release of \nHCCPD.  For these studies, exposure was evaluated as HCCPD vapor levels in air.\n\nFor animal data, inhalation and oral studies are available for most health effects.  Acute-, intermediate-, \nand chronic-duration studies are available for the inhalation route, while only acute- and intermediateduration studies are available for the oral route.  The dermal animal database is mostly limited to ocular \nand dermal effects, largely following exposure to HCCPD vapor.  The most examined endpoints in \nanimal studies were death, respiratory, hepatic, renal, and ocular.\n\n---\n\nA systematic review was conducted on potential targets of HCCPD exposure, which included respiratory \nand hematological effects for inhalation exposure and gastrointestinal and renal effects following oral \nexposure (see Appendix C for details).\n\n• **Respiratory Effects.** Respiratory effects are a presumed health effect associated with HCCPD \nexposure via inhalation based on inadequate evidence in humans and a high level of evidence in \nanimals.  WWTP workers and cleanup crew members reported respiratory symptoms including \ncoughing and respiratory tract irritation after exposure to HCCPD vapors following an \ninadvertent industrial release.  Several animal studies have reported altered respiratory patterns \nfollowing single or repeated exposures to HCCPD.  Upon histopathological examination, \nnonneoplastic lesions of the nasal, tracheobronchial, and pulmonary regions were consistently \nobserved in mice and rats exposed for intermediate durations to concentrations ≥0.2 or \n≥0.385 ppm, respectively.  Chronic-duration exposure to 0.2 ppm resulted in similar lesions in \nmice, but not rats.  Observed lesions (suppurative, serous, or necrotizing inflammation; epithelial \nhyperplasia) are consistent with chronic irritation at the portal of entry.\n\n• **Gastrointestinal Effects.** Gastrointestinal effects are a presumed health effect associated with \nHCCPD exposure via oral exposure based on no human data and a high level of evidence in \nanimal studies.  Diarrhea was reported in rodents following exposure to high acute doses \n≥464 mg/kg.  Forestomach lesions (epithelial hyperplasia and focal inflammation) were observed \nin rats and mice following intermediate-duration exposures of ≥38 and ≥75 mg/kg/day, \nrespectively.  Although humans lack a forestomach, effects associated with HCCPD are \nconsistent with chronic irritation at the portal of entry.  Thus, the upper gastrointestinal tract is\npresumably vulnerable to toxicity following oral exposure to HCCPD.\n\n• **Hematological Effects.** Hematological effects, specifically red blood cell parameters, are a \nsuspected health effect associated with HCCPD exposure via inhalation based on inadequate data \nin humans and a moderate level of evidence in animals.  No changes in blood counts were \nobserved in WWTP workers after exposure to HCCPD vapors following an inadvertent industrial \nrelease.  Several acute- and intermediate-duration inhalation studies reported altered red blood \ncell parameters (e.g., increased hemoglobin, red blood cell counts, and packed cell volume) at \nconcentrations as low as 0.14 and 0.039 ppm in rats and mice, respectively; however, these \nfindings were not consistent across sexes or species nor were they reproducible in targeted \nanalyses by the same researchers.  Observed red blood cell effects may be attributable to\ncompromised gas exchange following tissue damage to the respiratory tract, as no evidence of \nbone marrow hyperplasia was observed in rodents following repeated inhalation exposure to \nHCCPD. White blood cell effects are not classifiable as to the hazard to humans based on no data \nin humans and inadequate evidence in animals.  Available studies did not find consistent evidence \nof alterations in white blood cell parameters in rats or mice following intermediate- or chronicduration inhalation exposure to HCCPD.\n\n• **Renal Effects.** Renal effects are a presumed health effect associated with oral exposure to\nHCCPD based on no human data and a high level of evidence in animal studies.  Renal lesions, \nspecifically toxic nephrosis, were observed in rats and mice following intermediate-duration \nexposures to ≥38 and ≥75 mg/kg/day, respectively. Acute tubular necrosis was observed in male \nmice at a higher dose (300 mg/kg/day).  Available toxicokinetic data indicate that HCCPD and/or\n\n---\n\n###### 2. HEALTH EFFECTS\n\nits metabolites distribute to the kidneys of both rats and mice after oral dosing; however, it will \naccumulate to a higher degree in rats.\n\n---\n\n**Figure 2-1.  Overview of the Number of Studies Examining HCCPD Health Effects***\n\n**Most studies examined the potential death, respiratory, neurological, renal, hepatic, and ocular effects of HCCPD**\nFewer studies evaluated health effects in **humans** than **animals** (counts represent studies examining endpoint)\n\n| Category | Number of studies |\n| --- | --- |\n| Death | 57 |\n| Body weight | 18 |\n| Respiratory | 44 |\n| Cardiovascular | 35 |\n| Gastrointestinal | 16 |\n| Hematological | 13 |\n| Musculoskeletal | 10 |\n| Hepatic | 39 |\n| Renal | 39 |\n| Dermal | 16 |\n| Ocular | 39 |\n| Endocrine | 35 |\n| Immunological | 12 |\n| Neurolgical | 41 |\n| Reproductive | 11 |\n| Developmental | 3 |\n| Other Noncancer | 7 |\n| Cancer | 5 |\n\n**Exposure Route**\n\n| Category | Share of studies (%) |\n| --- | --- |\n| Inhalation | 40 |\n| Oral | 13 |\n| Dermal | 47 |\n\n**Exposure Duration**\n\n| Category | Share of studies (%) |\n| --- | --- |\n| Chronic | 2 |\n| Acute | 78 |\n| Intermediate | 20 |\n\n*Includes studies discussed in Chapter 2.  A total of 70 studies (including those finding no effect) have examined toxicity; most studies examined multiple \nendpoints.\n\n---\n\n**Table 2-1. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation\n(ppm)**\n\n| Species (strain) keya | No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| ACUTE EXPOSURE |  |  |  |  |  |  |  |  |  |\n| Alexander et al. 1980a; Rand et al. 1982a |  |  |  |  |  |  |  |  |  |\n| 1 | Rat (Sprague-Dawley) 10 M, 10 F | 1–2 weeks 5 days/week 6 hours/day (WB) | 0, 0.022, 0.11, 0.5 | LE, CS, BW, FI, HE, BC, GN, OW, HP | Death Bd wt | 0.11 |  | 0.5 M | 10/10 died or were sacrificed in moribund condition Decreased terminal body weight in females (29%) and males (32%) Labored respiration; increased absolute lung weight; bronchiole inflammation, hyperplasia, and epithelial erosion |\n| 1 | Rat (Sprague-Dawley) 10 M, 10 F | 1–2 weeks 5 days/week 6 hours/day (WB) | 0, 0.022, 0.11, 0.5 | LE, CS, BW, FI, HE, BC, GN, OW, HP | Resp | 0.11 |  | 0.5 | 10/10 died or were sacrificed in moribund condition Decreased terminal body weight in females (29%) and males (32%) Labored respiration; increased absolute lung weight; bronchiole inflammation, hyperplasia, and epithelial erosion |\n| 1 | Rat (Sprague-Dawley) 10 M, 10 F | 1–2 weeks 5 days/week 6 hours/day (WB) | 0, 0.022, 0.11, 0.5 | LE, CS, BW, FI, HE, BC, GN, OW, HP | Cardio Hematoc | 0.5 0.11 | 0.5 | 0.5 | Males: total white blood cell and lymphocyte counts reduced Females: neutrophils increased Both: red blood cell count, packed cell volume, and hemoglobin increased |\n| 1 | Rat (Sprague-Dawley) 10 M, 10 F | 1–2 weeks 5 days/week 6 hours/day (WB) | 0, 0.022, 0.11, 0.5 | LE, CS, BW, FI, HE, BC, GN, OW, HP | Hepatic Renal Immuno Neuro | 0.5 0.5 0.5 Other noncancer | 0.5 |  | Decreased food and water intake |\n| Jackson and Hardy 1986 |  |  |  |  |  |  |  |  |  |\n| 2 | Rat (Wistar) 5 M, 5 F | 1 hour (WB) | 0, 1.67, 2.38, 3.53, 6.25, 8.30 | LE, CS, BW, FI, WI, OW, GN | Death Bd wt | 1.67 |  | 3.69 | LC50 Decreased body weight at death or scheduled sacrifice (3-weeks post exposure) in males (41%) and females (26%) Abnormal respiratory pattern Decreased food consumption |\n| 2 | Rat (Wistar) 5 M, 5 F | 1 hour (WB) | 0, 1.67, 2.38, 3.53, 6.25, 8.30 | LE, CS, BW, FI, WI, OW, GN | Resp Other noncancer | 1.67 1.67 |  |  | LC50 Decreased body weight at death or scheduled sacrifice (3-weeks post exposure) in males (41%) and females (26%) Abnormal respiratory pattern Decreased food consumption |\n\n---\n\n**Table 2-1. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation\n(ppm)**\n\nAbnormal respiratory pattern\nDecreased food consumption\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Jackson and Hardy 1987 |  |  |  |  |  |  |  |  |  |\n| 3 | Rat (Wistar) 5 M, 5 F | 4 hours (WB) | 0, 1.68, 1.83, 3.31, 3.47 | LE, CS, BW, FI, WI, GN, OW | Death Bd wt |  |  | 2.9 1.68 M | LC50 23% decreased body weight at scheduled sacrifice (4 weeks post exposure) |\n| 3 | Rat (Wistar) 5 M, 5 F | 4 hours (WB) | 0, 1.68, 1.83, 3.31, 3.47 | LE, CS, BW, FI, WI, GN, OW | Resp Other noncancer | 1.68 F | 1.68 1.68 | 1.83 F | 24% decreased body weight at death or scheduled sacrifice (4 weeks post exposure) |\n| OxyChem 1972 |  |  |  |  |  |  |  |  |  |\n| 4 | Rat (Carworth CFE) 10 M | 4 hours (WB) | 176, 1,760 | LE, CS, GN | Death |  |  | 176 | 10/10 died within 48 hours |\n| Rand et al. 1982a |  |  |  |  |  |  |  |  |  |\n| 5 | Rat (Sprague-Dawley) 10 M, 10 F | 4 hours (WB) | 0.28, 1.4, 2.5, 3.1, 3.3, 3.4, 4, 5.8 | LE, CS, BW | Death |  |  | 3.5 F 1.6 M | LC50 LC50 |\n| 5 | Rat (Sprague-Dawley) 10 M, 10 F | 4 hours (WB) | 0.28, 1.4, 2.5, 3.1, 3.3, 3.4, 4, 5.8 | LE, CS, BW | Bd wt | 0.28 | 1.4 F | 1.4 M | 17% body weight loss 25% body weight loss |\n| 5 | Rat (Sprague-Dawley) 10 M, 10 F | 4 hours (WB) | 0.28, 1.4, 2.5, 3.1, 3.3, 3.4, 4, 5.8 | LE, CS, BW | Neuro | 0.28 | 1.4 | 5.8 | LOAEL: Sedation SLOAEL: Ataxia |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 6 | Rat 4 NS | 2 days 7 hours/day (WB) | 3.2 | LE, CS, GN | Death |  |  | 3.2 | 4/4 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 7 | Rat 4 NS | 3 days 7 hours/day (WB) | 1.4 | LE, CS, GN | Death |  |  | 1.4 | 3/4 died |\n\n---\n\n**Table 2-1. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation\n(ppm)**\n\n| Species |  |  |  |  |  |  |  |  |  |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Figure keya | No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 8 | Rat 4 NS | 2.6–3.6 hours (WB) | 1.4, 3.1, 7.1, 12.4, 12.7, 46.5, 56.9, 70.4 | LE, CS, GN | Death |  |  | 3.1 | 2/4 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 9 | Rat 4 NS | 7 hours (WB) | 1.5, 3.2, 6.7 | LE, CS, GN | Death |  |  | 3.2 | 3/4 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 10 | Rat 4 NS | 5 days 7 hours/day (WB) | 0.33, 1.0, 1.6 | LE, CS, GN | Death |  |  | 1 | 4/4 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 11 | Rat 4 NS | 0.25–1.25 hours (WB) | 1.4, 1.5, 3.1, 7.2, 13.0, 13.8, 19.4, 20.0, 20.2, 69.1, 69.2 | LE, CS, GN | Death |  |  | 7.2 | 2/4 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 12 | Rat 4 NS | 4 hours (WB) | 73.6 | LE, CS, GN | Death |  |  | 73.6 | 4/4 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 13 | Mouse 5 NS | 0.25–1.25 hours (WB) | 1.4, 1.5, 3.1, 7.2, 13.0, 13.8, 19.4, 20.0, 20.2, 69.1, 69.2 | LE, CS, GN | Death |  |  | 7.2 | 5/5 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 14 | Mouse 5 NS | 4 hours (WB) | 73.6 | LE, CS, GN | Death |  |  | 73.6 | 5/5 died |\n\n---\n\n**Table 2-1. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation\n(ppm)**\n\n| Species (strain) keya | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| 15 Mouse 5 NS | 2 days 7 hours/day (WB) | 3.2 | LE, CS, GN | Death |  |  | 3.2 | 4/5 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| 16 Mouse 5 NS | 3 days 7 hours/day (WB) | 1.4 | LE, CS, GN | Death |  |  | 1.4 | 5/5 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| 17 Mouse 5 NS | 7 hours (WB) | 1.5, 3.2, 6.7 | LE, CS, GN | Death |  |  | 1.5 | 4/5 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| 18 Mouse 5 NS | 2.6– 3.6 hours (WB) | 1.4, 3.1, 7.1, 12.4, 12.7, 46.5, 56.9, 70.4 | LE, CS, GN | Death |  |  | 3.1 | 4/5 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| 19 Mouse 5 NS | 5 days 7 hours/day (WB) | 0.33, 1.0, 1.6 | LE, CS, GN | Death |  |  | 1 | 4/5 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| 20 Rabbit 3 NS | 4 hours (WB) | 73.6 | LE, CS, GN | Death |  |  | 73.6 | 3/3 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| 21 Rabbit 3 NS | 3 days 7 hours/day (WB) | 1.4 | LE, CS, GN | Death |  |  | 1.4 | 3/3 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| 22 Rabbit 3 NS | 5 days 7 hours/day (WB) | 1, 1.6 | LE, CS, GN | Death |  |  | 1 | 3/3 died |\n\n---\n\n**Table 2-1. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation\n(ppm)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 23 | Rabbit 3 NS | 2.6–3.6 hours (WB) | 1.4, 3.1, 7.1, 12.4, 12.7, 46.5, 56.9, 70.4 | LE, CS, GN | Death |  |  | 1.4 | 2/3 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 24 | Rabbit 3 NS | 7 hours (WB) | 1.5, 3.2, 6.7 | LE, CS, GN | Death |  |  | 1.5 | 3/3 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 25 | Rabbit 3 NS | 0.25–1.25 hours (WB) | 1.4, 1.5, 3.1, 7.2, 13.0, 13.8, 19.4, 20.0, 20.2, 69.1, 69.2 | LE, CS, GN | Death |  |  | 3.1 | 2/3 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 26 | Rabbit 3 NS | 2 days 7 hours/day (WB) | 3.2 | LE, CS, GN | Death |  |  | 3.2 | 3/3 died |\n| INTERMEDIATE EXPOSURE |  |  |  |  |  |  |  |  |  |\n| Alexander et al. 1980b; Rand et al. 1982a, 1982b |  |  |  |  |  |  |  |  |  |\n| 27 | Monkey (Cynomolgus) 6 M, 6 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, HE, BC, UR, OP, GN, OW, HP, OF | Bd wt Resp Cardio Gastro Hemato Musc/skel Hepatic Renal Ocular Endocr Immuno | 0.2 0.2 0.2 0.2 0.2 0.2 |  |  |  |\n\n---\n\n**Table 2-1. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation\n(ppm)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n|  |  |  |  |  | Neuro | 0.2 |  |  |  |\n|  |  |  |  |  | Repro | 0.2 |  |  |  |\n|  |  |  |  |  | Other |  |  |  |  |\n|  |  |  |  |  | noncancer |  |  |  |  |\n| Alexander et al. 1980b; Huntingdon Research Centre 1980; Rand et al. 1982a, 1982b |  |  |  |  |  |  |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Bd wt | 0.2 |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Resp | 0.2 |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Cardio | 0.2 |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Gastro | 0.2 |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Hemat | 0.2 |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Musc/skel | 0.2 |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Hepatic | 0.2 |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Renal | 0.2 |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Ocular | 0.2 |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Endocr | 0.2 |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Immuno | 0.2 |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Neuro | 0.2 |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Repro | 0.2 |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Other |  |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | noncancer |  |  |  |  |\n\n---\n\n**Table 2-1. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation\n(ppm)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Clark 1981 |  |  |  |  |  |  |  |  |  |\n| 29 | Rat (Wistar) 18 M, 18 F | 30 weeks 5 days/week 6 hours/day (WB) | 0, 0.06, 0.14, 0.56 | LE, CS, BW, FI, WI, HE, BC, UR, GN, OW, HP | Death Bd wt Resp | 0.56 | 0.56 F | 0.56 M | 4/18 males and 2/18 females died |\n| 29 | Rat (Wistar) 18 M, 18 F | 30 weeks 5 days/week 6 hours/day (WB) | 0, 0.06, 0.14, 0.56 | LE, CS, BW, FI, WI, HE, BC, UR, GN, OW, HP | Resp | 0.14 | 0.56 F | 0.56 M | Females: perivascular/peribronchiolar inflammatory cell infiltration; sneezing Males: bronchiolar epithelial ulceration/thinning and perivascular/peribronchiolar inflammatory cell infiltration; sneezing |\n| 29 | Rat (Wistar) 18 M, 18 F | 30 weeks 5 days/week 6 hours/day (WB) | 0, 0.06, 0.14, 0.56 | LE, CS, BW, FI, WI, HE, BC, UR, GN, OW, HP | Cardio Gastro Hematoma | 0.56 0.56 F 0.06 M | 0.56 F 0.14 M |  | Decreased lymphocyte counts Increased red blood cell counts, hemoglobin, hematocrit, and neutrophil counts; decreased lymphocyte percentage |\n| 29 | Rat (Wistar) 18 M, 18 F | 30 weeks 5 days/week 6 hours/day (WB) | 0, 0.06, 0.14, 0.56 | LE, CS, BW, FI, WI, HE, BC, UR, GN, OW, HP | Musc/skel Hepatic Renal Dermal Ocular Endocr Immuno Neuro Repro | 0.56 0.56 0.56 0.56 0.56 0.56 |  |  |  |\n\n---\n\n**Table 2-1. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation\n(ppm)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n|  |  |  |  |  | Other noncancer | 0.56 |  |  |  |\n| NTP 1994 |  |  |  |  |  |  |  |  |  |\n| 30 | Rat (Fischer-344) 10 M, 10 F | 13 weeks 5 days/week 6 hours/day (WB) | 0, 0.039, 0.146, 0.385, 0.941, 2.065 | LE, CS, BW, HE, BC, GN, OW, HP | Death Bd wt Resp | 0.385 0.385 F 0.146b M | 0.385 M | 0.941 | 100% mortality during first 4 weeks |\n|  |  |  |  |  |  |  |  |  | Nasal squamous metaplasia and suppurative inflammation; suppurative and necrotizing inflammation of the bronchus/bronchiole; increased absolute and relative lung weights |\n|  |  |  |  |  |  |  |  | 0.941 | Increased respiration rate and mouth breathing; suppurative inflammation and hemorrhaging in the alveolus; necrotizing inflammation of the nose, larynx, trachea, and bronchus/bronchiole |\n|  |  |  |  |  | Cardio Gastro Hemato | 0.385 0.385 0.146 | 0.385 |  |  |\n|  |  |  |  |  | Musc/skel | 0.385 |  |  | Males: increased packed cell volume, hemoglobin, red blood cell count, and MCHC |\n|  |  |  |  |  | Hepatic | 0.385 |  |  |  |\n|  |  |  |  |  | Renal | 0.385 |  |  |  |\n|  |  |  |  |  | Endocr | 0.385 |  |  |  |\n|  |  |  |  |  | Immuno | 0.385 |  |  |  |\n|  |  |  |  |  | Neuro | 0.385 |  |  |  |\n|  |  |  |  |  | Repro | 0.385 |  |  |  |\n\n***DRAFT FOR PUBLIC COMMENT***\n\n---\n\n**Table 2-1. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation\n(ppm)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| NTP 1994 |  |  |  |  |  |  |  |  |  |\n| 31 | Rat (Fischer-344) 20 M, 20 F | 13 weeks 5 days/week 6 hours/day (WB) | 0, 0.039, 0.385, 2.065 | LE, HE, BC, UR | Death Hemato | 0.039 | 0.385 | 2.065 | 100% mortality Males: increased MCV; Females: increased MCV, packed cell volume, hemoglobin, and red blood cell count Increased AST |\n| 31 | Rat (Fischer-344) 20 M, 20 F | 13 weeks 5 days/week 6 hours/day (WB) | 0, 0.039, 0.385, 2.065 | LE, HE, BC, UR | Hepatic Renal | 0.385 2.065 | 2.065 | 2.065 | 100% mortality Males: increased MCV; Females: increased MCV, packed cell volume, hemoglobin, and red blood cell count Increased AST |\n| NTP 1994 |  |  |  |  |  |  |  |  |  |\n| 32 | Mouse (B6C3F1) 10 M | 42 weeks 5 days/week 6 hours/day (WB) | 0, 0.5 | LE, CS, BW, GN, OW, HP | Death Bd wt |  |  | 0.5 | 14% decreased survival at 45 weeks Decreased body weight (19%) and body weight gain (42%) at the end of the exposure period Suppurative inflammation of the nose, trachea, and lungs |\n| 32 | Mouse (B6C3F1) 10 M | 42 weeks 5 days/week 6 hours/day (WB) | 0, 0.5 | LE, CS, BW, GN, OW, HP | Resp |  | 0.5 | 0.5 | 14% decreased survival at 45 weeks Decreased body weight (19%) and body weight gain (42%) at the end of the exposure period Suppurative inflammation of the nose, trachea, and lungs |\n| 32 | Mouse (B6C3F1) 10 M | 42 weeks 5 days/week 6 hours/day (WB) | 0, 0.5 | LE, CS, BW, GN, OW, HP | Gastro Hepatic | 0.5 |  | 0.5 | 14% decreased survival at 45 weeks Decreased body weight (19%) and body weight gain (42%) at the end of the exposure period Suppurative inflammation of the nose, trachea, and lungs |\n| 32 | Mouse (B6C3F1) 10 M | 42 weeks 5 days/week 6 hours/day (WB) | 0, 0.5 | LE, CS, BW, GN, OW, HP | Renal | 0.5 |  | 0.5 | 14% decreased survival at 45 weeks Decreased body weight (19%) and body weight gain (42%) at the end of the exposure period Suppurative inflammation of the nose, trachea, and lungs |\n| 32 | Mouse (B6C3F1) 10 M | 42 weeks 5 days/week 6 hours/day (WB) | 0, 0.5 | LE, CS, BW, GN, OW, HP | Endocr Immuno | 0.5 |  | 0.5 | 14% decreased survival at 45 weeks Decreased body weight (19%) and body weight gain (42%) at the end of the exposure period Suppurative inflammation of the nose, trachea, and lungs |\n| 32 | Mouse (B6C3F1) 10 M | 42 weeks 5 days/week 6 hours/day (WB) | 0, 0.5 | LE, CS, BW, GN, OW, HP | Repro | 0.5 |  | 0.5 | 14% decreased survival at 45 weeks Decreased body weight (19%) and body weight gain (42%) at the end of the exposure period Suppurative inflammation of the nose, trachea, and lungs |\n| NTP 1994 |  |  |  |  |  |  |  |  |  |\n| 33 | Mouse (B6C3F1) 20 M, 20 F | 13 weeks 5 days/week 6 hours/day (WB) | 0, 0.039, 0.389, 2.142 | LE, HE, BC, UR | Death Hemato |  | 0.039 F 0.389 M | 2.142 | 100% mortality Increased MCHC Increased MCHC |\n| 33 | Mouse (B6C3F1) 20 M, 20 F | 13 weeks 5 days/week 6 hours/day (WB) | 0, 0.039, 0.389, 2.142 | LE, HE, BC, UR | Hepatic Renal | 0.039 M 2.142 2.142 | 0.039 F 0.389 M | 2.142 | 100% mortality Increased MCHC Increased MCHC |\n\n---\n\n**Table 2-1. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation\n(ppm)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| NTP 1994 |  |  |  |  |  |  |  |  |  |\n| 34 | Mouse (B6C3F1) 10 M | 26 weeks 5 days/week 6 hours/day (WB) | 0, 0.5 | LE, CS, BW, GN, OW, HP | Bd wt Resp | 0.5 | 0.5 |  | Nasal suppurative inflammation |\n| NTP 1994 |  |  |  |  |  |  |  |  |  |\n| 35 | Mouse (B6C3F1) 10 M | 33 weeks 5 days/week 6 hours/day (WB) | 0, 0.2 | LE, CS, BW, GN, OW, HP | Bd wt Resp Gastro Hepatic Renal Immuno Neuro Repro | 0.2 | 0.2 |  | Nasal suppurative inflammation |\n| NTP 1994 |  |  |  |  |  |  |  |  |  |\n| 36 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week 6 hours/day (WB) | 0, 0.039, 0.146, 0.389, 0.949, 2.142 | LE, CS, BW, HE, BC, OW, HP | Death |  |  | 0.949 F 0.389 M | 10/10 died 5/10 died |\n| 36 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week 6 hours/day (WB) | 0, 0.039, 0.146, 0.389, 0.949, 2.142 | LE, CS, BW, HE, BC, OW, HP | Bd wt Resp | 0.389 |  |  | Females: focal serous or suppurative inflammation of the nose Males: squamous metaplasia in the trachea, focal serous or suppurative inflammation of the nose |\n| 36 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week 6 hours/day (WB) | 0, 0.039, 0.146, 0.389, 0.949, 2.142 | LE, CS, BW, HE, BC, OW, HP | Cardio Gastro Hemato | 0.389 |  |  | Decreased MCV |\n| 36 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week 6 hours/day (WB) | 0, 0.039, 0.146, 0.389, 0.949, 2.142 | LE, CS, BW, HE, BC, OW, HP | Musc/skel | 0.389 |  |  |  |\n\n***DRAFT FOR PUBLIC COMMENT***\n\n---\n\n**Table 2-1. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation\n(ppm)**\n\n| Species Figure keya | Species (strain) No./group | Species Exposure parameters | Species Doses | Species Parameters monitored | Species Endpoint | Species NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n|  |  |  |  |  | Hepatic | 0.389 |  |  |  |\n|  |  |  |  |  | Renal | 0.389 |  |  |  |\n|  |  |  |  |  | Endocr | 0.389 |  |  |  |\n|  |  |  |  |  | Immuno | 0.389 |  |  |  |\n|  |  |  |  |  | Neuro | 0.389 |  |  |  |\n|  |  |  |  |  | Repro | 0.389 |  |  |  |\n| CHRONIC EXPOSURE |  |  |  |  |  |  |  |  |  |\n| NTP 1994 |  |  |  |  |  |  |  |  |  |\n| 37 | Rat (Fischer-344) 50 M, 50 F | 104 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, UR, GN, OW, HP | Bd wt | 0.2 |  |  |  |\n| 37 | Rat (Fischer-344) 50 M, 50 F | 104 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, UR, GN, OW, HP | Resp | 0.2 |  |  |  |\n| 37 | Rat (Fischer-344) 50 M, 50 F | 104 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, UR, GN, OW, HP | Cardio | 0.2 |  |  |  |\n| 37 | Rat (Fischer-344) 50 M, 50 F | 104 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, UR, GN, OW, HP | Gastro | 0.2 |  |  |  |\n| 37 | Rat (Fischer-344) 50 M, 50 F | 104 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, UR, GN, OW, HP | Hemat | 0.2 |  |  |  |\n| 37 | Rat (Fischer-344) 50 M, 50 F | 104 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, UR, GN, OW, HP | Musc/skel | 0.2 |  |  |  |\n| 37 | Rat (Fischer-344) 50 M, 50 F | 104 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, UR, GN, OW, HP | Hepatic | 0.2 |  |  |  |\n| 37 | Rat (Fischer-344) 50 M, 50 F | 104 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, UR, GN, OW, HP | Renal | 0.2 |  |  |  |\n| 37 | Rat (Fischer-344) 50 M, 50 F | 104 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, UR, GN, OW, HP | Dermal | 0.2 |  |  |  |\n| 37 | Rat (Fischer-344) 50 M, 50 F | 104 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, UR, GN, OW, HP | Endocr | 0.2 |  |  |  |\n| 37 | Rat (Fischer-344) 50 M, 50 F | 104 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, UR, GN, OW, HP | Immuno | 0.2 |  |  |  |\n| 37 | Rat (Fischer-344) 50 M, 50 F | 104 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, UR, GN, OW, HP | Neuro | 0.2 |  |  |  |\n| 37 | Rat (Fischer-344) 50 M, 50 F | 104 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, UR, GN, OW, HP | Repro | 0.2 |  |  |  |\n\n---\n\n**Table 2-1. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation\n(ppm)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| NTP 1994 |  |  |  |  |  |  |  |  |  |\n| 38 | Mouse (B6C3F1) 50 M, 50 F | 103 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, BW, GN, OW, HP | Death Bd wt Resp | 0.2 0.05c | 0.2 | 0.2 F | 57% mortality |\n| 38 | Mouse (B6C3F1) 50 M, 50 F | 103 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, BW, GN, OW, HP | Death Bd wt Resp | 0.2 0.05c | 0.2 | 0.2 F | Males: nasal suppurative inflammation, alveolar epithelium hyperplasia, and suppurative inflammation of the lung Females: nasal suppurative inflammation (BMCL10 for nasal suppurative inflammation in females = 0.0052 ppm)c |\n| 38 | Mouse (B6C3F1) 50 M, 50 F | 103 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, BW, GN, OW, HP | Cardio Gastro Hemat Muc/skel Hepatic Renal Dermal Endocr Immuno Neuro | 0.2 0.2 0.2 0.2 0.2 0.2 | 0.2 | 0.2 F | Males: nasal suppurative inflammation, alveolar epithelium hyperplasia, and suppurative inflammation of the lung Females: nasal suppurative inflammation (BMCL10 for nasal suppurative inflammation in females = 0.0052 ppm)c |\n\n---\n\n**Table 2-1. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation\n(ppm)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n|  |  |  |  |  | Repro | 0.01 F | 0.05 F | 0.2 F | LOAEL: Suppurative inflammation of the ovaries SLOAEL: Severe ovarian suppurative inflammation (associated with increased lethality) |\n|  |  |  |  |  |  | 0.2 M |  |  |  |\n\n<sup>a</sup>The number corresponds to entries in Figure 2-2; differences in levels of health effects and cancer effects between male and females are not indicated in \nFigure 2-2. Where such differences exist, only the levels of effect for the most sensitive sex are presented.\n\n$$\n1\\times10^{-4}\n$$\n\n<sup>b</sup>Used to derive a provisional intermediate-duration inhalation MRL of 1x10<sup>-4</sup> ppm based on a NOAEL of 0.146 ppm, which was converted into a NOAELHEC of \n0.00344 ppm and divided by an uncertainty factor of 30 (10 for human variability and 3 for animal to human extrapolation after dosimetric adjustment).\n<sup>c</sup>Used to derive a provisional chronic-duration inhalation MRL of 6x10<sup>-5</sup> ppm based on a BMCL10 of 0.052 ppm, which was converted into a BMCLHEC of \n0.0019 ppm and divided by an uncertainty factor of 30 (10 for human variability and 3 for animal to human extrapolation after dosimetric adjustment).\n\nGreen shading indicates the study selected for derivation of provisional inhalation MRLs.\n\nAST = aspartate aminotransferase; BC = blood chemistry; Bd wt or BW = body weight; BMCL = benchmark concentration lower confidence limit; BMCL10 = 95% \nlower confidence limit on the benchmark concentration (subscripts denote benchmark response: i.e., 10 = concentration associated with 10% extra risk); \nCardio = cardiovascular; CS = clinical signs; Endocr = endocrine; F = female(s); FI = food intake; Gastro = gastrointestinal; GN = gross necropsy; \nHE = hematology; HEC = human equivalent concentration; Hemato = hematological; HP = histopathology; Immuno = immunological; LC50 = median lethal \nconcentration; LE = lethality; LOAEL = lowest-observed-adverse-effect level; M = male(s); MCHC = mean corpuscular hemoglobin concentration; MCV = mean \ncorpuscular volume; MRL = Minimal Risk Level; Musc/skeletal = muscular/skeletal; Neuro = neurological; NOAEL = no-observed-adverse-effect level; NS = not \nspecified; OF = organ function; OP = ophthalmology; OW = organ weight; Repro = reproductive; Resp = respiratory; SLOAEL = serious lowest-observed-adverseeffect level; UR = urinalysis; (WB) = whole body; WI = water intake\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation**\nAcute (≤14 days)\n\n**Figure 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation Acute (≤14 days) - Death**\n\n| Category | Animal - LD50/LC50 (ppm) | Animal - NOAEL (ppm) | Animal - LOAEL (ppm) | Animal - SLOAEL (ppm) |\n| --- | --- | --- | --- | --- |\n| 1R |  |  |  | 0.45 |\n| 2R | 3.4 |  |  |  |\n| 3R | 2.6 |  |  |  |\n| 4R |  |  |  | 170 |\n| 5R | 1.6 |  |  |  |\n| 6R |  |  |  | 2.8 |\n| 7R |  |  | 1.4 |  |\n| 8R |  |  |  | 3.2 |\n| 9R |  |  |  | 2.8 |\n| 10R |  |  |  | 1.0 |\n| 11R |  |  |  | 7.0 |\n| 12R |  |  |  | 75 |\n| 13M |  |  |  | 7.5 |\n| 14M |  |  |  | 75 |\n| 15M |  |  |  | 3.2 |\n| 16M |  |  |  | 1.4 |\n| 17M |  |  |  | 1.5 |\n| 18M |  |  |  | 3.2 |\n| 19M |  |  |  | 1.0 |\n| 20H |  |  |  | 75 |\n| 21H |  |  |  | 1.4 |\n| 22H |  |  |  | 1.0 |\n| 23H |  |  |  | 1.4 |\n| 24H |  |  |  | 1.5 |\n| 25H |  |  |  | 3.2 |\n| 26H |  |  |  | 3.2 |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation**\nAcute (≤14 days)\n\n| Category | Body Weight Animal - LD50/LC50 (ppm) | Body Weight Animal - NOAEL (ppm) | Body Weight Animal - LOAEL (ppm) | Body Weight Animal - SLOAEL (ppm) | Respiratory Animal - LD50/LC50 (ppm) | Respiratory Animal - NOAEL (ppm) | Respiratory Animal - LOAEL (ppm) | Respiratory Animal - SLOAEL (ppm) | Cardiovascular Animal - LD50/LC50 (ppm) | Cardiovascular Animal - NOAEL (ppm) | Cardiovascular Animal - LOAEL (ppm) | Cardiovascular Animal - SLOAEL (ppm) | Hematological Animal - LD50/LC50 (ppm) | Hematological Animal - NOAEL (ppm) | Hematological Animal - LOAEL (ppm) | Hematological Animal - SLOAEL (ppm) |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| 1R |  | 0.12 |  | 0.5 |  | 0.12 |  | 0.5 |  | 0.5 |  |  |  | 0.12 |  | 0.5 |\n| 2R |  | 1.8 |  | 2.6 |  |  |  | 1.8 |  |  |  |  |  |  |  |  |\n| 3R |  |  |  | 1.8 |  |  |  | 1.8 |  |  |  |  |  |  |  |  |\n| 5R |  | 0.26 |  | 1.4 |  |  |  |  |  |  |  |  |  |  |  |  |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation**\nAcute (≤14 days)\n\n**Figure 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation Acute (≤14 days)**\n\n| Category | Animal - NOAEL (ppm) | Animal - LOAEL (ppm) | Animal - SLOAEL (ppm) |\n| --- | --- | --- | --- |\n| Hepatic | 0.5 |  |  |\n| Renal | 0.45 |  |  |\n| Immunological | 0.5 |  |  |\n| Neuological | 0.4 | 1.4 | 5.5 |\n| Other Noncancer | 0.12 | 0.45 | 1.7 |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation**\nIntermediate (15–364 days)\n\n**Figure 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation Intermediate (15–364 days)**\n\n| Category | Death Animal - NOAEL (ppm) | Death Animal - LOAEL (ppm) | Death Animal - SLOAEL (ppm) | Body Weight Animal - NOAEL (ppm) | Body Weight Animal - LOAEL (ppm) | Body Weight Animal - SLOAEL (ppm) | Respiratory Animal - NOAEL (ppm) | Respiratory Animal - LOAEL (ppm) | Respiratory Animal - SLOAEL (ppm) |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| 29R |  |  | 0.6 | 0.5 |  |  | 0.15 |  | 0.6 |\n| 30R |  |  | 1.0 | 0.4 |  |  | 0.15 | 0.45 | 1.0 |\n| 31R |  |  | 2.3 |  |  |  |  |  |  |\n| 32M |  |  | 0.55 |  | 0.5 |  |  | 0.5 |  |\n| 33M |  |  | 2.6 |  |  |  |  |  |  |\n| 36M |  |  | 0.4 | 0.45 |  |  | 0.15 | 0.45 |  |\n| 27K |  |  |  | 0.2 |  |  | 0.2 |  |  |\n| 28R |  |  |  | 0.2 |  |  | 0.2 |  |  |\n| 34M |  |  |  | 0.55 |  |  |  | 0.5 |  |\n| 35M |  |  |  | 0.2 |  |  |  | 0.2 |  |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation**\nIntermediate (15–364 days)\n\n**Figure 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation Intermediate (15–364 days)**\n\n| Category | Cardiovascular Animal - NOAEL (ppm) | Cardiovascular Animal - LOAEL (ppm) | Cardiovascular Animal - SLOAEL (ppm) | Gastrointestinal Animal - NOAEL (ppm) | Gastrointestinal Animal - LOAEL (ppm) | Gastrointestinal Animal - SLOAEL (ppm) | Hematological Animal - NOAEL (ppm) | Hematological Animal - LOAEL (ppm) | Hematological Animal - SLOAEL (ppm) |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| 27K | 0.22 |  |  | 0.22 |  |  | 0.22 |  |  |\n| 28R | 0.22 |  |  | 0.22 |  |  | 0.22 |  |  |\n| 29R | 0.55 |  |  | 0.55 |  |  | 0.060 | 0.15 |  |\n| 30R | 0.44 |  |  | 0.44 |  |  | 0.17 | 0.44 |  |\n| 36M | 0.44 |  |  | 0.44 |  |  | 0.17 | 0.44 |  |\n| 32M |  |  |  | 0.50 |  |  |  |  |  |\n| 35M |  |  |  | 0.22 |  |  |  |  |  |\n| 31R |  |  |  |  |  |  | 0.040 | 0.44 |  |\n| 33M |  |  |  |  |  |  |  | 0.044 |  |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation**\nIntermediate (15–364 days)\n\n**Figure 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation Intermediate (15–364 days)**\n\n| Category | Musculoskeletal Animal - NOAEL (ppm) | Musculoskeletal Animal - LOAEL (ppm) | Musculoskeletal Animal - SLOAEL (ppm) | Hepatic Animal - NOAEL (ppm) | Hepatic Animal - LOAEL (ppm) | Hepatic Animal - SLOAEL (ppm) | Renal Animal - NOAEL (ppm) | Renal Animal - LOAEL (ppm) | Renal Animal - SLOAEL (ppm) |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| 27K | 0.22 |  |  | 0.20 |  |  | 0.20 |  |  |\n| 28R | 0.20 |  |  | 0.22 |  |  | 0.20 |  |  |\n| 29R | 0.55 |  |  | 0.60 |  |  | 0.55 |  |  |\n| 30R | 0.44 |  |  | 0.40 |  |  | 0.40 |  |  |\n| 36M | 0.44 |  |  | 0.44 |  |  | 0.44 |  |  |\n| 31R |  |  |  | 0.44 |  |  | 2.2 |  |  |\n| 31R |  |  |  |  |  | 2.4 |  |  |  |\n| 32M |  |  |  | 0.55 |  |  | 0.60 |  |  |\n| 33M |  |  |  | 2.4 |  |  | 2.4 |  |  |\n| 35M |  |  |  | 0.20 |  |  | 0.20 |  |  |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation**\nIntermediate (15–364 days)\n\n**Figure 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation Intermediate (15–364 days)**\n\n| Category | Animal - NOAEL (ppm) | Animal - LOAEL (ppm) | Animal - SLOAEL (ppm) |\n| --- | --- | --- | --- |\n| Dermal 29R | 0.55 |  |  |\n| Ocular 27K | 0.20 |  |  |\n| Ocular 28R | 0.20 |  |  |\n| Ocular 29R | 0.55 |  |  |\n| Endocrine 27K | 0.20 |  |  |\n| Endocrine 28R | 0.20 |  |  |\n| Endocrine 29R | 0.60 |  |  |\n| Endocrine 30R | 0.40 |  |  |\n| Endocrine 32M | 0.50 |  |  |\n| Endocrine 36M | 0.40 |  |  |\n| Immunological 27K | 0.20 |  |  |\n| Immunological 28R | 0.20 |  |  |\n| Immunological 29R | 0.60 |  |  |\n| Immunological 30R | 0.40 |  |  |\n| Immunological 32M | 0.55 |  |  |\n| Immunological 35M | 0.20 |  |  |\n| Immunological 36M | 0.40 |  |  |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation**\nIntermediate (15–364 days)\n\n**Figure 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation Intermediate (15–364 days)**\n\n| Category | Neuropsychological Animal - NOAEL (ppm) | Neuropsychological Animal - LOAEL (ppm) | Neuropsychological Animal - SLOAEL (ppm) | Reproductive Animal - NOAEL (ppm) | Reproductive Animal - LOAEL (ppm) | Reproductive Animal - SLOAEL (ppm) | Other Noncancer Animal - NOAEL (ppm) | Other Noncancer Animal - LOAEL (ppm) | Other Noncancer Animal - SLOAEL (ppm) |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| 27K | 0.22 |  |  | 0.22 |  |  | 0.22 |  |  |\n| 28R | 0.22 |  |  | 0.22 |  |  | 0.22 |  |  |\n| 29R | 0.55 |  |  | 0.55 |  |  | 0.55 |  |  |\n| 30R | 0.44 |  |  | 0.44 |  |  |  |  |  |\n| 35M | 0.22 |  |  | 0.22 |  |  |  |  |  |\n| 36M | 0.44 |  |  | 0.44 |  |  |  |  |  |\n| 32M |  |  |  | 0.55 |  |  |  |  |  |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation**\nChronic (≥365 days)\n\n**Figure 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation Chronic (≥365 days)**\n\n| Category | R-Rat Animal - NOAEL (ppm) | R-Rat Animal - LOAEL (ppm) | R-Rat Animal - SLOAEL (ppm) | M-Mouse Animal - NOAEL (ppm) | M-Mouse Animal - LOAEL (ppm) | M-Mouse Animal - SLOAEL (ppm) | M-Mouse MRL for effect other than cancer (ppm) |\n| --- | --- | --- | --- | --- | --- | --- | --- |\n| Death |  |  |  |  |  | 0.22 |  |\n| Body Weight |  |  |  | 0.22 |  |  |  |\n| Respiratory | 0.22 |  |  |  | 0.055 | 0.22 | 0.006 |\n| Cardiovascular | 0.22 |  |  | 0.22 |  |  |  |\n| Gastrointestinal |  |  |  | 0.22 |  |  |  |\n| unlabelled 1 |  |  |  | 0.22 |  |  |  |\n\n---\n\n2.  HEALTH EFFECTS\n\n**Figure 2-2.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation**\nChronic (≥365 days)\n\n| Category | R-Rat (ppm) | M-Mouse (ppm) |\n| --- | --- | --- |\n| Hematological | 0.22 | 0.22 |\n| Musculoskeletal | 0.22 | 0.22 |\n| Hepatic | 0.22 | 0.22 |\n| Renal | 0.22 | 0.22 |\n| Dermal | 0.22 | 0.22 |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation**\nChronic (≥365 days)\n\n**Figure 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation Chronic (≥365 days)**\n\n| Category | Endocrine Animal - NOAEL (ppm) | Endocrine Animal - LOAEL (ppm) | Endocrine Animal - SLOAEL (ppm) | Immunological Animal - NOAEL (ppm) | Immunological Animal - LOAEL (ppm) | Immunological Animal - SLOAEL (ppm) | Neuological Animal - NOAEL (ppm) | Neuological Animal - LOAEL (ppm) | Neuological Animal - SLOAEL (ppm) | Reproductive Animal - NOAEL (ppm) | Reproductive Animal - LOAEL (ppm) | Reproductive Animal - SLOAEL (ppm) |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| 37R | 0.23 |  |  | 0.23 |  |  | 0.23 |  |  | 0.23 |  |  |\n| 38M | 0.23 |  |  | 0.23 |  |  | 0.23 |  |  | 0.011 | 0.055 | 0.23 |\n\n---\n\n**Table 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Oral\n(mg/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| ACUTE EXPOSURE |  |  |  |  |  |  |  |  |  |\n| Gardner 1986a |  |  |  |  |  |  |  |  |  |\n| 1 | Rat (CFY) 5 M, 5 F | Once (GO) | 1,260, 1,600, 2,000 | LE, CS, BW, GN | Death |  |  | 1,300 F 1,500 M | LD50 LD50 |\n| 1 | Rat (CFY) 5 M, 5 F | Once (GO) | 1,260, 1,600, 2,000 | LE, CS, BW, GN | Resp Gastro Neuro |  | 1,260 | 1,260 | Decreased respiratory rate Diarrhea Abnormal gait, lethargy |\n| OxyChem 1972 |  |  |  |  |  |  |  |  |  |\n| 2 | Rat (Spartan) 25 M, 25 F | Once (GO) | 315, 500, 794, 1,250, 1,984 | LE | Death |  |  | 530 F 630 M | LD50 LD50 |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 3 | Rat 9–11 M | Once (GO) | 280, 340, 420, 520, 620, 940, 1,400 | LE, CS, GN | Death |  |  | 505 | LD50 |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 4 | Rat 10 F | Once (GO) | 280, 940, 1,400, 2,100 | LE, CS, GN | Death |  |  | 940 | 9/10 died |\n| Chernoff and Kavlock 1982, 1983; Gray and Kavlock 1984; Gray et al. 1986 |  |  |  |  |  |  |  |  |  |\n| 5 | Mouse (CD-1) 16 F | 5 days GDs 8–12 (GO) | 0, 45 | BW, DX | Bd wt Develop | 45 |  |  |  |\n\n$$\n\\mathsf{L}\\mathsf{D}_{50}\n$$\n\nOffspring evaluated through PND 250 for postnatal viability, growth, locomotor activity, female sexual development, and reproductive function\n\n---\n\n**Table 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Oral\n(mg/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Dean 1977 |  |  |  |  |  |  |  |  |  |\n| 6 | Mouse (CD-1) 5 M, 5 F | Once (GO) | 21.5, 46.4, 100, 215, 464, 1,000, 2,150 | LE, CS, BW | Death Resp Gastro | 1,000 215 F 464 M 464 | 464 F 1,000 M 1,000 | 679 2,150 | LD50 Decreased respiratory rate Diarrhea Diarrhea Decreased limb tone in animals that died LOAEL: Hypoactivity SLOAEL: Ataxia |\n| 6 | Mouse (CD-1) 5 M, 5 F | Once (GO) | 21.5, 46.4, 100, 215, 464, 1,000, 2,150 | LE, CS, BW | Musc/skel | 215 | 464 | 1,000 | LOAEL: Hypoactivity SLOAEL: Ataxia |\n| Murray et al. 1980 |  |  |  |  |  |  |  |  |  |\n| 7 | Mouse (CF-1) NS F | 10 days GDs 6–15 (GO) | 0, 5, 25, 75 | LE, CS, BW, FI, WI, RX, DX | Bd wt Develop Other noncancer | 75 75 75 |  |  |  |\n| Murray et al. 1980 |  |  |  |  |  |  |  |  |  |\n| 8 | Mouse (CF-1) 5 F | 10 days GDs 6–15 (GO) | 0, 25, 75, 250, 500 | LE, CS, BW | Death |  |  | 250 | 3/5 dams died |\n| Murray et al. 1980 |  |  |  |  |  |  |  |  |  |\n| 9 | Rabbit (New Zealand) NS F | 13 days GDs 6–18 (GO) | 0, 5, 25, 75 | LE, CS, BW, RX, DX | Death Develop | 25 | 75 | 75 | Unspecified increased maternal death during pregnancy Increased proportion of fetuses with 13 ribs |\n| Murray et al. 1980 |  |  |  |  |  |  |  |  |  |\n| 10 | Rabbit (New Zealand) 5 F | 13 days GDs 6–18 (GO) | 0, 25, 75, 250, 500 | LE, CS, BW | Death |  |  | 250 | 4/5 does die |\n\n---\n\n**Table 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Oral\n(mg/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 11 | Rabbit 3 F | Once (GO) | 180, 280, 420, 620, 940 | LE, CS, GN | Death |  |  | 940 | 3/3 died |\n| INTERMEDIATE EXPOSURE |  |  |  |  |  |  |  |  |  |\n| Abdo et al. 1984; Velsicol 1981b |  |  |  |  |  |  |  |  |  |\n| 12 | Rat (Fischer-344) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 10, 19, 38, 75, 150 | LE, BW, GN, OW, HP | Death Bd wt | 38 F | 75 F | 150 M | 60% treatment-related mortality 15% decreased terminal body weight LOAEL: 13% decreased terminal body weight SLOAEL: 30% decreased terminal body weight Forestomach epithelial hyperplasia and focal inflammation (BMDL10 for combined incidence of forestomach lesions = 7.7 mg/kg/day)b |\n| 12 | Rat (Fischer-344) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 10, 19, 38, 75, 150 | LE, BW, GN, OW, HP | Resp Cardio Gastro | 150 150 19b | 38 |  |  |\n| 12 | Rat (Fischer-344) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 10, 19, 38, 75, 150 | LE, BW, GN, OW, HP | Hemato Musc/skel | 150 150 150 Renal | 38 |  | Toxic nephrosis |\n| 12 | Rat (Fischer-344) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 10, 19, 38, 75, 150 | LE, BW, GN, OW, HP | Dermal | 150 |  |  |  |\n| 12 | Rat (Fischer-344) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 10, 19, 38, 75, 150 | LE, BW, GN, OW, HP | Endocr | 150 |  |  |  |\n| 12 | Rat (Fischer-344) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 10, 19, 38, 75, 150 | LE, BW, GN, OW, HP | Immuno | 150 |  |  |  |\n| 12 | Rat (Fischer-344) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 10, 19, 38, 75, 150 | LE, BW, GN, OW, HP | Neuro | 150 |  |  |  |\n| 12 | Rat (Fischer-344) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 10, 19, 38, 75, 150 | LE, BW, GN, OW, HP | Repro | 150 |  |  |  |\n\n---\n\n**Table 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Oral\n(mg/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Abdo et al. 1984; Velsicol 1981a |  |  |  |  |  |  |  |  |  |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP | Death |  |  | 300 | 10/10 males died, 3/10 females died 11% decreased terminal body weight 13% decreased terminal body weight |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP | Bd wt | 75 M | 150 F | 300 | 10/10 males died, 3/10 females died 11% decreased terminal body weight 13% decreased terminal body weight |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP |  | 150 F | 300 F | 300 | 10/10 males died, 3/10 females died 11% decreased terminal body weight 13% decreased terminal body weight |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP | Resp | 300 |  |  |  |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP | Cardio | 300 |  |  |  |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP | Gastro | 38 | 75 |  | Focal inflammation and epithelial hyperplasia of the forestomach |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP | Hemato | 300 |  |  |  |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP | Musc/skel | 300 |  |  |  |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP | Hepatic | 300 |  |  |  |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP | Renal | 38 F | 75 F |  | Toxic nephrosis |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP |  | 150 M | 300 M |  | Acute tubular necrosis |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP | Dermal | 300 |  |  |  |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP | Endocr | 300 |  |  |  |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP | Immuno | 300 |  |  |  |\n\n---\n\n**Table 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Oral\n(mg/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n|  |  |  |  |  | Neuro Repro | 300 300 |  |  |  |\n\n<sup>a</sup>The number corresponds to entries in Figure 2-3; differences in levels of health effects between male and females are not indicated in Figure 2-3.  Where such \ndifferences exist, only the levels of effect for the most sensitive sex are presented.\n\n<sup>b</sup>Used to derive a provisional intermediate-duration oral MRL of 0.06 mg/kg/day based on a BMDL10 of 7.7 mg/kg/day, which was adjusted to continuous duration \nexposure to a BMDLADJ of 5.5 mg/kg/day and divided by an uncertainty factor of 100 (10 for human variability and 10 for animal to human extrapolation).  See \nAppendix A for more detailed information regarding the MRL.\n\nGreen shading indicates the study selected for derivation of the provisional oral MRL.\n\nADJ = adjusted; Bd wt or BW = body weight; BMDL = benchmark dose lower confidence limit; BMDL10 = 95% benchmark dose lower confidence limit (subscript \ndenotes benchmark response: i.e., 10 = dose associated with 10% extra risk); Cardio = cardiovascular; CS = clinical signs; Develop = developmental; \nDX = developmental toxicity; Endocr = endocrine; F = female(s); FI = food intake; Gastro = gastrointestinal; GD = gestation day; GN = gross necropsy; \n(GO) = gavage in oil; Hemato = hematological; HP = histopathology; Immuno = immunological; LD50 = median lethal dose; LE = lethality; LOAEL = lowestobserved-adverse-effect level; M = male(s); MRL = Minimal Risk Level; Musc/skeletal = muscular/skeletal; Neuro = neurological; NOAEL = no-observed-adverseeffect level; NS = not specified; OW = organ weight; PND = postnatal day; Repro = reproductive; Resp = respiratory; RX = reproductive function; \nSLOAEL = serious lowest-observed-adverse-effect level; WI = water intake\n\n---\n\n**Figure 2-3.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Oral**\nAcute (≤14 days)\n\n| Category | Animal - LD50/LC50 (mg/kg/day) | Animal - NOAEL (mg/kg/day) | Animal - LOAEL (mg/kg/day) | Animal - SLOAEL (mg/kg/day) |\n| --- | --- | --- | --- | --- |\n| 1R | 1300 |  |  |  |\n| 2R | 530 |  |  |  |\n| 3R | 500 |  |  |  |\n| 4R |  |  |  | 950 |\n| 6M | 660 |  |  |  |\n| 8M |  |  |  | 300 |\n| 9H |  |  |  | 75 |\n| 10H |  |  |  | 280 |\n| 11H |  |  |  | 950 |\n| 5M |  | 50 |  |  |\n| 7M |  | 80 |  |  |\n| 1R |  |  |  | 1200 |\n| 6M |  | 1000 |  | 2400 |\n\n---\n\n**Figure 2-3.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Oral**\nAcute (≤14 days)\n\n| Category | R-Rat (mg/kg/day) | M-Mouse (mg/kg/day) | H-Rabbit (mg/kg/day) |\n| --- | --- | --- | --- |\n| Animal - LD50/LC50 |  |  |  |\n| Animal - NOAEL |  | 130 |  |\n| Animal - LOAEL |  |  | 1300 |\n| Animal - SLOAEL |  |  | 1000 |\n\n---\n\n**Figure 2-3.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Oral**\nIntermediate (15–364 days)\n\n| Category | R-Rat Animal - NOAEL (mg/kg/day) | R-Rat Animal - LOAEL (mg/kg/day) | R-Rat Animal - SLOAEL (mg/kg/day) | M-Mouse Animal - NOAEL (mg/kg/day) | M-Mouse Animal - LOAEL (mg/kg/day) | M-Mouse Animal - SLOAEL (mg/kg/day) |\n| --- | --- | --- | --- | --- | --- | --- |\n| Death |  |  |  |  |  |  |\n| 12R |  |  | 150 |  |  |  |\n| 13M |  |  | 330 |  |  |  |\n| Body Weight |  |  |  |  |  |  |\n| 12R | 20 |  |  |  |  |  |\n| 12R |  | 40 |  |  |  |  |\n| 12R |  |  | 75 |  |  |  |\n| 13M |  | 80 |  |  |  |  |\n| 13M |  |  | 150 |  |  |  |\n| 13M |  |  | 160 |  |  |  |\n| Respiratory |  |  |  |  |  |  |\n| 12R | 160 |  |  |  |  |  |\n| 13M | 330 |  |  |  |  |  |\n| Cardiovascular |  |  |  |  |  |  |\n| 12R | 150 |  |  |  |  |  |\n| 13M | 330 |  |  |  |  |  |\n| Gastrointestinal |  |  |  |  |  |  |\n| 12R BMDL | 8.0 |  |  |  |  |  |\n| 12R | 20 |  |  |  |  |  |\n| 12R |  | 44 |  |  |  |  |\n| 13M | 40 |  |  |  |  |  |\n| 13M |  |  | 80 |  |  |  |\n\n---\n\n**Figure 2-3.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Oral**\nIntermediate (15–364 days)\n\n| Category | R-Rat Animal - NOAEL (mg/kg/day) | R-Rat Animal - LOAEL (mg/kg/day) | R-Rat Animal - SLOAEL (mg/kg/day) | M-Mouse Animal - NOAEL (mg/kg/day) | M-Mouse Animal - LOAEL (mg/kg/day) | M-Mouse Animal - SLOAEL (mg/kg/day) |\n| --- | --- | --- | --- | --- | --- | --- |\n| Hematological | 150 |  |  | 330 |  |  |\n| Musculoskeletal |  |  |  | 150 |  |  |\n| Hepatic |  |  |  | 150 |  |  |\n| Renal | 20 | 44 |  | 36 |  | 80 |\n| Dermal |  |  |  | 150 |  | 330 |\n\n---\n\n**Figure 2-3.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Oral**\nIntermediate (15–364 days)\n\n**Figure 2-3. Levels of Significant Exposure to Hexachlorocyclopentadiene – Oral Intermediate (15–364 days)**\n\n| Category | Animal - NOAEL (mg/kg/day) | Animal - LOAEL (mg/kg/day) | Animal - SLOAEL (mg/kg/day) |\n| --- | --- | --- | --- |\n| Endocrine 12R | 160 |  |  |\n| Endocrine 13M | 330 |  |  |\n| Immunological 12R | 160 |  |  |\n| Immunological 13M | 330 |  |  |\n| Neuological 12R | 160 |  |  |\n| Neuological 13M | 330 |  |  |\n| Reproductive 12R | 160 |  |  |\n| Reproductive 13M | 330 |  |  |\n\n---\n\n**Table 2-3. Levels of Significant Exposure to Hexachlorocyclopentadiene – Dermal**\n\n| Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| ACUTE EXPOSURE |  |  |  |  |  |  |  |  |\n| Kominsky et al. 1980 |  |  |  |  |  |  |  |  |\n| Human 154 M, 23 F | 3–15 days | ≤0.97 ppm | CS, BC | Dermal Ocular |  | 0.97 0.97 |  | Skin irritation Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Monkey 1 NS | Once | 0.001, 0.01, 0.1, 1, 10% (0.01 mL); 20, 40, 60, 90% (0.05 mL) | CS | Dermal | 10 | 20 |  | Skin discoloration and swelling |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Monkey 1 NS | 3 days Once/day | 10% | CS | Dermal |  |  | 10 | Skin irritation, necrosis, hemorrhaging |\n| Alexander et al. 1980a; Rand et al. 1982a |  |  |  |  |  |  |  |  |\n| Rat (Sprague-Dawley) 10 M, 10 F | 1–2 weeks 5 days/week 6 hours/day | 0, 0.022, 0.11, 0.5 ppm | CS | Ocular | 0.11 | 0.5 |  | Dark red eyes |\n| Gardner 1986b |  |  |  |  |  |  |  |  |\n| Rat (CFY) 5 M, 5 F | 24 hours | 1,600, 2,000, 3,200 mg/kg | LE, CS, BW, GN | Death |  |  | 3,100 F 2,600 M | LD50 LD50 |\n| Rat (CFY) 5 M, 5 F | 24 hours | 1,600, 2,000, 3,200 mg/kg | LE, CS, BW, GN | Dermal |  | 1,600 |  | Moderate to severe edema |\n| Jackson and Hardy 1986 |  |  |  |  |  |  |  |  |\n| Rat (Wistar) 5 M, 5 F | 1 hour | 0, 1.67, 2.38, 3.53, 6.25, 8.30 ppm | CS | Ocular |  | 1.67 |  | Total or partial closing of the eyes |\n| Jackson and Hardy 1987 |  |  |  |  |  |  |  |  |\n| Rat (Wistar) 5 M, 5 F | 4 hours | 0, 1.68, 1.83, 3.31, 3.47 ppm | CS | Ocular |  | 1.68 |  | Total or partial closing of the eyes |\n| Rand et al. 1982a |  |  |  |  |  |  |  |  |\n| Rat (Sprague-Dawley) 10 M, 10 F | 4 hours | 0.28, 1.4, 2.5, 3.1, 3.3, 3.4, 4, 5.8 ppm | CS | Ocular | 4 | 5.8 |  | Lacrimation |\n\n$$\n\\mathsf{L}\\mathsf{D}_{50}\n$$\n\n$$\n\\mathsf{L}\\mathsf{D}_{50}\n$$\n\n---\n\n**Table 2-3. Levels of Significant Exposure to Hexachlorocyclopentadiene – Dermal**\n\n| Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rat 4 NS | 5 days 7 hours/day | 0.33, 1, 1.6 ppm | CS | Ocular |  | 0.33 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rat 4 NS | 3 days 7 hours/day | 1.4 ppm | CS | Ocular |  | 1.4 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rat 4 NS | 4 hours | 73.6 ppm | CS | Ocular |  | 73.6 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rat 4 NS | 7 hours | 1.5, 3.2, 6.7 ppm | CS | Ocular |  | 1.5 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rat 4 NS | 2.6–3.6 hours | 1.4, 3.1, 7.1, 11.1, 12.7, 46.5, 56.9, 70.4 ppm | CS | Ocular |  | 1.4 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rat 3–4 NS | 0.25–1.25 hours | 1.4, 1.5, 3.1, 7.2, 13.0, 13.8, 19.4, 20.0, 20.2, 69.1, 69.2 ppm | CS | Ocular |  | 1.4 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rat 4 NS | 2 days 7 hours/day | 3.2 ppm | CS | Ocular |  | 3.2 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Mouse 4–5 NS | 0.25–1.25 hours | 1.4, 1.5, 3.1, 7.2, 13.0, 13.8, 19.4, 20.0, 20.2, 69.1, 69.2 ppm | CS | Ocular |  | 1.4 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Mouse 5 NS | 7 hours | 1.5, 3.2, 6.7 ppm | CS | Ocular |  | 1.5 |  | Eye irritation |\n\n---\n\n**Table 2-3. Levels of Significant Exposure to Hexachlorocyclopentadiene – Dermal**\n\n| Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Mouse 5 NS | 2.6–3.6 hours | 1.4, 3.1, 7.1, 12.4, 12.7, 46.5, 56.9, 70.4 ppm | CS | Ocular |  | 1.4 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Mouse 5 NS | 4 hours | 73.6 ppm | CS | Ocular |  | 73.6 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Mouse 5 NS | 2 days 7 hours/day | 3.2 ppm | CS | Ocular |  | 3.2 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Mouse 5 NS | 3 days 7 hours/day | 1.4 ppm | CS | Ocular |  | 1.4 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Mouse 5 NS | 5 days 7 hours/day | 0.33, 1.0, 1.6 ppm | CS | Ocular |  | 0.33 |  | Eye irritation |\n| OxyChem 1972 |  |  |  |  |  |  |  |  |\n| Rabbit (New Zealand) 3 M, 3 F | 4 hours | 0.5 mL | LE, CS | Death Dermal Neuro | 0.5 | 0.5 | 0.5 | 3/6 died Moderate to severe edema Ataxia and hypoactivity |\n| OxyChem 1972 |  |  |  |  |  |  |  |  |\n| Rabbit (New Zealand) 5 NS | 5 minutes | 0.1 mL | LE, CS | Death |  | 0.1 | 5/5 died within 9 days |  |\n| OxyChem 1972 |  |  |  |  |  |  |  |  |\n| Rabbit (New Zealand) 2 M, 2 F | Once | 200, 2,000 mg/kg | LE, CS, BW | Death |  | 200 M 2,000 F | 2/2 died within 14 days 2/2 died within 24 hours Dermal irritation and discoloration Hypoactivity |  |\n|  |  |  |  | Dermal Neuro | 200 200 M |  |  |  |\n\n---\n\n**Table 2-3. Levels of Significant Exposure to Hexachlorocyclopentadiene – Dermal**\n\n| Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| OxyChem 1972 |  |  |  |  |  |  |  |  |\n| Rabbit (New Zealand) 3 NS | 24 hours | 0.1 mL | LE, CS | Death Ocular |  |  | 0.1 0.1 | 3/3 died within 6 days Severe eye irritation and corrosion |\n| OxyChem 1992 |  |  |  |  |  |  |  |  |\n| Rabbit (New Zealand) 12 NS | 24 hours | 200 mg/kg | LE, CS | Death Dermal |  |  | 200 200 | 8/12 died Eschar formation |\n| OxyChem 1992 |  |  |  |  |  |  |  |  |\n| Rabbit (New Zealand) 6 NS | 4 hours | 0.5 mL | LE, CS | Dermal |  |  | 0.5 | Erythema, edema, necrosis |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rabbit 1–3 F | 24 hours | 430, 610, 1,020, 2,130, 6,130 mg/kg | LE, CS, GN | Death Dermal |  | 430 | 1020 | 2/3 died Skin irritation, discoloration, subcutaneous edema, acanthosis, epiulation, hyperkeratosis, chronic inflammation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rabbit 3 NS | 4 hours | 73.6 ppm | CS | Ocular |  | 73.6 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rabbit 3 NS | 2.6–3.6 hours | 1.4, 3.1, 7.1, 12.4, 12.7, 46.5, 56.9, 70.4 ppm | CS | Ocular |  | 1.4 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rabbit 3 NS | 7 hours | 1.5, 3.2, 6.7 ppm | CS | Ocular |  | 1.5 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rabbit 3 NS | 0.25–1.25 hours | 1.4, 1.5, 3.1, 7.2, 13.0, 13.8, 19.4, 20.0, 20.2, 69.1, 69.2 ppm | CS | Ocular |  | 1.4 |  | Eye irritation |\n\n---\n\n**Table 2-3. Levels of Significant Exposure to Hexachlorocyclopentadiene – Dermal**\n\n| Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rabbit 3 NS | 2 days 7 hours/day | 3.2 ppm | CS | Ocular |  | 3.2 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rabbit 3 NS | 3 days 7 hours/day | 1.4 ppm | CS | Ocular |  | 1.4 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rabbit 3 NS | 5 days 7 hours/day | 1, 1.6 ppm | CS | Ocular |  | 1 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Guinea pig 2 NS | Once | 0.01, 0.1, 1, 40, 60, 90% | CS | Dermal | 1 | 40 |  | Skin discoloration and irritation |\n| INTERMEDIATE EXPOSURE |  |  |  |  |  |  |  |  |\n| Alexander et al. 1980b; Rand et al. 1982a |  |  |  |  |  |  |  |  |\n| Monkey (Cynomolgus) 6 M, 6 F | 14 weeks 5 days/week 6 hours/day | 0, 0.01, 0.05, 0.2 ppm | CS | Ocular | 0.2 |  |  |  |\n| Alexander et al. 1980b; Rand et al. 1982a |  |  |  |  |  |  |  |  |\n| Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day | 0, 0.01, 0.05, 0.2 ppm | CS | Ocular | 0.01 | 0.05 |  | Dark red eyes |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rat 4 NS | 30 weeks 5 days/week 7 hours/day | 0.15 ppm | CS | Ocular | 0.15 |  |  |  |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rat 4 NS | 6 weeks 5 days/week 7 hours/day | 0.34 ppm | CS | Ocular |  | 0.34 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Mouse 5 NS | 30 weeks 5 days/week 7 hours/day | 0.15 ppm | CS | Ocular | 0.15 |  |  |  |\n\n***DRAFT FOR PUBLIC COMMENT***\n\n---\n\n**Table 2-3. Levels of Significant Exposure to Hexachlorocyclopentadiene – Dermal**\n\n| Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Mouse 5 NS | 6 weeks 5 days/week 7 hours/day (WB) | 0.34 ppm | CS | Ocular |  | 0.34 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rabbit 6 NS | 6 weeks 5 days/week 7 hours/day | 0.34 ppm | CS | Ocular |  | 0.34 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rabbit 2 NS | 30 weeks 5 days/week 7 hours/day | 0.15 ppm | CS | Ocular | 0.15 |  |  |  |\n\nBC = serum (blood) chemistry; BW = body weight; CS = clinical signs; F = female(s); GN = gross necropsy; LD50 = median lethal dose; LE = lethality; \nLOAEL = lowest-observed-adverse-effect level; M = male(s); Neuro = neurological; NOAEL = no-observed-adverse-effect level; NS = not specified; (WB) = wholebody exposure\n\n---\n\n###### 2.2 DEATH\n\nNo studies were located regarding mortality in humans after exposure to HCCPD.\n\nHCCPD induced death in experimental animals via the inhalation, oral, and dermal routes.  The lethality \nof HCCPD following inhalation exposures has been evaluated for acute-, intermediate-, and chronicduration studies.  Acute-duration inhalation exposures to HCCPD at 1.0–73.6 ppm were lethal to rats, \nmice, guinea pigs, and rabbits in a concentration- and exposure duration-related manner (Treon et al. \n1955).  For example, the concentrations that produced 50% fatalities in mice after 1-, 3.5-, and 7-hour \nexposures were 7.2, <3.1, and <1.5 ppm, respectively.  Species-specific differences were observed in the \nmortality data; the concentrations that produced 50% fatalities after 3.5-hour exposures were 7.1 ppm for \nguinea pigs, 3.1 ppm for rats, <3.1 ppm for mice, and <1.4 ppm for rabbits.  All 10 rats exposed to \n176 ppm HCCPD for 4 hours died within 48 hours of the exposure period (OxyChem 1972).  The 1- and \n4-hour inhalation LC50 values for rats are 3.69 ppm (Jackson and Hardy 1986) and 2.9 ppm (Jackson and \nHardy 1987), respectively.  Male rats appear to be more susceptible to HCCPD lethality than female rats; \nthe sex-specific 4-hour inhalation median lethal concentration (LC50) values are 1.6 ppm for males and \n3.5 ppm for females (Rand et al. 1982a).  With 2-week exposures to 0.5 ppm HCCPD, one rat of each sex \ndied, and nine male rats and one female rat were sacrificed in moribund condition by the end of the \nexposure period.  When the exposure duration was reduced to 5 days, three of five males and none of five\nfemales died at 0.5 ppm.  All animals exposed to ≤0.11 ppm survived until the scheduled sacrifice\n(Alexander et al. 1980a; Rand et al. 1982a).\n\n$$\n\\mathrm{LC}_{50}\n$$\n\n$$\n\\left(LC_{50}\\right)\n$$\n\nIn 13-week studies, all rats and mice exposed to ≥0.941 ppm HCCPD died during the exposure periods \n(NTP 1994).  As was observed after acute-duration inhalation exposures, mice appeared to be more \nsensitive to HCCPD-induced lethality; all mice exposed to 2.142 ppm died during the first week while \nrats exposed to 2.065 ppm survived for up to 3 weeks.  Additionally, no rat mortalities were observed at \n≤0.385 ppm, while 5 of 10 male mice died at 0.389 ppm.  NTP (1994) hypothesized that the sensitivity of \nmice to inhalation exposure was the result of HCCPD-induced inflammation of the breathing passages \nand the narrower diameter of the mouse air passages.  No treatment-related deaths were reported for rats \nor monkeys exposed to ≤0.2 ppm for 14 weeks (Alexander et al. 1980b; Rand et al. 1982a) and overall \nsurvival was not statistically significantly affected by HCCPD treatment in male mice exposed to 0.2 ppm \nfor 33 weeks or 0.5 ppm for 26 weeks (NTP 1994).  Although overall survival of male rats was not \naffected after exposure to 0.5 ppm for 42 weeks, survival in this group decreased 14% 3 weeks after \nexposure cessation (NTP 1994).  In a 30-week study, 22% of male rats exposed to 0.56 ppm died during\n\n$$\n\\leq0.385ppm\n$$ the exposure period (Clark 1981).  No mortality attributed to HCCPD was observed in rats exposed to \n0.06 or 0.14 ppm.\n\nSurvival of male and female rats and male mice chronically exposed to 0.01–0.2 ppm HCCPD for 2 years \nwas similar to controls.  Decreased survival was observed for female mice exposed to 0.2 ppm, but not at \nlower concentrations (NTP 1994).  Ovarian inflammation, possibly resulting from an infection, appeared \nto be the cause of premature deaths in female mice exposed to 0.2 ppm HCCPD.\n\nThe lethality of HCCPD in laboratory animals has been evaluated for acute- and intermediate-duration \noral exposures.  The oral median lethal dose (LD50) values were 505 mg/kg in male rats of an unspecified \nstrain (Treon et al. 1955), 630 and 530 mg/kg in male and female Spartan rats, respectively (OxyChem\n1972), and 1,500 and 1,300 mg/kg in male and female CFY rats, respectively (Gardner 1986a).  An oral\ndose of 940 mg/kg was lethal to ≥90% of the male and female rats (Treon et al. 1955).  Acute-duration \noral lethality data for species other than rats are more limited.  The oral LD50 value for male and female \nmice is 679 mg/kg (Dean 1977).  In rabbits, doses of 420, 620, and 940 mg/kg killed 0/3, 1/3, and \n3/3 animals, respectively (Treon et al. 1955).  In pregnant animals, several rabbits (exact number not \nidentified) did not survive 13 days of treatment with 75 mg/kg/day HCCPD on gestational days (GDs) 6–\n18 (Murray et al. 1980).  With intermediate-duration oral exposure, rats appeared to be more sensitive to \nHCCPD lethality than mice, a reverse of the sensitivity observed for inhalation exposures.  There were no \nmouse deaths following 13-week exposures to ≤150 mg/kg/day, but 6 of 10 male rat deaths at \n150 mg/kg/day were attributed to HCCPD treatment following 13 weeks of exposure (Abdo et al. 1984: \nVelsicol 1981a, 1981b).  All 10 male mice and 3 of 10 female mice died during the first 2 weeks of \nexposure to 300 mg/kg/day (Abdo et al. 1984; Velsicol 1981a).\n\n$$\n\\left(\\mathrm{LD}_{50}\\right)\n$$\n\n$$\n\\mathrm{LD}_{50}\n$$\n\n$$\n\\leqq150\n$$\n\nFor the dermal route, lethality of HCCPD in laboratory animals has only been evaluated for acuteduration exposures.  In rabbits administered topical applications of 200 mg/kg for 24 hours, deaths were \nreported in 2/2 males and 0/2 females (OxyChem 1972) and 8/12 rabbits of unspecified sex (OxyChem \n1992).  Dermal exposure to 2,000 mg/kg resulted in 100% mortality in male and female rabbits within \n24 hours (OxyChem 1972).  At lower doses, single dermal doses applied for 24 hours caused mortality in \n0/3, 1/3, and 2/3 rabbits at 430, 610, and 1,020 mg/kg, respectively (Treon et al. 1955).  In the multi-dose \nstudy by Treon et al. (1955), survival time was inversely proportional to the dose; rabbits survived 72, \n24–48, 20, and 17 hours after dermal dosing with 610, 1,020, 2,130, and 6,130 mg/kg, respectively.  None \nof the animals died with a dermal application of 430 mg/kg, although one rabbit was in poor condition \nand likely would have died had it not been sacrificed at 21 days.  In rats, the dermal LD50 values were\n\n$$\n\\mathrm{LD}_{50}\n$$\n\n---\n\n2,600 mg/kg in males and 3,100 mg/kg in females (Gardner 1986b).  These results suggest that rabbits are \nmore sensitive to HCCPD toxicity via the dermal route relative to rats.\n\nWhen 0.1 mL of HCCPD was instilled into the conjunctival sac of five rabbits for 5 minutes and then \nrinsed with water, the quantity of material absorbed was lethal to all the animals within 9 days (OxyChem\n1972).  When ocular rinsing was delayed until 24 hours post-instillation, all three rabbits administered\n0.1 mL of HCCPD died within 6 days.\n\n###### 2.3 BODY WEIGHT\n\nNo reports of body weight effects in humans after exposure to HCCPD were found.  The available data in \nlaboratory animals indicate that HCCPD produces body weight effects at sufficiently high inhalation and \noral exposure levels; no body weight data are available via the dermal route. In several of these studies, \nbody weight changes were associated with decreased food and/or water intake (see Section 2.18, Other \nNoncancer, for additional details).\n\nBody weight effects resulting from inhalation exposures to HCCPD have been assessed in acute-, \nintermediate-, and chronic-duration studies.  Inhalation exposures to sufficient HCCPD concentrations \nover acute and intermediate periods decrease body weights and/or suppress body weight gains.  A single \n1-hour exposure to HCCPD resulted in decreased body weights in rats during the 3-week post-exposure \nobservation period at concentrations ≥2.38 ppm; when animals that died prematurely and those sacrificed \nat the end of the observation period are combined, body weight decreases compared to control were 41% \nin males and 26% in females (Jackson and Hardy 1986).  A 4-hour exposure resulted in >20% decreases \nin body weight in male and female rats at ≥1.68 and 1.83 ppm, respectively, during the 4-week \nobservation period (Jackson and Hardy 1987).  In both studies by Jackson and Hardy (1986, 1987), body \nweight effects were associated with decreased food intake.  Similarly, after a 4-hour exposure to HCCPD, \nbody weight decreases of at least 25 and 17% relative to pre-exposure weights were observed for male \nand female rats, respectively, after exposures to 1.4–5.8 ppm; no food intake data were provided (Rand et \nal. 1982a).  With significantly decreased food intake, male and female rats exposed to 0.5 ppm HCCPD \nfor 1–2 weeks lost body weight; male body weights decreased 32% on day 10 and terminal female body \nweight decreased 29% (Alexander et al. 1980a; Rand et al. 1982a).\n\n$$\nt\\geqq1.68\n$$\n\nIn 13-week inhalation studies, terminal body weights remained within 10% of control values following \nexposure to HCCPD at concentrations up to 0.385 ppm in rats and 0.389 ppm in mice (NTP 1994).\n\n---\n\nSimilarly, no effects on body weight were observed in rats and monkeys exposed to ≤0.2 ppm HCCPD \nfor 14 weeks (Alexander et al. 1980b; Rand et al. 1982a).  Body weight decreased 19% and body weight \ngain decreased 42% in male mice exposed to 0.5 ppm for 42 weeks (NTP 1994).  No body weight deficits \nwere identified after exposure of male mice to 0.2 ppm for 33 weeks or to 0.5 ppm for 26 weeks (NTP \n1994).  Body weights remained within 10% of control values for male and female rats exposed to \n≤0.56 ppm for 30 weeks (Clark 1981), and in male and female mice and rats exposed to ≤0.2 ppm for \n2 years (NTP 1994).\n\nBody weight effects after oral exposure to HCCPD in experimental animals have been evaluated in acuteand intermediate-duration studies.  In intermediate-duration studies, sufficient oral dosing with HCCPD \ndecreased body weights and suppressed body weight gains.  Male and female rats and mice experienced \ndose-related decreased body weights and body weight gains when compared to controls after oral \nexposure to HCCPD for 13 weeks (Abdo et al. 1984; Velsicol 1981a, 1981b).  Male rats were affected \nmore than females, and rats were affected more than mice.  Terminal body weights in male rats decreased \n13–35% and overall body weight gains were reduced 21–58% at dose levels of ≥38 mg/kg/day. In female\nrats exposed to 75–150 mg/kg/day, terminal body weights were reduced 15–17% and overall body weight \ngains decreased 28–36%.  Terminal body weights in male mice were reduced 11% and overall body \nweight gains decreased 39% at 150 mg/kg/day.  In female mice, terminal body weights decreased 13% at \n300 mg/kg/day and overall body weight gains were reduced 22–44% at ≥150 mg/kg/day. Differences in \nterminal body weights and overall body weight gains were within 10% of control values for male rats at \n≤19 mg/kg/day, female rats at ≤38 mg/kg/day, and male and female mice at ≤75 mg/kg/day.  Maternal \nweight loss was observed in rabbits administered 75 mg/kg/day on GDs 6–18; the magnitude of weight \nloss was not reported (Murray et al. 1980).  No body weight effects were reported for rabbits dosed with \n≤25 mg/kg/day on GDs 6–18 or for mice dosed with ≤75 mg/kg/day on GDs 6–15.\n\n###### 2.4 RESPIRATORY\n\nThe data provide strong evidence that HCCPD produces portal-of-entry effects in the respiratory system \nfollowing inhalation exposures; no effects on the respiratory tract were observed following oral or dermal \nexposures to HCCPD.  Based upon systematic review (Appendix C), the respiratory system is a presumed \nhazard of HCCPD toxicity following inhalation exposure based on inadequate evidence in humans and a \nhigh level of evidence from laboratory animal studies.\n\n---\n\nThe available data on respiratory effects of HCCPD in humans are limited to reports of WWTP workers \nand cleanup crew members exposed to HCCPD for 3–15 days after an inadvertent industrial release of \nthis material into the sewage system (Kominsky et al. 1980; Morse et al. 1979).  Maximum atmospheric \nconcentrations for the treatment plant workers were unknown but were most likely >0.97 ppm, the \nmaximum concentration measured 4 days after compound identification (Morse et al. 1979).  The \nmaximum concentration recorded during cleanup was 19.2 ppm (Kominsky et al. 1980).  Symptoms of \ntracheobronchial irritation were reported by the treatment plant workers early in the exposure period.  \nThese symptoms were recounted by 39 of 145 (27%) employees who responded to a questionnaire shortly \nafter the exposure incident and by 16 of 177 (9%) employees who responded to a follow-up questionnaire \n6 weeks later (Morse et al. 1979).  Chest x-rays of 28 exposed workers were normal and tests of \npulmonary function were normal in a subset of 22 workers from this group (Kominsky et al. 1980).  \nMinor respiratory complaints included sore throat, cough, chest discomfort, and difficulty breathing.  \nThese effects were likely a consequence of the direct action of the HCCPD vapor on the mucous \nmembranes of the respiratory tract, rather than systemic effects due to exposure to HCCPD through the \nlungs.  One cleanup crew worker also reported respiratory difficulty when exposed for a few seconds to \n19.2 ppm HCCPD without protective equipment (Kominsky et al. 1980).  Chest discomfort persisted for \nseveral days in this individual.\n\nRespiratory effects induced by HCCPD in laboratory animals have been evaluated in acute-, \nintermediate-, and chronic-duration inhalation exposure studies.  Inhalation exposures to HCCPD \nproduced clinical signs of respiratory toxicity and/or irritation including abnormal respiratory pattern \n(irregular or exaggerated respiratory movements, fast or irregular respiration rate or pattern, rales and/or \nnoisy respiration, and/or gasping), labored respiration, sneezing, increased respiration rate, and/or mouth \nbreathing in rats exposed to 1.67 ppm for 1 hour (Jackson and Hardy 1986), 1.68 ppm for 4 hours \n(Jackson and Hardy 1987), 0.5 ppm for 1–2 weeks (Alexander et al. 1980a; Rand et al. 1982a), 0.56 ppm \nfor 30 weeks (Clark 1981), and ≥0.941 ppm for 13 weeks (NTP 1994).  No respiratory clinical signs were \nobserved in rats or monkeys exposed to 0.2 ppm for 14 weeks (Alexander et al. 1980b; Rand et al. \n1982a), mice exposed to ≤2.142 ppm for 13 weeks (NTP 1994), male mice exposed to 0.2 ppm for \n33 weeks or 0.5 ppm for 26 or 42 weeks (NTP 1994), or rats and mice exposed to ≤0.2 ppm for 2 years \n(NTP 1994).  Based on these data, it appears that rats are more susceptible to HCCPD-induced respiratory \nirritation effects than mice. Blood gas analysis, pulmonary ventilation, and lung mechanics were within \nnormal ranges in pulmonary function tests of monkeys exposed to ≤0.2 ppm HCCPD for 7 and 13 weeks \n(Alexander et al. 1980b; Rand et al. 1982a).\n\n---\n\nInhalation exposures to HCCPD vapor caused histopathological changes in the respiratory tracts of \nexperimental animals.  At nonlethal concentrations, these alterations were largely inflammatory or \nhyperplastic in nature, consistent with repetitive irritation at the portal of entry.  Inflammation of the \ntissues was followed by necrosis, exfoliation, and/or hemorrhage.  No histopathological examination was \nconducted, but gross necropsy of the lungs showed pale and swollen lungs in rats exposed to ≥1.68 ppm \nfor 4 hours; findings were associated with increased absolute and relative lung weights at ≥3.31 and \n1.83 ppm in male and female rats, respectively (Jackson and Hardy 1987).  Inflammation, hyperplasia, \nand epithelial erosion were identified in the lungs of rats exposed to HCCPD vapor at 0.5 ppm for 1–\n2 weeks; recovery was apparent 2 weeks after exposure ceased in surviving animals (Alexander et al. \n1980a; Rand et al. 1982a).  No histopathological changes were identified in respiratory tissues of rats\nexposed to ≤0.11 ppm in the same manner (Alexander et al. 1980a; Rand et al. 1982a) or in rats and \nmonkeys exposed to ≤0.2 ppm for 14 weeks (Alexander et al. 1980b; Rand et al. 1982a). Using electron \nmicroscopy, exposure-related increases in electron-lucent inclusions in club cells, formerly called Clara \ncells, were observed in rats exposed to 0.01–0.2 ppm for 14 weeks (Huntingdon Research Centre 1980; \nRand et al. 1982b); however, this findings is considered a biomarker of exposure rather than evidence of \ntoxicity due to the absence of histopathological findings or any other ultrastructural changes.  No \nexposure-related ultrastructural changes were observed in monkeys exposed to ≤0.2 ppm for 14 weeks\n(Rand et al. 1982b).  In a 30-week inhalation exposure study in rats, increased incidences of \nperivascular/peribronchiolar inflammatory cell infiltration were observed in males and females exposed to \n0.56 ppm; males exposed to this concentration also exhibited an increased incidence of bronchiolar \nepithelial thinning/ulceration (Clark 1981).  The incidences of bronchiolar epithelial hyperplasia, \nsloughing/loss, and edema also increased in male and female rats exposed to 0.56 ppm but did not reach \nstatistical significance.  Following a 14-week recovery period, no histopathological differences were \nidentified in the lungs of control and treated rats, indicating reversibility of these lesions.\n\n$$\nt_{0}\\geqq1.68\n$$\n\nIn 13-week studies, microscopic effects in the respiratory system produced by lethal HCCPD \nconcentrations included necrotizing inflammation of the nose, larynx, trachea, and bronchus/bronchiole \nand hemorrhaging of the alveolus in male and female rats exposed to 0.941–2.065 ppm; suppurative \ninflammation of the alveolus in male and female rats at 0.941 ppm; acute necrosis of the nose, larynx, \ntrachea, and lung epithelium and lung congestion in male and female mice at 2.142 ppm; tracheal \nsquamous metaplasia in male and female mice at 0.949 ppm; and suppurative inflammation of the nasal \nepithelium of male and female mice exposed to 0.949–2.142 ppm (NTP 1994).  Increased incidences of \nsuppurative inflammation and squamous metaplasia in the nose and necrotizing and suppurative \ninflammation of the bronchus/bronchiole were identified in male rats exposed to 0.385 ppm, increased incidences of nasal suppurative inflammation and tracheal squamous metaplasia were observed in male \nmice exposed to 0.389 ppm, and an increased incidence of nasal serous inflammation was present in \nfemale mice exposed to 0.389 ppm.  No statistically significant increases were identified for nonneoplastic lesions in the respiratory tract tissues of female rats exposed to ≤0.385 ppm, male rats exposed \nto 0.146 ppm, or male or female mice exposed to ≤0.146 ppm (NTP 1994).\n\nHistopathological findings in male and female mice exposed to 0.2 ppm for 2 years included nasal \nsuppurative inflammation characterized by accumulation of cellular debris, mucus, neutrophils, and fibrin \nin the nasal lumen and infiltration of mononuclear cells and neutrophils into the lamina propria (NTP \n1994).  After 2-year exposures, an increased incidence of squamous metaplasia of the larynx (minimal \nseverity) was identified in female rats at 0.01 and 0.2 ppm; the incidence at 0.05 ppm was also elevated \nbut was not statistically significantly different from the concurrent control incidence.  No treatmentrelated respiratory tract lesions were identified in male rats.  The toxicological relevance of the squamous \nmetaplasia was not clear to the NTP (1994) authors due to difficulties in obtaining consistent sections for \nanalysis and determination of the boundary between squamous and columnar epithelium.  Due to this, as \nwell as the lack of clear dose-response, a LOAEL determination for squamous metaplasia was not \nincluded in Table 2-1.\n\nTo examine the progression and permanence of non-neoplastic lesions in the respiratory tract, NTP \n(1994) conducted additional studies in male mice with the intent of evaluating the relative effects of \nconcentration and duration on development of these lesions.  In these studies, concentrations were 0 or \n0.2 ppm for 33 weeks and 0 or 0.5 ppm for 26 or 42 weeks.  Animals were sacrificed at interim \nevaluations after 27, 34, or 43 weeks or 15 months of exposure or were sacrificed after 2 years.  At the \nend of the exposure periods, the incidence of nasal suppurative inflammation increased in all treatment \ngroups and suppurative inflammation of the trachea and lungs and alveolar epithelial hyperplasia \nincreased in animals exposed to 0.5 ppm for 42 weeks.  The incidence of alveolar epithelial hyperplasia \nalso increased in male mice exposed to 0.5 ppm for 42 weeks.  An evaluation of the data indicated that \nboth concentration and duration of exposure influenced the development of these respiratory tract lesions; \nthe inflammation of the trachea and lungs was not observed unless the product of the concentration and \nduration was >20 or 21 ppm-weeks.\n\nIn the chronic-duration studies of rats and mice exposed to HCCPD for 2 years, accumulation of a \ngranular yellow-brown pigment was observed in the nasal epithelium in male and female rats and mice at \n≥0.01 ppm, tracheal epithelium of male and female mice at ≥0.01 ppm, bronchiole epithelium of female\n\n$$\n\\geqq0.01\n$$ rats at ≥0.01 ppm, and lung epithelium of male and female mice ≥0.05 ppm (NTP 1994).  At 0.2 ppm, \nminimal-to-mild tracheal, bronchiole, and peribronchiole pigmentation was observed in male rats and \nperibronchiole pigmentation was identified in female rats (NTP 1994).  The pigmentation incidence and \nseverity generally increased with concentration for each sex-species combination.  In male mice exposed \nto 0.2 ppm for 33 weeks or 0.5 ppm for 26 or 42 weeks and then maintained for up to 2 years, \npigmentation of the respiratory tract (nose, trachea, and/or lungs) was seen in the majority of exposed \nanimals and did not disappear following exposure cessation and evaluation at 2 years, indicating a lack of \nrecovery and physiological turnover of the pigment material.  The incidence and severity were similar \nafter 33, 66, and 104 weeks of exposure to 0.2 ppm HCCPD.  In the chronic-duration and additional \nstudies in male mice exposed to 0.2 ppm for 33 weeks and 0.5 ppm for 26 or 42 weeks, the pigmentation \ndid not co-occur with respiratory lesions and did not appear to be a precursor to more significant effects \n(i.e., did not indicate an initial phase in the progression of a disease state).  Results of several staining \nprocedures applied to the pigmented lung sections of rats and mice indicated the presence of reducing \nsubstances, but no further analytical identification was performed.  NTP (1994) indicated that the \npigmentation may be a unique response to HCCPD and could be due to lipid peroxidation.  Based on \nthese data, ATSDR concludes that it is more appropriate to characterize the pigmentation as a marker of \nexposure to HCCPD rather than an adverse effect attributable to HCCPD exposure.\n\nThe potential for oral exposure to HCCPD to induce respiratory effects has been evaluated in acute- and \nintermediate-duration studies.  In rats and mice administered lethal gavage doses of HCCPD, decreased \nrespiratory rates were observed prior to death (Dean 1977; Gardner 1986a); this clinical sign was likely a \nconsequence of significant morbidity prior to death rather than an effect of HCCPD on the respiratory \nsystem.  No gross or histopathological changes were identified in the nasal cavity, trachea, larynx, \nbronchi, or lungs of rats at doses ≤150 mg/kg/day or in mice at doses ≤300 mg/kg/day for 13 weeks \n(Abdo et al. 1984; Velsicol 1981a, 1981b).\n\nThe potential toxicological effects of HCCPD on the respiratory tract following dermal exposure were \nevaluated in one acute-duration dermal toxicity study.  A decreased rate of respiration was observed in \nrats administered topical doses ≥2,000 mg/kg for 24 hours (Gardner 1986b).  The animals appeared \nnormal 5–9 days after dosing and no gross pathological changes were identified in the lungs of animals \nthat survived to the scheduled sacrifice.\n\n---\n\n###### 2.5 CARDIOVASCULAR\n\nNo studies were located regarding cardiovascular effects in humans after exposure to HCCPD. Available\ndata from laboratory animals indicate that the cardiovascular system is not a sensitive toxicity target \nfollowing inhalation or oral exposure to HCCPD.\n\nThe cardiovascular system has been evaluated in experimental animals exposed to HCCPD via inhalation \nin acute-, intermediate-, and chronic-duration studies.  Diffuse degenerative changes were observed in the \nhearts of rats, mice, and rabbits that died following acute exposure to lethal concentrations of HCCPD \nranging from 0.3 to 66 ppm for 15 minutes to 2 weeks; incidence data were not provided, and findings \nwere potentially attributable to autolysis (Treon et al. 1955).  In another acute-duration study, there were \nno histopathological changes in the heart in rats exposed to concentrations up to 0.5 ppm after either 1 or \n2 weeks (Alexander et al. 1980a; Rand et al. 1982a).  In longer-term inhalation studies, there was no \nevidence for histopathological changes in the heart at intermediate-duration concentrations up to \n0.56 ppm in rats, 0.389 ppm in mice, or 0.2 ppm in monkeys (Alexander et al. 1980b; Clark 1981; NTP \n1994; Rand et al. 1982a) or chronic-duration concentrations up to 0.2 ppm in rats or mice (NTP 1994).\n\nPotential cardiovascular effects of HCCPD oral exposures in experimental animals were evaluated in \nacute- and intermediate-duration studies.  Single oral doses of 280–2,100 mg/kg caused degenerative \nchanges in the hearts of rats and rabbits, possibly due to tissue autolysis; incidence data were not provided\n(Treon et al. 1955).  In contrast, there were no gross or histopathological changes in the hearts of rats \nexposed to doses ≤150 mg/kg/day or mice exposed to doses ≤300 mg/kg/day for 13 weeks (Abdo et al. \n1984; Velsicol 1981a, 1981b).\n\nRabbits that died following single dermal doses of 610–6,130 mg/kg displayed degenerative changes in \nthe heart, possibly because of tissue autolysis; incidence data were not provided (Treon et al. 1955).\n\n###### 2.6 GASTROINTESTINAL\n\nThe data provide evidence that HCCPD produces portal-of-entry effects in the gastrointestinal system, \nspecifically the stomach, following oral exposures.  Data on adverse gastrointestinal effects following \ninhalation exposure are limited to clinical signs following accidental occupational exposure; no effects on \nthe gastrointestinal system were observed following dermal exposure to HCCPD.  Based upon systematic \nreview (Appendix C), the gastrointestinal system is a presumed hazard of HCCPD toxicity following oral exposure based on no route-specific data in humans and a high level of evidence from laboratory animal \nstudies.\n\nWWTP workers exposed to HCCPD for 3–15 days due to an inadvertent industrial release complained of \nnausea (22% of 177 workers) and abdominal cramps (prevalence not specified) (Kominsky et al. 1980; \nMorse et al. 1979).  One member of the cleanup crew who was exposed to 19.2 ppm for several seconds \nwithout protective equipment experienced nausea several minutes after the exposure (Kominsky et al. \n1980).  While classified as gastrointestinal in this profile, it is possible that nausea may be neurological in \norigin.\n\nGastrointestinal effects of HCCPD have been evaluated in laboratory animals following intermediate- and \nchronic-duration inhalation exposures.  No microscopic changes were seen in the stomach, esophagus, or \nintestines of monkeys, rats, or mice exposed to concentrations up to 0.2, 0.56, or 0.5 ppm, respectively, in\nintermediate-duration studies (Alexander et al. 1980b; Clark 1981; NTP 1994; Rand et al. 1982a), or rats \nor mice following chronic-duration exposure to concentrations up to 0.2 ppm (NTP 1994).  The \ngastrointestinal tract does not appear to be a sensitive target for HCCPD in animals following inhalation \nexposures.\n\nThe potential impact of HCCPD exposure on gastrointestinal tissues has been evaluated in acute- and \nintermediate-duration oral exposure studies in experimental animals.  Increased incidences of diarrhea \nwere observed in rats dosed with ≥1,260 mg/kg (Gardner 1986a) and female and male mice dosed with \n464 and 1,000 mg/kg, respectively (Dean 1977).  Acute necrotic lesions of the forestomach were noted in \nsome rats administered an oral dose of 280–2,100 mg/kg; incidence data were not provided (Treon et al. \n1955).  After 13-week exposures to HCCPD, increased incidences of forestomach epithelial hyperplasia \nwere observed in male and female rats at 38 mg/kg/day and male and female mice at 75 mg/kg/day (Abdo \net al. 1984; Velsicol 1981a, 1981b).  Increased incidences of focal inflammation in the forestomach were \nidentified in male and female rats at 38 mg/kg/day and male and female mice at 75 mg/kg/day.  The \nincidences and ranges of lesion severities were directly related to the dose.  No histopathological changes \nwere identified in the esophagus, duodenum, jejunum, ileum, or colon of males and females of either \nspecies.  These data suggest that rats are more sensitive to HCCPD-induced effects to the forestomach \nthan mice.  The presence of the forestomach lesions and lack of histopathological changes in other \nregions of the gastrointestinal tract suggests that the forestomach effects result from direct contact of \nthese tissues with HCCPD.\n\n---\n\n###### 2.7 HEMATOLOGICAL\n\nThe data indicate HCCPD may alter red blood cell hematology parameters following inhalation exposure \nwithout causing histopathological changes to bone marrow; no consistent effects were noted in white \nblood cell parameters following inhalation exposure and no effects on the hematological system were \nobserved in animals following oral exposures to HCCPD.  Data are not available via the dermal route.  \nBased upon systematic review (Appendix C), the hematological system, specifically red blood cell \nparameters, is a suspected hazard of HCCPD toxicity following inhalation exposure based on inadequate \ndata in humans and a moderate level of evidence from laboratory animal studies.  White blood cell effects \nare not classifiable as to the hazard to humans based on inadequate data in humans and animals.\n\nNo changes in blood counts were observed in workers exposed to HCCPD at a WWTP after an industrial \ndischarge of the material into the sewage system (Kominsky et al. 1980).\n\nThe potential hematological effects of HCCPD were evaluated in experimental animals exposed via \ninhalation after acute-, intermediate-, and chronic-duration exposures.  No effects on bone marrow \nhistopathology were reported in rats exposed to 0.5 ppm for 1–2 weeks (Alexander et al. 1980a; Rand et \nal. 1982a), rats and mice exposed to ≤0.385 and ≤0.389 ppm, respectively, for 13 weeks, or rats and mice \nexposed to ≤0.2 ppm for 2 years (Alexander et al. 1980b; NTP 1994; Rand et al. 1982a).  Across acuteand intermediate-duration multiple exposure studies, altered red blood cell hematology parameters were \nidentified in rats, particularly males, as seen in Table 2-4.\n\n**Table 2-4. LOAEL Values for Red Blood Cell Hematological Effects of Rats** \n**Exposed to HCCPD Vapor in Acute- and Intermediate-Duration Inhalation**\n**Studies**\n\n| Hematology parameter | Rand et al. 1982aa: 1–2 weeks | Rand et al. 1982aa: 1–2 weeks (recovery group) | NTP 1994: 13 weeks | NTP 1994: 13-week special hematology study | Clark 1981: 30 weeks |\n| --- | --- | --- | --- | --- | --- |\n| Males |  |  |  |  |  |\n| PCV | \\(\\uparrow (0.5^{{b}})\\) | ↔ | \\(\\uparrow (0.385)\\) | ↔ | - |\n| Hb | \\(\\uparrow (0.5)\\) | \\(\\uparrow (0.5)\\) | \\(\\uparrow (0.385)\\) | ↔ | \\(\\uparrow (0.14)\\) |\n| RBC | \\(\\uparrow (0.5)\\) | ↔ | \\(\\uparrow (0.385)\\) | ↔ | \\(\\uparrow (0.14)\\) |\n| MCV | ↔ | ↔ | ↔ | \\(\\uparrow (0.385)\\) | ↔ |\n| MCH | - | - | \\(\\uparrow (0.385)\\) | ↔ | ↔ |\n| MCHC | ↔ | \\(\\uparrow (0.5)\\) | ↔ | ↔ | ↔ |\n\n---\n\n**Table 2-4. LOAEL Values for Red Blood Cell Hematological Effects of Rats** \n**Exposed to HCCPD Vapor in Acute- and Intermediate-Duration Inhalation**\n**Studies**\n\n| Hematology parameter | Rand et al. 1982aa: 1–2 weeks | Rand et al. 1982aa: 1–2 weeks (recovery group) | NTP 1994: 13 weeks | NTP 1994: 13-week special hematology study | Clark 1981: 30 weeks |\n| --- | --- | --- | --- | --- | --- |\n| HCT | - | - | - | - | \\(\\uparrow\\) (0.14) |\n| Females |  |  |  |  |  |\n| PCV | \\(\\uparrow\\) (0.5) | ↔ | ↔ | \\(\\uparrow\\) (0.385) | - |\n| Hb | \\(\\uparrow\\) (0.5) | ↔ | ↔ | \\(\\uparrow\\) (0.385) | ↔ |\n| RBC | \\(\\uparrow\\) (0.5) | ↔ | \\(\\downarrow\\) (0.385) | \\(\\uparrow\\) (0.385) | ↔ |\n| MCV | ↔ | ↔ | \\(\\uparrow\\) (0.385) | \\(\\uparrow\\) (0.385) | ↔ |\n| MCH | - | - | ↔ | \\(\\uparrow\\) (0.385) | ↔ |\n| MCHC | ↔ | ↔ | ↔ | ↔ | ↔ |\n| HCT | - | - | - | - | ↔ |\n\n<sup>a</sup>Data are also available in the unpublished industry report by Alexander et al. (1980a).\n\n<sup>b</sup>LOAEL concentrations are in ppm.\n\n↑ = increased mean value; ↓ = decreased mean value; ↔ = no significant, dose-related change in mean value;\n\n– = not assessed; Hb = hemoglobin; HCT =hematocrit; MCH = mean cell hemoglobin; MCHC = mean cell\n\nhemoglobin concentration; MCV = mean cell volume; PCV = packed cell volume; RBC = red blood cell count\n\nThe most consistently observed effects were increased hemoglobin levels in male and female rats and \nincreased red blood cell counts in male rats.  Generally, effects were observed at concentrations \n≥0.14 ppm and had magnitudes of effect that were <10% of control values.  The exceptions are for the 1–\n2-week range-finding study (Alexander et al. 1980a; Rand et al. 1982a), where 20–30% increases in red \nblood cell parameters were identified at 0.5 ppm, a concentration that co-occurred with significantly \ndecreased water intake and produced significant mortality and morbidity (see Section 2.2).  Drinking \nwater intakes were not assessed in the NTP (1994) studies and were not affected by HCCPD exposure in \nthe Clark (1981) study (see Section 2.18).  While statistically significant altered hemoglobin, mean cell \nvolume (MCV), and mean cell hemoglobin concentration (MCHC) values were reported in rats following \na 14-week exposure at concentrations as low as 0.01 ppm, these changes were sporadically observed and\nwere not dose-responsive, and the magnitudes of effect were generally low (≤5%) (Alexander et al. \n1980b; Rand et al. 1982a).  Therefore, they were not considered to be biologically significant in this \nassessment and are not presented in Table 2-4.  For intermediate-duration exposures in rats, the NOAEL \nvalues were 0.039–0.146 ppm for the NTP (1994) 13-week studies and 0.06 ppm for the Clark (1981) \n30-week study.\n\n---\n\nRand et al. (1982a) postulated that these minor variances in hematological parameters were a \nconsequence of hemorrhagic lesions in the lungs and not a direct influence of HCCPD on hematopoiesis \nor red cell turnover.  Since the red blood cell hematology parameters were more consistently altered in \nmale rats than in female rats, this hypothesis correlates with the increased absolute and relative lung \nweights and more severe histopathological effects observed in the lungs of male rats in the 1–2-week\nRand et al. (1982a) study.  NTP (1994) suggested that the red blood cell hematology alterations were not \nattributable to HCCPD treatment due to the inconsistent dose-response and lack of correlation in the \nresults across sexes and between the core and special 13-week hematology studies.  While there are \ninconsistencies in the red blood cell parameter results obtained from the NTP (1994) studies, common \nalterations in hemoglobin levels and red blood cell counts across repeated inhalation exposure studies \nsuggest a consistent biological response to HCCPD.  In the absence of additional data and based on the \nlack of histopathological effects to bone marrow, ATSDR considers the altered red blood cell parameters \nto be plausibly related to respiratory tract damage resulting in compromised gas exchange.\n\nIn mice, the only consistent HCCPD treatment-related effect on red blood cell hematology parameters \nacross studies was decreased MCV in female mice after exposure to 0.389 ppm for 13 weeks in the core\nand special hematology studies (NTP 1994).  Other red blood cell effects were limited to increased \nMCHC in male mice at 0.389 ppm and in female mice at 0.039–0.389 ppm in the special 13-week \nhematology study.  The magnitudes of effect were within 5% of control values.  HCCPD treatmentrelated effects on other hematological parameters following inhalation exposures were limited to \ndecreased reticulocytes (40%) in female rats exposed to 0.385 ppm in the special hematology study (NTP \n1994); decreased total white blood cells (46%) and lymphocyte count (53%) in male rats, and increased \nneutrophil count (114%) in female rats exposed to 0.5 ppm for 1–2 weeks (Alexander et al. 1980a; Rand \net al. 1982a); and decreased percent lymphocytes (8–10%) and increased neutrophil count (27–36%) in \nmale rats exposed to ≥0.14 ppm and decreased lymphocyte count (16%) in female rats exposed to \n0.56 ppm for 30 weeks (Clark 1981).  No clear biological basis can be identified for these effects based \non the lack of consistency across studies.\n\nIn intermediate-duration oral exposure studies, no histopathological changes were identified in the bone \nmarrow of rats dosed with ≤150 mg/kg/day or mice dosed with ≤300 mg/kg/day for 13 weeks (Abdo et al. \n1984; Velsicol 1981a, 1981b).  Hematology parameters were not evaluated in this study.\n\n---\n\n###### 2.8 MUSCULOSKELETAL\n\nNo studies were located regarding musculoskeletal effects in humans after exposure to HCCPD.  \nAvailable inhalation and oral data in laboratory animals indicate the musculoskeletal system is not a \nsensitive target of toxicity following exposure to HCCPD; no dermal studies were identified.\n\nThe potential effect of HCCPD on musculoskeletal tissues has been evaluated in laboratory animals \nfollowing intermediate- and chronic-duration inhalation exposures and acute- and intermediate-duration \noral exposures.  HCCPD did not affect skeletal muscle of rats or monkeys exposed to up to 0.2 ppm for \n14 weeks (Alexander et al. 1980b; Rand et al. 1982a); femoral muscle, knee joint, or femur of male and \nfemale rats exposed to ≤0.56 ppm for 30 weeks (Clark 1981); bone histopathology of mice or rats \nexposed to ≤0.389 ppm for 13 weeks or ≤0.2 ppm for 2 years (NTP 1994).  Similarly, no \nhistopathological changes were identified in thigh muscle, rib (costochondral junction), or femur of rats \nexposed to ≤150 mg/kg/day or mice exposed to ≤300 mg/kg/day via gavage for 13 weeks (Abdo et al. \n1984; Velsicol 1981a, 1981b). In animals that died, decreased limb tone was observed in mice (prior to \ndeath) after a single exposure to 1,000 mg/kg via gavage (Dean 1977).\n\n###### 2.9 HEPATIC\n\nThe data indicate that the hepatic system is not a sensitive target of HCCPD toxicity.\n\nSerum markers of hepatotoxicity were evaluated in 97 cleanup workers exposed to HCCPD vapors at a \nWWTP because of an inadvertent industrial release (Kominsky et al. 1980).  Abnormal serum marker \nranges were identified for 18 of the 97 workers (19%); aspartate aminotransferase (AST) values were \nelevated for 12 workers, alkaline phosphatase (ALP) was elevated for 5 workers, and total bilirubin was \nelevated for 1 worker (Kominsky et al. 1980).  For 8 of the 97 cleanup crew members, these biochemical \nparameters were abnormal on more than one occasion, and 7 workers had values that were temporallyrelated to exposure conditions.  It should be noted that evaluations were not performed on unexposed \nworkers, and it is not known if the abnormal values observed in exposed workers differ from the \nunexposed local general population.\n\nRelative to a group of 35 controls, 73 male operators employed for an average of 8.2 years (range 0.5–\n23 years) in a plant producing chlorinated hydrocarbons, including HCCPD, showed no evidence of \nhepatotoxicity (Boogaard et al. 1993).  Clinical tests included measurement of alanine aminotransferase\n\n---\n\n(ALT), AST, ALP, total bilirubin, γ-glutamyltransferase (GGT), lactate dehydrogenase (LDH), and total \nbile acids.  Personal air sampling for HCCPD was performed on a subset of study participants but was not \nused to evaluate associations between HCCPD exposure and liver function values.\n\nThe hepatotoxic potential of HCCPD has been evaluated in laboratory animals following acute-, \nintermediate-, and chronic-duration inhalation exposures.  Mild-to-moderate hepatic tissue degeneration \nwas observed following acute-duration inhalation exposures to 0.34–73.6 ppm for 15 minutes to 5 days, \nand to intermediate-duration exposures to 0.34 ppm for 6 weeks or 0.15 ppm for 30 weeks; incidence data \nwere not provided (Treon et al. 1955).  Hepatic damage was more pronounced in the animals that died \nthan in those that survived and, thus, may have been, at least partially, the result of autolysis in moribund \nor dying animals.  An apparent dose-related increase in perivascular/peribiliary inflammatory cell \ninfiltrates in the liver was observed in female rats exposed to 0.06–0.56 ppm; however, incidences did not \ndiffer significantly from control and no hepatic lesions were observed in similarly exposed male rats \n(Clark 1981).  In other inhalation studies, no exposure-related hepatic lesions were seen following acuteduration exposure in rats to concentrations up to 0.5 ppm (Alexander et al. 1980a; Rand et al. 1982a); \nintermediate-duration exposure in monkeys, rats, or mice to concentrations up to 0.2, 0.385, or 0.5 ppm, \nrespectively (Alexander et al. 1980b; NTP 1994; Rand et al. 1982a); or chronic-duration exposure in rats \nor mice to concentrations up to 0.2 ppm (NTP 1994).\n\nNo consistent evidence of exposure-related changes in hepatic serum biochemistry or liver weight was \nobserved following inhalation exposure to HCCPD.  Serum concentrations of the biochemical parameters\nLDH, AST, ALP, and ALT in rats and mice were not influenced by inhalation exposure to HCCPD \nconcentrations ≤0.389 ppm for 13–14 weeks (Alexander et al. 1980b; NTP 1994; Rand et al. 1982a).  \nDuring the 13-week special hematology, clinical chemistry, and urinalysis study conducted in rats by \nNTP (1994), the highest concentration of 2.065 ppm caused elevated serum AST concentrations (1.7–\n7.6-fold) in male and female rats on days 4–16; however, this concentration was lethal to all the animals \nprior to the day 46 clinical evaluation, and a comparable increase was not observed in mice (NTP 1994).  \nRelative liver weights of rats were significantly reduced by 3–15% in males and females exposed to 0.01–\n0.2 ppm for 13 weeks, but the decreases were not dose-related (Alexander et al. 1980b; Rand et al. \n1982a).  No changes in liver weights were observed in rats or mice exposed to concentrations ≤0.389 ppm \nfor 13 weeks or ≤0.2 ppm for 2 years (NTP 1994).\n\nAcute- and intermediate-duration oral toxicity studies have evaluated the potential effects of HCCPD\nexposure on the liver.  High, acute-duration oral doses of HCCPD were associated with liver necrosis and tissue degeneration in rats (261–1,959 mg/kg) and rabbits (579–877 mg/kg); incidence data were not \nprovided (Treon et al. 1955).  HCCPD did not induce histopathological changes in hepatic tissues of rats \nand mice exposed to doses up to 150 and 300 mg/kg/day, respectively, via gavage for 13 weeks (Abdo et \nal. 1984; Velsicol 1981a, 1981b).\n\nThe potential for HCCPD to cause hepatotoxicity following dermal exposure was evaluated only for \nacute-duration exposures.  Rabbits exposed to single dermal doses of 401–5,719 mg/kg displayed necrosis \nof the liver; incidence data were not provided (Treon et al. 1955).  The study authors stated that \ndegenerative changes persisted even 21 days after the exposure period in surviving animals.\n\n###### 2.10 RENAL\n\nThe data indicate that the renal system is a potential target for HCCPD via the oral route; it does not \nappear to be a sensitive target for HCCPD via the inhalation or dermal routes.  Based upon systematic \nreview (Appendix C), the kidney is a presumed hazard of HCCPD toxicity following oral exposure based \non no data in humans and a high level of evidence from laboratory animal studies.\n\nUrine samples were collected from 41 workers exposed for 3–15 days to HCCPD at a WWTP as the \nresult of an inadvertent industrial release into the sewage system (Morse et al. 1979).  Proteinuria was \nidentified in 6 of 41 workers immediately after exposure but no abnormalities were detected 3 weeks \nlater.  Urinalysis parameters were normal in all 97 cleanup crew workers evaluated (Kominsky et al. \n1980).  It should be noted that urinalysis was not performed on unexposed workers, and it is not known if \nproteinuria values observed in exposed workers differ from the local general population.\n\nRelative to a group of 35 controls, 73 male operators employed for an average of 8.2 years in a plant \nproducing chlorinated hydrocarbons, including HCCPD, showed no evidence of damage to the renal \ntubules (Boogaard et al. 1993).  The investigations included measurement of urinary alanine \naminopeptidase, N-acetyl-β-D-glucosaminidase, and retinol binding protein.  Although total urinary \nprotein concentrations did not differ between the two groups, urinary albumin was significantly higher in \nthe exposed group.  The difference, however, was not related to time of employment, and there was no \ndifference in urinary albumin concentration in workers involved in the manufacture of HCCPD and those \ninvolved in the preparation of other chlorinated hydrocarbon.  Thus, the effect was not considered to be \ndue to the damage to the glomerulus caused by exposure to HCCPD.  Personal air sampling for HCCPD\n\n---\n\n2.  HEALTH EFFECTS\n\nwas performed on a subset of study participants but was not used to evaluate associations with renal \nfunction values.\n\nThe potential renal effects following inhalation exposure to HCCPD have been evaluated in laboratory \nanimals following acute, intermediate, and chronic durations.  Inhalation exposure of HCCPD caused \nrenal tubular necrosis in rats, mice, guinea pigs, and rabbits at 0.34–73.6 ppm for 15 minutes to 7 days, \n0.34 ppm for 6 weeks, and 0.15 ppm for 30 weeks; incidence data were not provided (Treon et al. 1955).  \nIn other inhalation studies, no significant, exposure-related renal lesions were seen following acuteduration exposure in rats to concentrations up to 0.5 ppm (Alexander et al. 1980a; Rand et al. 1982a); \nintermediate-duration exposure in monkeys, rats, or mice to concentrations up to 0.2, 0.56, or 0.5 ppm, \nrespectively (Alexander et al. 1980b; Clark 1981; NTP 1994; Rand et al. 1982a); or chronic-duration \nexposure in rats or mice to concentrations up to 0.2 ppm (NTP 1994).\n\nThe potential toxicological effects of HCCPD on the kidneys have been evaluated in laboratory animals \nin acute-and intermediate-duration oral studies.  Degenerative lesions in the kidney tubules resulted from \nsingle gavage doses of 261–1,959 mg/kg in rats and 579–877 mg/kg in rabbits; incidence data were not \nprovided (Treon et al. 1955).  Toxic nephrosis was observed in male and female rats exposed to \n≥38 mg/kg/day and female mice exposed to ≥75 mg/kg/day via gavage for 13 weeks (Abdo et al. 1984; \nVelsicol 1981a, 1981b). These lesions were located in the terminal sections of the proximal tubules of the \nrenal cortex and were characterized by mild dilation of the tubules and karyomegaly, cytomegaly, and \nanisokaryosis accompanied by cytoplasmic and nuclear vacuolization.  Additionally, brown granular \npigment debris protruded into the lumen.  In male mice, tubular necrosis was present in 70% of the male \nmice receiving the 300 mg/kg/day dose but not at lower doses; this lesion was morphologically distinct \nfrom the toxic nephrosis seen in the other animals and may have contributed to the early deaths observed \nat this dose level.  No renal histopathological effects were identified in male and female rats at\n≤19 mg/kg/day, female mice at ≤38 mg/kg/day, or male mice at ≤150 mg/kg/day (Abdo et al. 1984; \nVelsicol 1981a, 1981b).\n\nRabbits exposed to single dermal doses of 401–5,719 mg/kg displayed degeneration and necrosis of the \nkidney tubules; incidence data were not provided (Treon et al. 1955). The study authors stated that renal \neffects were still apparent 21 days after dosing in surviving animals.\n\n---\n\n2.  HEALTH EFFECTS\n\n###### 2.11 DERMAL\n\nHuman and animal data indicate HCCPD causes skin irritation following direct dermal contact with \nHCCPD liquid or vapor.\n\nAn unspecified percentage of 145 workers exposed to HCCPD vapors for 3–15 days at a WWTP as a \nresult of an inadvertent industrial release reported skin irritation, with five employees verified to exhibit\nvisible signs of skin irritation (Morse et al. 1979).  In a subsequent publication, 21% of 177 employees \nwith usable medical questionnaire responses reported skin irritation following HCCPD release and prior \nto plant closure; 10% of the 177 employees reported experiencing skin irritation approximately 6 weeks \nlater (Kominsky et al. 1980).\n\nIn acute-duration dermal toxicity studies, topical application of HCCPD in either its pure form or in \nsolution appears to have a pronounced effect upon the epidermis of experimental animals.  Generally, \nHCCPD initially causes edema that progressed to hardening or encrustation at the application site \n(Gardner 1986b; OxyChem 1972; Treon et al. 1955).  In a series of studies, severe irritation and skin \nnecrosis were observed in a monkey administered 0.05 mL of a 10% (v/v) solution for 3 days; necrotic, \nhardened, encrusted, and discolored skin was identified following application of Ultrasene solutions \ncontaining ≥40% HCCPD to guinea pigs; and subcutaneous edema and local discoloration that progressed \nto encrustation and fissuring were observed after a dermal dose of ≥430 mg/kg was applied to rabbit skin; \nincidence data were not provided (Treon et al. 1955).  The lesions generally healed with time in the \nsurviving animals.  Thirteen months after exposure, the monkey’s treated skin was scarred and hairless.  \nNo evidence of dermal effects was identified in a monkey administered 0.01 mL of Ultrasene solutions \ncontaining up to 10% HCCPD, but application of 0.05 mL of solutions containing ≥20% HCCPD caused \nthe skin to become discolored and swell.  No evidence of skin irritation was observed in guinea pigs after \ndermal doses of 0.05 mL of Ultrasene solutions containing ≤1% HCCPD (Treon et al. 1955).  Eschar \nformation was noted after dermal application of 200 mg/kg HCCPD to rabbits (OxyChem 1992).  Results \nof standard dermal irritation tests indicated that 0.5 mL HCCPD produced slight to severe edema and \nnecrosis at the application sites (OxyChem 1972, 1992).\n\nThe potential effects of systemic HCCPD exposure on skin histopathology of laboratory animals were \nevaluated in intermediate- and chronic-duration inhalation studies and intermediate-duration oral studies.  \nNo histopathological changes were identified in the skin (specific location not identified) of male or \nfemale rats exposed to concentrations ≤0.56 ppm for 30 weeks (Clark 1981) or in male or female rats and mice exposed to concentrations ≤0.2 ppm for 2 years (NTP 1994).  Additionally, no histopathological \nchanges were identified in skin (specific location not identified) of rats and mice at gavage doses up to \n150 or 300 mg/kg/day, respectively, for 13 weeks (Abdo et al. 1984; Velsicol 1981a, 1981b).\n\n###### 2.12 OCULAR\n\nHuman and animal data indicate that direct ocular contact with HCCPD vapor may produce ocular \nirritation at sufficiently high concentrations.\n\nEye irritation was one of the major symptoms reported by sewage treatment plant workers exposed to \nHCCPD vapors for 3–15 days at a WWTP because of an inadvertent industrial release (Kominsky et al. \n1980; Morse et al. 1979).  From the 145 individuals who responded to a questionnaire immediately after \nexposure occurred, 85 (59%) complained of eye irritation (Morse et al. 1979).  In a follow-up \nquestionnaire 6 weeks later, 9% of 177 respondents were still experiencing ocular irritation (Kominsky et \nal. 1980; Morse et al. 1979).  Tearing and redness of the eyes were present in five individuals on the day \nof exposure.\n\nEye irritation, as evidenced by lacrimation, was also observed in animals exposed to HCCPD vapors for \nup to 7 hours (Jackson and Hardy 1986, 1987; OxyChem 1972; Rand et al. 1982a; Treon et al. 1955).  \nPartially or completely closed eyes were identified in rats exposed to ≥1.67 ppm for 1 hour (Jackson and \nHardy 1986) and ≥1.68 ppm for 4 hours (Jackson and Hardy 1987).  Direct ocular exposure to HCCPD\nvapors most likely contributed to these effects.  Irritation of the eyes or eyelids was observed for rats, \nmice, guinea pigs, and rabbits following single exposures to HCCPD concentrations as low as 1.0 ppm \nand multiple exposures to concentrations as low as 0.33 ppm for up to 6 weeks; ocular irritation was not \nobserved in any species exposed to 0.15 ppm for up to 30 weeks (Treon et al. 1955).  Lacrimation was \nevident in rats exposed to 5.8 ppm HCCPD for 4 hours and dark red eyes were observed in rats exposed \nto 0.5 ppm for 5–10 days and ≥0.05 ppm for 14 weeks (Alexander et al. 1980a, 1980b; Rand et al. 1982a).  \nNo clinical signs of eye irritation were noted in monkeys exposed to HCCPD vapor at concentrations up \nto 0.2 ppm for 14 weeks (Alexander et al. 1980b; Rand et al. 1982a).  No ophthalmological or\nhistopathological changes were identified in the ocular tissues of rats or monkeys exposed to \nconcentrations up to 0.2 ppm for 14 weeks (Alexander et al. 1980b; Rand et al. 1982a).  HCCPD \nexposure did not cause histopathological changes in the eyes of rats exposed to concentrations up to \n0.56 ppm for 30 weeks (Clark 1981).\n\n---\n\nSevere eye irritation was produced when 0.1 mL of HCCPD was placed in the conjunctival eye sac for \n5 minutes and then rinsed with water (OxyChem 1972).  Corrosion of the ocular tissues occurred when \nthe material was left in place for 24 hours prior to rinsing (OxyChem 1972).\n\n###### 2.13 ENDOCRINE\n\n2.13  ENDOCRINE\n\nNo reports of changes in human endocrine parameters or organs after exposure to HCCPD were found. \nBased on available data in laboratory animals, HCCPD does not produce histopathological changes to \nendocrine organs.  Insufficient data are available to assess the potential effects of HCCPD exposure on \nendocrine function, including endocrine hormone levels.\n\nPotential histopathological and organ weight effects in endocrine organs have been evaluated in \nlaboratory animals following acute-, intermediate-, and chronic-duration inhalation exposure to HCCPD.  \nDegenerative changes in the adrenal glands of rats, mice, guinea pigs, and rabbits were observed after \nexposures to concentrations of 0.34–73.6 ppm for periods of 15 minutes to 1 week, 0.34 ppm for 6 weeks, \nand 0.15 ppm for 30 weeks; incidence data were not provided (Treon et al. 1955).  Due to the high \nmortality observed at these concentrations, these changes may have been the result of tissue autolysis in \nmoribund or dying animals.  Effects on the adrenal, thyroid, parathyroid, pancreas, and pituitary glands \nfollowing inhalation exposure of male mice to 0.039–0.389 ppm HCCPD for 13 weeks were limited to \nincreased relative adrenal weights; no histopathological changes were noted in these organs in treated \nmale mice and no effects on adrenal, thyroid, parathyroid, pancreas, or pituitary gland weights or\nhistopathology were observed in female mice exposed to ≤0.389 and male and female rats exposed to \n≤0.385 ppm for 13 weeks (NTP 1994).  The biological significance of these adrenal weight changes\ncannot be assessed quantitatively in the absence of hormone product measurements or concurrent \nhistopathological findings.  There were no organ weight or histopathological changes in the adrenal \nglands, pancreas, thyroid, parathyroid gland, and/or pituitary gland identified in male and female rats and \nmonkeys exposed for 14 weeks at ≤0.2 ppm (Alexander et al. 1980b; Rand et al. 1982a), in male and \nfemale rats after 30-week exposures to ≤0.56 ppm (Clark 1981), or in rats and mice following 2-year \nexposures to ≤0.2 ppm (NTP 1994).  Additionally, no effects on the adrenal glands were identified in \nmale mice exposed to 0.5 ppm for 26–42 weeks (NTP 1994).\n\n$$\n\\leq0.385ppm\n$$\n\nPotential effects of HCCPD on endocrine organ weight and histology have also been evaluated in \nlaboratory animals following acute- and intermediate-duration oral exposures and acute-duration dermal \nexposures.  Degenerative changes in the adrenal tissues resulted from exposure to single oral doses of\n\n---\n\n280–2,100 mg/kg in rats and 620–940 mg/kg in rabbits; these changes may have resulted from tissue \nautolysis in moribund or dying animals, but no incidence data were reported (Treon et al. 1955).  There \nwere no histopathological changes in the adrenals, thyroid, parathyroid, or pituitary glands in 13-week \nstudies at gavage doses up to 150 mg/kg/day in rats and 300 mg/kg/day in mice (Abdo et al. 1984; \nVelsicol 1981a, 1981b).  Rabbits that were dermally exposed to HCCPD (430–6,130 mg/kg) had \ndegenerative changes of the adrenal glands that were still apparent in survivors 21 days after exposure; \nincidence data were not provided (Treon et al. 1955).\n\nNo data were identified evaluating endocrine function following *in vivo* exposure to HCCPD; however, \nlimited *in vitro* screening data are available.  HCCPD exhibited statistically significant radioactive iodide \nuptake inhibition in a ToxCast high-throughput screening assay (Wang et al. 2019).  Iodide uptake is the \nfirst step in thyroid hormone biosynthesis.\n\n###### 2.14 IMMUNOLOGICAL\n\n2.14  IMMUNOLOGICAL\n\nNo studies were located regarding immunological effects in humans after exposure to HCCPD. Based on \navailable data in laboratory animals, HCCPD does not cause histopathological alterations to \nimmunological organs.  However, no studies evaluating immune function following exposure to HCCPD \nwere identified.\n\nPotential effects of HCCPD on immune organ weight and histology have also been evaluated in acute-, \nintermediate-, and chronic-duration inhalation exposure studies and intermediate-duration oral exposure \nstudies in laboratory animals.  No exposure-related changes were identified in these studies.  There were \nno histopathological changes in the spleen of rats exposed to ≤0.5 ppm for 1–2 weeks (Alexander et al. \n1980a; Rand et al. 1982a).  In intermediate-duration studies, no histopathological changes were identified \nin immune organs (spleen, thymus, and/or lymph nodes) of monkeys, rats, or mice to concentrations up to \n0.2, 0.56, or 0.5 ppm, respectively (Alexander et al. 1980b; Clark 1981; NTP 1994; Rand et al. 1982a).  \nSimilarly, no histopathological effects were observed in immune organs of rats or mice exposed to \n≤0.2 ppm for 2 years (NTP 1994).  In a 13-week oral study, no treatment-related histopathological \nfindings were identified in the mandibular and mesenteric lymph nodes, thymus, or spleen at gavage \ndoses up to 150 mg/kg/day in rats or 300 mg/kg/day in mice (Abdo et al. 1984; Velsicol 1981a, 1981b).\n\n---\n\n2.  HEALTH EFFECTS\n\n###### 2.15 NEUROLOGICAL\n\n2.15  NEUROLOGICAL\n\nBased on available data, HCCPD does not cause histopathological alterations in the nervous system.  \nEvaluation of neurological function is limited to clinical signs of toxicity; therefore, insufficient data are \navailable to assess the potential effect of HCCPD exposure on neurological function, including behavior.\n\nAmong sewage treatment plant workers exposed to HCCPD at a WWTP because of an inadvertent \nindustrial release, headaches were self-reported by 65 of 145 workers (45%) after exposure for 3–15 days \n(Morse et al. 1979).  Six weeks later, 32 of 177 workers (18%) responding to a questionnaire were still \nexperiencing headaches (Kominsky et al. 1980). No studies were located regarding neurological effects \nin humans after oral or dermal exposure to HCCPD.\n\nNeurological clinical signs of toxicity and nervous system histopathology were evaluated in acute-, \nintermediate-, and chronic-duration inhalation exposure studies.  Rats and mice exposed to concentrations \nof 0.385–2.142 ppm HCCPD were described as listless after 1–3 weeks of exposure (NTP 1994).  \nIncidence data for clinical signs were not provided, so it is unclear how many animals exhibited this effect \nor how frequently; however, the study authors did note that listlessness was observed earlier during the \nexposure period with higher HCCPD concentrations.  Some rats, mice, guinea pigs, and rabbits exposed \nto high lethal concentrations of HCCPD (≥46.5 ppm) by acute-duration inhalation experienced tremors; \nincidence data were not provided (Treon et al. 1955).  At necropsy, diffuse degenerative changes in the \nbrain were observed in all rats, mice, guinea pigs, and rabbits after exposures to 0.34–73.6 ppm for \nperiods of 15 minutes to 1 week, 0.34 ppm for 6 weeks, and 0.15 ppm for 30 weeks; incidence data were \nnot provided (Treon et al. 1955).  These degenerative changes may have been the result of tissue \nautolysis.  In contrast, there were no histopathological changes in the brains of rats exposed to 0.5 ppm \nfor 1–2 weeks (Alexander et al. 1980a; Rand et al. 1982a), male mice exposed to 0.2 ppm for 33 weeks \n(NTP 1994), or rats and mice exposed to ≤0.389 ppm for 13 weeks or ≤0.2 ppm for 2 years (NTP 1994).  \nSimilarly, no histopathological changes were observed in the brains or sciatic nerve of rats or monkeys \nexposed to ≤0.2 ppm for 14 weeks (Alexander et al. 1980b; Rand et al. 1982a) or in brain, spinal cord, or \nsciatic or posterior tibial nerves of rats exposed to ≤0.56 ppm for 30 weeks (Clark 1981).\n\nThe potential neurotoxicity of HCCPD has been evaluated in acute- and intermediate-duration oral \nexposure studies.  Clinical signs of neurotoxicity were observed following acute-duration gavage \nexposure in mice, including hypoactivity at 464 mg/kg and ataxia at 1,000 mg/kg, a dose associated with \nlethality (Dean 1977).  Similarly, all rats exposed once to ≥1,260 mg/kg via gavage exhibited abnormal gait (high stepping, waddling) and lethargy (Gardner 1986a).  Single oral doses ≥180 mg/kg caused \nlethargy in rats and rabbits in the period “immediately after exposure” (Treon et al. 1955).  During \npostmortem examination of tissues, degenerative lesions of the brain were observed in the rats and rabbits \nthat succumbed to exposure and in the rats that survived to the scheduled sacrifice; incidence data were \nnot provided.  No histopathological lesions of the brain, sciatic nerve, or spinal cord were noted in rats or \nmice exposed to gavage doses up to 150 or 300 mg/kg/day, respectively, for 13 weeks (Abdo et al. 1984; \nVelsicol 1981a, 1981b). These data suggest that brain lesions occur only with exposures to high oral \ndoses of HCCPD.\n\nRabbits exposed to single dermal doses of HCCPD (430–6,130 mg/kg) displayed degenerative changes in \nthe brain at necropsy; incidence data were not provided (Treon et al. 1955).  These changes were still \napparent 21 days after exposure in surviving animals.  Ataxia, hypoactivity, and a depressed breathing \npattern have been observed in rabbits at lethal dermal doses of HCCPD (OxyChem 1972).\n\n###### 2.16 REPRODUCTIVE\n\n2.16  REPRODUCTIVE\n\nNo studies were located regarding reproductive effects in humans after exposure to HCCPD.  The \navailable animal data do not indicate that HCCPD causes histopathological alterations to reproductive \norgans.  However, insufficient data are available to thoroughly assess the potential for toxicity to the \nreproductive system, as no studies evaluating reproductive function following inhalation, oral, or dermal \nexposure to HCCPD were identified.\n\nThe potential effects of HCCPD on reproductive organ weight and histology have been evaluated in \nexperimental animals exposed by inhalation for intermediate and chronic durations.  The sole effect on \nreproductive organs identified with HCCPD treatment is an increased incidence of ovarian suppurative \ninflammation in female mice exposed to HCCPD at 0.05–0.2 ppm for 2 years; no histopathological \nchanges were identified in the uterus (NTP 1994).  While this lesion is clearly adverse, as it was the \nsuspected cause of increased mortality at 0.2 ppm, the causal relationship between HCCPD exposure and \nlesion development is unclear.  The study authors noted that lesions were similar to those observed in \nother NTP studies attributed to stress-related susceptibility to utero-ovarian infection by *Klebsiella* \nspecies (NTP 1994).  In contrast, no treatment-related histopathological lesions of the female (ovaries and \nuterus) or male (testes, prostate, and/or seminal vesicle) reproductive organs were identified in monkeys, \nrats, or mice exposed to concentrations up to 0.2, 0.385, or 0.389 ppm for 13–14 weeks (Alexander et al. \n1980b; NTP 1994; Rand et al. 1982a); male mice exposed to 0.2 ppm for 33 weeks or 0.5 ppm for\n\n---\n\n42 weeks (NTP 1994); rats exposed to ≤0.56 ppm for 30 weeks (Clark 1981); or rats or male mice \nexposed to ≤0.2 ppm for 2 years (NTP 1994).\n\n$$\n\\leqq0.56\n$$\n\nThe potential effects of HCCPD on reproductive organ weight and histology have also been evaluated in \nlaboratory animals following intermediate-duration oral exposure.  HCCPD did not cause treatmentrelated effects on the testes, seminal vesicles, prostate, ovaries, or uterus in rats or mice exposed to doses \nup to 150 or 300 mg/kg/day, respectively, via gavage for 13 weeks (Abdo et al. 1984; Velsicol 1981a, \n1981b).\n\nNo data were identified evaluating reproductive function following inhalation, oral, or dermal exposure to \nHCCPD; however, limited screening data are available.  Although it exhibited some estrogen receptor \nbinding affinity in a recombinant human estrogen receptor α (hERα) binding assay, HCCPD did not \nexhibit estrogenic or anti-estrogenic activity in an immature uterotrophic assay in female rats following \nsubcutaneous injection (Akahori et al. 2008).  No anti-androgenic activity was detected for HCCPD in \nChinese hamster ovary (CHO) cells transfected with human androgen receptor (hAR) in an androgenresponsive luciferase reporter assay (Roy et al. 2004).\n\n###### 2.17 DEVELOPMENTAL\n\n2.17  DEVELOPMENTAL\n\nNo studies were located regarding developmental effects in humans after exposure to HCCPD.  Animal \ndata are available only via the oral route and are too limited to assess whether or not the developing \norganism is a target of HCCPD toxicity at doses below those associated with maternal toxicity.\n\nHCCPD was not embryotoxic, fetotoxic, or teratogenic in mice following maternal exposure to gavage \ndoses up to 75 mg/kg/day during GDs 6–15 (Murray et al. 1980).  In rabbits, a dose-dependent increase in \nthe incidence of 13 ribs was identified in the offspring of does exposed to 75 mg/kg/day via gavage \nduring GDs 6–18; nonstatistically significant increases were also identified at 5 and 25 mg/kg/day.  No \nother evidence of embryotoxicity, fetotoxicity, or teratogenicity was identified in rabbits (Murray et al. \n1980).  The natural variation in the number of ribs for rabbits is 12–13.  It should be noted that the \ncompound was not maternally toxic in mice, but maternal mortalities and weight loss were observed in \nrabbits at 75 mg/kg/day (numbers affected and magnitude of effect not specified).\n\nA screening study was performed to evaluate prenatal and postnatal development of mice exposed to \nHCCPD during gestation.  Mice born to dams administered 45 mg/kg/day HCCPD via gavage during\n\n---\n\nGDs 8–12 did not exhibit evidence of developmental toxicity when evaluated on postnatal days (PNDs) 1 \nand 3 (Chernoff and Kavlock 1982, 1983).  When the offspring were evaluated over a 250-day postnatal \nperiod (including through puberty and breeding), there were no adverse effects on postnatal viability, \ngrowth, locomotor activity, sexual development (percent vaginal patency at day 30), or reproductive \nfunction (Gray and Kavlock 1984; Gray et al. 1986).\n\n###### 2.18 OTHER NONCANCER\n\n2.18  OTHER NONCANCER\n\nNo studies were located regarding other noncancer effects in humans after exposure to HCCPD.\n\nOther noncancer effects of HCCPD identified in experimental animals are limited to food and water \nintake.  During the first few days of the post-exposure observation periods, decreased food and water \nintake were observed in rats exposed for 1 hour to ≥1.67 ppm (Jackson and Hardy 1986) and rats exposed \nfor 4 hours to ≥1.68 ppm (Jackson and Hardy 1987); these concentrations were associated with overt \nsigns of toxicity during exposure (e.g., abnormal respiratory pattern).  After a 1–2-week exposure to \nHCCPD, male and female rats exposed to 0.5 ppm had decreased food and water intake (Alexander et al. \n1980a; Rand et al. 1982a).  All males exposed to 0.5 ppm died or were sacrificed in moribund condition \nby the end of the exposure period.  Minor decreases in food intake were also observed for male rats \nexposed to 0.11 ppm without meaningful changes to body weight; the biological significance of this \nfinding is uncertain.  Food intake was not affected in rats or monkeys and water intake was not affected in \nrats exposed to ≤0.2 ppm for 14 weeks (Alexander et al. 1980b; Rand et al. 1982a).  In a 30-week study, \nno treatment-related deficits were identified for male or female rats regarding food or water intake\nfollowing exposure to ≤0.56 ppm (Clark 1981). No treatment-related effects were observed for food and \nwater intake of pregnant mice administered gavage doses of HCCPD at ≤75 mg/kg/day on GDs 6–15 \n(Murray et al. 1980).  Where deficits in food and/or water intake were observed after exposure to \nHCCPD, these effects were likely the result of nonspecific toxicity following exposures to high \nconcentrations of an irritating/corrosive chemical.\n\n$$\n\\mathrm{to}\\geq1.67\\mathrm{ppm}\n$$\n\n$$\nt0\\geq1.68\n$$\n\n$$\nt o\\leqq0.2\n$$\n\n$$\n0.56ppm\n$$\n\n###### 2.19 CANCER\n\nNo studies were located regarding cancer in humans following exposure to HCCPD.\n\nThe carcinogenicity of HCCPD has been evaluated in 2-year rodent bioassays in which male and female \nrats and mice were exposed to concentrations up to 0.2 ppm for 104 weeks (NTP 1994).  There were no statistically significant increases in tumor incidence in rats or mice.  There was a slight increase in the \nincidence of adenomas of the pituitary pars distalis in male rats at 0.2 ppm and in thyroid follicle cell \nadenomas in female mice at 0.05 ppm, but, since the incidences were similar to the historical control \nmeans, were within the historical control range, or did not exhibit a dose-dependency, NTP (1994) did not \nconsider these tumors to be related to HCCPD exposure.  In male mice exposed to 0.5 ppm for 26 or \n42 weeks, then evaluated at 105 weeks, the incidence of alveolar/bronchiolar carcinomas was \nsignificantly increased but was within the historical range for the laboratory (NTP 1994).  Thus, \nalveolar/bronchiolar carcinomas may n", 'pages': None, 'truncated': True, 'extraction': 'firecrawl-public-document-markdown', 'request_id': 'f55ece8d-03a0-45b7-b220-29efe5d1d238', 'source_url': 'https://downloads.regulations.gov/ATSDR-2026-0133-0003/attachment_1.pdf', 'observed_at': '2026-10-04T00:40:37.145404+00:00', 'content_hash': '063c002435b7a13b9144e8da7119795794d56ee2e0ab2fe90a88e51b9525c505'}, 'title': 'Draft Tox Profile for Hexachlorocyclopentadiene'}, {'url': 'https://downloads.regulations.gov/ATSDR-2026-0133-0003/content.pdf', 'body': {'text': "## Toxicological Profile for Hexachlorocyclopentadiene (HCCPD)\nDraft for Public Comment\nOctober 2026\n\nU.S. Department of Health and Human Services\nAgency for Toxic Substances and Disease Registry\n\n---\n\n## DISCLAIMER\n\nUse of trade names is for identification only and does not imply endorsement by the Agency for Toxic \nSubstances and Disease Registry, the Public Health Service, or the U.S. Department of Health and Human \nServices.\n\nThis information is distributed solely for the purpose of pre-dissemination for public comment under \napplicable information quality guidelines.  It has not been formally disseminated by the Agency for Toxic \nSubstances and Disease Registry.  It does not represent and should not be construed to represent any \nagency determination or policy.\n\n---\n\n## FOREWORD\n\nThis toxicological profile is prepared in accordance with guidelines developed by the Agency for Toxic \nSubstances and Disease Registry (ATSDR) and the Environmental Protection Agency (EPA).  The \noriginal guidelines were published in the *Federal Register* on April 17, 1987.  Each profile will be revised \nand republished as necessary.\n\nThe ATSDR toxicological profile succinctly characterizes the toxicologic and adverse health effects \ninformation for these toxic substances described therein.  Each peer-reviewed profile identifies and \nreviews the key literature that describes a substance's toxicologic properties.  Other pertinent literature is \nalso presented but is described in less detail than the key studies.  The profile is not intended to be an \nexhaustive document; however, more comprehensive sources of specialty information are referenced.\n\nThe focus of the profiles is on health and toxicologic information; therefore, each toxicological profile \nbegins with a relevance to public health discussion which would allow a public health professional to \nmake a real-time determination of whether the presence of a particular substance in the environment \nposes a potential threat to human health.  The adequacy of information to determine a substance's health \neffects is described in a health effects summary.  Data needs that are of significance to the protection of \npublic health are identified by ATSDR.\n\nEach profile includes the following:\n\n(A) The examination, summary, and interpretation of available toxicologic information and \nepidemiologic evaluations on a toxic substance to ascertain the levels of significant \nhuman exposure for the substance due to associated acute-, intermediate-, and chronicduration exposures;\n\n(B) A determination of whether adequate information on the health effects of each substance \nis available or in the process of development to determine the levels of exposure that \npresent a significant risk to human health due to acute-, intermediate-, and chronicduration exposures; and\n\n(C) Where appropriate, identification of toxicologic testing needed to identify the types or \nlevels of exposure that may present significant risk of adverse health effects in humans.\n\nThe principal audiences for the toxicological profiles are health professionals at the Federal, State, and \nlocal levels; interested private sector organizations and groups; and members of the public.  ATSDR plans \nto revise these documents in response to public comments and as additional data become available.  \nTherefore, we encourage comments that will make the toxicological profile series of the greatest use.\n\nElectronic comments may be submitted via: www.regulations.gov. Follow the on-line instructions for \nsubmitting comments.\n\nWritten comments may also be sent to:\n\nAgency for Toxic Substances and Disease Registry\n\nOffice of Innovation and Analytics\n\nToxicology Section\n\n1600 Clifton Road, N.E.\n\nMail Stop S106-5\n\nAtlanta, Georgia 30329-4027\n\n---\n\nThe toxicological profiles are developed under the Comprehensive Environmental Response, \nCompensation, and Liability Act of 1980, as amended (CERCLA or Superfund).  CERCLA \nSection 104(i)(1) directs the Administrator of ATSDR to “…effectuate and implement the health-related \nauthorities” of the statute.  This includes the preparation of toxicological profiles for hazardous \nsubstances most commonly found at facilities on the CERCLA National Priorities List (NPL) and that \npose the most significant potential threat to human health, as determined by ATSDR and the EPA.  \nSection 104(i)(3) of CERCLA, as amended, directs the Administrator of ATSDR to prepare a \ntoxicological profile for each substance on the list.  In addition, ATSDR has the authority to prepare \ntoxicological profiles for substances not found at sites on the NPL, in an effort to “…establish and \nmaintain inventory of literature, research, and studies on the health effects of toxic substances” under \nCERCLA Section 104(i)(1)(B), to respond to requests for consultation under Section 104(i)(4), and as \notherwise necessary to support the site-specific response actions conducted by ATSDR.\n\nThis profile reflects ATSDR’s assessment of all relevant toxicologic testing and information that has been \npeer-reviewed.  Staffs of the Centers for Disease Control and Prevention and other Federal scientists have \nalso reviewed the profile.  In addition, this profile has been peer-reviewed by a nongovernmental panel \nand is being made available for public review.  Final responsibility for the contents and views expressed \nin this toxicological profile resides with ATSDR.\n\nChristopher M. Reh, Ph.D. \nAssociate Director, \nAgency for Toxic Substances and Disease Registry \nCenters for Disease Control and Prevention\n\n---\n\n**VERSION HISTORY**\n\n| Date | Description |\n| --- | --- |\n| October 2026 | Draft for public comment toxicological profile released |\n| July 1999 | Final toxicological profile released |\n\n---\n\n# CONTRIBUTORS & REVIEWERS\n\n# CHEMICAL MANAGER TEAM\n\nGaston Casillas, Ph.D. (Lead)\nFahim Atif, Ph.D.\nJennifer Przybyla, Ph.D.\nNickolette Roney, M.P.H.\nBrittany Szafran, D.V.M., Ph.D., D.A.B.T.\n\nZach Guerrette, Ph.D., D.A.B.T.\nChristina Coley, M.S.\nLisa Ingerman, Ph.D., D.A.B.T.\nKimberly Zaccaria, Ph.D., D.A.B.T.\nMario Citra, Ph.D.\n\nATSDR, Office of Innovation and Analytics, \nToxicology Section, Atlanta, GA\n\nSRC, Inc., North Syracuse, NY\n\n### REVIEWERS\n\n#### Interagency Minimal Risk Level Workgroup:\n\nIncludes ATSDR; National Center for Environmental Health (NCEH); U.S. Environmental Protection \nAgency (EPA); National Toxicology Program (NTP).\n\n#### Additional reviews for science and/or policy:\n\nATSDR, Office of Community Health Hazard Assessment; ATSDR, Office of Capacity Development \nand Applied Prevention Science; ATSDR, Office of Science; NCEH, Division of Laboratory Sciences; \nNCEH, Division of Environmental Health Science and Practice; EPA, Office of Research and \nDevelopment; EPA, Office of Water.\n\n### PEER REVIEWERS\n\n1. David Dorman, D.V.M., Ph.D., D.A.B.V.T., D.A.B.T.; Professor of Toxicology; North Carolina \nState University; College of Veterinary Medicine; Department of Molecular Biomedical \nSciences; Raleigh, North Carolina\n\n2. Slawo Lomnicki, Ph.D.; Assistant Professor of Environmental Sciences; Louisiana State \nUniversity, Chemistry Department; LSU Superfund Research Materials Core leader; Baton \nRouge, Louisiana\n\n3. Deborah A. Slechta, Ph.D., M.A.; University of Rochester; Professor - Department of \nEnvironmental Medicine (SMD); Professor - Department of Neuroscience (SMD) -– Joint; \nProfessor - Department of Public Health Sciences (SMD) - Joint; Rochester, New York\n\nThese experts collectively have knowledge of toxicology, chemistry, and/or health effects.  All reviewers \nwere selected in conformity with Section 104(I)(13) of the Comprehensive Environmental Response, \nCompensation, and Liability Act, as amended.\n\nATSDR scientists review peer reviewers’ comments and determine whether changes will be made to the \nprofile based on comments.  The peer reviewers’ comments and responses to these comments are part of \nthe administrative record for this compound.\n\nThe listing of peer reviewers should not be understood to imply their approval of the profile's final \ncontent.  The responsibility for the content of this profile lies with ATSDR.\n\n---\n\n## CONTENTS\n\nDISCLAIMER .............................................................................................................................................. ii\nFOREWORD ............................................................................................................................................... iii\nVERSION HISTORY ................................................................................................................................... v\nCONTRIBUTORS & REVIEWERS ........................................................................................................... vi\nCONTENTS ................................................................................................................................................ vii\nLIST OF FIGURES ..................................................................................................................................... ix\nLIST OF TABLES ........................................................................................................................................ x\nCHAPTER 1. RELEVANCE TO PUBLIC HEALTH ................................................................................. 1\n1.1 OVERVIEW AND U.S. EXPOSURES ......................................................................................... 1\n1.2 SUMMARY OF HEALTH EFFECTS........................................................................................... 1\n1.3 MINIMAL RISK LEVELS (MRLs) .............................................................................................. 6\nCHAPTER 2. HEALTH EFFECTS ............................................................................................................ 10\n2.1 INTRODUCTION ........................................................................................................................ 10\n2.2 DEATH ........................................................................................................................................ 55\n2.3 BODY WEIGHT .......................................................................................................................... 57\n2.4 RESPIRATORY .......................................................................................................................... 58\n2.5 CARDIOVASCULAR ................................................................................................................. 63\n2.6 GASTROINTESTINAL ............................................................................................................... 63\n2.7 HEMATOLOGICAL ................................................................................................................... 65\n2.8 MUSCULOSKELETAL .............................................................................................................. 68\n2.9 HEPATIC ..................................................................................................................................... 68\n2.10 RENAL ........................................................................................................................................ 70\n2.11 DERMAL ..................................................................................................................................... 72\n2.12 OCULAR ..................................................................................................................................... 73\n2.13 ENDOCRINE ............................................................................................................................... 74\n2.14 IMMUNOLOGICAL ................................................................................................................... 75\n2.15 NEUROLOGICAL....................................................................................................................... 76\n2.16 REPRODUCTIVE ....................................................................................................................... 77\n2.17 DEVELOPMENTAL ................................................................................................................... 78\n2.18 OTHER NONCANCER ............................................................................................................... 79\n2.19 CANCER ...................................................................................................................................... 79\n2.20 GENOTOXICITY ........................................................................................................................ 80\n2.21 MECHANISM OF ACTION ....................................................................................................... 82\nCHAPTER 3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, \nCHEMICAL INTERACTIONS ........................................................................................... 84\n3.1 TOXICOKINETICS..................................................................................................................... 84\n3.1.1 Absorption ............................................................................................................................. 84\n3.1.2 Distribution ........................................................................................................................... 86\n3.1.3 Metabolism ............................................................................................................................ 88\n3.1.4 Excretion ............................................................................................................................... 90\n3.1.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models ............. 92\n3.1.6 Animal-to-Human Extrapolations ......................................................................................... 93\n3.2 CHILDREN AND OTHER POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE ..... 93\n3.3 BIOMARKERS OF EXPOSURE AND EFFECT ....................................................................... 95\n\n---\n\n3.3.1 Biomarkers of Exposure ........................................................................................................ 95\n3.3.2 Biomarkers of Effect ............................................................................................................. 96\n3.4 INTERACTIONS WITH OTHER CHEMICALS ....................................................................... 97\nCHAPTER 4. CHEMICAL AND PHYSICAL INFORMATION ............................................................. 98\n4.1 CHEMICAL IDENTITY ............................................................................................................. 98\n4.2 PHYSICAL AND CHEMICAL PROPERTIES .......................................................................... 98\nCHAPTER 5. POTENTIAL FOR HUMAN EXPOSURE ....................................................................... 100\n5.1 OVERVIEW .............................................................................................................................. 100\n5.2 PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL ................................................ 101\n5.2.1 Production ........................................................................................................................... 101\n5.2.2 Import/Export ...................................................................................................................... 103\n5.2.3 Use ...................................................................................................................................... 103\n5.2.4 Disposal ............................................................................................................................... 104\n5.3 RELEASES TO THE ENVIRONMENT ................................................................................... 104\n5.3.1 Air ....................................................................................................................................... 105\n5.3.2 Water ................................................................................................................................... 107\n5.3.3 Soil ...................................................................................................................................... 108\n5.4 ENVIRONMENTAL FATE ...................................................................................................... 109\n5.4.1 Transport and Partitioning ................................................................................................... 109\n5.4.2 Transformation and Degradation ........................................................................................ 112\n5.5 LEVELS IN THE ENVIRONMENT ......................................................................................... 116\n5.5.1 Air ....................................................................................................................................... 117\n5.5.2 Water ................................................................................................................................... 118\n5.5.3 Sediment and Soil ............................................................................................................... 122\n5.5.4 Other Media ........................................................................................................................ 123\n5.6 GENERAL POPULATION EXPOSURE.................................................................................. 124\n5.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES .............................................. 125\nCHAPTER 6. ADEQUACY OF THE DATABASE ................................................................................ 126\n6.1 EXISTING INFORMATION ON HEALTH EFFECTS ........................................................... 126\n6.2 IDENTIFICATION OF DATA NEEDS .................................................................................... 126\n6.3 ONGOING STUDIES ................................................................................................................ 135\nCHAPTER 7. REGULATIONS AND GUIDELINES ............................................................................. 136\nCHAPTER 8. REFERENCES .................................................................................................................. 138\nAPPENDICES\nAPPENDIX A.  ATSDR MINIMAL RISK LEVEL WORKSHEETS .................................................... A-1 \nAPPENDIX B. LITERATURE SEARCH FRAMEWORK FOR HCCPD ............................................. B-1 \nAPPENDIX C. FRAMEWORK FOR ATSDR’S SYSTEMATIC REVIEW OF HEALTH EFFECTS \nDATA FOR HCCPD ...................................................................................................... C-1 \nAPPENDIX D.  USER’S GUIDE ............................................................................................................. D-1 \nAPPENDIX E.  QUICK REFERENCE FOR HEALTH CARE PROVIDERS ....................................... E-1 \nAPPENDIX F.  GLOSSARY .................................................................................................................... F-1 \nAPPENDIX G.  ACRONYMS, ABBREVIATIONS, AND SYMBOLS................................................. G-1\n\n---\n\n## LIST OF FIGURES\n\n1-1.  Health Effects Found in Animals Following Inhalation Exposure to HCCPD .................................... 3\n1-2.  Health Effects Found in Animals Following Oral Exposure to HCCPD .............................................. 4\n1-3.  Summary of Sensitive Targets of HCCPD – Inhalation ....................................................................... 7\n1-4.  Summary of Sensitive Targets of HCCPD – Oral ................................................................................ 8\n2-1.  Overview of the Number of Studies Examining HCCPD Health Effects .......................................... 14\n2-2.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation ..................................... 28\n2-3.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Oral .............................................. 44\n5-1.  Number of NPL Sites with Hexachlorocyclopentadiene Contamination ......................................... 100\n5-2.  Transformation of Hexachlorocyclopentadiene ................................................................................ 113\n6-1.  Summary of Existing Health Effects Studies on HCCPD by Route and Endpoint .......................... 127\n\n---\n\n## LIST OF TABLES\n\n1-1.  Provisional Minimal Risk Levels (MRLs) for HCCPD ........................................................................ 9\n2-1.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation ..................................... 15\n2-2.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Oral .............................................. 39\n2-3.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Dermal ......................................... 49\n2-4.  LOAEL Values for Red Blood Cell Hematological Effects of Rats Exposed to HCCPD \nVapor in Acute- and Intermediate-Duration Inhalation  Studies ........................................................ 65\n2-5.  Genotoxicity of Hexachlorocyclopentadiene *In Vivo* ......................................................................... 81\n2-6.  Genotoxicity of Hexachlorocyclopentadiene *In Vitro* ........................................................................ 81\n4-1.  Chemical Identity of Hexachlorocyclopentadiene .............................................................................. 98\n4-2.  Physical and Chemical Properties of Hexachlorocyclopentadiene ..................................................... 98\n5-1.  Facilities that Produce, Process, or Use Hexachlorocyclopentadiene .............................................. 102\n5-2.  Summary of National Aggregate Volumes Reported to U.S. Environmental Protection \nAgency (EPA) Chemical Data  Reporting (CDR) ............................................................................ 103\n5-3.  Releases to the Environment from Facilities that Produce, Process, or Use \nHexachlorocyclopentadiene .............................................................................................................. 105\n5-4.  Summary of Releases to the Environment from the Emissions Inventory System (EIS) \nGateway Emission Sectors in 2020 .................................................................................................. 106\n5-5.  Summary of Releases to the Environment from the Emissions Inventory System (EIS) \nGateway Emission Sectors in 2021 .................................................................................................. 107\n5-6.  Lowest Limit of Detection Based on Standards ............................................................................... 117\n5-7.  Summary of Environmental Levels of HCCPD ............................................................................... 117\n5-*8.*  Summary of Water Monitoring Data for Hexachlorocyclopentadiene Across the \nUnited States ..................................................................................................................................... 119\n7-1.  Regulations and Guidelines Applicable to Hexachlorocyclopentadiene .......................................... 136\n\n---\n\n# CHAPTER 1. RELEVANCE TO PUBLIC HEALTH\n\n###### 1.1 OVERVIEW AND U.S. EXPOSURES\n\nHexachlorocyclopentadiene (HCCPD) is a highly volatile, reactive liquid.  HCCPD is an anthropogenic \nchemical that has entered the environment primarily because of its use in the production of chlorinated \npesticides and flame-retardant chemicals.  Restriction of pesticides synthesized from HCCPD has \ndecreased the possibility of exposure to HCCPD and pesticide residues among most members of the \ngeneral population.  Exposure to materials containing HCCPD at hazardous waste sites is still possible.\n\nThe potential for persistence of HCCPD in the environment is low.  Due to its high vapor pressure, \nHCCPD is most likely released to the environment through volatilization, especially from surface waters \nand soils.  The main degradation processes expected include photolysis and photooxidation, hydrolysis, \nand, to a lesser extent, biodegradation.  HCCPD in the air is expected to degrade with estimated half-lives \nranging from 5 hours to <1 day, which limits its potential for long-range transport. HCCPD in water is \nexpected to degrade rapidly, with half-lives for photolysis of ~2–4 minutes and half-lives for hydrolysis \nof ~3–5.45 days.\n\nOccupational exposure to HCCPD is most likely to occur via inhalation and dermal routes.  The general \npopulation may be exposed to HCCPD through inhalation of air contaminated with this chemical and \ningestion of drinking water contaminated with this chemical.\n\n###### 1.2 SUMMARY OF HEALTH EFFECTS\n\nInformation on the noncancer toxicity of HCCPD in humans is limited to reports by wastewater treatment \nplant (WWTP) workers and cleanup crew members exposed after an inadvertent industrial release.  No \noccupational studies evaluating health effects in workers exposed during regular manufacture or use of \nHCCPD are available.  Additionally, no observational epidemiological studies of workers or the public \nare available for HCCPD.  Further information on the noncancer toxicity of HCCPD comes from \ninhalation and oral studies in animals.  Data following dermal exposure are very limited in humans and \nanimals.\n\nIn laboratory animals, evaluation of available dose-response data by route and duration indicates that \nsensitive noncancer targets of HCCPD toxicity are respiratory and hematological effects following inhalation exposure (Figure 1-1).  Ovarian inflammation was noted in mice following chronic-duration \ninhalation exposure; however, the causal relationship between the effect and HCCPD exposure could not \nbe determined due to apparent association with stress-induced susceptibility to an infection in the mouse \ncolony (see Section 2.16).  Due to this, female reproductive (ovarian) effects were not considered as \npotential sensitive effects or included in Figure 1-1.  The oral database is very limited; the only potential \ntargets identified below doses associated with lethality include the gastrointestinal tract and kidney \n(Figure 1-2). General toxicity (decreased body weight) was also observed at similar doses.  A systematic \nreview of sensitive target organs/systems by exposure route resulted in the following hazard identification \nconclusions:\n\n• Respiratory effects are a presumed health effect for humans following inhalation exposure.\n\n• Gastrointestinal effects are a presumed health effect for humans following oral exposure.\n\n• Hematological (red blood cell) effects are suspected health effects for humans following \ninhalation exposure; white blood cell effects are not classifiable as to the hazard to humans.\n\n• Renal effects are a presumed health effect for humans following oral exposure.\n\n**_Respiratory Effects (Inhalation Route)._**  The respiratory tract is sensitive to HCCPD toxicity after \ninhalation exposure; findings are attributed to compound reactivity upon contact with respiratory tissues \nat the portal of entry.  WWTP workers and cleanup crew members reported respiratory symptoms \nincluding coughing, nose and throat irritation, and difficulty breathing following inhalation of HCCPD \nvapors from an inadvertent industrial discharge (Kominsky et al. 1980; Morse et al. 1979).  Acuteduration inhalation exposure studies in animals identified increased or labored respiration or abnormal \nrespiratory patterns at concentrations ≥0.5 ppm (Alexander et al. 1980a; Jackson and Hardy 1986, 1987; \nRand et al. 1982a).  Sneezing and altered respiratory rates/patterns were observed in rodents at \nintermediate-duration exposures of ≥0.56 ppm (Clark 1981; NTP 1994).  Histopathological evaluation \nidentified changes to the nasal, tracheobronchial, and/or pulmonary epithelium in rats and mice at \n≥0.385 and ≥0.2 ppm, respectively; these changes consisted of inflammation (suppurative or necrotizing) \nor metaplasia at nonlethal concentrations (Clark 1981; NTP 1994) and hemorrhaging or necrosis at lethal \nconcentrations (NTP 1994).  Nasal and pulmonary lesions were observed in mice exposed to 0.2 ppm \nHCCPD for 2 years, while no lesions were observed in rats under the same exposure conditions (NTP \n1994).\n\n$$\n\\geq0.385and\\geq0.2\n$$\n\n---\n\n**Figure 1-1.  Health Effects Found in Animals Following Inhalation Exposure to** \n**HCCPD**\n\n**Concentration (ppm)**\n\n**≥1.4**\n\n**Effects in Animals**\n\n**Acute:**  Neurobehavioral effects\n\n**Intermediate:**  Hepatic effects\n\n**0.5**\n\n**Acute:**  Death, respiratory lesions, altered hematology parameters, \ndecreased body weight, decreased food and water intake\n\n**Intermediate:**  Decreased body weight\n\n**0.389**\n\n**Intermediate:**  Death\n\n**0.2**\n\n**0.039**\n\n**Intermediate:**  Respiratory lesions\n\n**Chronic:**  Death, respiratory lesions\n\n**Intermediate:**  Altered red blood cell parameters\n\n1x10<sup>-4</sup> ppm\n6x10<sup>-5</sup> ppm\n\n**Provisional Intermediate MRL**\n**Provisional Chronic MRL**\n\n---\n\n**Figure 1-2.  Health Effects Found in Animals Following Oral Exposure to HCCPD**\n\nDose (mg/kg/day) Effects in Animals\n≥464 Acute:  Gastrointestinal, neurological, respiratory, and musculoskeletal  \neffects \n150 Intermediate:  Death\n75 Acute:  Death, developmental effects\n38 Intermediate:  Gastrointestinal and renal lesions, decreased body \nweight\n0.06 mg/kg/day Provisional Intermediate MRL\n\n**_Gastrointestinal Effects (Oral Route)._** The gastrointestinal tract is sensitive to HCCPD after oral \nexposure; findings are attributed to compound reactivity upon contact with gastrointestinal tissues at the \nportal of entry.  No human data are available evaluating potential gastrointestinal effects of HCCPD \nfollowing oral exposure.  Diarrhea was reported in rodents administered single oral doses of ≥464 mg/kg \n(Dean 1977; Gardner 1986a); this effect was not reported at lower doses in intermediate-duration studies \nup to 150 mg/kg/day in rats or 300 mg/kg/day in mice (Abdo et al. 1984).  In the only available \nintermediate-duration oral study in animals, focal inflammation and epithelial hyperplasia of the \nforestomach were observed in rats and mice exposed to ≥38 and ≥75 mg/kg/day, respectively (Abdo et al.\n1984).  While humans lack a forestomach, analogous lesions could occur in the proximate portions of the \nhuman gastrointestinal tract, including oral, pharyngeal, and/or esophageal tissues, due to portal-of-entry \nreactivity following oral exposure to HCCPD.\n\n**_Hematological Effects (Inhalation Route)._**  No changes in blood counts were observed in workers \nexposed to HCCPD at a WWTP following an inadvertent industrial discharge (Kominsky et al. 1980).  \nAlterations in red blood cell parameters, primarily elevated red blood cell counts and hemoglobin levels, were reported in rats following acute- and intermediate-duration inhalation exposure to HCCPD at \nconcentrations of 0.5 and ≥0.14 ppm, respectively (Clark 1981; NTP 1994; Rand et al. 1982a); similar \nfindings were observed in mice at intermediate-duration inhalation concentrations ≥0.039 ppm (NTP \n1994).  Based on the absence of histopathological changes to bone marrow, observed red blood cell \neffects have been hypothesized to be a compensatory response to hemorrhagic damage to the lungs \nfollowing inhalation exposure rather than direct effects on hematopoiesis (Rand et al. 1982a).  However,\nrats showed sex-specific findings (females were less sensitive), and there were inconsistencies between \nthe main 13-week (comprehensive) study and the 13-week specialized hematological study conducted by \nNTP (1994).  In mice, findings were limited and inconsistent with respect to alterations in red blood cell \nparameters after exposure for 13–42 weeks (NTP 1994).  Additionally, no hematological effects were \nobserved in the 2-year inhalation studies in rats or mice at concentrations up to 2 ppm (NTP 1994).  No \nconsistent effects on white blood cell parameters were observed with inhalation exposures in animal \nstudies (Clark 1981; NTP 1994; Rand et al. 1982a).\n\n**_Renal Effects (Oral Route)._** No human data are available to assess the potential for HCCPD to cause \nrenal toxicity.  In the only available oral study in animals evaluating the kidney, HCCPD produced toxic \nnephrosis in male and female rats at ≥38 mg/kg/day and in female mice at ≥75 mg/kg/day (Abdo et al. \n1984).  Toxic nephrosis was not identified in male mice, but acute tubular necrosis was identified in male \nmice exposed to 300 mg/kg/day. Available toxicokinetic data indicate that HCCPD and/or its metabolites \ndistribute to the kidneys in both rats and mice after oral dosing; however, the highest distribution is to the \nkidney in the rat and to the liver in the mouse (Dorough and Ranieri 1984).  This observed difference in \ndistribution may explain the observed species sensitivity.\n\n**_Cancer Effects._**  There were no data from studies in humans pertaining to the carcinogenicity of HCCPD.  \nThe National Toxicology Program (NTP) conducted 2-year bioassays of HCCPD in mice and rats and \nconcluded that it is not a carcinogen in either species (NTP 1994).  Although the incidence of \nalveolar/bronchiolar carcinomas was significantly increased in male mice exposed to 0.5 ppm for 26 or \n42 weeks and evaluated at 2 years, the incidence was within the historical range for the laboratory and \nwas not elevated in animals exposed to 0.2 ppm for 2 years. There was also a slight increase in the \nincidence of adenomas of the pituitary pars distalis in male rats and thyroid follicle cell adenomas in \nfemale mice, but these tumors were not considered to be exposure-related since the incidences were \nsimilar to the historical control means, were within the historical control range, or did not exhibit a dosedependency.  Based on these results, the U.S. Environmental Protection Agency (EPA) determined that \nHCCPD is not likely to be a human carcinogen by the inhalation route (IRIS 2003).  The International\n\n---\n\nAgency for Research on Cancer (IARC) has not evaluated the carcinogenicity of HCCPD (IARC 2025).  \nThe U.S. Department of Health and Human Services (HHS) has not evaluated a cancer classification \ncategory for HCCPD (NTP 2021).\n\n###### 1.3 MINIMAL RISK LEVELS (MRLs)\n\nAs illustrated in Figure 1-3, available inhalation data for HCCPD suggest that the respiratory and \nhematological systems are the most sensitive targets for toxicity. The inhalation database was considered \nadequate for derivation of provisional intermediate- and chronic-duration MRLs.  As discussed in \nSection 1.2, ovarian effects observed in the chronic-duration mouse study were not considered as \npotential sensitive effects due to potential confounding by a utero-ovarian infection (see Appendix A for \ndetails).  Therefore, female reproductive effects are not included in Figure 1-3.\n\nAs illustrated in Figure 1-4, gastrointestinal, renal, and body weight effects appear to be the most \nsensitive targets of HCCPD toxicity following oral exposure. The oral database was considered adequate \nfor derivation of a provisional intermediate-duration MRL for HCCPD.  The acute- and chronic-duration \noral data were insufficient for deriving MRLs.\n\nThe provisional MRL values are summarized in Table 1-1 and discussed in greater detail in Appendix A.\n\n---\n\n**Figure 1-3.  Summary of Sensitive Targets of HCCPD – Inhalation**\n\n**Available data indicate that the hematological and respiratory systems are the most sensitive \ntargets of HCCPD inhalation exposure.**\n\nNumbers in circles are the lowest LOAELs for all health effects in animals. No reliable dose response \ndata were available for humans.\n\n**Acute (ppm)**\n\n| Category | Acute (ppm) | Intermediate (ppm) | Chronic (ppm) |\n| --- | --- | --- | --- |\n| Death | 0.5 | 0.389 | 0.2 |\n| Body weight | 0.5 |  |  |\n| Respiratory | 0.5 | 0.2 | 0.2 |\n| Hematological | 0.5 | 0.039 |  |\n| Other noncancer | 0.5 |  |  |\n\n---\n\n**Figure 1-4. Summary of Sensitive Targets of HCCPD – Oral**\n\n**Available data indicate that the gastrointestinal tract, renal system, and body weight are the most\nsensitive targets of HCCPD oral exposure.**\nNumbers in circles are the lowest LOAELs for all health effects in animals. \nNo reliable dose response data were available for humans.\n\n## Acute (mg/kg/day)\n\n| Category | Lowest LOAEL (mg/kg/day) |\n| --- | --- |\n| Death (Acute) | 75 |\n| Developmental (Acute) | 75 |\n| Gastrointestinal (Acute) | 464 |\n| Neuological (Acute) | 464 |\n| Body weight (Intermediate) | 38 |\n| Gastrointestinal (Intermediate) | 38 |\n| Renal (Intermediate) | 38 |\n| Death (Intermediate) | 150 |\n\n---\n\nTable 1-1. Provisional Minimal Risk Levels (MRLs) for HCCPD<sup>a</sup>\n\n| Exposure route | Exposure duration | Provisional MRL | Critical effect | POD type | POD value | Uncertainty/modifying factor | Reference |\n| --- | --- | --- | --- | --- | --- | --- | --- |\n| Inhalation | Acute | None | - | - | - | - | - |\n| Inhalation | Intermediate | 1 × 10-4 ppm (1 × 10-3 mg/m3) | Nasal suppurative inflammation in rats | NOAELHEC | 0.00344 ppm | UF: 30 | NTP 1994 |\n| Inhalation | Chronic | 6 × 10-5 ppm (7 × 10-4 mg/m3) | Nasal suppurative inflammation in mice | BMCLHEC | 0.0019 ppm | UF: 30 | NTP 1994 |\n| Oral | Acute | None | - | - | - | - | - |\n| Oral | Intermediate | 0.06 mg/kg/day | Combined incidence of forestomach epithelial hyperplasia and focal inflammation in rats | BMDLADJ | 5.5 mg/kg/day | UF: 100 | Abdo et al. 1984: Velsicol 1981b |\n| Oral | Chronic | None | - | - | - | - | - |\n\n$$\n1\\times10^{-4}ppm\n$$\n\n$$\n(1\\times10^{-3}mg/m^3)\n$$\n\n$$\n6\\times10^{-5}ppm\n$$\n\n$$\n(7\\times10^{-4}mg/m^3)\n$$\n\n<sup>a</sup>See Appendix A for additional information.\n\nADJ = adjusted for intermittent exposure; BMCL = benchmark concentration lower confidence limit; BMDL = benchmark dose lower confidence limit;\n\nHEC = human equivalent concentration; NOAEL = no-observed-adverse-effect level; POD = point of departure; UF = uncertainty factor\n\n---\n\n# CHAPTER 2. HEALTH EFFECTS\n\n###### 2.1 INTRODUCTION\n\nThe primary purpose of this chapter is to provide public health officials, physicians, toxicologists, and \nother interested individuals and groups with an overall perspective on the toxicology of HCCPD.  It \ncontains descriptions and evaluations of toxicological studies and epidemiological investigations and \nprovides conclusions, where possible, on the relevance of toxicity and toxicokinetic data to public health.  \nWhen available, mechanisms of action are discussed along with the health effects data; toxicokinetic \nmechanistic data are discussed in Section 3.1.\n\nA glossary and list of acronyms, abbreviations, and symbols can be found at the end of this profile.\n\nTo help public health professionals and others address the needs of persons living or working near hazardous \nwaste sites, the information in this section is organized by health effects.  These data are discussed in terms \nof route of exposure (inhalation, oral, and dermal) and three exposure periods:  acute (≤14 days), \nintermediate (15–364 days), and chronic (≥365 days).\n\nAs discussed in Appendix B, a literature search was conducted to identify relevant studies examining health \neffect endpoints.  Figure 2-1 provides an overview of the database of studies in humans or experimental \nanimals included in this chapter of the profile.  These studies evaluate the potential health effects associated \nwith inhalation, oral, or dermal exposure to HCCPD, but may not be inclusive of the entire body of literature.  \nA systematic review of the scientific evidence of the health effects associated with exposure to HCCPD was \nalso conducted; the results of this review are presented in Appendix C.\n\nHuman and animal inhalation studies are presented in Table 2-1 and Figure 2-2, animal oral studies are \npresented in Table 2-2 and Figure 2-3, and human and animal dermal studies are presented in Table 2-3.  \nDue to the limited nature of the database, several older studies lacking quantitative data reporting are \nincluded in Chapter 2 to provide data potentially relevant for hazard identification; however, data that are \nonly reported qualitatively (i.e., histopathological data lacking incidence data) are not included in \nTables 2-1, 2-2, or 2-3.\n\nLevels of significant exposure (LSEs) for each route and duration are presented in tables and illustrated in \nfigures.  The points in the figures showing no-observed-adverse-effect levels (NOAELs) or lowest- observed-adverse-effect levels (LOAELs) reflect the actual doses (levels of exposure) used in the studies.  \nEffects have been classified into “less serious LOAELs” or “serious LOAELs (SLOAELs).”  “Serious” \neffects are those that evoke failure in a biological system and can lead to morbidity or mortality (e.g., \nacute respiratory distress or death).  “Less serious” effects are those that are not expected to cause \nsignificant dysfunction or death, or those whose significance to the organism is not entirely clear.  \nATSDR acknowledges that a considerable amount of judgment may be required in establishing whether \nan endpoint should be classified as a NOAEL, “less serious” LOAEL, or “serious” LOAEL, and that in \nsome cases, there will be insufficient data to decide whether the effect is indicative of significant \ndysfunction.  However, the Agency has established guidelines and policies that are used to classify these \nendpoints.  ATSDR believes that there is sufficient merit in this approach to warrant an attempt at \ndistinguishing between “less serious” and “serious” effects.  The distinction between “less serious” effects \nand “serious” effects is considered to be important because it helps the users of the profiles to identify \nlevels of exposure at which major health effects start to appear.  LOAELs or NOAELs should also help in \ndetermining whether or not the effects vary with dose and/or duration, and place into perspective the \npossible significance of these effects to human health.\n\nA User's Guide has been provided at the end of this profile (see Appendix C).  This guide should aid in \nthe interpretation of the tables and figures for LSEs and MRLs.\n\nThe health effects of HCCPD have been evaluated in 2 human studies and 68 animal studies.  As \nillustrated in Figure 2-1, most of the health effect data come from dermal and inhalation studies in \nanimals.  In both human and animal studies, the ocular effects observed in HCCPD inhalation studies are \nlikely attributable to direct contact with HCCPD vapors.  Therefore, ocular effects from inhalation studies \nare counted as dermal exposure in Figure 2-1 and are listed in the dermal LSE table.\n\nThe available human studies were predominantly focused on evaluation of dermal, ocular, and respiratory \neffects in WWTP workers and cleanup crew members following an inadvertent industrial release of \nHCCPD.  For these studies, exposure was evaluated as HCCPD vapor levels in air.\n\nFor animal data, inhalation and oral studies are available for most health effects.  Acute-, intermediate-, \nand chronic-duration studies are available for the inhalation route, while only acute- and intermediateduration studies are available for the oral route.  The dermal animal database is mostly limited to ocular \nand dermal effects, largely following exposure to HCCPD vapor.  The most examined endpoints in \nanimal studies were death, respiratory, hepatic, renal, and ocular.\n\n---\n\nA systematic review was conducted on potential targets of HCCPD exposure, which included respiratory \nand hematological effects for inhalation exposure and gastrointestinal and renal effects following oral \nexposure (see Appendix C for details).\n\n• **Respiratory Effects.** Respiratory effects are a presumed health effect associated with HCCPD \nexposure via inhalation based on inadequate evidence in humans and a high level of evidence in \nanimals.  WWTP workers and cleanup crew members reported respiratory symptoms including \ncoughing and respiratory tract irritation after exposure to HCCPD vapors following an \ninadvertent industrial release.  Several animal studies have reported altered respiratory patterns \nfollowing single or repeated exposures to HCCPD.  Upon histopathological examination, \nnonneoplastic lesions of the nasal, tracheobronchial, and pulmonary regions were consistently \nobserved in mice and rats exposed for intermediate durations to concentrations ≥0.2 or \n≥0.385 ppm, respectively.  Chronic-duration exposure to 0.2 ppm resulted in similar lesions in \nmice, but not rats.  Observed lesions (suppurative, serous, or necrotizing inflammation; epithelial \nhyperplasia) are consistent with chronic irritation at the portal of entry.\n\n• **Gastrointestinal Effects.** Gastrointestinal effects are a presumed health effect associated with \nHCCPD exposure via oral exposure based on no human data and a high level of evidence in \nanimal studies.  Diarrhea was reported in rodents following exposure to high acute doses \n≥464 mg/kg.  Forestomach lesions (epithelial hyperplasia and focal inflammation) were observed \nin rats and mice following intermediate-duration exposures of ≥38 and ≥75 mg/kg/day, \nrespectively.  Although humans lack a forestomach, effects associated with HCCPD are \nconsistent with chronic irritation at the portal of entry.  Thus, the upper gastrointestinal tract is\npresumably vulnerable to toxicity following oral exposure to HCCPD.\n\n• **Hematological Effects.** Hematological effects, specifically red blood cell parameters, are a \nsuspected health effect associated with HCCPD exposure via inhalation based on inadequate data \nin humans and a moderate level of evidence in animals.  No changes in blood counts were \nobserved in WWTP workers after exposure to HCCPD vapors following an inadvertent industrial \nrelease.  Several acute- and intermediate-duration inhalation studies reported altered red blood \ncell parameters (e.g., increased hemoglobin, red blood cell counts, and packed cell volume) at \nconcentrations as low as 0.14 and 0.039 ppm in rats and mice, respectively; however, these \nfindings were not consistent across sexes or species nor were they reproducible in targeted \nanalyses by the same researchers.  Observed red blood cell effects may be attributable to\ncompromised gas exchange following tissue damage to the respiratory tract, as no evidence of \nbone marrow hyperplasia was observed in rodents following repeated inhalation exposure to \nHCCPD. White blood cell effects are not classifiable as to the hazard to humans based on no data \nin humans and inadequate evidence in animals.  Available studies did not find consistent evidence \nof alterations in white blood cell parameters in rats or mice following intermediate- or chronicduration inhalation exposure to HCCPD.\n\n• **Renal Effects.** Renal effects are a presumed health effect associated with oral exposure to\nHCCPD based on no human data and a high level of evidence in animal studies.  Renal lesions, \nspecifically toxic nephrosis, were observed in rats and mice following intermediate-duration \nexposures to ≥38 and ≥75 mg/kg/day, respectively. Acute tubular necrosis was observed in male \nmice at a higher dose (300 mg/kg/day).  Available toxicokinetic data indicate that HCCPD and/or\n\n---\n\n###### 2. HEALTH EFFECTS\n\nits metabolites distribute to the kidneys of both rats and mice after oral dosing; however, it will \naccumulate to a higher degree in rats.\n\n---\n\n**Figure 2-1.  Overview of the Number of Studies Examining HCCPD Health Effects***\n\n**Most studies examined the potential death, respiratory, neurological, renal, hepatic, and ocular effects of HCCPD**\nFewer studies evaluated health effects in **humans** than **animals** (counts represent studies examining endpoint)\n\n| Category | Number of studies |\n| --- | --- |\n| Death | 57 |\n| Body weight | 18 |\n| Respiratory | 44 |\n| Cardiovascular | 35 |\n| Gastrointestinal | 16 |\n| Hematological | 13 |\n| Musculoskeletal | 10 |\n| Hepatic | 39 |\n| Renal | 39 |\n| Dermal | 16 |\n| Ocular | 39 |\n| Endocrine | 35 |\n| Immunological | 12 |\n| Neurolgical | 41 |\n| Reproductive | 11 |\n| Developmental | 3 |\n| Other Noncancer | 7 |\n| Cancer | 5 |\n\n**Exposure Route**\n\n| Category | Share of studies (%) |\n| --- | --- |\n| Inhalation | 40 |\n| Oral | 13 |\n| Dermal | 47 |\n\n**Exposure Duration**\n\n| Category | Share of studies (%) |\n| --- | --- |\n| Chronic | 2 |\n| Acute | 78 |\n| Intermediate | 20 |\n\n*Includes studies discussed in Chapter 2.  A total of 70 studies (including those finding no effect) have examined toxicity; most studies examined multiple \nendpoints.\n\n---\n\n**Table 2-1. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation\n(ppm)**\n\n| Species (strain) keya | No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| ACUTE EXPOSURE |  |  |  |  |  |  |  |  |  |\n| Alexander et al. 1980a; Rand et al. 1982a |  |  |  |  |  |  |  |  |  |\n| 1 | Rat (Sprague-Dawley) 10 M, 10 F | 1–2 weeks 5 days/week 6 hours/day (WB) | 0, 0.022, 0.11, 0.5 | LE, CS, BW, FI, HE, BC, GN, OW, HP | Death Bd wt | 0.11 |  | 0.5 M | 10/10 died or were sacrificed in moribund condition Decreased terminal body weight in females (29%) and males (32%) Labored respiration; increased absolute lung weight; bronchiole inflammation, hyperplasia, and epithelial erosion |\n| 1 | Rat (Sprague-Dawley) 10 M, 10 F | 1–2 weeks 5 days/week 6 hours/day (WB) | 0, 0.022, 0.11, 0.5 | LE, CS, BW, FI, HE, BC, GN, OW, HP | Resp | 0.11 |  | 0.5 | 10/10 died or were sacrificed in moribund condition Decreased terminal body weight in females (29%) and males (32%) Labored respiration; increased absolute lung weight; bronchiole inflammation, hyperplasia, and epithelial erosion |\n| 1 | Rat (Sprague-Dawley) 10 M, 10 F | 1–2 weeks 5 days/week 6 hours/day (WB) | 0, 0.022, 0.11, 0.5 | LE, CS, BW, FI, HE, BC, GN, OW, HP | Cardio Hematoc | 0.5 0.11 | 0.5 | 0.5 | Males: total white blood cell and lymphocyte counts reduced Females: neutrophils increased Both: red blood cell count, packed cell volume, and hemoglobin increased |\n| 1 | Rat (Sprague-Dawley) 10 M, 10 F | 1–2 weeks 5 days/week 6 hours/day (WB) | 0, 0.022, 0.11, 0.5 | LE, CS, BW, FI, HE, BC, GN, OW, HP | Hepatic Renal Immuno Neuro | 0.5 0.5 0.5 Other noncancer | 0.5 |  | Decreased food and water intake |\n| Jackson and Hardy 1986 |  |  |  |  |  |  |  |  |  |\n| 2 | Rat (Wistar) 5 M, 5 F | 1 hour (WB) | 0, 1.67, 2.38, 3.53, 6.25, 8.30 | LE, CS, BW, FI, WI, OW, GN | Death Bd wt | 1.67 |  | 3.69 | LC50 Decreased body weight at death or scheduled sacrifice (3-weeks post exposure) in males (41%) and females (26%) Abnormal respiratory pattern Decreased food consumption |\n| 2 | Rat (Wistar) 5 M, 5 F | 1 hour (WB) | 0, 1.67, 2.38, 3.53, 6.25, 8.30 | LE, CS, BW, FI, WI, OW, GN | Resp Other noncancer | 1.67 1.67 |  |  | LC50 Decreased body weight at death or scheduled sacrifice (3-weeks post exposure) in males (41%) and females (26%) Abnormal respiratory pattern Decreased food consumption |\n\n---\n\n**Table 2-1. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation\n(ppm)**\n\nAbnormal respiratory pattern\nDecreased food consumption\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Jackson and Hardy 1987 |  |  |  |  |  |  |  |  |  |\n| 3 | Rat (Wistar) 5 M, 5 F | 4 hours (WB) | 0, 1.68, 1.83, 3.31, 3.47 | LE, CS, BW, FI, WI, GN, OW | Death Bd wt |  |  | 2.9 1.68 M | LC50 23% decreased body weight at scheduled sacrifice (4 weeks post exposure) |\n| 3 | Rat (Wistar) 5 M, 5 F | 4 hours (WB) | 0, 1.68, 1.83, 3.31, 3.47 | LE, CS, BW, FI, WI, GN, OW | Resp Other noncancer | 1.68 F | 1.68 1.68 | 1.83 F | 24% decreased body weight at death or scheduled sacrifice (4 weeks post exposure) |\n| OxyChem 1972 |  |  |  |  |  |  |  |  |  |\n| 4 | Rat (Carworth CFE) 10 M | 4 hours (WB) | 176, 1,760 | LE, CS, GN | Death |  |  | 176 | 10/10 died within 48 hours |\n| Rand et al. 1982a |  |  |  |  |  |  |  |  |  |\n| 5 | Rat (Sprague-Dawley) 10 M, 10 F | 4 hours (WB) | 0.28, 1.4, 2.5, 3.1, 3.3, 3.4, 4, 5.8 | LE, CS, BW | Death |  |  | 3.5 F 1.6 M | LC50 LC50 |\n| 5 | Rat (Sprague-Dawley) 10 M, 10 F | 4 hours (WB) | 0.28, 1.4, 2.5, 3.1, 3.3, 3.4, 4, 5.8 | LE, CS, BW | Bd wt | 0.28 | 1.4 F | 1.4 M | 17% body weight loss 25% body weight loss |\n| 5 | Rat (Sprague-Dawley) 10 M, 10 F | 4 hours (WB) | 0.28, 1.4, 2.5, 3.1, 3.3, 3.4, 4, 5.8 | LE, CS, BW | Neuro | 0.28 | 1.4 | 5.8 | LOAEL: Sedation SLOAEL: Ataxia |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 6 | Rat 4 NS | 2 days 7 hours/day (WB) | 3.2 | LE, CS, GN | Death |  |  | 3.2 | 4/4 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 7 | Rat 4 NS | 3 days 7 hours/day (WB) | 1.4 | LE, CS, GN | Death |  |  | 1.4 | 3/4 died |\n\n---\n\n**Table 2-1. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation\n(ppm)**\n\n| Species |  |  |  |  |  |  |  |  |  |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Figure keya | No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 8 | Rat 4 NS | 2.6–3.6 hours (WB) | 1.4, 3.1, 7.1, 12.4, 12.7, 46.5, 56.9, 70.4 | LE, CS, GN | Death |  |  | 3.1 | 2/4 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 9 | Rat 4 NS | 7 hours (WB) | 1.5, 3.2, 6.7 | LE, CS, GN | Death |  |  | 3.2 | 3/4 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 10 | Rat 4 NS | 5 days 7 hours/day (WB) | 0.33, 1.0, 1.6 | LE, CS, GN | Death |  |  | 1 | 4/4 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 11 | Rat 4 NS | 0.25–1.25 hours (WB) | 1.4, 1.5, 3.1, 7.2, 13.0, 13.8, 19.4, 20.0, 20.2, 69.1, 69.2 | LE, CS, GN | Death |  |  | 7.2 | 2/4 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 12 | Rat 4 NS | 4 hours (WB) | 73.6 | LE, CS, GN | Death |  |  | 73.6 | 4/4 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 13 | Mouse 5 NS | 0.25–1.25 hours (WB) | 1.4, 1.5, 3.1, 7.2, 13.0, 13.8, 19.4, 20.0, 20.2, 69.1, 69.2 | LE, CS, GN | Death |  |  | 7.2 | 5/5 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 14 | Mouse 5 NS | 4 hours (WB) | 73.6 | LE, CS, GN | Death |  |  | 73.6 | 5/5 died |\n\n---\n\n**Table 2-1. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation\n(ppm)**\n\n| Species (strain) keya | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| 15 Mouse 5 NS | 2 days 7 hours/day (WB) | 3.2 | LE, CS, GN | Death |  |  | 3.2 | 4/5 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| 16 Mouse 5 NS | 3 days 7 hours/day (WB) | 1.4 | LE, CS, GN | Death |  |  | 1.4 | 5/5 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| 17 Mouse 5 NS | 7 hours (WB) | 1.5, 3.2, 6.7 | LE, CS, GN | Death |  |  | 1.5 | 4/5 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| 18 Mouse 5 NS | 2.6– 3.6 hours (WB) | 1.4, 3.1, 7.1, 12.4, 12.7, 46.5, 56.9, 70.4 | LE, CS, GN | Death |  |  | 3.1 | 4/5 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| 19 Mouse 5 NS | 5 days 7 hours/day (WB) | 0.33, 1.0, 1.6 | LE, CS, GN | Death |  |  | 1 | 4/5 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| 20 Rabbit 3 NS | 4 hours (WB) | 73.6 | LE, CS, GN | Death |  |  | 73.6 | 3/3 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| 21 Rabbit 3 NS | 3 days 7 hours/day (WB) | 1.4 | LE, CS, GN | Death |  |  | 1.4 | 3/3 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| 22 Rabbit 3 NS | 5 days 7 hours/day (WB) | 1, 1.6 | LE, CS, GN | Death |  |  | 1 | 3/3 died |\n\n---\n\n**Table 2-1. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation\n(ppm)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 23 | Rabbit 3 NS | 2.6–3.6 hours (WB) | 1.4, 3.1, 7.1, 12.4, 12.7, 46.5, 56.9, 70.4 | LE, CS, GN | Death |  |  | 1.4 | 2/3 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 24 | Rabbit 3 NS | 7 hours (WB) | 1.5, 3.2, 6.7 | LE, CS, GN | Death |  |  | 1.5 | 3/3 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 25 | Rabbit 3 NS | 0.25–1.25 hours (WB) | 1.4, 1.5, 3.1, 7.2, 13.0, 13.8, 19.4, 20.0, 20.2, 69.1, 69.2 | LE, CS, GN | Death |  |  | 3.1 | 2/3 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 26 | Rabbit 3 NS | 2 days 7 hours/day (WB) | 3.2 | LE, CS, GN | Death |  |  | 3.2 | 3/3 died |\n| INTERMEDIATE EXPOSURE |  |  |  |  |  |  |  |  |  |\n| Alexander et al. 1980b; Rand et al. 1982a, 1982b |  |  |  |  |  |  |  |  |  |\n| 27 | Monkey (Cynomolgus) 6 M, 6 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, HE, BC, UR, OP, GN, OW, HP, OF | Bd wt Resp Cardio Gastro Hemato Musc/skel Hepatic Renal Ocular Endocr Immuno | 0.2 0.2 0.2 0.2 0.2 0.2 |  |  |  |\n\n---\n\n**Table 2-1. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation\n(ppm)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n|  |  |  |  |  | Neuro | 0.2 |  |  |  |\n|  |  |  |  |  | Repro | 0.2 |  |  |  |\n|  |  |  |  |  | Other |  |  |  |  |\n|  |  |  |  |  | noncancer |  |  |  |  |\n| Alexander et al. 1980b; Huntingdon Research Centre 1980; Rand et al. 1982a, 1982b |  |  |  |  |  |  |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Bd wt | 0.2 |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Resp | 0.2 |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Cardio | 0.2 |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Gastro | 0.2 |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Hemat | 0.2 |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Musc/skel | 0.2 |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Hepatic | 0.2 |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Renal | 0.2 |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Ocular | 0.2 |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Endocr | 0.2 |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Immuno | 0.2 |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Neuro | 0.2 |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Repro | 0.2 |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Other |  |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | noncancer |  |  |  |  |\n\n---\n\n**Table 2-1. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation\n(ppm)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Clark 1981 |  |  |  |  |  |  |  |  |  |\n| 29 | Rat (Wistar) 18 M, 18 F | 30 weeks 5 days/week 6 hours/day (WB) | 0, 0.06, 0.14, 0.56 | LE, CS, BW, FI, WI, HE, BC, UR, GN, OW, HP | Death Bd wt Resp | 0.56 | 0.56 F | 0.56 M | 4/18 males and 2/18 females died |\n| 29 | Rat (Wistar) 18 M, 18 F | 30 weeks 5 days/week 6 hours/day (WB) | 0, 0.06, 0.14, 0.56 | LE, CS, BW, FI, WI, HE, BC, UR, GN, OW, HP | Resp | 0.14 | 0.56 F | 0.56 M | Females: perivascular/peribronchiolar inflammatory cell infiltration; sneezing Males: bronchiolar epithelial ulceration/thinning and perivascular/peribronchiolar inflammatory cell infiltration; sneezing |\n| 29 | Rat (Wistar) 18 M, 18 F | 30 weeks 5 days/week 6 hours/day (WB) | 0, 0.06, 0.14, 0.56 | LE, CS, BW, FI, WI, HE, BC, UR, GN, OW, HP | Cardio Gastro Hematoma | 0.56 0.56 F 0.06 M | 0.56 F 0.14 M |  | Decreased lymphocyte counts Increased red blood cell counts, hemoglobin, hematocrit, and neutrophil counts; decreased lymphocyte percentage |\n| 29 | Rat (Wistar) 18 M, 18 F | 30 weeks 5 days/week 6 hours/day (WB) | 0, 0.06, 0.14, 0.56 | LE, CS, BW, FI, WI, HE, BC, UR, GN, OW, HP | Musc/skel Hepatic Renal Dermal Ocular Endocr Immuno Neuro Repro | 0.56 0.56 0.56 0.56 0.56 0.56 |  |  |  |\n\n---\n\n**Table 2-1. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation\n(ppm)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n|  |  |  |  |  | Other noncancer | 0.56 |  |  |  |\n| NTP 1994 |  |  |  |  |  |  |  |  |  |\n| 30 | Rat (Fischer-344) 10 M, 10 F | 13 weeks 5 days/week 6 hours/day (WB) | 0, 0.039, 0.146, 0.385, 0.941, 2.065 | LE, CS, BW, HE, BC, GN, OW, HP | Death Bd wt Resp | 0.385 0.385 F 0.146b M | 0.385 M | 0.941 | 100% mortality during first 4 weeks |\n|  |  |  |  |  |  |  |  |  | Nasal squamous metaplasia and suppurative inflammation; suppurative and necrotizing inflammation of the bronchus/bronchiole; increased absolute and relative lung weights |\n|  |  |  |  |  |  |  |  | 0.941 | Increased respiration rate and mouth breathing; suppurative inflammation and hemorrhaging in the alveolus; necrotizing inflammation of the nose, larynx, trachea, and bronchus/bronchiole |\n|  |  |  |  |  | Cardio Gastro Hemato | 0.385 0.385 0.146 | 0.385 |  |  |\n|  |  |  |  |  | Musc/skel | 0.385 |  |  | Males: increased packed cell volume, hemoglobin, red blood cell count, and MCHC |\n|  |  |  |  |  | Hepatic | 0.385 |  |  |  |\n|  |  |  |  |  | Renal | 0.385 |  |  |  |\n|  |  |  |  |  | Endocr | 0.385 |  |  |  |\n|  |  |  |  |  | Immuno | 0.385 |  |  |  |\n|  |  |  |  |  | Neuro | 0.385 |  |  |  |\n|  |  |  |  |  | Repro | 0.385 |  |  |  |\n\n***DRAFT FOR PUBLIC COMMENT***\n\n---\n\n**Table 2-1. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation\n(ppm)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| NTP 1994 |  |  |  |  |  |  |  |  |  |\n| 31 | Rat (Fischer-344) 20 M, 20 F | 13 weeks 5 days/week 6 hours/day (WB) | 0, 0.039, 0.385, 2.065 | LE, HE, BC, UR | Death Hemato | 0.039 | 0.385 | 2.065 | 100% mortality Males: increased MCV; Females: increased MCV, packed cell volume, hemoglobin, and red blood cell count Increased AST |\n| 31 | Rat (Fischer-344) 20 M, 20 F | 13 weeks 5 days/week 6 hours/day (WB) | 0, 0.039, 0.385, 2.065 | LE, HE, BC, UR | Hepatic Renal | 0.385 2.065 | 2.065 | 2.065 | 100% mortality Males: increased MCV; Females: increased MCV, packed cell volume, hemoglobin, and red blood cell count Increased AST |\n| NTP 1994 |  |  |  |  |  |  |  |  |  |\n| 32 | Mouse (B6C3F1) 10 M | 42 weeks 5 days/week 6 hours/day (WB) | 0, 0.5 | LE, CS, BW, GN, OW, HP | Death Bd wt |  |  | 0.5 | 14% decreased survival at 45 weeks Decreased body weight (19%) and body weight gain (42%) at the end of the exposure period Suppurative inflammation of the nose, trachea, and lungs |\n| 32 | Mouse (B6C3F1) 10 M | 42 weeks 5 days/week 6 hours/day (WB) | 0, 0.5 | LE, CS, BW, GN, OW, HP | Resp |  | 0.5 | 0.5 | 14% decreased survival at 45 weeks Decreased body weight (19%) and body weight gain (42%) at the end of the exposure period Suppurative inflammation of the nose, trachea, and lungs |\n| 32 | Mouse (B6C3F1) 10 M | 42 weeks 5 days/week 6 hours/day (WB) | 0, 0.5 | LE, CS, BW, GN, OW, HP | Gastro Hepatic | 0.5 |  | 0.5 | 14% decreased survival at 45 weeks Decreased body weight (19%) and body weight gain (42%) at the end of the exposure period Suppurative inflammation of the nose, trachea, and lungs |\n| 32 | Mouse (B6C3F1) 10 M | 42 weeks 5 days/week 6 hours/day (WB) | 0, 0.5 | LE, CS, BW, GN, OW, HP | Renal | 0.5 |  | 0.5 | 14% decreased survival at 45 weeks Decreased body weight (19%) and body weight gain (42%) at the end of the exposure period Suppurative inflammation of the nose, trachea, and lungs |\n| 32 | Mouse (B6C3F1) 10 M | 42 weeks 5 days/week 6 hours/day (WB) | 0, 0.5 | LE, CS, BW, GN, OW, HP | Endocr Immuno | 0.5 |  | 0.5 | 14% decreased survival at 45 weeks Decreased body weight (19%) and body weight gain (42%) at the end of the exposure period Suppurative inflammation of the nose, trachea, and lungs |\n| 32 | Mouse (B6C3F1) 10 M | 42 weeks 5 days/week 6 hours/day (WB) | 0, 0.5 | LE, CS, BW, GN, OW, HP | Repro | 0.5 |  | 0.5 | 14% decreased survival at 45 weeks Decreased body weight (19%) and body weight gain (42%) at the end of the exposure period Suppurative inflammation of the nose, trachea, and lungs |\n| NTP 1994 |  |  |  |  |  |  |  |  |  |\n| 33 | Mouse (B6C3F1) 20 M, 20 F | 13 weeks 5 days/week 6 hours/day (WB) | 0, 0.039, 0.389, 2.142 | LE, HE, BC, UR | Death Hemato |  | 0.039 F 0.389 M | 2.142 | 100% mortality Increased MCHC Increased MCHC |\n| 33 | Mouse (B6C3F1) 20 M, 20 F | 13 weeks 5 days/week 6 hours/day (WB) | 0, 0.039, 0.389, 2.142 | LE, HE, BC, UR | Hepatic Renal | 0.039 M 2.142 2.142 | 0.039 F 0.389 M | 2.142 | 100% mortality Increased MCHC Increased MCHC |\n\n---\n\n**Table 2-1. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation\n(ppm)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| NTP 1994 |  |  |  |  |  |  |  |  |  |\n| 34 | Mouse (B6C3F1) 10 M | 26 weeks 5 days/week 6 hours/day (WB) | 0, 0.5 | LE, CS, BW, GN, OW, HP | Bd wt Resp | 0.5 | 0.5 |  | Nasal suppurative inflammation |\n| NTP 1994 |  |  |  |  |  |  |  |  |  |\n| 35 | Mouse (B6C3F1) 10 M | 33 weeks 5 days/week 6 hours/day (WB) | 0, 0.2 | LE, CS, BW, GN, OW, HP | Bd wt Resp Gastro Hepatic Renal Immuno Neuro Repro | 0.2 | 0.2 |  | Nasal suppurative inflammation |\n| NTP 1994 |  |  |  |  |  |  |  |  |  |\n| 36 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week 6 hours/day (WB) | 0, 0.039, 0.146, 0.389, 0.949, 2.142 | LE, CS, BW, HE, BC, OW, HP | Death |  |  | 0.949 F 0.389 M | 10/10 died 5/10 died |\n| 36 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week 6 hours/day (WB) | 0, 0.039, 0.146, 0.389, 0.949, 2.142 | LE, CS, BW, HE, BC, OW, HP | Bd wt Resp | 0.389 |  |  | Females: focal serous or suppurative inflammation of the nose Males: squamous metaplasia in the trachea, focal serous or suppurative inflammation of the nose |\n| 36 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week 6 hours/day (WB) | 0, 0.039, 0.146, 0.389, 0.949, 2.142 | LE, CS, BW, HE, BC, OW, HP | Cardio Gastro Hemato | 0.389 |  |  | Decreased MCV |\n| 36 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week 6 hours/day (WB) | 0, 0.039, 0.146, 0.389, 0.949, 2.142 | LE, CS, BW, HE, BC, OW, HP | Musc/skel | 0.389 |  |  |  |\n\n***DRAFT FOR PUBLIC COMMENT***\n\n---\n\n**Table 2-1. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation\n(ppm)**\n\n| Species Figure keya | Species (strain) No./group | Species Exposure parameters | Species Doses | Species Parameters monitored | Species Endpoint | Species NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n|  |  |  |  |  | Hepatic | 0.389 |  |  |  |\n|  |  |  |  |  | Renal | 0.389 |  |  |  |\n|  |  |  |  |  | Endocr | 0.389 |  |  |  |\n|  |  |  |  |  | Immuno | 0.389 |  |  |  |\n|  |  |  |  |  | Neuro | 0.389 |  |  |  |\n|  |  |  |  |  | Repro | 0.389 |  |  |  |\n| CHRONIC EXPOSURE |  |  |  |  |  |  |  |  |  |\n| NTP 1994 |  |  |  |  |  |  |  |  |  |\n| 37 | Rat (Fischer-344) 50 M, 50 F | 104 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, UR, GN, OW, HP | Bd wt | 0.2 |  |  |  |\n| 37 | Rat (Fischer-344) 50 M, 50 F | 104 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, UR, GN, OW, HP | Resp | 0.2 |  |  |  |\n| 37 | Rat (Fischer-344) 50 M, 50 F | 104 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, UR, GN, OW, HP | Cardio | 0.2 |  |  |  |\n| 37 | Rat (Fischer-344) 50 M, 50 F | 104 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, UR, GN, OW, HP | Gastro | 0.2 |  |  |  |\n| 37 | Rat (Fischer-344) 50 M, 50 F | 104 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, UR, GN, OW, HP | Hemat | 0.2 |  |  |  |\n| 37 | Rat (Fischer-344) 50 M, 50 F | 104 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, UR, GN, OW, HP | Musc/skel | 0.2 |  |  |  |\n| 37 | Rat (Fischer-344) 50 M, 50 F | 104 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, UR, GN, OW, HP | Hepatic | 0.2 |  |  |  |\n| 37 | Rat (Fischer-344) 50 M, 50 F | 104 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, UR, GN, OW, HP | Renal | 0.2 |  |  |  |\n| 37 | Rat (Fischer-344) 50 M, 50 F | 104 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, UR, GN, OW, HP | Dermal | 0.2 |  |  |  |\n| 37 | Rat (Fischer-344) 50 M, 50 F | 104 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, UR, GN, OW, HP | Endocr | 0.2 |  |  |  |\n| 37 | Rat (Fischer-344) 50 M, 50 F | 104 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, UR, GN, OW, HP | Immuno | 0.2 |  |  |  |\n| 37 | Rat (Fischer-344) 50 M, 50 F | 104 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, UR, GN, OW, HP | Neuro | 0.2 |  |  |  |\n| 37 | Rat (Fischer-344) 50 M, 50 F | 104 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, UR, GN, OW, HP | Repro | 0.2 |  |  |  |\n\n---\n\n**Table 2-1. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation\n(ppm)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| NTP 1994 |  |  |  |  |  |  |  |  |  |\n| 38 | Mouse (B6C3F1) 50 M, 50 F | 103 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, BW, GN, OW, HP | Death Bd wt Resp | 0.2 0.05c | 0.2 | 0.2 F | 57% mortality |\n| 38 | Mouse (B6C3F1) 50 M, 50 F | 103 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, BW, GN, OW, HP | Death Bd wt Resp | 0.2 0.05c | 0.2 | 0.2 F | Males: nasal suppurative inflammation, alveolar epithelium hyperplasia, and suppurative inflammation of the lung Females: nasal suppurative inflammation (BMCL10 for nasal suppurative inflammation in females = 0.0052 ppm)c |\n| 38 | Mouse (B6C3F1) 50 M, 50 F | 103 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, BW, GN, OW, HP | Cardio Gastro Hemat Muc/skel Hepatic Renal Dermal Endocr Immuno Neuro | 0.2 0.2 0.2 0.2 0.2 0.2 | 0.2 | 0.2 F | Males: nasal suppurative inflammation, alveolar epithelium hyperplasia, and suppurative inflammation of the lung Females: nasal suppurative inflammation (BMCL10 for nasal suppurative inflammation in females = 0.0052 ppm)c |\n\n---\n\n**Table 2-1. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation\n(ppm)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n|  |  |  |  |  | Repro | 0.01 F | 0.05 F | 0.2 F | LOAEL: Suppurative inflammation of the ovaries SLOAEL: Severe ovarian suppurative inflammation (associated with increased lethality) |\n|  |  |  |  |  |  | 0.2 M |  |  |  |\n\n<sup>a</sup>The number corresponds to entries in Figure 2-2; differences in levels of health effects and cancer effects between male and females are not indicated in \nFigure 2-2. Where such differences exist, only the levels of effect for the most sensitive sex are presented.\n\n$$\n1\\times10^{-4}\n$$\n\n<sup>b</sup>Used to derive a provisional intermediate-duration inhalation MRL of 1x10<sup>-4</sup> ppm based on a NOAEL of 0.146 ppm, which was converted into a NOAELHEC of \n0.00344 ppm and divided by an uncertainty factor of 30 (10 for human variability and 3 for animal to human extrapolation after dosimetric adjustment).\n<sup>c</sup>Used to derive a provisional chronic-duration inhalation MRL of 6x10<sup>-5</sup> ppm based on a BMCL10 of 0.052 ppm, which was converted into a BMCLHEC of \n0.0019 ppm and divided by an uncertainty factor of 30 (10 for human variability and 3 for animal to human extrapolation after dosimetric adjustment).\n\nGreen shading indicates the study selected for derivation of provisional inhalation MRLs.\n\nAST = aspartate aminotransferase; BC = blood chemistry; Bd wt or BW = body weight; BMCL = benchmark concentration lower confidence limit; BMCL10 = 95% \nlower confidence limit on the benchmark concentration (subscripts denote benchmark response: i.e., 10 = concentration associated with 10% extra risk); \nCardio = cardiovascular; CS = clinical signs; Endocr = endocrine; F = female(s); FI = food intake; Gastro = gastrointestinal; GN = gross necropsy; \nHE = hematology; HEC = human equivalent concentration; Hemato = hematological; HP = histopathology; Immuno = immunological; LC50 = median lethal \nconcentration; LE = lethality; LOAEL = lowest-observed-adverse-effect level; M = male(s); MCHC = mean corpuscular hemoglobin concentration; MCV = mean \ncorpuscular volume; MRL = Minimal Risk Level; Musc/skeletal = muscular/skeletal; Neuro = neurological; NOAEL = no-observed-adverse-effect level; NS = not \nspecified; OF = organ function; OP = ophthalmology; OW = organ weight; Repro = reproductive; Resp = respiratory; SLOAEL = serious lowest-observed-adverseeffect level; UR = urinalysis; (WB) = whole body; WI = water intake\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation**\nAcute (≤14 days)\n\n**Figure 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation Acute (≤14 days) - Death**\n\n| Category | Animal - LD50/LC50 (ppm) | Animal - NOAEL (ppm) | Animal - LOAEL (ppm) | Animal - SLOAEL (ppm) |\n| --- | --- | --- | --- | --- |\n| 1R |  |  |  | 0.45 |\n| 2R | 3.4 |  |  |  |\n| 3R | 2.6 |  |  |  |\n| 4R |  |  |  | 170 |\n| 5R | 1.6 |  |  |  |\n| 6R |  |  |  | 2.8 |\n| 7R |  |  | 1.4 |  |\n| 8R |  |  |  | 3.2 |\n| 9R |  |  |  | 2.8 |\n| 10R |  |  |  | 1.0 |\n| 11R |  |  |  | 7.0 |\n| 12R |  |  |  | 75 |\n| 13M |  |  |  | 7.5 |\n| 14M |  |  |  | 75 |\n| 15M |  |  |  | 3.2 |\n| 16M |  |  |  | 1.4 |\n| 17M |  |  |  | 1.5 |\n| 18M |  |  |  | 3.2 |\n| 19M |  |  |  | 1.0 |\n| 20H |  |  |  | 75 |\n| 21H |  |  |  | 1.4 |\n| 22H |  |  |  | 1.0 |\n| 23H |  |  |  | 1.4 |\n| 24H |  |  |  | 1.5 |\n| 25H |  |  |  | 3.2 |\n| 26H |  |  |  | 3.2 |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation**\nAcute (≤14 days)\n\n| Category | Body Weight Animal - LD50/LC50 (ppm) | Body Weight Animal - NOAEL (ppm) | Body Weight Animal - LOAEL (ppm) | Body Weight Animal - SLOAEL (ppm) | Respiratory Animal - LD50/LC50 (ppm) | Respiratory Animal - NOAEL (ppm) | Respiratory Animal - LOAEL (ppm) | Respiratory Animal - SLOAEL (ppm) | Cardiovascular Animal - LD50/LC50 (ppm) | Cardiovascular Animal - NOAEL (ppm) | Cardiovascular Animal - LOAEL (ppm) | Cardiovascular Animal - SLOAEL (ppm) | Hematological Animal - LD50/LC50 (ppm) | Hematological Animal - NOAEL (ppm) | Hematological Animal - LOAEL (ppm) | Hematological Animal - SLOAEL (ppm) |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| 1R |  | 0.12 |  | 0.5 |  | 0.12 |  | 0.5 |  | 0.5 |  |  |  | 0.12 |  | 0.5 |\n| 2R |  | 1.8 |  | 2.6 |  |  |  | 1.8 |  |  |  |  |  |  |  |  |\n| 3R |  |  |  | 1.8 |  |  |  | 1.8 |  |  |  |  |  |  |  |  |\n| 5R |  | 0.26 |  | 1.4 |  |  |  |  |  |  |  |  |  |  |  |  |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation**\nAcute (≤14 days)\n\n**Figure 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation Acute (≤14 days)**\n\n| Category | Animal - NOAEL (ppm) | Animal - LOAEL (ppm) | Animal - SLOAEL (ppm) |\n| --- | --- | --- | --- |\n| Hepatic | 0.5 |  |  |\n| Renal | 0.45 |  |  |\n| Immunological | 0.5 |  |  |\n| Neuological | 0.4 | 1.4 | 5.5 |\n| Other Noncancer | 0.12 | 0.45 | 1.7 |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation**\nIntermediate (15–364 days)\n\n**Figure 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation Intermediate (15–364 days)**\n\n| Category | Death Animal - NOAEL (ppm) | Death Animal - LOAEL (ppm) | Death Animal - SLOAEL (ppm) | Body Weight Animal - NOAEL (ppm) | Body Weight Animal - LOAEL (ppm) | Body Weight Animal - SLOAEL (ppm) | Respiratory Animal - NOAEL (ppm) | Respiratory Animal - LOAEL (ppm) | Respiratory Animal - SLOAEL (ppm) |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| 29R |  |  | 0.6 | 0.5 |  |  | 0.15 |  | 0.6 |\n| 30R |  |  | 1.0 | 0.4 |  |  | 0.15 | 0.45 | 1.0 |\n| 31R |  |  | 2.3 |  |  |  |  |  |  |\n| 32M |  |  | 0.55 |  | 0.5 |  |  | 0.5 |  |\n| 33M |  |  | 2.6 |  |  |  |  |  |  |\n| 36M |  |  | 0.4 | 0.45 |  |  | 0.15 | 0.45 |  |\n| 27K |  |  |  | 0.2 |  |  | 0.2 |  |  |\n| 28R |  |  |  | 0.2 |  |  | 0.2 |  |  |\n| 34M |  |  |  | 0.55 |  |  |  | 0.5 |  |\n| 35M |  |  |  | 0.2 |  |  |  | 0.2 |  |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation**\nIntermediate (15–364 days)\n\n**Figure 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation Intermediate (15–364 days)**\n\n| Category | Cardiovascular Animal - NOAEL (ppm) | Cardiovascular Animal - LOAEL (ppm) | Cardiovascular Animal - SLOAEL (ppm) | Gastrointestinal Animal - NOAEL (ppm) | Gastrointestinal Animal - LOAEL (ppm) | Gastrointestinal Animal - SLOAEL (ppm) | Hematological Animal - NOAEL (ppm) | Hematological Animal - LOAEL (ppm) | Hematological Animal - SLOAEL (ppm) |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| 27K | 0.22 |  |  | 0.22 |  |  | 0.22 |  |  |\n| 28R | 0.22 |  |  | 0.22 |  |  | 0.22 |  |  |\n| 29R | 0.55 |  |  | 0.55 |  |  | 0.060 | 0.15 |  |\n| 30R | 0.44 |  |  | 0.44 |  |  | 0.17 | 0.44 |  |\n| 36M | 0.44 |  |  | 0.44 |  |  | 0.17 | 0.44 |  |\n| 32M |  |  |  | 0.50 |  |  |  |  |  |\n| 35M |  |  |  | 0.22 |  |  |  |  |  |\n| 31R |  |  |  |  |  |  | 0.040 | 0.44 |  |\n| 33M |  |  |  |  |  |  |  | 0.044 |  |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation**\nIntermediate (15–364 days)\n\n**Figure 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation Intermediate (15–364 days)**\n\n| Category | Musculoskeletal Animal - NOAEL (ppm) | Musculoskeletal Animal - LOAEL (ppm) | Musculoskeletal Animal - SLOAEL (ppm) | Hepatic Animal - NOAEL (ppm) | Hepatic Animal - LOAEL (ppm) | Hepatic Animal - SLOAEL (ppm) | Renal Animal - NOAEL (ppm) | Renal Animal - LOAEL (ppm) | Renal Animal - SLOAEL (ppm) |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| 27K | 0.22 |  |  | 0.20 |  |  | 0.20 |  |  |\n| 28R | 0.20 |  |  | 0.22 |  |  | 0.20 |  |  |\n| 29R | 0.55 |  |  | 0.60 |  |  | 0.55 |  |  |\n| 30R | 0.44 |  |  | 0.40 |  |  | 0.40 |  |  |\n| 36M | 0.44 |  |  | 0.44 |  |  | 0.44 |  |  |\n| 31R |  |  |  | 0.44 |  |  | 2.2 |  |  |\n| 31R |  |  |  |  |  | 2.4 |  |  |  |\n| 32M |  |  |  | 0.55 |  |  | 0.60 |  |  |\n| 33M |  |  |  | 2.4 |  |  | 2.4 |  |  |\n| 35M |  |  |  | 0.20 |  |  | 0.20 |  |  |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation**\nIntermediate (15–364 days)\n\n**Figure 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation Intermediate (15–364 days)**\n\n| Category | Animal - NOAEL (ppm) | Animal - LOAEL (ppm) | Animal - SLOAEL (ppm) |\n| --- | --- | --- | --- |\n| Dermal 29R | 0.55 |  |  |\n| Ocular 27K | 0.20 |  |  |\n| Ocular 28R | 0.20 |  |  |\n| Ocular 29R | 0.55 |  |  |\n| Endocrine 27K | 0.20 |  |  |\n| Endocrine 28R | 0.20 |  |  |\n| Endocrine 29R | 0.60 |  |  |\n| Endocrine 30R | 0.40 |  |  |\n| Endocrine 32M | 0.50 |  |  |\n| Endocrine 36M | 0.40 |  |  |\n| Immunological 27K | 0.20 |  |  |\n| Immunological 28R | 0.20 |  |  |\n| Immunological 29R | 0.60 |  |  |\n| Immunological 30R | 0.40 |  |  |\n| Immunological 32M | 0.55 |  |  |\n| Immunological 35M | 0.20 |  |  |\n| Immunological 36M | 0.40 |  |  |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation**\nIntermediate (15–364 days)\n\n**Figure 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation Intermediate (15–364 days)**\n\n| Category | Neuropsychological Animal - NOAEL (ppm) | Neuropsychological Animal - LOAEL (ppm) | Neuropsychological Animal - SLOAEL (ppm) | Reproductive Animal - NOAEL (ppm) | Reproductive Animal - LOAEL (ppm) | Reproductive Animal - SLOAEL (ppm) | Other Noncancer Animal - NOAEL (ppm) | Other Noncancer Animal - LOAEL (ppm) | Other Noncancer Animal - SLOAEL (ppm) |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| 27K | 0.22 |  |  | 0.22 |  |  | 0.22 |  |  |\n| 28R | 0.22 |  |  | 0.22 |  |  | 0.22 |  |  |\n| 29R | 0.55 |  |  | 0.55 |  |  | 0.55 |  |  |\n| 30R | 0.44 |  |  | 0.44 |  |  |  |  |  |\n| 35M | 0.22 |  |  | 0.22 |  |  |  |  |  |\n| 36M | 0.44 |  |  | 0.44 |  |  |  |  |  |\n| 32M |  |  |  | 0.55 |  |  |  |  |  |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation**\nChronic (≥365 days)\n\n**Figure 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation Chronic (≥365 days)**\n\n| Category | R-Rat Animal - NOAEL (ppm) | R-Rat Animal - LOAEL (ppm) | R-Rat Animal - SLOAEL (ppm) | M-Mouse Animal - NOAEL (ppm) | M-Mouse Animal - LOAEL (ppm) | M-Mouse Animal - SLOAEL (ppm) | M-Mouse MRL for effect other than cancer (ppm) |\n| --- | --- | --- | --- | --- | --- | --- | --- |\n| Death |  |  |  |  |  | 0.22 |  |\n| Body Weight |  |  |  | 0.22 |  |  |  |\n| Respiratory | 0.22 |  |  |  | 0.055 | 0.22 | 0.006 |\n| Cardiovascular | 0.22 |  |  | 0.22 |  |  |  |\n| Gastrointestinal |  |  |  | 0.22 |  |  |  |\n| unlabelled 1 |  |  |  | 0.22 |  |  |  |\n\n---\n\n2.  HEALTH EFFECTS\n\n**Figure 2-2.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation**\nChronic (≥365 days)\n\n| Category | R-Rat (ppm) | M-Mouse (ppm) |\n| --- | --- | --- |\n| Hematological | 0.22 | 0.22 |\n| Musculoskeletal | 0.22 | 0.22 |\n| Hepatic | 0.22 | 0.22 |\n| Renal | 0.22 | 0.22 |\n| Dermal | 0.22 | 0.22 |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation**\nChronic (≥365 days)\n\n**Figure 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation Chronic (≥365 days)**\n\n| Category | Endocrine Animal - NOAEL (ppm) | Endocrine Animal - LOAEL (ppm) | Endocrine Animal - SLOAEL (ppm) | Immunological Animal - NOAEL (ppm) | Immunological Animal - LOAEL (ppm) | Immunological Animal - SLOAEL (ppm) | Neuological Animal - NOAEL (ppm) | Neuological Animal - LOAEL (ppm) | Neuological Animal - SLOAEL (ppm) | Reproductive Animal - NOAEL (ppm) | Reproductive Animal - LOAEL (ppm) | Reproductive Animal - SLOAEL (ppm) |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| 37R | 0.23 |  |  | 0.23 |  |  | 0.23 |  |  | 0.23 |  |  |\n| 38M | 0.23 |  |  | 0.23 |  |  | 0.23 |  |  | 0.011 | 0.055 | 0.23 |\n\n---\n\n**Table 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Oral\n(mg/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| ACUTE EXPOSURE |  |  |  |  |  |  |  |  |  |\n| Gardner 1986a |  |  |  |  |  |  |  |  |  |\n| 1 | Rat (CFY) 5 M, 5 F | Once (GO) | 1,260, 1,600, 2,000 | LE, CS, BW, GN | Death |  |  | 1,300 F 1,500 M | LD50 LD50 |\n| 1 | Rat (CFY) 5 M, 5 F | Once (GO) | 1,260, 1,600, 2,000 | LE, CS, BW, GN | Resp Gastro Neuro |  | 1,260 | 1,260 | Decreased respiratory rate Diarrhea Abnormal gait, lethargy |\n| OxyChem 1972 |  |  |  |  |  |  |  |  |  |\n| 2 | Rat (Spartan) 25 M, 25 F | Once (GO) | 315, 500, 794, 1,250, 1,984 | LE | Death |  |  | 530 F 630 M | LD50 LD50 |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 3 | Rat 9–11 M | Once (GO) | 280, 340, 420, 520, 620, 940, 1,400 | LE, CS, GN | Death |  |  | 505 | LD50 |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 4 | Rat 10 F | Once (GO) | 280, 940, 1,400, 2,100 | LE, CS, GN | Death |  |  | 940 | 9/10 died |\n| Chernoff and Kavlock 1982, 1983; Gray and Kavlock 1984; Gray et al. 1986 |  |  |  |  |  |  |  |  |  |\n| 5 | Mouse (CD-1) 16 F | 5 days GDs 8–12 (GO) | 0, 45 | BW, DX | Bd wt Develop | 45 |  |  |  |\n\n$$\n\\mathsf{L}\\mathsf{D}_{50}\n$$\n\nOffspring evaluated through PND 250 for postnatal viability, growth, locomotor activity, female sexual development, and reproductive function\n\n---\n\n**Table 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Oral\n(mg/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Dean 1977 |  |  |  |  |  |  |  |  |  |\n| 6 | Mouse (CD-1) 5 M, 5 F | Once (GO) | 21.5, 46.4, 100, 215, 464, 1,000, 2,150 | LE, CS, BW | Death Resp Gastro | 1,000 215 F 464 M 464 | 464 F 1,000 M 1,000 | 679 2,150 | LD50 Decreased respiratory rate Diarrhea Diarrhea Decreased limb tone in animals that died LOAEL: Hypoactivity SLOAEL: Ataxia |\n| 6 | Mouse (CD-1) 5 M, 5 F | Once (GO) | 21.5, 46.4, 100, 215, 464, 1,000, 2,150 | LE, CS, BW | Musc/skel | 215 | 464 | 1,000 | LOAEL: Hypoactivity SLOAEL: Ataxia |\n| Murray et al. 1980 |  |  |  |  |  |  |  |  |  |\n| 7 | Mouse (CF-1) NS F | 10 days GDs 6–15 (GO) | 0, 5, 25, 75 | LE, CS, BW, FI, WI, RX, DX | Bd wt Develop Other noncancer | 75 75 75 |  |  |  |\n| Murray et al. 1980 |  |  |  |  |  |  |  |  |  |\n| 8 | Mouse (CF-1) 5 F | 10 days GDs 6–15 (GO) | 0, 25, 75, 250, 500 | LE, CS, BW | Death |  |  | 250 | 3/5 dams died |\n| Murray et al. 1980 |  |  |  |  |  |  |  |  |  |\n| 9 | Rabbit (New Zealand) NS F | 13 days GDs 6–18 (GO) | 0, 5, 25, 75 | LE, CS, BW, RX, DX | Death Develop | 25 | 75 | 75 | Unspecified increased maternal death during pregnancy Increased proportion of fetuses with 13 ribs |\n| Murray et al. 1980 |  |  |  |  |  |  |  |  |  |\n| 10 | Rabbit (New Zealand) 5 F | 13 days GDs 6–18 (GO) | 0, 25, 75, 250, 500 | LE, CS, BW | Death |  |  | 250 | 4/5 does die |\n\n---\n\n**Table 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Oral\n(mg/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 11 | Rabbit 3 F | Once (GO) | 180, 280, 420, 620, 940 | LE, CS, GN | Death |  |  | 940 | 3/3 died |\n| INTERMEDIATE EXPOSURE |  |  |  |  |  |  |  |  |  |\n| Abdo et al. 1984; Velsicol 1981b |  |  |  |  |  |  |  |  |  |\n| 12 | Rat (Fischer-344) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 10, 19, 38, 75, 150 | LE, BW, GN, OW, HP | Death Bd wt | 38 F | 75 F | 150 M | 60% treatment-related mortality 15% decreased terminal body weight LOAEL: 13% decreased terminal body weight SLOAEL: 30% decreased terminal body weight Forestomach epithelial hyperplasia and focal inflammation (BMDL10 for combined incidence of forestomach lesions = 7.7 mg/kg/day)b |\n| 12 | Rat (Fischer-344) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 10, 19, 38, 75, 150 | LE, BW, GN, OW, HP | Resp Cardio Gastro | 150 150 19b | 38 |  |  |\n| 12 | Rat (Fischer-344) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 10, 19, 38, 75, 150 | LE, BW, GN, OW, HP | Hemato Musc/skel | 150 150 150 Renal | 38 |  | Toxic nephrosis |\n| 12 | Rat (Fischer-344) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 10, 19, 38, 75, 150 | LE, BW, GN, OW, HP | Dermal | 150 |  |  |  |\n| 12 | Rat (Fischer-344) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 10, 19, 38, 75, 150 | LE, BW, GN, OW, HP | Endocr | 150 |  |  |  |\n| 12 | Rat (Fischer-344) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 10, 19, 38, 75, 150 | LE, BW, GN, OW, HP | Immuno | 150 |  |  |  |\n| 12 | Rat (Fischer-344) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 10, 19, 38, 75, 150 | LE, BW, GN, OW, HP | Neuro | 150 |  |  |  |\n| 12 | Rat (Fischer-344) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 10, 19, 38, 75, 150 | LE, BW, GN, OW, HP | Repro | 150 |  |  |  |\n\n---\n\n**Table 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Oral\n(mg/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Abdo et al. 1984; Velsicol 1981a |  |  |  |  |  |  |  |  |  |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP | Death |  |  | 300 | 10/10 males died, 3/10 females died 11% decreased terminal body weight 13% decreased terminal body weight |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP | Bd wt | 75 M | 150 F | 300 | 10/10 males died, 3/10 females died 11% decreased terminal body weight 13% decreased terminal body weight |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP |  | 150 F | 300 F | 300 | 10/10 males died, 3/10 females died 11% decreased terminal body weight 13% decreased terminal body weight |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP | Resp | 300 |  |  |  |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP | Cardio | 300 |  |  |  |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP | Gastro | 38 | 75 |  | Focal inflammation and epithelial hyperplasia of the forestomach |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP | Hemato | 300 |  |  |  |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP | Musc/skel | 300 |  |  |  |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP | Hepatic | 300 |  |  |  |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP | Renal | 38 F | 75 F |  | Toxic nephrosis |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP |  | 150 M | 300 M |  | Acute tubular necrosis |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP | Dermal | 300 |  |  |  |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP | Endocr | 300 |  |  |  |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP | Immuno | 300 |  |  |  |\n\n---\n\n**Table 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Oral\n(mg/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n|  |  |  |  |  | Neuro Repro | 300 300 |  |  |  |\n\n<sup>a</sup>The number corresponds to entries in Figure 2-3; differences in levels of health effects between male and females are not indicated in Figure 2-3.  Where such \ndifferences exist, only the levels of effect for the most sensitive sex are presented.\n\n<sup>b</sup>Used to derive a provisional intermediate-duration oral MRL of 0.06 mg/kg/day based on a BMDL10 of 7.7 mg/kg/day, which was adjusted to continuous duration \nexposure to a BMDLADJ of 5.5 mg/kg/day and divided by an uncertainty factor of 100 (10 for human variability and 10 for animal to human extrapolation).  See \nAppendix A for more detailed information regarding the MRL.\n\nGreen shading indicates the study selected for derivation of the provisional oral MRL.\n\nADJ = adjusted; Bd wt or BW = body weight; BMDL = benchmark dose lower confidence limit; BMDL10 = 95% benchmark dose lower confidence limit (subscript \ndenotes benchmark response: i.e., 10 = dose associated with 10% extra risk); Cardio = cardiovascular; CS = clinical signs; Develop = developmental; \nDX = developmental toxicity; Endocr = endocrine; F = female(s); FI = food intake; Gastro = gastrointestinal; GD = gestation day; GN = gross necropsy; \n(GO) = gavage in oil; Hemato = hematological; HP = histopathology; Immuno = immunological; LD50 = median lethal dose; LE = lethality; LOAEL = lowestobserved-adverse-effect level; M = male(s); MRL = Minimal Risk Level; Musc/skeletal = muscular/skeletal; Neuro = neurological; NOAEL = no-observed-adverseeffect level; NS = not specified; OW = organ weight; PND = postnatal day; Repro = reproductive; Resp = respiratory; RX = reproductive function; \nSLOAEL = serious lowest-observed-adverse-effect level; WI = water intake\n\n---\n\n**Figure 2-3.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Oral**\nAcute (≤14 days)\n\n| Category | Animal - LD50/LC50 (mg/kg/day) | Animal - NOAEL (mg/kg/day) | Animal - LOAEL (mg/kg/day) | Animal - SLOAEL (mg/kg/day) |\n| --- | --- | --- | --- | --- |\n| 1R | 1300 |  |  |  |\n| 2R | 530 |  |  |  |\n| 3R | 500 |  |  |  |\n| 4R |  |  |  | 950 |\n| 6M | 660 |  |  |  |\n| 8M |  |  |  | 300 |\n| 9H |  |  |  | 75 |\n| 10H |  |  |  | 280 |\n| 11H |  |  |  | 950 |\n| 5M |  | 50 |  |  |\n| 7M |  | 80 |  |  |\n| 1R |  |  |  | 1200 |\n| 6M |  | 1000 |  | 2400 |\n\n---\n\n**Figure 2-3.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Oral**\nAcute (≤14 days)\n\n| Category | R-Rat (mg/kg/day) | M-Mouse (mg/kg/day) | H-Rabbit (mg/kg/day) |\n| --- | --- | --- | --- |\n| Animal - LD50/LC50 |  |  |  |\n| Animal - NOAEL |  | 130 |  |\n| Animal - LOAEL |  |  | 1300 |\n| Animal - SLOAEL |  |  | 1000 |\n\n---\n\n**Figure 2-3.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Oral**\nIntermediate (15–364 days)\n\n| Category | R-Rat Animal - NOAEL (mg/kg/day) | R-Rat Animal - LOAEL (mg/kg/day) | R-Rat Animal - SLOAEL (mg/kg/day) | M-Mouse Animal - NOAEL (mg/kg/day) | M-Mouse Animal - LOAEL (mg/kg/day) | M-Mouse Animal - SLOAEL (mg/kg/day) |\n| --- | --- | --- | --- | --- | --- | --- |\n| Death |  |  |  |  |  |  |\n| 12R |  |  | 150 |  |  |  |\n| 13M |  |  | 330 |  |  |  |\n| Body Weight |  |  |  |  |  |  |\n| 12R | 20 |  |  |  |  |  |\n| 12R |  | 40 |  |  |  |  |\n| 12R |  |  | 75 |  |  |  |\n| 13M |  | 80 |  |  |  |  |\n| 13M |  |  | 150 |  |  |  |\n| 13M |  |  | 160 |  |  |  |\n| Respiratory |  |  |  |  |  |  |\n| 12R | 160 |  |  |  |  |  |\n| 13M | 330 |  |  |  |  |  |\n| Cardiovascular |  |  |  |  |  |  |\n| 12R | 150 |  |  |  |  |  |\n| 13M | 330 |  |  |  |  |  |\n| Gastrointestinal |  |  |  |  |  |  |\n| 12R BMDL | 8.0 |  |  |  |  |  |\n| 12R | 20 |  |  |  |  |  |\n| 12R |  | 44 |  |  |  |  |\n| 13M | 40 |  |  |  |  |  |\n| 13M |  |  | 80 |  |  |  |\n\n---\n\n**Figure 2-3.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Oral**\nIntermediate (15–364 days)\n\n| Category | R-Rat Animal - NOAEL (mg/kg/day) | R-Rat Animal - LOAEL (mg/kg/day) | R-Rat Animal - SLOAEL (mg/kg/day) | M-Mouse Animal - NOAEL (mg/kg/day) | M-Mouse Animal - LOAEL (mg/kg/day) | M-Mouse Animal - SLOAEL (mg/kg/day) |\n| --- | --- | --- | --- | --- | --- | --- |\n| Hematological | 150 |  |  | 330 |  |  |\n| Musculoskeletal |  |  |  | 150 |  |  |\n| Hepatic |  |  |  | 150 |  |  |\n| Renal | 20 | 44 |  | 36 |  | 80 |\n| Dermal |  |  |  | 150 |  | 330 |\n\n---\n\n**Figure 2-3.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Oral**\nIntermediate (15–364 days)\n\n**Figure 2-3. Levels of Significant Exposure to Hexachlorocyclopentadiene – Oral Intermediate (15–364 days)**\n\n| Category | Animal - NOAEL (mg/kg/day) | Animal - LOAEL (mg/kg/day) | Animal - SLOAEL (mg/kg/day) |\n| --- | --- | --- | --- |\n| Endocrine 12R | 160 |  |  |\n| Endocrine 13M | 330 |  |  |\n| Immunological 12R | 160 |  |  |\n| Immunological 13M | 330 |  |  |\n| Neuological 12R | 160 |  |  |\n| Neuological 13M | 330 |  |  |\n| Reproductive 12R | 160 |  |  |\n| Reproductive 13M | 330 |  |  |\n\n---\n\n**Table 2-3. Levels of Significant Exposure to Hexachlorocyclopentadiene – Dermal**\n\n| Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| ACUTE EXPOSURE |  |  |  |  |  |  |  |  |\n| Kominsky et al. 1980 |  |  |  |  |  |  |  |  |\n| Human 154 M, 23 F | 3–15 days | ≤0.97 ppm | CS, BC | Dermal Ocular |  | 0.97 0.97 |  | Skin irritation Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Monkey 1 NS | Once | 0.001, 0.01, 0.1, 1, 10% (0.01 mL); 20, 40, 60, 90% (0.05 mL) | CS | Dermal | 10 | 20 |  | Skin discoloration and swelling |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Monkey 1 NS | 3 days Once/day | 10% | CS | Dermal |  |  | 10 | Skin irritation, necrosis, hemorrhaging |\n| Alexander et al. 1980a; Rand et al. 1982a |  |  |  |  |  |  |  |  |\n| Rat (Sprague-Dawley) 10 M, 10 F | 1–2 weeks 5 days/week 6 hours/day | 0, 0.022, 0.11, 0.5 ppm | CS | Ocular | 0.11 | 0.5 |  | Dark red eyes |\n| Gardner 1986b |  |  |  |  |  |  |  |  |\n| Rat (CFY) 5 M, 5 F | 24 hours | 1,600, 2,000, 3,200 mg/kg | LE, CS, BW, GN | Death |  |  | 3,100 F 2,600 M | LD50 LD50 |\n| Rat (CFY) 5 M, 5 F | 24 hours | 1,600, 2,000, 3,200 mg/kg | LE, CS, BW, GN | Dermal |  | 1,600 |  | Moderate to severe edema |\n| Jackson and Hardy 1986 |  |  |  |  |  |  |  |  |\n| Rat (Wistar) 5 M, 5 F | 1 hour | 0, 1.67, 2.38, 3.53, 6.25, 8.30 ppm | CS | Ocular |  | 1.67 |  | Total or partial closing of the eyes |\n| Jackson and Hardy 1987 |  |  |  |  |  |  |  |  |\n| Rat (Wistar) 5 M, 5 F | 4 hours | 0, 1.68, 1.83, 3.31, 3.47 ppm | CS | Ocular |  | 1.68 |  | Total or partial closing of the eyes |\n| Rand et al. 1982a |  |  |  |  |  |  |  |  |\n| Rat (Sprague-Dawley) 10 M, 10 F | 4 hours | 0.28, 1.4, 2.5, 3.1, 3.3, 3.4, 4, 5.8 ppm | CS | Ocular | 4 | 5.8 |  | Lacrimation |\n\n$$\n\\mathsf{L}\\mathsf{D}_{50}\n$$\n\n$$\n\\mathsf{L}\\mathsf{D}_{50}\n$$\n\n---\n\n**Table 2-3. Levels of Significant Exposure to Hexachlorocyclopentadiene – Dermal**\n\n| Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rat 4 NS | 5 days 7 hours/day | 0.33, 1, 1.6 ppm | CS | Ocular |  | 0.33 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rat 4 NS | 3 days 7 hours/day | 1.4 ppm | CS | Ocular |  | 1.4 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rat 4 NS | 4 hours | 73.6 ppm | CS | Ocular |  | 73.6 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rat 4 NS | 7 hours | 1.5, 3.2, 6.7 ppm | CS | Ocular |  | 1.5 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rat 4 NS | 2.6–3.6 hours | 1.4, 3.1, 7.1, 11.1, 12.7, 46.5, 56.9, 70.4 ppm | CS | Ocular |  | 1.4 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rat 3–4 NS | 0.25–1.25 hours | 1.4, 1.5, 3.1, 7.2, 13.0, 13.8, 19.4, 20.0, 20.2, 69.1, 69.2 ppm | CS | Ocular |  | 1.4 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rat 4 NS | 2 days 7 hours/day | 3.2 ppm | CS | Ocular |  | 3.2 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Mouse 4–5 NS | 0.25–1.25 hours | 1.4, 1.5, 3.1, 7.2, 13.0, 13.8, 19.4, 20.0, 20.2, 69.1, 69.2 ppm | CS | Ocular |  | 1.4 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Mouse 5 NS | 7 hours | 1.5, 3.2, 6.7 ppm | CS | Ocular |  | 1.5 |  | Eye irritation |\n\n---\n\n**Table 2-3. Levels of Significant Exposure to Hexachlorocyclopentadiene – Dermal**\n\n| Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Mouse 5 NS | 2.6–3.6 hours | 1.4, 3.1, 7.1, 12.4, 12.7, 46.5, 56.9, 70.4 ppm | CS | Ocular |  | 1.4 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Mouse 5 NS | 4 hours | 73.6 ppm | CS | Ocular |  | 73.6 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Mouse 5 NS | 2 days 7 hours/day | 3.2 ppm | CS | Ocular |  | 3.2 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Mouse 5 NS | 3 days 7 hours/day | 1.4 ppm | CS | Ocular |  | 1.4 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Mouse 5 NS | 5 days 7 hours/day | 0.33, 1.0, 1.6 ppm | CS | Ocular |  | 0.33 |  | Eye irritation |\n| OxyChem 1972 |  |  |  |  |  |  |  |  |\n| Rabbit (New Zealand) 3 M, 3 F | 4 hours | 0.5 mL | LE, CS | Death Dermal Neuro | 0.5 | 0.5 | 0.5 | 3/6 died Moderate to severe edema Ataxia and hypoactivity |\n| OxyChem 1972 |  |  |  |  |  |  |  |  |\n| Rabbit (New Zealand) 5 NS | 5 minutes | 0.1 mL | LE, CS | Death |  | 0.1 | 5/5 died within 9 days |  |\n| OxyChem 1972 |  |  |  |  |  |  |  |  |\n| Rabbit (New Zealand) 2 M, 2 F | Once | 200, 2,000 mg/kg | LE, CS, BW | Death |  | 200 M 2,000 F | 2/2 died within 14 days 2/2 died within 24 hours Dermal irritation and discoloration Hypoactivity |  |\n|  |  |  |  | Dermal Neuro | 200 200 M |  |  |  |\n\n---\n\n**Table 2-3. Levels of Significant Exposure to Hexachlorocyclopentadiene – Dermal**\n\n| Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| OxyChem 1972 |  |  |  |  |  |  |  |  |\n| Rabbit (New Zealand) 3 NS | 24 hours | 0.1 mL | LE, CS | Death Ocular |  |  | 0.1 0.1 | 3/3 died within 6 days Severe eye irritation and corrosion |\n| OxyChem 1992 |  |  |  |  |  |  |  |  |\n| Rabbit (New Zealand) 12 NS | 24 hours | 200 mg/kg | LE, CS | Death Dermal |  |  | 200 200 | 8/12 died Eschar formation |\n| OxyChem 1992 |  |  |  |  |  |  |  |  |\n| Rabbit (New Zealand) 6 NS | 4 hours | 0.5 mL | LE, CS | Dermal |  |  | 0.5 | Erythema, edema, necrosis |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rabbit 1–3 F | 24 hours | 430, 610, 1,020, 2,130, 6,130 mg/kg | LE, CS, GN | Death Dermal |  | 430 | 1020 | 2/3 died Skin irritation, discoloration, subcutaneous edema, acanthosis, epiulation, hyperkeratosis, chronic inflammation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rabbit 3 NS | 4 hours | 73.6 ppm | CS | Ocular |  | 73.6 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rabbit 3 NS | 2.6–3.6 hours | 1.4, 3.1, 7.1, 12.4, 12.7, 46.5, 56.9, 70.4 ppm | CS | Ocular |  | 1.4 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rabbit 3 NS | 7 hours | 1.5, 3.2, 6.7 ppm | CS | Ocular |  | 1.5 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rabbit 3 NS | 0.25–1.25 hours | 1.4, 1.5, 3.1, 7.2, 13.0, 13.8, 19.4, 20.0, 20.2, 69.1, 69.2 ppm | CS | Ocular |  | 1.4 |  | Eye irritation |\n\n---\n\n**Table 2-3. Levels of Significant Exposure to Hexachlorocyclopentadiene – Dermal**\n\n| Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rabbit 3 NS | 2 days 7 hours/day | 3.2 ppm | CS | Ocular |  | 3.2 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rabbit 3 NS | 3 days 7 hours/day | 1.4 ppm | CS | Ocular |  | 1.4 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rabbit 3 NS | 5 days 7 hours/day | 1, 1.6 ppm | CS | Ocular |  | 1 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Guinea pig 2 NS | Once | 0.01, 0.1, 1, 40, 60, 90% | CS | Dermal | 1 | 40 |  | Skin discoloration and irritation |\n| INTERMEDIATE EXPOSURE |  |  |  |  |  |  |  |  |\n| Alexander et al. 1980b; Rand et al. 1982a |  |  |  |  |  |  |  |  |\n| Monkey (Cynomolgus) 6 M, 6 F | 14 weeks 5 days/week 6 hours/day | 0, 0.01, 0.05, 0.2 ppm | CS | Ocular | 0.2 |  |  |  |\n| Alexander et al. 1980b; Rand et al. 1982a |  |  |  |  |  |  |  |  |\n| Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day | 0, 0.01, 0.05, 0.2 ppm | CS | Ocular | 0.01 | 0.05 |  | Dark red eyes |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rat 4 NS | 30 weeks 5 days/week 7 hours/day | 0.15 ppm | CS | Ocular | 0.15 |  |  |  |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rat 4 NS | 6 weeks 5 days/week 7 hours/day | 0.34 ppm | CS | Ocular |  | 0.34 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Mouse 5 NS | 30 weeks 5 days/week 7 hours/day | 0.15 ppm | CS | Ocular | 0.15 |  |  |  |\n\n***DRAFT FOR PUBLIC COMMENT***\n\n---\n\n**Table 2-3. Levels of Significant Exposure to Hexachlorocyclopentadiene – Dermal**\n\n| Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Mouse 5 NS | 6 weeks 5 days/week 7 hours/day (WB) | 0.34 ppm | CS | Ocular |  | 0.34 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rabbit 6 NS | 6 weeks 5 days/week 7 hours/day | 0.34 ppm | CS | Ocular |  | 0.34 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rabbit 2 NS | 30 weeks 5 days/week 7 hours/day | 0.15 ppm | CS | Ocular | 0.15 |  |  |  |\n\nBC = serum (blood) chemistry; BW = body weight; CS = clinical signs; F = female(s); GN = gross necropsy; LD50 = median lethal dose; LE = lethality; \nLOAEL = lowest-observed-adverse-effect level; M = male(s); Neuro = neurological; NOAEL = no-observed-adverse-effect level; NS = not specified; (WB) = wholebody exposure\n\n---\n\n###### 2.2 DEATH\n\nNo studies were located regarding mortality in humans after exposure to HCCPD.\n\nHCCPD induced death in experimental animals via the inhalation, oral, and dermal routes.  The lethality \nof HCCPD following inhalation exposures has been evaluated for acute-, intermediate-, and chronicduration studies.  Acute-duration inhalation exposures to HCCPD at 1.0–73.6 ppm were lethal to rats, \nmice, guinea pigs, and rabbits in a concentration- and exposure duration-related manner (Treon et al. \n1955).  For example, the concentrations that produced 50% fatalities in mice after 1-, 3.5-, and 7-hour \nexposures were 7.2, <3.1, and <1.5 ppm, respectively.  Species-specific differences were observed in the \nmortality data; the concentrations that produced 50% fatalities after 3.5-hour exposures were 7.1 ppm for \nguinea pigs, 3.1 ppm for rats, <3.1 ppm for mice, and <1.4 ppm for rabbits.  All 10 rats exposed to \n176 ppm HCCPD for 4 hours died within 48 hours of the exposure period (OxyChem 1972).  The 1- and \n4-hour inhalation LC50 values for rats are 3.69 ppm (Jackson and Hardy 1986) and 2.9 ppm (Jackson and \nHardy 1987), respectively.  Male rats appear to be more susceptible to HCCPD lethality than female rats; \nthe sex-specific 4-hour inhalation median lethal concentration (LC50) values are 1.6 ppm for males and \n3.5 ppm for females (Rand et al. 1982a).  With 2-week exposures to 0.5 ppm HCCPD, one rat of each sex \ndied, and nine male rats and one female rat were sacrificed in moribund condition by the end of the \nexposure period.  When the exposure duration was reduced to 5 days, three of five males and none of five\nfemales died at 0.5 ppm.  All animals exposed to ≤0.11 ppm survived until the scheduled sacrifice\n(Alexander et al. 1980a; Rand et al. 1982a).\n\n$$\n\\mathrm{LC}_{50}\n$$\n\n$$\n\\left(LC_{50}\\right)\n$$\n\nIn 13-week studies, all rats and mice exposed to ≥0.941 ppm HCCPD died during the exposure periods \n(NTP 1994).  As was observed after acute-duration inhalation exposures, mice appeared to be more \nsensitive to HCCPD-induced lethality; all mice exposed to 2.142 ppm died during the first week while \nrats exposed to 2.065 ppm survived for up to 3 weeks.  Additionally, no rat mortalities were observed at \n≤0.385 ppm, while 5 of 10 male mice died at 0.389 ppm.  NTP (1994) hypothesized that the sensitivity of \nmice to inhalation exposure was the result of HCCPD-induced inflammation of the breathing passages \nand the narrower diameter of the mouse air passages.  No treatment-related deaths were reported for rats \nor monkeys exposed to ≤0.2 ppm for 14 weeks (Alexander et al. 1980b; Rand et al. 1982a) and overall \nsurvival was not statistically significantly affected by HCCPD treatment in male mice exposed to 0.2 ppm \nfor 33 weeks or 0.5 ppm for 26 weeks (NTP 1994).  Although overall survival of male rats was not \naffected after exposure to 0.5 ppm for 42 weeks, survival in this group decreased 14% 3 weeks after \nexposure cessation (NTP 1994).  In a 30-week study, 22% of male rats exposed to 0.56 ppm died during\n\n$$\n\\leq0.385ppm\n$$ the exposure period (Clark 1981).  No mortality attributed to HCCPD was observed in rats exposed to \n0.06 or 0.14 ppm.\n\nSurvival of male and female rats and male mice chronically exposed to 0.01–0.2 ppm HCCPD for 2 years \nwas similar to controls.  Decreased survival was observed for female mice exposed to 0.2 ppm, but not at \nlower concentrations (NTP 1994).  Ovarian inflammation, possibly resulting from an infection, appeared \nto be the cause of premature deaths in female mice exposed to 0.2 ppm HCCPD.\n\nThe lethality of HCCPD in laboratory animals has been evaluated for acute- and intermediate-duration \noral exposures.  The oral median lethal dose (LD50) values were 505 mg/kg in male rats of an unspecified \nstrain (Treon et al. 1955), 630 and 530 mg/kg in male and female Spartan rats, respectively (OxyChem\n1972), and 1,500 and 1,300 mg/kg in male and female CFY rats, respectively (Gardner 1986a).  An oral\ndose of 940 mg/kg was lethal to ≥90% of the male and female rats (Treon et al. 1955).  Acute-duration \noral lethality data for species other than rats are more limited.  The oral LD50 value for male and female \nmice is 679 mg/kg (Dean 1977).  In rabbits, doses of 420, 620, and 940 mg/kg killed 0/3, 1/3, and \n3/3 animals, respectively (Treon et al. 1955).  In pregnant animals, several rabbits (exact number not \nidentified) did not survive 13 days of treatment with 75 mg/kg/day HCCPD on gestational days (GDs) 6–\n18 (Murray et al. 1980).  With intermediate-duration oral exposure, rats appeared to be more sensitive to \nHCCPD lethality than mice, a reverse of the sensitivity observed for inhalation exposures.  There were no \nmouse deaths following 13-week exposures to ≤150 mg/kg/day, but 6 of 10 male rat deaths at \n150 mg/kg/day were attributed to HCCPD treatment following 13 weeks of exposure (Abdo et al. 1984: \nVelsicol 1981a, 1981b).  All 10 male mice and 3 of 10 female mice died during the first 2 weeks of \nexposure to 300 mg/kg/day (Abdo et al. 1984; Velsicol 1981a).\n\n$$\n\\left(\\mathrm{LD}_{50}\\right)\n$$\n\n$$\n\\mathrm{LD}_{50}\n$$\n\n$$\n\\leqq150\n$$\n\nFor the dermal route, lethality of HCCPD in laboratory animals has only been evaluated for acuteduration exposures.  In rabbits administered topical applications of 200 mg/kg for 24 hours, deaths were \nreported in 2/2 males and 0/2 females (OxyChem 1972) and 8/12 rabbits of unspecified sex (OxyChem \n1992).  Dermal exposure to 2,000 mg/kg resulted in 100% mortality in male and female rabbits within \n24 hours (OxyChem 1972).  At lower doses, single dermal doses applied for 24 hours caused mortality in \n0/3, 1/3, and 2/3 rabbits at 430, 610, and 1,020 mg/kg, respectively (Treon et al. 1955).  In the multi-dose \nstudy by Treon et al. (1955), survival time was inversely proportional to the dose; rabbits survived 72, \n24–48, 20, and 17 hours after dermal dosing with 610, 1,020, 2,130, and 6,130 mg/kg, respectively.  None \nof the animals died with a dermal application of 430 mg/kg, although one rabbit was in poor condition \nand likely would have died had it not been sacrificed at 21 days.  In rats, the dermal LD50 values were\n\n$$\n\\mathrm{LD}_{50}\n$$\n\n---\n\n2,600 mg/kg in males and 3,100 mg/kg in females (Gardner 1986b).  These results suggest that rabbits are \nmore sensitive to HCCPD toxicity via the dermal route relative to rats.\n\nWhen 0.1 mL of HCCPD was instilled into the conjunctival sac of five rabbits for 5 minutes and then \nrinsed with water, the quantity of material absorbed was lethal to all the animals within 9 days (OxyChem\n1972).  When ocular rinsing was delayed until 24 hours post-instillation, all three rabbits administered\n0.1 mL of HCCPD died within 6 days.\n\n###### 2.3 BODY WEIGHT\n\nNo reports of body weight effects in humans after exposure to HCCPD were found.  The available data in \nlaboratory animals indicate that HCCPD produces body weight effects at sufficiently high inhalation and \noral exposure levels; no body weight data are available via the dermal route. In several of these studies, \nbody weight changes were associated with decreased food and/or water intake (see Section 2.18, Other \nNoncancer, for additional details).\n\nBody weight effects resulting from inhalation exposures to HCCPD have been assessed in acute-, \nintermediate-, and chronic-duration studies.  Inhalation exposures to sufficient HCCPD concentrations \nover acute and intermediate periods decrease body weights and/or suppress body weight gains.  A single \n1-hour exposure to HCCPD resulted in decreased body weights in rats during the 3-week post-exposure \nobservation period at concentrations ≥2.38 ppm; when animals that died prematurely and those sacrificed \nat the end of the observation period are combined, body weight decreases compared to control were 41% \nin males and 26% in females (Jackson and Hardy 1986).  A 4-hour exposure resulted in >20% decreases \nin body weight in male and female rats at ≥1.68 and 1.83 ppm, respectively, during the 4-week \nobservation period (Jackson and Hardy 1987).  In both studies by Jackson and Hardy (1986, 1987), body \nweight effects were associated with decreased food intake.  Similarly, after a 4-hour exposure to HCCPD, \nbody weight decreases of at least 25 and 17% relative to pre-exposure weights were observed for male \nand female rats, respectively, after exposures to 1.4–5.8 ppm; no food intake data were provided (Rand et \nal. 1982a).  With significantly decreased food intake, male and female rats exposed to 0.5 ppm HCCPD \nfor 1–2 weeks lost body weight; male body weights decreased 32% on day 10 and terminal female body \nweight decreased 29% (Alexander et al. 1980a; Rand et al. 1982a).\n\n$$\nt\\geqq1.68\n$$\n\nIn 13-week inhalation studies, terminal body weights remained within 10% of control values following \nexposure to HCCPD at concentrations up to 0.385 ppm in rats and 0.389 ppm in mice (NTP 1994).\n\n---\n\nSimilarly, no effects on body weight were observed in rats and monkeys exposed to ≤0.2 ppm HCCPD \nfor 14 weeks (Alexander et al. 1980b; Rand et al. 1982a).  Body weight decreased 19% and body weight \ngain decreased 42% in male mice exposed to 0.5 ppm for 42 weeks (NTP 1994).  No body weight deficits \nwere identified after exposure of male mice to 0.2 ppm for 33 weeks or to 0.5 ppm for 26 weeks (NTP \n1994).  Body weights remained within 10% of control values for male and female rats exposed to \n≤0.56 ppm for 30 weeks (Clark 1981), and in male and female mice and rats exposed to ≤0.2 ppm for \n2 years (NTP 1994).\n\nBody weight effects after oral exposure to HCCPD in experimental animals have been evaluated in acuteand intermediate-duration studies.  In intermediate-duration studies, sufficient oral dosing with HCCPD \ndecreased body weights and suppressed body weight gains.  Male and female rats and mice experienced \ndose-related decreased body weights and body weight gains when compared to controls after oral \nexposure to HCCPD for 13 weeks (Abdo et al. 1984; Velsicol 1981a, 1981b).  Male rats were affected \nmore than females, and rats were affected more than mice.  Terminal body weights in male rats decreased \n13–35% and overall body weight gains were reduced 21–58% at dose levels of ≥38 mg/kg/day. In female\nrats exposed to 75–150 mg/kg/day, terminal body weights were reduced 15–17% and overall body weight \ngains decreased 28–36%.  Terminal body weights in male mice were reduced 11% and overall body \nweight gains decreased 39% at 150 mg/kg/day.  In female mice, terminal body weights decreased 13% at \n300 mg/kg/day and overall body weight gains were reduced 22–44% at ≥150 mg/kg/day. Differences in \nterminal body weights and overall body weight gains were within 10% of control values for male rats at \n≤19 mg/kg/day, female rats at ≤38 mg/kg/day, and male and female mice at ≤75 mg/kg/day.  Maternal \nweight loss was observed in rabbits administered 75 mg/kg/day on GDs 6–18; the magnitude of weight \nloss was not reported (Murray et al. 1980).  No body weight effects were reported for rabbits dosed with \n≤25 mg/kg/day on GDs 6–18 or for mice dosed with ≤75 mg/kg/day on GDs 6–15.\n\n###### 2.4 RESPIRATORY\n\nThe data provide strong evidence that HCCPD produces portal-of-entry effects in the respiratory system \nfollowing inhalation exposures; no effects on the respiratory tract were observed following oral or dermal \nexposures to HCCPD.  Based upon systematic review (Appendix C), the respiratory system is a presumed \nhazard of HCCPD toxicity following inhalation exposure based on inadequate evidence in humans and a \nhigh level of evidence from laboratory animal studies.\n\n---\n\nThe available data on respiratory effects of HCCPD in humans are limited to reports of WWTP workers \nand cleanup crew members exposed to HCCPD for 3–15 days after an inadvertent industrial release of \nthis material into the sewage system (Kominsky et al. 1980; Morse et al. 1979).  Maximum atmospheric \nconcentrations for the treatment plant workers were unknown but were most likely >0.97 ppm, the \nmaximum concentration measured 4 days after compound identification (Morse et al. 1979).  The \nmaximum concentration recorded during cleanup was 19.2 ppm (Kominsky et al. 1980).  Symptoms of \ntracheobronchial irritation were reported by the treatment plant workers early in the exposure period.  \nThese symptoms were recounted by 39 of 145 (27%) employees who responded to a questionnaire shortly \nafter the exposure incident and by 16 of 177 (9%) employees who responded to a follow-up questionnaire \n6 weeks later (Morse et al. 1979).  Chest x-rays of 28 exposed workers were normal and tests of \npulmonary function were normal in a subset of 22 workers from this group (Kominsky et al. 1980).  \nMinor respiratory complaints included sore throat, cough, chest discomfort, and difficulty breathing.  \nThese effects were likely a consequence of the direct action of the HCCPD vapor on the mucous \nmembranes of the respiratory tract, rather than systemic effects due to exposure to HCCPD through the \nlungs.  One cleanup crew worker also reported respiratory difficulty when exposed for a few seconds to \n19.2 ppm HCCPD without protective equipment (Kominsky et al. 1980).  Chest discomfort persisted for \nseveral days in this individual.\n\nRespiratory effects induced by HCCPD in laboratory animals have been evaluated in acute-, \nintermediate-, and chronic-duration inhalation exposure studies.  Inhalation exposures to HCCPD \nproduced clinical signs of respiratory toxicity and/or irritation including abnormal respiratory pattern \n(irregular or exaggerated respiratory movements, fast or irregular respiration rate or pattern, rales and/or \nnoisy respiration, and/or gasping), labored respiration, sneezing, increased respiration rate, and/or mouth \nbreathing in rats exposed to 1.67 ppm for 1 hour (Jackson and Hardy 1986), 1.68 ppm for 4 hours \n(Jackson and Hardy 1987), 0.5 ppm for 1–2 weeks (Alexander et al. 1980a; Rand et al. 1982a), 0.56 ppm \nfor 30 weeks (Clark 1981), and ≥0.941 ppm for 13 weeks (NTP 1994).  No respiratory clinical signs were \nobserved in rats or monkeys exposed to 0.2 ppm for 14 weeks (Alexander et al. 1980b; Rand et al. \n1982a), mice exposed to ≤2.142 ppm for 13 weeks (NTP 1994), male mice exposed to 0.2 ppm for \n33 weeks or 0.5 ppm for 26 or 42 weeks (NTP 1994), or rats and mice exposed to ≤0.2 ppm for 2 years \n(NTP 1994).  Based on these data, it appears that rats are more susceptible to HCCPD-induced respiratory \nirritation effects than mice. Blood gas analysis, pulmonary ventilation, and lung mechanics were within \nnormal ranges in pulmonary function tests of monkeys exposed to ≤0.2 ppm HCCPD for 7 and 13 weeks \n(Alexander et al. 1980b; Rand et al. 1982a).\n\n---\n\nInhalation exposures to HCCPD vapor caused histopathological changes in the respiratory tracts of \nexperimental animals.  At nonlethal concentrations, these alterations were largely inflammatory or \nhyperplastic in nature, consistent with repetitive irritation at the portal of entry.  Inflammation of the \ntissues was followed by necrosis, exfoliation, and/or hemorrhage.  No histopathological examination was \nconducted, but gross necropsy of the lungs showed pale and swollen lungs in rats exposed to ≥1.68 ppm \nfor 4 hours; findings were associated with increased absolute and relative lung weights at ≥3.31 and \n1.83 ppm in male and female rats, respectively (Jackson and Hardy 1987).  Inflammation, hyperplasia, \nand epithelial erosion were identified in the lungs of rats exposed to HCCPD vapor at 0.5 ppm for 1–\n2 weeks; recovery was apparent 2 weeks after exposure ceased in surviving animals (Alexander et al. \n1980a; Rand et al. 1982a).  No histopathological changes were identified in respiratory tissues of rats\nexposed to ≤0.11 ppm in the same manner (Alexander et al. 1980a; Rand et al. 1982a) or in rats and \nmonkeys exposed to ≤0.2 ppm for 14 weeks (Alexander et al. 1980b; Rand et al. 1982a). Using electron \nmicroscopy, exposure-related increases in electron-lucent inclusions in club cells, formerly called Clara \ncells, were observed in rats exposed to 0.01–0.2 ppm for 14 weeks (Huntingdon Research Centre 1980; \nRand et al. 1982b); however, this findings is considered a biomarker of exposure rather than evidence of \ntoxicity due to the absence of histopathological findings or any other ultrastructural changes.  No \nexposure-related ultrastructural changes were observed in monkeys exposed to ≤0.2 ppm for 14 weeks\n(Rand et al. 1982b).  In a 30-week inhalation exposure study in rats, increased incidences of \nperivascular/peribronchiolar inflammatory cell infiltration were observed in males and females exposed to \n0.56 ppm; males exposed to this concentration also exhibited an increased incidence of bronchiolar \nepithelial thinning/ulceration (Clark 1981).  The incidences of bronchiolar epithelial hyperplasia, \nsloughing/loss, and edema also increased in male and female rats exposed to 0.56 ppm but did not reach \nstatistical significance.  Following a 14-week recovery period, no histopathological differences were \nidentified in the lungs of control and treated rats, indicating reversibility of these lesions.\n\n$$\nt_{0}\\geqq1.68\n$$\n\nIn 13-week studies, microscopic effects in the respiratory system produced by lethal HCCPD \nconcentrations included necrotizing inflammation of the nose, larynx, trachea, and bronchus/bronchiole \nand hemorrhaging of the alveolus in male and female rats exposed to 0.941–2.065 ppm; suppurative \ninflammation of the alveolus in male and female rats at 0.941 ppm; acute necrosis of the nose, larynx, \ntrachea, and lung epithelium and lung congestion in male and female mice at 2.142 ppm; tracheal \nsquamous metaplasia in male and female mice at 0.949 ppm; and suppurative inflammation of the nasal \nepithelium of male and female mice exposed to 0.949–2.142 ppm (NTP 1994).  Increased incidences of \nsuppurative inflammation and squamous metaplasia in the nose and necrotizing and suppurative \ninflammation of the bronchus/bronchiole were identified in male rats exposed to 0.385 ppm, increased incidences of nasal suppurative inflammation and tracheal squamous metaplasia were observed in male \nmice exposed to 0.389 ppm, and an increased incidence of nasal serous inflammation was present in \nfemale mice exposed to 0.389 ppm.  No statistically significant increases were identified for nonneoplastic lesions in the respiratory tract tissues of female rats exposed to ≤0.385 ppm, male rats exposed \nto 0.146 ppm, or male or female mice exposed to ≤0.146 ppm (NTP 1994).\n\nHistopathological findings in male and female mice exposed to 0.2 ppm for 2 years included nasal \nsuppurative inflammation characterized by accumulation of cellular debris, mucus, neutrophils, and fibrin \nin the nasal lumen and infiltration of mononuclear cells and neutrophils into the lamina propria (NTP \n1994).  After 2-year exposures, an increased incidence of squamous metaplasia of the larynx (minimal \nseverity) was identified in female rats at 0.01 and 0.2 ppm; the incidence at 0.05 ppm was also elevated \nbut was not statistically significantly different from the concurrent control incidence.  No treatmentrelated respiratory tract lesions were identified in male rats.  The toxicological relevance of the squamous \nmetaplasia was not clear to the NTP (1994) authors due to difficulties in obtaining consistent sections for \nanalysis and determination of the boundary between squamous and columnar epithelium.  Due to this, as \nwell as the lack of clear dose-response, a LOAEL determination for squamous metaplasia was not \nincluded in Table 2-1.\n\nTo examine the progression and permanence of non-neoplastic lesions in the respiratory tract, NTP \n(1994) conducted additional studies in male mice with the intent of evaluating the relative effects of \nconcentration and duration on development of these lesions.  In these studies, concentrations were 0 or \n0.2 ppm for 33 weeks and 0 or 0.5 ppm for 26 or 42 weeks.  Animals were sacrificed at interim \nevaluations after 27, 34, or 43 weeks or 15 months of exposure or were sacrificed after 2 years.  At the \nend of the exposure periods, the incidence of nasal suppurative inflammation increased in all treatment \ngroups and suppurative inflammation of the trachea and lungs and alveolar epithelial hyperplasia \nincreased in animals exposed to 0.5 ppm for 42 weeks.  The incidence of alveolar epithelial hyperplasia \nalso increased in male mice exposed to 0.5 ppm for 42 weeks.  An evaluation of the data indicated that \nboth concentration and duration of exposure influenced the development of these respiratory tract lesions; \nthe inflammation of the trachea and lungs was not observed unless the product of the concentration and \nduration was >20 or 21 ppm-weeks.\n\nIn the chronic-duration studies of rats and mice exposed to HCCPD for 2 years, accumulation of a \ngranular yellow-brown pigment was observed in the nasal epithelium in male and female rats and mice at \n≥0.01 ppm, tracheal epithelium of male and female mice at ≥0.01 ppm, bronchiole epithelium of female\n\n$$\n\\geqq0.01\n$$ rats at ≥0.01 ppm, and lung epithelium of male and female mice ≥0.05 ppm (NTP 1994).  At 0.2 ppm, \nminimal-to-mild tracheal, bronchiole, and peribronchiole pigmentation was observed in male rats and \nperibronchiole pigmentation was identified in female rats (NTP 1994).  The pigmentation incidence and \nseverity generally increased with concentration for each sex-species combination.  In male mice exposed \nto 0.2 ppm for 33 weeks or 0.5 ppm for 26 or 42 weeks and then maintained for up to 2 years, \npigmentation of the respiratory tract (nose, trachea, and/or lungs) was seen in the majority of exposed \nanimals and did not disappear following exposure cessation and evaluation at 2 years, indicating a lack of \nrecovery and physiological turnover of the pigment material.  The incidence and severity were similar \nafter 33, 66, and 104 weeks of exposure to 0.2 ppm HCCPD.  In the chronic-duration and additional \nstudies in male mice exposed to 0.2 ppm for 33 weeks and 0.5 ppm for 26 or 42 weeks, the pigmentation \ndid not co-occur with respiratory lesions and did not appear to be a precursor to more significant effects \n(i.e., did not indicate an initial phase in the progression of a disease state).  Results of several staining \nprocedures applied to the pigmented lung sections of rats and mice indicated the presence of reducing \nsubstances, but no further analytical identification was performed.  NTP (1994) indicated that the \npigmentation may be a unique response to HCCPD and could be due to lipid peroxidation.  Based on \nthese data, ATSDR concludes that it is more appropriate to characterize the pigmentation as a marker of \nexposure to HCCPD rather than an adverse effect attributable to HCCPD exposure.\n\nThe potential for oral exposure to HCCPD to induce respiratory effects has been evaluated in acute- and \nintermediate-duration studies.  In rats and mice administered lethal gavage doses of HCCPD, decreased \nrespiratory rates were observed prior to death (Dean 1977; Gardner 1986a); this clinical sign was likely a \nconsequence of significant morbidity prior to death rather than an effect of HCCPD on the respiratory \nsystem.  No gross or histopathological changes were identified in the nasal cavity, trachea, larynx, \nbronchi, or lungs of rats at doses ≤150 mg/kg/day or in mice at doses ≤300 mg/kg/day for 13 weeks \n(Abdo et al. 1984; Velsicol 1981a, 1981b).\n\nThe potential toxicological effects of HCCPD on the respiratory tract following dermal exposure were \nevaluated in one acute-duration dermal toxicity study.  A decreased rate of respiration was observed in \nrats administered topical doses ≥2,000 mg/kg for 24 hours (Gardner 1986b).  The animals appeared \nnormal 5–9 days after dosing and no gross pathological changes were identified in the lungs of animals \nthat survived to the scheduled sacrifice.\n\n---\n\n###### 2.5 CARDIOVASCULAR\n\nNo studies were located regarding cardiovascular effects in humans after exposure to HCCPD. Available\ndata from laboratory animals indicate that the cardiovascular system is not a sensitive toxicity target \nfollowing inhalation or oral exposure to HCCPD.\n\nThe cardiovascular system has been evaluated in experimental animals exposed to HCCPD via inhalation \nin acute-, intermediate-, and chronic-duration studies.  Diffuse degenerative changes were observed in the \nhearts of rats, mice, and rabbits that died following acute exposure to lethal concentrations of HCCPD \nranging from 0.3 to 66 ppm for 15 minutes to 2 weeks; incidence data were not provided, and findings \nwere potentially attributable to autolysis (Treon et al. 1955).  In another acute-duration study, there were \nno histopathological changes in the heart in rats exposed to concentrations up to 0.5 ppm after either 1 or \n2 weeks (Alexander et al. 1980a; Rand et al. 1982a).  In longer-term inhalation studies, there was no \nevidence for histopathological changes in the heart at intermediate-duration concentrations up to \n0.56 ppm in rats, 0.389 ppm in mice, or 0.2 ppm in monkeys (Alexander et al. 1980b; Clark 1981; NTP \n1994; Rand et al. 1982a) or chronic-duration concentrations up to 0.2 ppm in rats or mice (NTP 1994).\n\nPotential cardiovascular effects of HCCPD oral exposures in experimental animals were evaluated in \nacute- and intermediate-duration studies.  Single oral doses of 280–2,100 mg/kg caused degenerative \nchanges in the hearts of rats and rabbits, possibly due to tissue autolysis; incidence data were not provided\n(Treon et al. 1955).  In contrast, there were no gross or histopathological changes in the hearts of rats \nexposed to doses ≤150 mg/kg/day or mice exposed to doses ≤300 mg/kg/day for 13 weeks (Abdo et al. \n1984; Velsicol 1981a, 1981b).\n\nRabbits that died following single dermal doses of 610–6,130 mg/kg displayed degenerative changes in \nthe heart, possibly because of tissue autolysis; incidence data were not provided (Treon et al. 1955).\n\n###### 2.6 GASTROINTESTINAL\n\nThe data provide evidence that HCCPD produces portal-of-entry effects in the gastrointestinal system, \nspecifically the stomach, following oral exposures.  Data on adverse gastrointestinal effects following \ninhalation exposure are limited to clinical signs following accidental occupational exposure; no effects on \nthe gastrointestinal system were observed following dermal exposure to HCCPD.  Based upon systematic \nreview (Appendix C), the gastrointestinal system is a presumed hazard of HCCPD toxicity following oral exposure based on no route-specific data in humans and a high level of evidence from laboratory animal \nstudies.\n\nWWTP workers exposed to HCCPD for 3–15 days due to an inadvertent industrial release complained of \nnausea (22% of 177 workers) and abdominal cramps (prevalence not specified) (Kominsky et al. 1980; \nMorse et al. 1979).  One member of the cleanup crew who was exposed to 19.2 ppm for several seconds \nwithout protective equipment experienced nausea several minutes after the exposure (Kominsky et al. \n1980).  While classified as gastrointestinal in this profile, it is possible that nausea may be neurological in \norigin.\n\nGastrointestinal effects of HCCPD have been evaluated in laboratory animals following intermediate- and \nchronic-duration inhalation exposures.  No microscopic changes were seen in the stomach, esophagus, or \nintestines of monkeys, rats, or mice exposed to concentrations up to 0.2, 0.56, or 0.5 ppm, respectively, in\nintermediate-duration studies (Alexander et al. 1980b; Clark 1981; NTP 1994; Rand et al. 1982a), or rats \nor mice following chronic-duration exposure to concentrations up to 0.2 ppm (NTP 1994).  The \ngastrointestinal tract does not appear to be a sensitive target for HCCPD in animals following inhalation \nexposures.\n\nThe potential impact of HCCPD exposure on gastrointestinal tissues has been evaluated in acute- and \nintermediate-duration oral exposure studies in experimental animals.  Increased incidences of diarrhea \nwere observed in rats dosed with ≥1,260 mg/kg (Gardner 1986a) and female and male mice dosed with \n464 and 1,000 mg/kg, respectively (Dean 1977).  Acute necrotic lesions of the forestomach were noted in \nsome rats administered an oral dose of 280–2,100 mg/kg; incidence data were not provided (Treon et al. \n1955).  After 13-week exposures to HCCPD, increased incidences of forestomach epithelial hyperplasia \nwere observed in male and female rats at 38 mg/kg/day and male and female mice at 75 mg/kg/day (Abdo \net al. 1984; Velsicol 1981a, 1981b).  Increased incidences of focal inflammation in the forestomach were \nidentified in male and female rats at 38 mg/kg/day and male and female mice at 75 mg/kg/day.  The \nincidences and ranges of lesion severities were directly related to the dose.  No histopathological changes \nwere identified in the esophagus, duodenum, jejunum, ileum, or colon of males and females of either \nspecies.  These data suggest that rats are more sensitive to HCCPD-induced effects to the forestomach \nthan mice.  The presence of the forestomach lesions and lack of histopathological changes in other \nregions of the gastrointestinal tract suggests that the forestomach effects result from direct contact of \nthese tissues with HCCPD.\n\n---\n\n###### 2.7 HEMATOLOGICAL\n\nThe data indicate HCCPD may alter red blood cell hematology parameters following inhalation exposure \nwithout causing histopathological changes to bone marrow; no consistent effects were noted in white \nblood cell parameters following inhalation exposure and no effects on the hematological system were \nobserved in animals following oral exposures to HCCPD.  Data are not available via the dermal route.  \nBased upon systematic review (Appendix C), the hematological system, specifically red blood cell \nparameters, is a suspected hazard of HCCPD toxicity following inhalation exposure based on inadequate \ndata in humans and a moderate level of evidence from laboratory animal studies.  White blood cell effects \nare not classifiable as to the hazard to humans based on inadequate data in humans and animals.\n\nNo changes in blood counts were observed in workers exposed to HCCPD at a WWTP after an industrial \ndischarge of the material into the sewage system (Kominsky et al. 1980).\n\nThe potential hematological effects of HCCPD were evaluated in experimental animals exposed via \ninhalation after acute-, intermediate-, and chronic-duration exposures.  No effects on bone marrow \nhistopathology were reported in rats exposed to 0.5 ppm for 1–2 weeks (Alexander et al. 1980a; Rand et \nal. 1982a), rats and mice exposed to ≤0.385 and ≤0.389 ppm, respectively, for 13 weeks, or rats and mice \nexposed to ≤0.2 ppm for 2 years (Alexander et al. 1980b; NTP 1994; Rand et al. 1982a).  Across acuteand intermediate-duration multiple exposure studies, altered red blood cell hematology parameters were \nidentified in rats, particularly males, as seen in Table 2-4.\n\n**Table 2-4. LOAEL Values for Red Blood Cell Hematological Effects of Rats** \n**Exposed to HCCPD Vapor in Acute- and Intermediate-Duration Inhalation**\n**Studies**\n\n| Hematology parameter | Rand et al. 1982aa: 1–2 weeks | Rand et al. 1982aa: 1–2 weeks (recovery group) | NTP 1994: 13 weeks | NTP 1994: 13-week special hematology study | Clark 1981: 30 weeks |\n| --- | --- | --- | --- | --- | --- |\n| Males |  |  |  |  |  |\n| PCV | \\(\\uparrow (0.5^{{b}})\\) | ↔ | \\(\\uparrow (0.385)\\) | ↔ | - |\n| Hb | \\(\\uparrow (0.5)\\) | \\(\\uparrow (0.5)\\) | \\(\\uparrow (0.385)\\) | ↔ | \\(\\uparrow (0.14)\\) |\n| RBC | \\(\\uparrow (0.5)\\) | ↔ | \\(\\uparrow (0.385)\\) | ↔ | \\(\\uparrow (0.14)\\) |\n| MCV | ↔ | ↔ | ↔ | \\(\\uparrow (0.385)\\) | ↔ |\n| MCH | - | - | \\(\\uparrow (0.385)\\) | ↔ | ↔ |\n| MCHC | ↔ | \\(\\uparrow (0.5)\\) | ↔ | ↔ | ↔ |\n\n---\n\n**Table 2-4. LOAEL Values for Red Blood Cell Hematological Effects of Rats** \n**Exposed to HCCPD Vapor in Acute- and Intermediate-Duration Inhalation**\n**Studies**\n\n| Hematology parameter | Rand et al. 1982aa: 1–2 weeks | Rand et al. 1982aa: 1–2 weeks (recovery group) | NTP 1994: 13 weeks | NTP 1994: 13-week special hematology study | Clark 1981: 30 weeks |\n| --- | --- | --- | --- | --- | --- |\n| HCT | - | - | - | - | \\(\\uparrow\\) (0.14) |\n| Females |  |  |  |  |  |\n| PCV | \\(\\uparrow\\) (0.5) | ↔ | ↔ | \\(\\uparrow\\) (0.385) | - |\n| Hb | \\(\\uparrow\\) (0.5) | ↔ | ↔ | \\(\\uparrow\\) (0.385) | ↔ |\n| RBC | \\(\\uparrow\\) (0.5) | ↔ | \\(\\downarrow\\) (0.385) | \\(\\uparrow\\) (0.385) | ↔ |\n| MCV | ↔ | ↔ | \\(\\uparrow\\) (0.385) | \\(\\uparrow\\) (0.385) | ↔ |\n| MCH | - | - | ↔ | \\(\\uparrow\\) (0.385) | ↔ |\n| MCHC | ↔ | ↔ | ↔ | ↔ | ↔ |\n| HCT | - | - | - | - | ↔ |\n\n<sup>a</sup>Data are also available in the unpublished industry report by Alexander et al. (1980a).\n\n<sup>b</sup>LOAEL concentrations are in ppm.\n\n↑ = increased mean value; ↓ = decreased mean value; ↔ = no significant, dose-related change in mean value;\n\n– = not assessed; Hb = hemoglobin; HCT =hematocrit; MCH = mean cell hemoglobin; MCHC = mean cell\n\nhemoglobin concentration; MCV = mean cell volume; PCV = packed cell volume; RBC = red blood cell count\n\nThe most consistently observed effects were increased hemoglobin levels in male and female rats and \nincreased red blood cell counts in male rats.  Generally, effects were observed at concentrations \n≥0.14 ppm and had magnitudes of effect that were <10% of control values.  The exceptions are for the 1–\n2-week range-finding study (Alexander et al. 1980a; Rand et al. 1982a), where 20–30% increases in red \nblood cell parameters were identified at 0.5 ppm, a concentration that co-occurred with significantly \ndecreased water intake and produced significant mortality and morbidity (see Section 2.2).  Drinking \nwater intakes were not assessed in the NTP (1994) studies and were not affected by HCCPD exposure in \nthe Clark (1981) study (see Section 2.18).  While statistically significant altered hemoglobin, mean cell \nvolume (MCV), and mean cell hemoglobin concentration (MCHC) values were reported in rats following \na 14-week exposure at concentrations as low as 0.01 ppm, these changes were sporadically observed and\nwere not dose-responsive, and the magnitudes of effect were generally low (≤5%) (Alexander et al. \n1980b; Rand et al. 1982a).  Therefore, they were not considered to be biologically significant in this \nassessment and are not presented in Table 2-4.  For intermediate-duration exposures in rats, the NOAEL \nvalues were 0.039–0.146 ppm for the NTP (1994) 13-week studies and 0.06 ppm for the Clark (1981) \n30-week study.\n\n---\n\nRand et al. (1982a) postulated that these minor variances in hematological parameters were a \nconsequence of hemorrhagic lesions in the lungs and not a direct influence of HCCPD on hematopoiesis \nor red cell turnover.  Since the red blood cell hematology parameters were more consistently altered in \nmale rats than in female rats, this hypothesis correlates with the increased absolute and relative lung \nweights and more severe histopathological effects observed in the lungs of male rats in the 1–2-week\nRand et al. (1982a) study.  NTP (1994) suggested that the red blood cell hematology alterations were not \nattributable to HCCPD treatment due to the inconsistent dose-response and lack of correlation in the \nresults across sexes and between the core and special 13-week hematology studies.  While there are \ninconsistencies in the red blood cell parameter results obtained from the NTP (1994) studies, common \nalterations in hemoglobin levels and red blood cell counts across repeated inhalation exposure studies \nsuggest a consistent biological response to HCCPD.  In the absence of additional data and based on the \nlack of histopathological effects to bone marrow, ATSDR considers the altered red blood cell parameters \nto be plausibly related to respiratory tract damage resulting in compromised gas exchange.\n\nIn mice, the only consistent HCCPD treatment-related effect on red blood cell hematology parameters \nacross studies was decreased MCV in female mice after exposure to 0.389 ppm for 13 weeks in the core\nand special hematology studies (NTP 1994).  Other red blood cell effects were limited to increased \nMCHC in male mice at 0.389 ppm and in female mice at 0.039–0.389 ppm in the special 13-week \nhematology study.  The magnitudes of effect were within 5% of control values.  HCCPD treatmentrelated effects on other hematological parameters following inhalation exposures were limited to \ndecreased reticulocytes (40%) in female rats exposed to 0.385 ppm in the special hematology study (NTP \n1994); decreased total white blood cells (46%) and lymphocyte count (53%) in male rats, and increased \nneutrophil count (114%) in female rats exposed to 0.5 ppm for 1–2 weeks (Alexander et al. 1980a; Rand \net al. 1982a); and decreased percent lymphocytes (8–10%) and increased neutrophil count (27–36%) in \nmale rats exposed to ≥0.14 ppm and decreased lymphocyte count (16%) in female rats exposed to \n0.56 ppm for 30 weeks (Clark 1981).  No clear biological basis can be identified for these effects based \non the lack of consistency across studies.\n\nIn intermediate-duration oral exposure studies, no histopathological changes were identified in the bone \nmarrow of rats dosed with ≤150 mg/kg/day or mice dosed with ≤300 mg/kg/day for 13 weeks (Abdo et al. \n1984; Velsicol 1981a, 1981b).  Hematology parameters were not evaluated in this study.\n\n---\n\n###### 2.8 MUSCULOSKELETAL\n\nNo studies were located regarding musculoskeletal effects in humans after exposure to HCCPD.  \nAvailable inhalation and oral data in laboratory animals indicate the musculoskeletal system is not a \nsensitive target of toxicity following exposure to HCCPD; no dermal studies were identified.\n\nThe potential effect of HCCPD on musculoskeletal tissues has been evaluated in laboratory animals \nfollowing intermediate- and chronic-duration inhalation exposures and acute- and intermediate-duration \noral exposures.  HCCPD did not affect skeletal muscle of rats or monkeys exposed to up to 0.2 ppm for \n14 weeks (Alexander et al. 1980b; Rand et al. 1982a); femoral muscle, knee joint, or femur of male and \nfemale rats exposed to ≤0.56 ppm for 30 weeks (Clark 1981); bone histopathology of mice or rats \nexposed to ≤0.389 ppm for 13 weeks or ≤0.2 ppm for 2 years (NTP 1994).  Similarly, no \nhistopathological changes were identified in thigh muscle, rib (costochondral junction), or femur of rats \nexposed to ≤150 mg/kg/day or mice exposed to ≤300 mg/kg/day via gavage for 13 weeks (Abdo et al. \n1984; Velsicol 1981a, 1981b). In animals that died, decreased limb tone was observed in mice (prior to \ndeath) after a single exposure to 1,000 mg/kg via gavage (Dean 1977).\n\n###### 2.9 HEPATIC\n\nThe data indicate that the hepatic system is not a sensitive target of HCCPD toxicity.\n\nSerum markers of hepatotoxicity were evaluated in 97 cleanup workers exposed to HCCPD vapors at a \nWWTP because of an inadvertent industrial release (Kominsky et al. 1980).  Abnormal serum marker \nranges were identified for 18 of the 97 workers (19%); aspartate aminotransferase (AST) values were \nelevated for 12 workers, alkaline phosphatase (ALP) was elevated for 5 workers, and total bilirubin was \nelevated for 1 worker (Kominsky et al. 1980).  For 8 of the 97 cleanup crew members, these biochemical \nparameters were abnormal on more than one occasion, and 7 workers had values that were temporallyrelated to exposure conditions.  It should be noted that evaluations were not performed on unexposed \nworkers, and it is not known if the abnormal values observed in exposed workers differ from the \nunexposed local general population.\n\nRelative to a group of 35 controls, 73 male operators employed for an average of 8.2 years (range 0.5–\n23 years) in a plant producing chlorinated hydrocarbons, including HCCPD, showed no evidence of \nhepatotoxicity (Boogaard et al. 1993).  Clinical tests included measurement of alanine aminotransferase\n\n---\n\n(ALT), AST, ALP, total bilirubin, γ-glutamyltransferase (GGT), lactate dehydrogenase (LDH), and total \nbile acids.  Personal air sampling for HCCPD was performed on a subset of study participants but was not \nused to evaluate associations between HCCPD exposure and liver function values.\n\nThe hepatotoxic potential of HCCPD has been evaluated in laboratory animals following acute-, \nintermediate-, and chronic-duration inhalation exposures.  Mild-to-moderate hepatic tissue degeneration \nwas observed following acute-duration inhalation exposures to 0.34–73.6 ppm for 15 minutes to 5 days, \nand to intermediate-duration exposures to 0.34 ppm for 6 weeks or 0.15 ppm for 30 weeks; incidence data \nwere not provided (Treon et al. 1955).  Hepatic damage was more pronounced in the animals that died \nthan in those that survived and, thus, may have been, at least partially, the result of autolysis in moribund \nor dying animals.  An apparent dose-related increase in perivascular/peribiliary inflammatory cell \ninfiltrates in the liver was observed in female rats exposed to 0.06–0.56 ppm; however, incidences did not \ndiffer significantly from control and no hepatic lesions were observed in similarly exposed male rats \n(Clark 1981).  In other inhalation studies, no exposure-related hepatic lesions were seen following acuteduration exposure in rats to concentrations up to 0.5 ppm (Alexander et al. 1980a; Rand et al. 1982a); \nintermediate-duration exposure in monkeys, rats, or mice to concentrations up to 0.2, 0.385, or 0.5 ppm, \nrespectively (Alexander et al. 1980b; NTP 1994; Rand et al. 1982a); or chronic-duration exposure in rats \nor mice to concentrations up to 0.2 ppm (NTP 1994).\n\nNo consistent evidence of exposure-related changes in hepatic serum biochemistry or liver weight was \nobserved following inhalation exposure to HCCPD.  Serum concentrations of the biochemical parameters\nLDH, AST, ALP, and ALT in rats and mice were not influenced by inhalation exposure to HCCPD \nconcentrations ≤0.389 ppm for 13–14 weeks (Alexander et al. 1980b; NTP 1994; Rand et al. 1982a).  \nDuring the 13-week special hematology, clinical chemistry, and urinalysis study conducted in rats by \nNTP (1994), the highest concentration of 2.065 ppm caused elevated serum AST concentrations (1.7–\n7.6-fold) in male and female rats on days 4–16; however, this concentration was lethal to all the animals \nprior to the day 46 clinical evaluation, and a comparable increase was not observed in mice (NTP 1994).  \nRelative liver weights of rats were significantly reduced by 3–15% in males and females exposed to 0.01–\n0.2 ppm for 13 weeks, but the decreases were not dose-related (Alexander et al. 1980b; Rand et al. \n1982a).  No changes in liver weights were observed in rats or mice exposed to concentrations ≤0.389 ppm \nfor 13 weeks or ≤0.2 ppm for 2 years (NTP 1994).\n\nAcute- and intermediate-duration oral toxicity studies have evaluated the potential effects of HCCPD\nexposure on the liver.  High, acute-duration oral doses of HCCPD were associated with liver necrosis and tissue degeneration in rats (261–1,959 mg/kg) and rabbits (579–877 mg/kg); incidence data were not \nprovided (Treon et al. 1955).  HCCPD did not induce histopathological changes in hepatic tissues of rats \nand mice exposed to doses up to 150 and 300 mg/kg/day, respectively, via gavage for 13 weeks (Abdo et \nal. 1984; Velsicol 1981a, 1981b).\n\nThe potential for HCCPD to cause hepatotoxicity following dermal exposure was evaluated only for \nacute-duration exposures.  Rabbits exposed to single dermal doses of 401–5,719 mg/kg displayed necrosis \nof the liver; incidence data were not provided (Treon et al. 1955).  The study authors stated that \ndegenerative changes persisted even 21 days after the exposure period in surviving animals.\n\n###### 2.10 RENAL\n\nThe data indicate that the renal system is a potential target for HCCPD via the oral route; it does not \nappear to be a sensitive target for HCCPD via the inhalation or dermal routes.  Based upon systematic \nreview (Appendix C), the kidney is a presumed hazard of HCCPD toxicity following oral exposure based \non no data in humans and a high level of evidence from laboratory animal studies.\n\nUrine samples were collected from 41 workers exposed for 3–15 days to HCCPD at a WWTP as the \nresult of an inadvertent industrial release into the sewage system (Morse et al. 1979).  Proteinuria was \nidentified in 6 of 41 workers immediately after exposure but no abnormalities were detected 3 weeks \nlater.  Urinalysis parameters were normal in all 97 cleanup crew workers evaluated (Kominsky et al. \n1980).  It should be noted that urinalysis was not performed on unexposed workers, and it is not known if \nproteinuria values observed in exposed workers differ from the local general population.\n\nRelative to a group of 35 controls, 73 male operators employed for an average of 8.2 years in a plant \nproducing chlorinated hydrocarbons, including HCCPD, showed no evidence of damage to the renal \ntubules (Boogaard et al. 1993).  The investigations included measurement of urinary alanine \naminopeptidase, N-acetyl-β-D-glucosaminidase, and retinol binding protein.  Although total urinary \nprotein concentrations did not differ between the two groups, urinary albumin was significantly higher in \nthe exposed group.  The difference, however, was not related to time of employment, and there was no \ndifference in urinary albumin concentration in workers involved in the manufacture of HCCPD and those \ninvolved in the preparation of other chlorinated hydrocarbon.  Thus, the effect was not considered to be \ndue to the damage to the glomerulus caused by exposure to HCCPD.  Personal air sampling for HCCPD\n\n---\n\n2.  HEALTH EFFECTS\n\nwas performed on a subset of study participants but was not used to evaluate associations with renal \nfunction values.\n\nThe potential renal effects following inhalation exposure to HCCPD have been evaluated in laboratory \nanimals following acute, intermediate, and chronic durations.  Inhalation exposure of HCCPD caused \nrenal tubular necrosis in rats, mice, guinea pigs, and rabbits at 0.34–73.6 ppm for 15 minutes to 7 days, \n0.34 ppm for 6 weeks, and 0.15 ppm for 30 weeks; incidence data were not provided (Treon et al. 1955).  \nIn other inhalation studies, no significant, exposure-related renal lesions were seen following acuteduration exposure in rats to concentrations up to 0.5 ppm (Alexander et al. 1980a; Rand et al. 1982a); \nintermediate-duration exposure in monkeys, rats, or mice to concentrations up to 0.2, 0.56, or 0.5 ppm, \nrespectively (Alexander et al. 1980b; Clark 1981; NTP 1994; Rand et al. 1982a); or chronic-duration \nexposure in rats or mice to concentrations up to 0.2 ppm (NTP 1994).\n\nThe potential toxicological effects of HCCPD on the kidneys have been evaluated in laboratory animals \nin acute-and intermediate-duration oral studies.  Degenerative lesions in the kidney tubules resulted from \nsingle gavage doses of 261–1,959 mg/kg in rats and 579–877 mg/kg in rabbits; incidence data were not \nprovided (Treon et al. 1955).  Toxic nephrosis was observed in male and female rats exposed to \n≥38 mg/kg/day and female mice exposed to ≥75 mg/kg/day via gavage for 13 weeks (Abdo et al. 1984; \nVelsicol 1981a, 1981b). These lesions were located in the terminal sections of the proximal tubules of the \nrenal cortex and were characterized by mild dilation of the tubules and karyomegaly, cytomegaly, and \nanisokaryosis accompanied by cytoplasmic and nuclear vacuolization.  Additionally, brown granular \npigment debris protruded into the lumen.  In male mice, tubular necrosis was present in 70% of the male \nmice receiving the 300 mg/kg/day dose but not at lower doses; this lesion was morphologically distinct \nfrom the toxic nephrosis seen in the other animals and may have contributed to the early deaths observed \nat this dose level.  No renal histopathological effects were identified in male and female rats at\n≤19 mg/kg/day, female mice at ≤38 mg/kg/day, or male mice at ≤150 mg/kg/day (Abdo et al. 1984; \nVelsicol 1981a, 1981b).\n\nRabbits exposed to single dermal doses of 401–5,719 mg/kg displayed degeneration and necrosis of the \nkidney tubules; incidence data were not provided (Treon et al. 1955). The study authors stated that renal \neffects were still apparent 21 days after dosing in surviving animals.\n\n---\n\n2.  HEALTH EFFECTS\n\n###### 2.11 DERMAL\n\nHuman and animal data indicate HCCPD causes skin irritation following direct dermal contact with \nHCCPD liquid or vapor.\n\nAn unspecified percentage of 145 workers exposed to HCCPD vapors for 3–15 days at a WWTP as a \nresult of an inadvertent industrial release reported skin irritation, with five employees verified to exhibit\nvisible signs of skin irritation (Morse et al. 1979).  In a subsequent publication, 21% of 177 employees \nwith usable medical questionnaire responses reported skin irritation following HCCPD release and prior \nto plant closure; 10% of the 177 employees reported experiencing skin irritation approximately 6 weeks \nlater (Kominsky et al. 1980).\n\nIn acute-duration dermal toxicity studies, topical application of HCCPD in either its pure form or in \nsolution appears to have a pronounced effect upon the epidermis of experimental animals.  Generally, \nHCCPD initially causes edema that progressed to hardening or encrustation at the application site \n(Gardner 1986b; OxyChem 1972; Treon et al. 1955).  In a series of studies, severe irritation and skin \nnecrosis were observed in a monkey administered 0.05 mL of a 10% (v/v) solution for 3 days; necrotic, \nhardened, encrusted, and discolored skin was identified following application of Ultrasene solutions \ncontaining ≥40% HCCPD to guinea pigs; and subcutaneous edema and local discoloration that progressed \nto encrustation and fissuring were observed after a dermal dose of ≥430 mg/kg was applied to rabbit skin; \nincidence data were not provided (Treon et al. 1955).  The lesions generally healed with time in the \nsurviving animals.  Thirteen months after exposure, the monkey’s treated skin was scarred and hairless.  \nNo evidence of dermal effects was identified in a monkey administered 0.01 mL of Ultrasene solutions \ncontaining up to 10% HCCPD, but application of 0.05 mL of solutions containing ≥20% HCCPD caused \nthe skin to become discolored and swell.  No evidence of skin irritation was observed in guinea pigs after \ndermal doses of 0.05 mL of Ultrasene solutions containing ≤1% HCCPD (Treon et al. 1955).  Eschar \nformation was noted after dermal application of 200 mg/kg HCCPD to rabbits (OxyChem 1992).  Results \nof standard dermal irritation tests indicated that 0.5 mL HCCPD produced slight to severe edema and \nnecrosis at the application sites (OxyChem 1972, 1992).\n\nThe potential effects of systemic HCCPD exposure on skin histopathology of laboratory animals were \nevaluated in intermediate- and chronic-duration inhalation studies and intermediate-duration oral studies.  \nNo histopathological changes were identified in the skin (specific location not identified) of male or \nfemale rats exposed to concentrations ≤0.56 ppm for 30 weeks (Clark 1981) or in male or female rats and mice exposed to concentrations ≤0.2 ppm for 2 years (NTP 1994).  Additionally, no histopathological \nchanges were identified in skin (specific location not identified) of rats and mice at gavage doses up to \n150 or 300 mg/kg/day, respectively, for 13 weeks (Abdo et al. 1984; Velsicol 1981a, 1981b).\n\n###### 2.12 OCULAR\n\nHuman and animal data indicate that direct ocular contact with HCCPD vapor may produce ocular \nirritation at sufficiently high concentrations.\n\nEye irritation was one of the major symptoms reported by sewage treatment plant workers exposed to \nHCCPD vapors for 3–15 days at a WWTP because of an inadvertent industrial release (Kominsky et al. \n1980; Morse et al. 1979).  From the 145 individuals who responded to a questionnaire immediately after \nexposure occurred, 85 (59%) complained of eye irritation (Morse et al. 1979).  In a follow-up \nquestionnaire 6 weeks later, 9% of 177 respondents were still experiencing ocular irritation (Kominsky et \nal. 1980; Morse et al. 1979).  Tearing and redness of the eyes were present in five individuals on the day \nof exposure.\n\nEye irritation, as evidenced by lacrimation, was also observed in animals exposed to HCCPD vapors for \nup to 7 hours (Jackson and Hardy 1986, 1987; OxyChem 1972; Rand et al. 1982a; Treon et al. 1955).  \nPartially or completely closed eyes were identified in rats exposed to ≥1.67 ppm for 1 hour (Jackson and \nHardy 1986) and ≥1.68 ppm for 4 hours (Jackson and Hardy 1987).  Direct ocular exposure to HCCPD\nvapors most likely contributed to these effects.  Irritation of the eyes or eyelids was observed for rats, \nmice, guinea pigs, and rabbits following single exposures to HCCPD concentrations as low as 1.0 ppm \nand multiple exposures to concentrations as low as 0.33 ppm for up to 6 weeks; ocular irritation was not \nobserved in any species exposed to 0.15 ppm for up to 30 weeks (Treon et al. 1955).  Lacrimation was \nevident in rats exposed to 5.8 ppm HCCPD for 4 hours and dark red eyes were observed in rats exposed \nto 0.5 ppm for 5–10 days and ≥0.05 ppm for 14 weeks (Alexander et al. 1980a, 1980b; Rand et al. 1982a).  \nNo clinical signs of eye irritation were noted in monkeys exposed to HCCPD vapor at concentrations up \nto 0.2 ppm for 14 weeks (Alexander et al. 1980b; Rand et al. 1982a).  No ophthalmological or\nhistopathological changes were identified in the ocular tissues of rats or monkeys exposed to \nconcentrations up to 0.2 ppm for 14 weeks (Alexander et al. 1980b; Rand et al. 1982a).  HCCPD \nexposure did not cause histopathological changes in the eyes of rats exposed to concentrations up to \n0.56 ppm for 30 weeks (Clark 1981).\n\n---\n\nSevere eye irritation was produced when 0.1 mL of HCCPD was placed in the conjunctival eye sac for \n5 minutes and then rinsed with water (OxyChem 1972).  Corrosion of the ocular tissues occurred when \nthe material was left in place for 24 hours prior to rinsing (OxyChem 1972).\n\n###### 2.13 ENDOCRINE\n\n2.13  ENDOCRINE\n\nNo reports of changes in human endocrine parameters or organs after exposure to HCCPD were found. \nBased on available data in laboratory animals, HCCPD does not produce histopathological changes to \nendocrine organs.  Insufficient data are available to assess the potential effects of HCCPD exposure on \nendocrine function, including endocrine hormone levels.\n\nPotential histopathological and organ weight effects in endocrine organs have been evaluated in \nlaboratory animals following acute-, intermediate-, and chronic-duration inhalation exposure to HCCPD.  \nDegenerative changes in the adrenal glands of rats, mice, guinea pigs, and rabbits were observed after \nexposures to concentrations of 0.34–73.6 ppm for periods of 15 minutes to 1 week, 0.34 ppm for 6 weeks, \nand 0.15 ppm for 30 weeks; incidence data were not provided (Treon et al. 1955).  Due to the high \nmortality observed at these concentrations, these changes may have been the result of tissue autolysis in \nmoribund or dying animals.  Effects on the adrenal, thyroid, parathyroid, pancreas, and pituitary glands \nfollowing inhalation exposure of male mice to 0.039–0.389 ppm HCCPD for 13 weeks were limited to \nincreased relative adrenal weights; no histopathological changes were noted in these organs in treated \nmale mice and no effects on adrenal, thyroid, parathyroid, pancreas, or pituitary gland weights or\nhistopathology were observed in female mice exposed to ≤0.389 and male and female rats exposed to \n≤0.385 ppm for 13 weeks (NTP 1994).  The biological significance of these adrenal weight changes\ncannot be assessed quantitatively in the absence of hormone product measurements or concurrent \nhistopathological findings.  There were no organ weight or histopathological changes in the adrenal \nglands, pancreas, thyroid, parathyroid gland, and/or pituitary gland identified in male and female rats and \nmonkeys exposed for 14 weeks at ≤0.2 ppm (Alexander et al. 1980b; Rand et al. 1982a), in male and \nfemale rats after 30-week exposures to ≤0.56 ppm (Clark 1981), or in rats and mice following 2-year \nexposures to ≤0.2 ppm (NTP 1994).  Additionally, no effects on the adrenal glands were identified in \nmale mice exposed to 0.5 ppm for 26–42 weeks (NTP 1994).\n\n$$\n\\leq0.385ppm\n$$\n\nPotential effects of HCCPD on endocrine organ weight and histology have also been evaluated in \nlaboratory animals following acute- and intermediate-duration oral exposures and acute-duration dermal \nexposures.  Degenerative changes in the adrenal tissues resulted from exposure to single oral doses of\n\n---\n\n280–2,100 mg/kg in rats and 620–940 mg/kg in rabbits; these changes may have resulted from tissue \nautolysis in moribund or dying animals, but no incidence data were reported (Treon et al. 1955).  There \nwere no histopathological changes in the adrenals, thyroid, parathyroid, or pituitary glands in 13-week \nstudies at gavage doses up to 150 mg/kg/day in rats and 300 mg/kg/day in mice (Abdo et al. 1984; \nVelsicol 1981a, 1981b).  Rabbits that were dermally exposed to HCCPD (430–6,130 mg/kg) had \ndegenerative changes of the adrenal glands that were still apparent in survivors 21 days after exposure; \nincidence data were not provided (Treon et al. 1955).\n\nNo data were identified evaluating endocrine function following *in vivo* exposure to HCCPD; however, \nlimited *in vitro* screening data are available.  HCCPD exhibited statistically significant radioactive iodide \nuptake inhibition in a ToxCast high-throughput screening assay (Wang et al. 2019).  Iodide uptake is the \nfirst step in thyroid hormone biosynthesis.\n\n###### 2.14 IMMUNOLOGICAL\n\n2.14  IMMUNOLOGICAL\n\nNo studies were located regarding immunological effects in humans after exposure to HCCPD. Based on \navailable data in laboratory animals, HCCPD does not cause histopathological alterations to \nimmunological organs.  However, no studies evaluating immune function following exposure to HCCPD \nwere identified.\n\nPotential effects of HCCPD on immune organ weight and histology have also been evaluated in acute-, \nintermediate-, and chronic-duration inhalation exposure studies and intermediate-duration oral exposure \nstudies in laboratory animals.  No exposure-related changes were identified in these studies.  There were \nno histopathological changes in the spleen of rats exposed to ≤0.5 ppm for 1–2 weeks (Alexander et al. \n1980a; Rand et al. 1982a).  In intermediate-duration studies, no histopathological changes were identified \nin immune organs (spleen, thymus, and/or lymph nodes) of monkeys, rats, or mice to concentrations up to \n0.2, 0.56, or 0.5 ppm, respectively (Alexander et al. 1980b; Clark 1981; NTP 1994; Rand et al. 1982a).  \nSimilarly, no histopathological effects were observed in immune organs of rats or mice exposed to \n≤0.2 ppm for 2 years (NTP 1994).  In a 13-week oral study, no treatment-related histopathological \nfindings were identified in the mandibular and mesenteric lymph nodes, thymus, or spleen at gavage \ndoses up to 150 mg/kg/day in rats or 300 mg/kg/day in mice (Abdo et al. 1984; Velsicol 1981a, 1981b).\n\n---\n\n2.  HEALTH EFFECTS\n\n###### 2.15 NEUROLOGICAL\n\n2.15  NEUROLOGICAL\n\nBased on available data, HCCPD does not cause histopathological alterations in the nervous system.  \nEvaluation of neurological function is limited to clinical signs of toxicity; therefore, insufficient data are \navailable to assess the potential effect of HCCPD exposure on neurological function, including behavior.\n\nAmong sewage treatment plant workers exposed to HCCPD at a WWTP because of an inadvertent \nindustrial release, headaches were self-reported by 65 of 145 workers (45%) after exposure for 3–15 days \n(Morse et al. 1979).  Six weeks later, 32 of 177 workers (18%) responding to a questionnaire were still \nexperiencing headaches (Kominsky et al. 1980). No studies were located regarding neurological effects \nin humans after oral or dermal exposure to HCCPD.\n\nNeurological clinical signs of toxicity and nervous system histopathology were evaluated in acute-, \nintermediate-, and chronic-duration inhalation exposure studies.  Rats and mice exposed to concentrations \nof 0.385–2.142 ppm HCCPD were described as listless after 1–3 weeks of exposure (NTP 1994).  \nIncidence data for clinical signs were not provided, so it is unclear how many animals exhibited this effect \nor how frequently; however, the study authors did note that listlessness was observed earlier during the \nexposure period with higher HCCPD concentrations.  Some rats, mice, guinea pigs, and rabbits exposed \nto high lethal concentrations of HCCPD (≥46.5 ppm) by acute-duration inhalation experienced tremors; \nincidence data were not provided (Treon et al. 1955).  At necropsy, diffuse degenerative changes in the \nbrain were observed in all rats, mice, guinea pigs, and rabbits after exposures to 0.34–73.6 ppm for \nperiods of 15 minutes to 1 week, 0.34 ppm for 6 weeks, and 0.15 ppm for 30 weeks; incidence data were \nnot provided (Treon et al. 1955).  These degenerative changes may have been the result of tissue \nautolysis.  In contrast, there were no histopathological changes in the brains of rats exposed to 0.5 ppm \nfor 1–2 weeks (Alexander et al. 1980a; Rand et al. 1982a), male mice exposed to 0.2 ppm for 33 weeks \n(NTP 1994), or rats and mice exposed to ≤0.389 ppm for 13 weeks or ≤0.2 ppm for 2 years (NTP 1994).  \nSimilarly, no histopathological changes were observed in the brains or sciatic nerve of rats or monkeys \nexposed to ≤0.2 ppm for 14 weeks (Alexander et al. 1980b; Rand et al. 1982a) or in brain, spinal cord, or \nsciatic or posterior tibial nerves of rats exposed to ≤0.56 ppm for 30 weeks (Clark 1981).\n\nThe potential neurotoxicity of HCCPD has been evaluated in acute- and intermediate-duration oral \nexposure studies.  Clinical signs of neurotoxicity were observed following acute-duration gavage \nexposure in mice, including hypoactivity at 464 mg/kg and ataxia at 1,000 mg/kg, a dose associated with \nlethality (Dean 1977).  Similarly, all rats exposed once to ≥1,260 mg/kg via gavage exhibited abnormal gait (high stepping, waddling) and lethargy (Gardner 1986a).  Single oral doses ≥180 mg/kg caused \nlethargy in rats and rabbits in the period “immediately after exposure” (Treon et al. 1955).  During \npostmortem examination of tissues, degenerative lesions of the brain were observed in the rats and rabbits \nthat succumbed to exposure and in the rats that survived to the scheduled sacrifice; incidence data were \nnot provided.  No histopathological lesions of the brain, sciatic nerve, or spinal cord were noted in rats or \nmice exposed to gavage doses up to 150 or 300 mg/kg/day, respectively, for 13 weeks (Abdo et al. 1984; \nVelsicol 1981a, 1981b). These data suggest that brain lesions occur only with exposures to high oral \ndoses of HCCPD.\n\nRabbits exposed to single dermal doses of HCCPD (430–6,130 mg/kg) displayed degenerative changes in \nthe brain at necropsy; incidence data were not provided (Treon et al. 1955).  These changes were still \napparent 21 days after exposure in surviving animals.  Ataxia, hypoactivity, and a depressed breathing \npattern have been observed in rabbits at lethal dermal doses of HCCPD (OxyChem 1972).\n\n###### 2.16 REPRODUCTIVE\n\n2.16  REPRODUCTIVE\n\nNo studies were located regarding reproductive effects in humans after exposure to HCCPD.  The \navailable animal data do not indicate that HCCPD causes histopathological alterations to reproductive \norgans.  However, insufficient data are available to thoroughly assess the potential for toxicity to the \nreproductive system, as no studies evaluating reproductive function following inhalation, oral, or dermal \nexposure to HCCPD were identified.\n\nThe potential effects of HCCPD on reproductive organ weight and histology have been evaluated in \nexperimental animals exposed by inhalation for intermediate and chronic durations.  The sole effect on \nreproductive organs identified with HCCPD treatment is an increased incidence of ovarian suppurative \ninflammation in female mice exposed to HCCPD at 0.05–0.2 ppm for 2 years; no histopathological \nchanges were identified in the uterus (NTP 1994).  While this lesion is clearly adverse, as it was the \nsuspected cause of increased mortality at 0.2 ppm, the causal relationship between HCCPD exposure and \nlesion development is unclear.  The study authors noted that lesions were similar to those observed in \nother NTP studies attributed to stress-related susceptibility to utero-ovarian infection by *Klebsiella* \nspecies (NTP 1994).  In contrast, no treatment-related histopathological lesions of the female (ovaries and \nuterus) or male (testes, prostate, and/or seminal vesicle) reproductive organs were identified in monkeys, \nrats, or mice exposed to concentrations up to 0.2, 0.385, or 0.389 ppm for 13–14 weeks (Alexander et al. \n1980b; NTP 1994; Rand et al. 1982a); male mice exposed to 0.2 ppm for 33 weeks or 0.5 ppm for\n\n---\n\n42 weeks (NTP 1994); rats exposed to ≤0.56 ppm for 30 weeks (Clark 1981); or rats or male mice \nexposed to ≤0.2 ppm for 2 years (NTP 1994).\n\n$$\n\\leqq0.56\n$$\n\nThe potential effects of HCCPD on reproductive organ weight and histology have also been evaluated in \nlaboratory animals following intermediate-duration oral exposure.  HCCPD did not cause treatmentrelated effects on the testes, seminal vesicles, prostate, ovaries, or uterus in rats or mice exposed to doses \nup to 150 or 300 mg/kg/day, respectively, via gavage for 13 weeks (Abdo et al. 1984; Velsicol 1981a, \n1981b).\n\nNo data were identified evaluating reproductive function following inhalation, oral, or dermal exposure to \nHCCPD; however, limited screening data are available.  Although it exhibited some estrogen receptor \nbinding affinity in a recombinant human estrogen receptor α (hERα) binding assay, HCCPD did not \nexhibit estrogenic or anti-estrogenic activity in an immature uterotrophic assay in female rats following \nsubcutaneous injection (Akahori et al. 2008).  No anti-androgenic activity was detected for HCCPD in \nChinese hamster ovary (CHO) cells transfected with human androgen receptor (hAR) in an androgenresponsive luciferase reporter assay (Roy et al. 2004).\n\n###### 2.17 DEVELOPMENTAL\n\n2.17  DEVELOPMENTAL\n\nNo studies were located regarding developmental effects in humans after exposure to HCCPD.  Animal \ndata are available only via the oral route and are too limited to assess whether or not the developing \norganism is a target of HCCPD toxicity at doses below those associated with maternal toxicity.\n\nHCCPD was not embryotoxic, fetotoxic, or teratogenic in mice following maternal exposure to gavage \ndoses up to 75 mg/kg/day during GDs 6–15 (Murray et al. 1980).  In rabbits, a dose-dependent increase in \nthe incidence of 13 ribs was identified in the offspring of does exposed to 75 mg/kg/day via gavage \nduring GDs 6–18; nonstatistically significant increases were also identified at 5 and 25 mg/kg/day.  No \nother evidence of embryotoxicity, fetotoxicity, or teratogenicity was identified in rabbits (Murray et al. \n1980).  The natural variation in the number of ribs for rabbits is 12–13.  It should be noted that the \ncompound was not maternally toxic in mice, but maternal mortalities and weight loss were observed in \nrabbits at 75 mg/kg/day (numbers affected and magnitude of effect not specified).\n\nA screening study was performed to evaluate prenatal and postnatal development of mice exposed to \nHCCPD during gestation.  Mice born to dams administered 45 mg/kg/day HCCPD via gavage during\n\n---\n\nGDs 8–12 did not exhibit evidence of developmental toxicity when evaluated on postnatal days (PNDs) 1 \nand 3 (Chernoff and Kavlock 1982, 1983).  When the offspring were evaluated over a 250-day postnatal \nperiod (including through puberty and breeding), there were no adverse effects on postnatal viability, \ngrowth, locomotor activity, sexual development (percent vaginal patency at day 30), or reproductive \nfunction (Gray and Kavlock 1984; Gray et al. 1986).\n\n###### 2.18 OTHER NONCANCER\n\n2.18  OTHER NONCANCER\n\nNo studies were located regarding other noncancer effects in humans after exposure to HCCPD.\n\nOther noncancer effects of HCCPD identified in experimental animals are limited to food and water \nintake.  During the first few days of the post-exposure observation periods, decreased food and water \nintake were observed in rats exposed for 1 hour to ≥1.67 ppm (Jackson and Hardy 1986) and rats exposed \nfor 4 hours to ≥1.68 ppm (Jackson and Hardy 1987); these concentrations were associated with overt \nsigns of toxicity during exposure (e.g., abnormal respiratory pattern).  After a 1–2-week exposure to \nHCCPD, male and female rats exposed to 0.5 ppm had decreased food and water intake (Alexander et al. \n1980a; Rand et al. 1982a).  All males exposed to 0.5 ppm died or were sacrificed in moribund condition \nby the end of the exposure period.  Minor decreases in food intake were also observed for male rats \nexposed to 0.11 ppm without meaningful changes to body weight; the biological significance of this \nfinding is uncertain.  Food intake was not affected in rats or monkeys and water intake was not affected in \nrats exposed to ≤0.2 ppm for 14 weeks (Alexander et al. 1980b; Rand et al. 1982a).  In a 30-week study, \nno treatment-related deficits were identified for male or female rats regarding food or water intake\nfollowing exposure to ≤0.56 ppm (Clark 1981). No treatment-related effects were observed for food and \nwater intake of pregnant mice administered gavage doses of HCCPD at ≤75 mg/kg/day on GDs 6–15 \n(Murray et al. 1980).  Where deficits in food and/or water intake were observed after exposure to \nHCCPD, these effects were likely the result of nonspecific toxicity following exposures to high \nconcentrations of an irritating/corrosive chemical.\n\n$$\n\\mathrm{to}\\geq1.67\\mathrm{ppm}\n$$\n\n$$\nt0\\geq1.68\n$$\n\n$$\nt o\\leqq0.2\n$$\n\n$$\n0.56ppm\n$$\n\n###### 2.19 CANCER\n\nNo studies were located regarding cancer in humans following exposure to HCCPD.\n\nThe carcinogenicity of HCCPD has been evaluated in 2-year rodent bioassays in which male and female \nrats and mice were exposed to concentrations up to 0.2 ppm for 104 weeks (NTP 1994).  There were no statistically significant increases in tumor incidence in rats or mice.  There was a slight increase in the \nincidence of adenomas of the pituitary pars distalis in male rats at 0.2 ppm and in thyroid follicle cell \nadenomas in female mice at 0.05 ppm, but, since the incidences were similar to the historical control \nmeans, were within the historical control range, or did not exhibit a dose-dependency, NTP (1994) did not \nconsider these tumors to be related to HCCPD exposure.  In male mice exposed to 0.5 ppm for 26 or \n42 weeks, then evaluated at 105 weeks, the incidence of alveolar/bronchiolar carcinomas was \nsignificantly increased but was within the historical range for the laboratory (NTP 1994).  Thus, \nalveolar/bronchiolar carcinomas may n", 'pages': None, 'truncated': True, 'extraction': 'firecrawl-public-document-markdown', 'request_id': '2f7ac126-1735-4f43-b7f0-10aa05b9cde7', 'source_url': 'https://downloads.regulations.gov/ATSDR-2026-0133-0003/content.pdf', 'observed_at': '2026-10-04T00:40:40.278109+00:00', 'content_hash': '063c002435b7a13b9144e8da7119795794d56ee2e0ab2fe90a88e51b9525c505'}, 'title': 'pdf'}]}

Oct. 4, 2026, 12:40 a.m.: attachments changed since Oct. 4, 2026, 12:36 a.m..

{'attachments': [{'url': 'https://downloads.regulations.gov/ATSDR-2026-0133-0003/attachment_1.pdf', 'title': 'Draft Tox Profile for Hexachlorocyclopentadiene'}, {'url': 'https://downloads.regulations.gov/ATSDR-2026-0133-0003/content.pdf', 'title': 'pdf'}]}

{'attachments': [{'url': 'https://downloads.regulations.gov/ATSDR-2026-0133-0003/attachment_1.pdf', 'body': {'text': "## Toxicological Profile for Hexachlorocyclopentadiene (HCCPD)\nDraft for Public Comment\nOctober 2026\n\nU.S. Department of Health and Human Services\nAgency for Toxic Substances and Disease Registry\n\n---\n\n## DISCLAIMER\n\nUse of trade names is for identification only and does not imply endorsement by the Agency for Toxic \nSubstances and Disease Registry, the Public Health Service, or the U.S. Department of Health and Human \nServices.\n\nThis information is distributed solely for the purpose of pre-dissemination for public comment under \napplicable information quality guidelines.  It has not been formally disseminated by the Agency for Toxic \nSubstances and Disease Registry.  It does not represent and should not be construed to represent any \nagency determination or policy.\n\n---\n\n## FOREWORD\n\nThis toxicological profile is prepared in accordance with guidelines developed by the Agency for Toxic \nSubstances and Disease Registry (ATSDR) and the Environmental Protection Agency (EPA).  The \noriginal guidelines were published in the *Federal Register* on April 17, 1987.  Each profile will be revised \nand republished as necessary.\n\nThe ATSDR toxicological profile succinctly characterizes the toxicologic and adverse health effects \ninformation for these toxic substances described therein.  Each peer-reviewed profile identifies and \nreviews the key literature that describes a substance's toxicologic properties.  Other pertinent literature is \nalso presented but is described in less detail than the key studies.  The profile is not intended to be an \nexhaustive document; however, more comprehensive sources of specialty information are referenced.\n\nThe focus of the profiles is on health and toxicologic information; therefore, each toxicological profile \nbegins with a relevance to public health discussion which would allow a public health professional to \nmake a real-time determination of whether the presence of a particular substance in the environment \nposes a potential threat to human health.  The adequacy of information to determine a substance's health \neffects is described in a health effects summary.  Data needs that are of significance to the protection of \npublic health are identified by ATSDR.\n\nEach profile includes the following:\n\n(A) The examination, summary, and interpretation of available toxicologic information and \nepidemiologic evaluations on a toxic substance to ascertain the levels of significant \nhuman exposure for the substance due to associated acute-, intermediate-, and chronicduration exposures;\n\n(B) A determination of whether adequate information on the health effects of each substance \nis available or in the process of development to determine the levels of exposure that \npresent a significant risk to human health due to acute-, intermediate-, and chronicduration exposures; and\n\n(C) Where appropriate, identification of toxicologic testing needed to identify the types or \nlevels of exposure that may present significant risk of adverse health effects in humans.\n\nThe principal audiences for the toxicological profiles are health professionals at the Federal, State, and \nlocal levels; interested private sector organizations and groups; and members of the public.  ATSDR plans \nto revise these documents in response to public comments and as additional data become available.  \nTherefore, we encourage comments that will make the toxicological profile series of the greatest use.\n\nElectronic comments may be submitted via: www.regulations.gov. Follow the on-line instructions for \nsubmitting comments.\n\nWritten comments may also be sent to:\n\nAgency for Toxic Substances and Disease Registry\n\nOffice of Innovation and Analytics\n\nToxicology Section\n\n1600 Clifton Road, N.E.\n\nMail Stop S106-5\n\nAtlanta, Georgia 30329-4027\n\n---\n\nThe toxicological profiles are developed under the Comprehensive Environmental Response, \nCompensation, and Liability Act of 1980, as amended (CERCLA or Superfund).  CERCLA \nSection 104(i)(1) directs the Administrator of ATSDR to “…effectuate and implement the health-related \nauthorities” of the statute.  This includes the preparation of toxicological profiles for hazardous \nsubstances most commonly found at facilities on the CERCLA National Priorities List (NPL) and that \npose the most significant potential threat to human health, as determined by ATSDR and the EPA.  \nSection 104(i)(3) of CERCLA, as amended, directs the Administrator of ATSDR to prepare a \ntoxicological profile for each substance on the list.  In addition, ATSDR has the authority to prepare \ntoxicological profiles for substances not found at sites on the NPL, in an effort to “…establish and \nmaintain inventory of literature, research, and studies on the health effects of toxic substances” under \nCERCLA Section 104(i)(1)(B), to respond to requests for consultation under Section 104(i)(4), and as \notherwise necessary to support the site-specific response actions conducted by ATSDR.\n\nThis profile reflects ATSDR’s assessment of all relevant toxicologic testing and information that has been \npeer-reviewed.  Staffs of the Centers for Disease Control and Prevention and other Federal scientists have \nalso reviewed the profile.  In addition, this profile has been peer-reviewed by a nongovernmental panel \nand is being made available for public review.  Final responsibility for the contents and views expressed \nin this toxicological profile resides with ATSDR.\n\nChristopher M. Reh, Ph.D. \nAssociate Director, \nAgency for Toxic Substances and Disease Registry \nCenters for Disease Control and Prevention\n\n---\n\n**VERSION HISTORY**\n\n| Date | Description |\n| --- | --- |\n| October 2026 | Draft for public comment toxicological profile released |\n| July 1999 | Final toxicological profile released |\n\n---\n\n# CONTRIBUTORS & REVIEWERS\n\n# CHEMICAL MANAGER TEAM\n\nGaston Casillas, Ph.D. (Lead)\nFahim Atif, Ph.D.\nJennifer Przybyla, Ph.D.\nNickolette Roney, M.P.H.\nBrittany Szafran, D.V.M., Ph.D., D.A.B.T.\n\nZach Guerrette, Ph.D., D.A.B.T.\nChristina Coley, M.S.\nLisa Ingerman, Ph.D., D.A.B.T.\nKimberly Zaccaria, Ph.D., D.A.B.T.\nMario Citra, Ph.D.\n\nATSDR, Office of Innovation and Analytics, \nToxicology Section, Atlanta, GA\n\nSRC, Inc., North Syracuse, NY\n\n### REVIEWERS\n\n#### Interagency Minimal Risk Level Workgroup:\n\nIncludes ATSDR; National Center for Environmental Health (NCEH); U.S. Environmental Protection \nAgency (EPA); National Toxicology Program (NTP).\n\n#### Additional reviews for science and/or policy:\n\nATSDR, Office of Community Health Hazard Assessment; ATSDR, Office of Capacity Development \nand Applied Prevention Science; ATSDR, Office of Science; NCEH, Division of Laboratory Sciences; \nNCEH, Division of Environmental Health Science and Practice; EPA, Office of Research and \nDevelopment; EPA, Office of Water.\n\n### PEER REVIEWERS\n\n1. David Dorman, D.V.M., Ph.D., D.A.B.V.T., D.A.B.T.; Professor of Toxicology; North Carolina \nState University; College of Veterinary Medicine; Department of Molecular Biomedical \nSciences; Raleigh, North Carolina\n\n2. Slawo Lomnicki, Ph.D.; Assistant Professor of Environmental Sciences; Louisiana State \nUniversity, Chemistry Department; LSU Superfund Research Materials Core leader; Baton \nRouge, Louisiana\n\n3. Deborah A. Slechta, Ph.D., M.A.; University of Rochester; Professor - Department of \nEnvironmental Medicine (SMD); Professor - Department of Neuroscience (SMD) -– Joint; \nProfessor - Department of Public Health Sciences (SMD) - Joint; Rochester, New York\n\nThese experts collectively have knowledge of toxicology, chemistry, and/or health effects.  All reviewers \nwere selected in conformity with Section 104(I)(13) of the Comprehensive Environmental Response, \nCompensation, and Liability Act, as amended.\n\nATSDR scientists review peer reviewers’ comments and determine whether changes will be made to the \nprofile based on comments.  The peer reviewers’ comments and responses to these comments are part of \nthe administrative record for this compound.\n\nThe listing of peer reviewers should not be understood to imply their approval of the profile's final \ncontent.  The responsibility for the content of this profile lies with ATSDR.\n\n---\n\n## CONTENTS\n\nDISCLAIMER .............................................................................................................................................. ii\nFOREWORD ............................................................................................................................................... iii\nVERSION HISTORY ................................................................................................................................... v\nCONTRIBUTORS & REVIEWERS ........................................................................................................... vi\nCONTENTS ................................................................................................................................................ vii\nLIST OF FIGURES ..................................................................................................................................... ix\nLIST OF TABLES ........................................................................................................................................ x\nCHAPTER 1. RELEVANCE TO PUBLIC HEALTH ................................................................................. 1\n1.1 OVERVIEW AND U.S. EXPOSURES ......................................................................................... 1\n1.2 SUMMARY OF HEALTH EFFECTS........................................................................................... 1\n1.3 MINIMAL RISK LEVELS (MRLs) .............................................................................................. 6\nCHAPTER 2. HEALTH EFFECTS ............................................................................................................ 10\n2.1 INTRODUCTION ........................................................................................................................ 10\n2.2 DEATH ........................................................................................................................................ 55\n2.3 BODY WEIGHT .......................................................................................................................... 57\n2.4 RESPIRATORY .......................................................................................................................... 58\n2.5 CARDIOVASCULAR ................................................................................................................. 63\n2.6 GASTROINTESTINAL ............................................................................................................... 63\n2.7 HEMATOLOGICAL ................................................................................................................... 65\n2.8 MUSCULOSKELETAL .............................................................................................................. 68\n2.9 HEPATIC ..................................................................................................................................... 68\n2.10 RENAL ........................................................................................................................................ 70\n2.11 DERMAL ..................................................................................................................................... 72\n2.12 OCULAR ..................................................................................................................................... 73\n2.13 ENDOCRINE ............................................................................................................................... 74\n2.14 IMMUNOLOGICAL ................................................................................................................... 75\n2.15 NEUROLOGICAL....................................................................................................................... 76\n2.16 REPRODUCTIVE ....................................................................................................................... 77\n2.17 DEVELOPMENTAL ................................................................................................................... 78\n2.18 OTHER NONCANCER ............................................................................................................... 79\n2.19 CANCER ...................................................................................................................................... 79\n2.20 GENOTOXICITY ........................................................................................................................ 80\n2.21 MECHANISM OF ACTION ....................................................................................................... 82\nCHAPTER 3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, \nCHEMICAL INTERACTIONS ........................................................................................... 84\n3.1 TOXICOKINETICS..................................................................................................................... 84\n3.1.1 Absorption ............................................................................................................................. 84\n3.1.2 Distribution ........................................................................................................................... 86\n3.1.3 Metabolism ............................................................................................................................ 88\n3.1.4 Excretion ............................................................................................................................... 90\n3.1.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models ............. 92\n3.1.6 Animal-to-Human Extrapolations ......................................................................................... 93\n3.2 CHILDREN AND OTHER POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE ..... 93\n3.3 BIOMARKERS OF EXPOSURE AND EFFECT ....................................................................... 95\n\n---\n\n3.3.1 Biomarkers of Exposure ........................................................................................................ 95\n3.3.2 Biomarkers of Effect ............................................................................................................. 96\n3.4 INTERACTIONS WITH OTHER CHEMICALS ....................................................................... 97\nCHAPTER 4. CHEMICAL AND PHYSICAL INFORMATION ............................................................. 98\n4.1 CHEMICAL IDENTITY ............................................................................................................. 98\n4.2 PHYSICAL AND CHEMICAL PROPERTIES .......................................................................... 98\nCHAPTER 5. POTENTIAL FOR HUMAN EXPOSURE ....................................................................... 100\n5.1 OVERVIEW .............................................................................................................................. 100\n5.2 PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL ................................................ 101\n5.2.1 Production ........................................................................................................................... 101\n5.2.2 Import/Export ...................................................................................................................... 103\n5.2.3 Use ...................................................................................................................................... 103\n5.2.4 Disposal ............................................................................................................................... 104\n5.3 RELEASES TO THE ENVIRONMENT ................................................................................... 104\n5.3.1 Air ....................................................................................................................................... 105\n5.3.2 Water ................................................................................................................................... 107\n5.3.3 Soil ...................................................................................................................................... 108\n5.4 ENVIRONMENTAL FATE ...................................................................................................... 109\n5.4.1 Transport and Partitioning ................................................................................................... 109\n5.4.2 Transformation and Degradation ........................................................................................ 112\n5.5 LEVELS IN THE ENVIRONMENT ......................................................................................... 116\n5.5.1 Air ....................................................................................................................................... 117\n5.5.2 Water ................................................................................................................................... 118\n5.5.3 Sediment and Soil ............................................................................................................... 122\n5.5.4 Other Media ........................................................................................................................ 123\n5.6 GENERAL POPULATION EXPOSURE.................................................................................. 124\n5.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES .............................................. 125\nCHAPTER 6. ADEQUACY OF THE DATABASE ................................................................................ 126\n6.1 EXISTING INFORMATION ON HEALTH EFFECTS ........................................................... 126\n6.2 IDENTIFICATION OF DATA NEEDS .................................................................................... 126\n6.3 ONGOING STUDIES ................................................................................................................ 135\nCHAPTER 7. REGULATIONS AND GUIDELINES ............................................................................. 136\nCHAPTER 8. REFERENCES .................................................................................................................. 138\nAPPENDICES\nAPPENDIX A.  ATSDR MINIMAL RISK LEVEL WORKSHEETS .................................................... A-1 \nAPPENDIX B. LITERATURE SEARCH FRAMEWORK FOR HCCPD ............................................. B-1 \nAPPENDIX C. FRAMEWORK FOR ATSDR’S SYSTEMATIC REVIEW OF HEALTH EFFECTS \nDATA FOR HCCPD ...................................................................................................... C-1 \nAPPENDIX D.  USER’S GUIDE ............................................................................................................. D-1 \nAPPENDIX E.  QUICK REFERENCE FOR HEALTH CARE PROVIDERS ....................................... E-1 \nAPPENDIX F.  GLOSSARY .................................................................................................................... F-1 \nAPPENDIX G.  ACRONYMS, ABBREVIATIONS, AND SYMBOLS................................................. G-1\n\n---\n\n## LIST OF FIGURES\n\n1-1.  Health Effects Found in Animals Following Inhalation Exposure to HCCPD .................................... 3\n1-2.  Health Effects Found in Animals Following Oral Exposure to HCCPD .............................................. 4\n1-3.  Summary of Sensitive Targets of HCCPD – Inhalation ....................................................................... 7\n1-4.  Summary of Sensitive Targets of HCCPD – Oral ................................................................................ 8\n2-1.  Overview of the Number of Studies Examining HCCPD Health Effects .......................................... 14\n2-2.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation ..................................... 28\n2-3.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Oral .............................................. 44\n5-1.  Number of NPL Sites with Hexachlorocyclopentadiene Contamination ......................................... 100\n5-2.  Transformation of Hexachlorocyclopentadiene ................................................................................ 113\n6-1.  Summary of Existing Health Effects Studies on HCCPD by Route and Endpoint .......................... 127\n\n---\n\n## LIST OF TABLES\n\n1-1.  Provisional Minimal Risk Levels (MRLs) for HCCPD ........................................................................ 9\n2-1.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation ..................................... 15\n2-2.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Oral .............................................. 39\n2-3.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Dermal ......................................... 49\n2-4.  LOAEL Values for Red Blood Cell Hematological Effects of Rats Exposed to HCCPD \nVapor in Acute- and Intermediate-Duration Inhalation  Studies ........................................................ 65\n2-5.  Genotoxicity of Hexachlorocyclopentadiene *In Vivo* ......................................................................... 81\n2-6.  Genotoxicity of Hexachlorocyclopentadiene *In Vitro* ........................................................................ 81\n4-1.  Chemical Identity of Hexachlorocyclopentadiene .............................................................................. 98\n4-2.  Physical and Chemical Properties of Hexachlorocyclopentadiene ..................................................... 98\n5-1.  Facilities that Produce, Process, or Use Hexachlorocyclopentadiene .............................................. 102\n5-2.  Summary of National Aggregate Volumes Reported to U.S. Environmental Protection \nAgency (EPA) Chemical Data  Reporting (CDR) ............................................................................ 103\n5-3.  Releases to the Environment from Facilities that Produce, Process, or Use \nHexachlorocyclopentadiene .............................................................................................................. 105\n5-4.  Summary of Releases to the Environment from the Emissions Inventory System (EIS) \nGateway Emission Sectors in 2020 .................................................................................................. 106\n5-5.  Summary of Releases to the Environment from the Emissions Inventory System (EIS) \nGateway Emission Sectors in 2021 .................................................................................................. 107\n5-6.  Lowest Limit of Detection Based on Standards ............................................................................... 117\n5-7.  Summary of Environmental Levels of HCCPD ............................................................................... 117\n5-*8.*  Summary of Water Monitoring Data for Hexachlorocyclopentadiene Across the \nUnited States ..................................................................................................................................... 119\n7-1.  Regulations and Guidelines Applicable to Hexachlorocyclopentadiene .......................................... 136\n\n---\n\n# CHAPTER 1. RELEVANCE TO PUBLIC HEALTH\n\n###### 1.1 OVERVIEW AND U.S. EXPOSURES\n\nHexachlorocyclopentadiene (HCCPD) is a highly volatile, reactive liquid.  HCCPD is an anthropogenic \nchemical that has entered the environment primarily because of its use in the production of chlorinated \npesticides and flame-retardant chemicals.  Restriction of pesticides synthesized from HCCPD has \ndecreased the possibility of exposure to HCCPD and pesticide residues among most members of the \ngeneral population.  Exposure to materials containing HCCPD at hazardous waste sites is still possible.\n\nThe potential for persistence of HCCPD in the environment is low.  Due to its high vapor pressure, \nHCCPD is most likely released to the environment through volatilization, especially from surface waters \nand soils.  The main degradation processes expected include photolysis and photooxidation, hydrolysis, \nand, to a lesser extent, biodegradation.  HCCPD in the air is expected to degrade with estimated half-lives \nranging from 5 hours to <1 day, which limits its potential for long-range transport. HCCPD in water is \nexpected to degrade rapidly, with half-lives for photolysis of ~2–4 minutes and half-lives for hydrolysis \nof ~3–5.45 days.\n\nOccupational exposure to HCCPD is most likely to occur via inhalation and dermal routes.  The general \npopulation may be exposed to HCCPD through inhalation of air contaminated with this chemical and \ningestion of drinking water contaminated with this chemical.\n\n###### 1.2 SUMMARY OF HEALTH EFFECTS\n\nInformation on the noncancer toxicity of HCCPD in humans is limited to reports by wastewater treatment \nplant (WWTP) workers and cleanup crew members exposed after an inadvertent industrial release.  No \noccupational studies evaluating health effects in workers exposed during regular manufacture or use of \nHCCPD are available.  Additionally, no observational epidemiological studies of workers or the public \nare available for HCCPD.  Further information on the noncancer toxicity of HCCPD comes from \ninhalation and oral studies in animals.  Data following dermal exposure are very limited in humans and \nanimals.\n\nIn laboratory animals, evaluation of available dose-response data by route and duration indicates that \nsensitive noncancer targets of HCCPD toxicity are respiratory and hematological effects following inhalation exposure (Figure 1-1).  Ovarian inflammation was noted in mice following chronic-duration \ninhalation exposure; however, the causal relationship between the effect and HCCPD exposure could not \nbe determined due to apparent association with stress-induced susceptibility to an infection in the mouse \ncolony (see Section 2.16).  Due to this, female reproductive (ovarian) effects were not considered as \npotential sensitive effects or included in Figure 1-1.  The oral database is very limited; the only potential \ntargets identified below doses associated with lethality include the gastrointestinal tract and kidney \n(Figure 1-2). General toxicity (decreased body weight) was also observed at similar doses.  A systematic \nreview of sensitive target organs/systems by exposure route resulted in the following hazard identification \nconclusions:\n\n• Respiratory effects are a presumed health effect for humans following inhalation exposure.\n\n• Gastrointestinal effects are a presumed health effect for humans following oral exposure.\n\n• Hematological (red blood cell) effects are suspected health effects for humans following \ninhalation exposure; white blood cell effects are not classifiable as to the hazard to humans.\n\n• Renal effects are a presumed health effect for humans following oral exposure.\n\n**_Respiratory Effects (Inhalation Route)._**  The respiratory tract is sensitive to HCCPD toxicity after \ninhalation exposure; findings are attributed to compound reactivity upon contact with respiratory tissues \nat the portal of entry.  WWTP workers and cleanup crew members reported respiratory symptoms \nincluding coughing, nose and throat irritation, and difficulty breathing following inhalation of HCCPD \nvapors from an inadvertent industrial discharge (Kominsky et al. 1980; Morse et al. 1979).  Acuteduration inhalation exposure studies in animals identified increased or labored respiration or abnormal \nrespiratory patterns at concentrations ≥0.5 ppm (Alexander et al. 1980a; Jackson and Hardy 1986, 1987; \nRand et al. 1982a).  Sneezing and altered respiratory rates/patterns were observed in rodents at \nintermediate-duration exposures of ≥0.56 ppm (Clark 1981; NTP 1994).  Histopathological evaluation \nidentified changes to the nasal, tracheobronchial, and/or pulmonary epithelium in rats and mice at \n≥0.385 and ≥0.2 ppm, respectively; these changes consisted of inflammation (suppurative or necrotizing) \nor metaplasia at nonlethal concentrations (Clark 1981; NTP 1994) and hemorrhaging or necrosis at lethal \nconcentrations (NTP 1994).  Nasal and pulmonary lesions were observed in mice exposed to 0.2 ppm \nHCCPD for 2 years, while no lesions were observed in rats under the same exposure conditions (NTP \n1994).\n\n$$\n\\geq0.385and\\geq0.2\n$$\n\n---\n\n**Figure 1-1.  Health Effects Found in Animals Following Inhalation Exposure to** \n**HCCPD**\n\n**Concentration (ppm)**\n\n**≥1.4**\n\n**Effects in Animals**\n\n**Acute:**  Neurobehavioral effects\n\n**Intermediate:**  Hepatic effects\n\n**0.5**\n\n**Acute:**  Death, respiratory lesions, altered hematology parameters, \ndecreased body weight, decreased food and water intake\n\n**Intermediate:**  Decreased body weight\n\n**0.389**\n\n**Intermediate:**  Death\n\n**0.2**\n\n**0.039**\n\n**Intermediate:**  Respiratory lesions\n\n**Chronic:**  Death, respiratory lesions\n\n**Intermediate:**  Altered red blood cell parameters\n\n1x10<sup>-4</sup> ppm\n6x10<sup>-5</sup> ppm\n\n**Provisional Intermediate MRL**\n**Provisional Chronic MRL**\n\n---\n\n**Figure 1-2.  Health Effects Found in Animals Following Oral Exposure to HCCPD**\n\nDose (mg/kg/day) Effects in Animals\n≥464 Acute:  Gastrointestinal, neurological, respiratory, and musculoskeletal  \neffects \n150 Intermediate:  Death\n75 Acute:  Death, developmental effects\n38 Intermediate:  Gastrointestinal and renal lesions, decreased body \nweight\n0.06 mg/kg/day Provisional Intermediate MRL\n\n**_Gastrointestinal Effects (Oral Route)._** The gastrointestinal tract is sensitive to HCCPD after oral \nexposure; findings are attributed to compound reactivity upon contact with gastrointestinal tissues at the \nportal of entry.  No human data are available evaluating potential gastrointestinal effects of HCCPD \nfollowing oral exposure.  Diarrhea was reported in rodents administered single oral doses of ≥464 mg/kg \n(Dean 1977; Gardner 1986a); this effect was not reported at lower doses in intermediate-duration studies \nup to 150 mg/kg/day in rats or 300 mg/kg/day in mice (Abdo et al. 1984).  In the only available \nintermediate-duration oral study in animals, focal inflammation and epithelial hyperplasia of the \nforestomach were observed in rats and mice exposed to ≥38 and ≥75 mg/kg/day, respectively (Abdo et al.\n1984).  While humans lack a forestomach, analogous lesions could occur in the proximate portions of the \nhuman gastrointestinal tract, including oral, pharyngeal, and/or esophageal tissues, due to portal-of-entry \nreactivity following oral exposure to HCCPD.\n\n**_Hematological Effects (Inhalation Route)._**  No changes in blood counts were observed in workers \nexposed to HCCPD at a WWTP following an inadvertent industrial discharge (Kominsky et al. 1980).  \nAlterations in red blood cell parameters, primarily elevated red blood cell counts and hemoglobin levels, were reported in rats following acute- and intermediate-duration inhalation exposure to HCCPD at \nconcentrations of 0.5 and ≥0.14 ppm, respectively (Clark 1981; NTP 1994; Rand et al. 1982a); similar \nfindings were observed in mice at intermediate-duration inhalation concentrations ≥0.039 ppm (NTP \n1994).  Based on the absence of histopathological changes to bone marrow, observed red blood cell \neffects have been hypothesized to be a compensatory response to hemorrhagic damage to the lungs \nfollowing inhalation exposure rather than direct effects on hematopoiesis (Rand et al. 1982a).  However,\nrats showed sex-specific findings (females were less sensitive), and there were inconsistencies between \nthe main 13-week (comprehensive) study and the 13-week specialized hematological study conducted by \nNTP (1994).  In mice, findings were limited and inconsistent with respect to alterations in red blood cell \nparameters after exposure for 13–42 weeks (NTP 1994).  Additionally, no hematological effects were \nobserved in the 2-year inhalation studies in rats or mice at concentrations up to 2 ppm (NTP 1994).  No \nconsistent effects on white blood cell parameters were observed with inhalation exposures in animal \nstudies (Clark 1981; NTP 1994; Rand et al. 1982a).\n\n**_Renal Effects (Oral Route)._** No human data are available to assess the potential for HCCPD to cause \nrenal toxicity.  In the only available oral study in animals evaluating the kidney, HCCPD produced toxic \nnephrosis in male and female rats at ≥38 mg/kg/day and in female mice at ≥75 mg/kg/day (Abdo et al. \n1984).  Toxic nephrosis was not identified in male mice, but acute tubular necrosis was identified in male \nmice exposed to 300 mg/kg/day. Available toxicokinetic data indicate that HCCPD and/or its metabolites \ndistribute to the kidneys in both rats and mice after oral dosing; however, the highest distribution is to the \nkidney in the rat and to the liver in the mouse (Dorough and Ranieri 1984).  This observed difference in \ndistribution may explain the observed species sensitivity.\n\n**_Cancer Effects._**  There were no data from studies in humans pertaining to the carcinogenicity of HCCPD.  \nThe National Toxicology Program (NTP) conducted 2-year bioassays of HCCPD in mice and rats and \nconcluded that it is not a carcinogen in either species (NTP 1994).  Although the incidence of \nalveolar/bronchiolar carcinomas was significantly increased in male mice exposed to 0.5 ppm for 26 or \n42 weeks and evaluated at 2 years, the incidence was within the historical range for the laboratory and \nwas not elevated in animals exposed to 0.2 ppm for 2 years. There was also a slight increase in the \nincidence of adenomas of the pituitary pars distalis in male rats and thyroid follicle cell adenomas in \nfemale mice, but these tumors were not considered to be exposure-related since the incidences were \nsimilar to the historical control means, were within the historical control range, or did not exhibit a dosedependency.  Based on these results, the U.S. Environmental Protection Agency (EPA) determined that \nHCCPD is not likely to be a human carcinogen by the inhalation route (IRIS 2003).  The International\n\n---\n\nAgency for Research on Cancer (IARC) has not evaluated the carcinogenicity of HCCPD (IARC 2025).  \nThe U.S. Department of Health and Human Services (HHS) has not evaluated a cancer classification \ncategory for HCCPD (NTP 2021).\n\n###### 1.3 MINIMAL RISK LEVELS (MRLs)\n\nAs illustrated in Figure 1-3, available inhalation data for HCCPD suggest that the respiratory and \nhematological systems are the most sensitive targets for toxicity. The inhalation database was considered \nadequate for derivation of provisional intermediate- and chronic-duration MRLs.  As discussed in \nSection 1.2, ovarian effects observed in the chronic-duration mouse study were not considered as \npotential sensitive effects due to potential confounding by a utero-ovarian infection (see Appendix A for \ndetails).  Therefore, female reproductive effects are not included in Figure 1-3.\n\nAs illustrated in Figure 1-4, gastrointestinal, renal, and body weight effects appear to be the most \nsensitive targets of HCCPD toxicity following oral exposure. The oral database was considered adequate \nfor derivation of a provisional intermediate-duration MRL for HCCPD.  The acute- and chronic-duration \noral data were insufficient for deriving MRLs.\n\nThe provisional MRL values are summarized in Table 1-1 and discussed in greater detail in Appendix A.\n\n---\n\n**Figure 1-3.  Summary of Sensitive Targets of HCCPD – Inhalation**\n\n**Available data indicate that the hematological and respiratory systems are the most sensitive \ntargets of HCCPD inhalation exposure.**\n\nNumbers in circles are the lowest LOAELs for all health effects in animals. No reliable dose response \ndata were available for humans.\n\n**Acute (ppm)**\n\n| Category | Acute (ppm) | Intermediate (ppm) | Chronic (ppm) |\n| --- | --- | --- | --- |\n| Death | 0.5 | 0.389 | 0.2 |\n| Body weight | 0.5 |  |  |\n| Respiratory | 0.5 | 0.2 | 0.2 |\n| Hematological | 0.5 | 0.039 |  |\n| Other noncancer | 0.5 |  |  |\n\n---\n\n**Figure 1-4. Summary of Sensitive Targets of HCCPD – Oral**\n\n**Available data indicate that the gastrointestinal tract, renal system, and body weight are the most\nsensitive targets of HCCPD oral exposure.**\nNumbers in circles are the lowest LOAELs for all health effects in animals. \nNo reliable dose response data were available for humans.\n\n## Acute (mg/kg/day)\n\n| Category | Lowest LOAEL (mg/kg/day) |\n| --- | --- |\n| Death (Acute) | 75 |\n| Developmental (Acute) | 75 |\n| Gastrointestinal (Acute) | 464 |\n| Neuological (Acute) | 464 |\n| Body weight (Intermediate) | 38 |\n| Gastrointestinal (Intermediate) | 38 |\n| Renal (Intermediate) | 38 |\n| Death (Intermediate) | 150 |\n\n---\n\nTable 1-1. Provisional Minimal Risk Levels (MRLs) for HCCPD<sup>a</sup>\n\n| Exposure route | Exposure duration | Provisional MRL | Critical effect | POD type | POD value | Uncertainty/modifying factor | Reference |\n| --- | --- | --- | --- | --- | --- | --- | --- |\n| Inhalation | Acute | None | - | - | - | - | - |\n| Inhalation | Intermediate | 1 × 10-4 ppm (1 × 10-3 mg/m3) | Nasal suppurative inflammation in rats | NOAELHEC | 0.00344 ppm | UF: 30 | NTP 1994 |\n| Inhalation | Chronic | 6 × 10-5 ppm (7 × 10-4 mg/m3) | Nasal suppurative inflammation in mice | BMCLHEC | 0.0019 ppm | UF: 30 | NTP 1994 |\n| Oral | Acute | None | - | - | - | - | - |\n| Oral | Intermediate | 0.06 mg/kg/day | Combined incidence of forestomach epithelial hyperplasia and focal inflammation in rats | BMDLADJ | 5.5 mg/kg/day | UF: 100 | Abdo et al. 1984: Velsicol 1981b |\n| Oral | Chronic | None | - | - | - | - | - |\n\n$$\n1\\times10^{-4}ppm\n$$\n\n$$\n(1\\times10^{-3}mg/m^3)\n$$\n\n$$\n6\\times10^{-5}ppm\n$$\n\n$$\n(7\\times10^{-4}mg/m^3)\n$$\n\n<sup>a</sup>See Appendix A for additional information.\n\nADJ = adjusted for intermittent exposure; BMCL = benchmark concentration lower confidence limit; BMDL = benchmark dose lower confidence limit;\n\nHEC = human equivalent concentration; NOAEL = no-observed-adverse-effect level; POD = point of departure; UF = uncertainty factor\n\n---\n\n# CHAPTER 2. HEALTH EFFECTS\n\n###### 2.1 INTRODUCTION\n\nThe primary purpose of this chapter is to provide public health officials, physicians, toxicologists, and \nother interested individuals and groups with an overall perspective on the toxicology of HCCPD.  It \ncontains descriptions and evaluations of toxicological studies and epidemiological investigations and \nprovides conclusions, where possible, on the relevance of toxicity and toxicokinetic data to public health.  \nWhen available, mechanisms of action are discussed along with the health effects data; toxicokinetic \nmechanistic data are discussed in Section 3.1.\n\nA glossary and list of acronyms, abbreviations, and symbols can be found at the end of this profile.\n\nTo help public health professionals and others address the needs of persons living or working near hazardous \nwaste sites, the information in this section is organized by health effects.  These data are discussed in terms \nof route of exposure (inhalation, oral, and dermal) and three exposure periods:  acute (≤14 days), \nintermediate (15–364 days), and chronic (≥365 days).\n\nAs discussed in Appendix B, a literature search was conducted to identify relevant studies examining health \neffect endpoints.  Figure 2-1 provides an overview of the database of studies in humans or experimental \nanimals included in this chapter of the profile.  These studies evaluate the potential health effects associated \nwith inhalation, oral, or dermal exposure to HCCPD, but may not be inclusive of the entire body of literature.  \nA systematic review of the scientific evidence of the health effects associated with exposure to HCCPD was \nalso conducted; the results of this review are presented in Appendix C.\n\nHuman and animal inhalation studies are presented in Table 2-1 and Figure 2-2, animal oral studies are \npresented in Table 2-2 and Figure 2-3, and human and animal dermal studies are presented in Table 2-3.  \nDue to the limited nature of the database, several older studies lacking quantitative data reporting are \nincluded in Chapter 2 to provide data potentially relevant for hazard identification; however, data that are \nonly reported qualitatively (i.e., histopathological data lacking incidence data) are not included in \nTables 2-1, 2-2, or 2-3.\n\nLevels of significant exposure (LSEs) for each route and duration are presented in tables and illustrated in \nfigures.  The points in the figures showing no-observed-adverse-effect levels (NOAELs) or lowest- observed-adverse-effect levels (LOAELs) reflect the actual doses (levels of exposure) used in the studies.  \nEffects have been classified into “less serious LOAELs” or “serious LOAELs (SLOAELs).”  “Serious” \neffects are those that evoke failure in a biological system and can lead to morbidity or mortality (e.g., \nacute respiratory distress or death).  “Less serious” effects are those that are not expected to cause \nsignificant dysfunction or death, or those whose significance to the organism is not entirely clear.  \nATSDR acknowledges that a considerable amount of judgment may be required in establishing whether \nan endpoint should be classified as a NOAEL, “less serious” LOAEL, or “serious” LOAEL, and that in \nsome cases, there will be insufficient data to decide whether the effect is indicative of significant \ndysfunction.  However, the Agency has established guidelines and policies that are used to classify these \nendpoints.  ATSDR believes that there is sufficient merit in this approach to warrant an attempt at \ndistinguishing between “less serious” and “serious” effects.  The distinction between “less serious” effects \nand “serious” effects is considered to be important because it helps the users of the profiles to identify \nlevels of exposure at which major health effects start to appear.  LOAELs or NOAELs should also help in \ndetermining whether or not the effects vary with dose and/or duration, and place into perspective the \npossible significance of these effects to human health.\n\nA User's Guide has been provided at the end of this profile (see Appendix C).  This guide should aid in \nthe interpretation of the tables and figures for LSEs and MRLs.\n\nThe health effects of HCCPD have been evaluated in 2 human studies and 68 animal studies.  As \nillustrated in Figure 2-1, most of the health effect data come from dermal and inhalation studies in \nanimals.  In both human and animal studies, the ocular effects observed in HCCPD inhalation studies are \nlikely attributable to direct contact with HCCPD vapors.  Therefore, ocular effects from inhalation studies \nare counted as dermal exposure in Figure 2-1 and are listed in the dermal LSE table.\n\nThe available human studies were predominantly focused on evaluation of dermal, ocular, and respiratory \neffects in WWTP workers and cleanup crew members following an inadvertent industrial release of \nHCCPD.  For these studies, exposure was evaluated as HCCPD vapor levels in air.\n\nFor animal data, inhalation and oral studies are available for most health effects.  Acute-, intermediate-, \nand chronic-duration studies are available for the inhalation route, while only acute- and intermediateduration studies are available for the oral route.  The dermal animal database is mostly limited to ocular \nand dermal effects, largely following exposure to HCCPD vapor.  The most examined endpoints in \nanimal studies were death, respiratory, hepatic, renal, and ocular.\n\n---\n\nA systematic review was conducted on potential targets of HCCPD exposure, which included respiratory \nand hematological effects for inhalation exposure and gastrointestinal and renal effects following oral \nexposure (see Appendix C for details).\n\n• **Respiratory Effects.** Respiratory effects are a presumed health effect associated with HCCPD \nexposure via inhalation based on inadequate evidence in humans and a high level of evidence in \nanimals.  WWTP workers and cleanup crew members reported respiratory symptoms including \ncoughing and respiratory tract irritation after exposure to HCCPD vapors following an \ninadvertent industrial release.  Several animal studies have reported altered respiratory patterns \nfollowing single or repeated exposures to HCCPD.  Upon histopathological examination, \nnonneoplastic lesions of the nasal, tracheobronchial, and pulmonary regions were consistently \nobserved in mice and rats exposed for intermediate durations to concentrations ≥0.2 or \n≥0.385 ppm, respectively.  Chronic-duration exposure to 0.2 ppm resulted in similar lesions in \nmice, but not rats.  Observed lesions (suppurative, serous, or necrotizing inflammation; epithelial \nhyperplasia) are consistent with chronic irritation at the portal of entry.\n\n• **Gastrointestinal Effects.** Gastrointestinal effects are a presumed health effect associated with \nHCCPD exposure via oral exposure based on no human data and a high level of evidence in \nanimal studies.  Diarrhea was reported in rodents following exposure to high acute doses \n≥464 mg/kg.  Forestomach lesions (epithelial hyperplasia and focal inflammation) were observed \nin rats and mice following intermediate-duration exposures of ≥38 and ≥75 mg/kg/day, \nrespectively.  Although humans lack a forestomach, effects associated with HCCPD are \nconsistent with chronic irritation at the portal of entry.  Thus, the upper gastrointestinal tract is\npresumably vulnerable to toxicity following oral exposure to HCCPD.\n\n• **Hematological Effects.** Hematological effects, specifically red blood cell parameters, are a \nsuspected health effect associated with HCCPD exposure via inhalation based on inadequate data \nin humans and a moderate level of evidence in animals.  No changes in blood counts were \nobserved in WWTP workers after exposure to HCCPD vapors following an inadvertent industrial \nrelease.  Several acute- and intermediate-duration inhalation studies reported altered red blood \ncell parameters (e.g., increased hemoglobin, red blood cell counts, and packed cell volume) at \nconcentrations as low as 0.14 and 0.039 ppm in rats and mice, respectively; however, these \nfindings were not consistent across sexes or species nor were they reproducible in targeted \nanalyses by the same researchers.  Observed red blood cell effects may be attributable to\ncompromised gas exchange following tissue damage to the respiratory tract, as no evidence of \nbone marrow hyperplasia was observed in rodents following repeated inhalation exposure to \nHCCPD. White blood cell effects are not classifiable as to the hazard to humans based on no data \nin humans and inadequate evidence in animals.  Available studies did not find consistent evidence \nof alterations in white blood cell parameters in rats or mice following intermediate- or chronicduration inhalation exposure to HCCPD.\n\n• **Renal Effects.** Renal effects are a presumed health effect associated with oral exposure to\nHCCPD based on no human data and a high level of evidence in animal studies.  Renal lesions, \nspecifically toxic nephrosis, were observed in rats and mice following intermediate-duration \nexposures to ≥38 and ≥75 mg/kg/day, respectively. Acute tubular necrosis was observed in male \nmice at a higher dose (300 mg/kg/day).  Available toxicokinetic data indicate that HCCPD and/or\n\n---\n\n###### 2. HEALTH EFFECTS\n\nits metabolites distribute to the kidneys of both rats and mice after oral dosing; however, it will \naccumulate to a higher degree in rats.\n\n---\n\n**Figure 2-1.  Overview of the Number of Studies Examining HCCPD Health Effects***\n\n**Most studies examined the potential death, respiratory, neurological, renal, hepatic, and ocular effects of HCCPD**\nFewer studies evaluated health effects in **humans** than **animals** (counts represent studies examining endpoint)\n\n| Category | Number of studies |\n| --- | --- |\n| Death | 57 |\n| Body weight | 18 |\n| Respiratory | 44 |\n| Cardiovascular | 35 |\n| Gastrointestinal | 16 |\n| Hematological | 13 |\n| Musculoskeletal | 10 |\n| Hepatic | 39 |\n| Renal | 39 |\n| Dermal | 16 |\n| Ocular | 39 |\n| Endocrine | 35 |\n| Immunological | 12 |\n| Neurolgical | 41 |\n| Reproductive | 11 |\n| Developmental | 3 |\n| Other Noncancer | 7 |\n| Cancer | 5 |\n\n**Exposure Route**\n\n| Category | Share of studies (%) |\n| --- | --- |\n| Inhalation | 40 |\n| Oral | 13 |\n| Dermal | 47 |\n\n**Exposure Duration**\n\n| Category | Share of studies (%) |\n| --- | --- |\n| Chronic | 2 |\n| Acute | 78 |\n| Intermediate | 20 |\n\n*Includes studies discussed in Chapter 2.  A total of 70 studies (including those finding no effect) have examined toxicity; most studies examined multiple \nendpoints.\n\n---\n\n**Table 2-1. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation\n(ppm)**\n\n| Species (strain) keya | No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| ACUTE EXPOSURE |  |  |  |  |  |  |  |  |  |\n| Alexander et al. 1980a; Rand et al. 1982a |  |  |  |  |  |  |  |  |  |\n| 1 | Rat (Sprague-Dawley) 10 M, 10 F | 1–2 weeks 5 days/week 6 hours/day (WB) | 0, 0.022, 0.11, 0.5 | LE, CS, BW, FI, HE, BC, GN, OW, HP | Death Bd wt | 0.11 |  | 0.5 M | 10/10 died or were sacrificed in moribund condition Decreased terminal body weight in females (29%) and males (32%) Labored respiration; increased absolute lung weight; bronchiole inflammation, hyperplasia, and epithelial erosion |\n| 1 | Rat (Sprague-Dawley) 10 M, 10 F | 1–2 weeks 5 days/week 6 hours/day (WB) | 0, 0.022, 0.11, 0.5 | LE, CS, BW, FI, HE, BC, GN, OW, HP | Resp | 0.11 |  | 0.5 | 10/10 died or were sacrificed in moribund condition Decreased terminal body weight in females (29%) and males (32%) Labored respiration; increased absolute lung weight; bronchiole inflammation, hyperplasia, and epithelial erosion |\n| 1 | Rat (Sprague-Dawley) 10 M, 10 F | 1–2 weeks 5 days/week 6 hours/day (WB) | 0, 0.022, 0.11, 0.5 | LE, CS, BW, FI, HE, BC, GN, OW, HP | Cardio Hematoc | 0.5 0.11 | 0.5 | 0.5 | Males: total white blood cell and lymphocyte counts reduced Females: neutrophils increased Both: red blood cell count, packed cell volume, and hemoglobin increased |\n| 1 | Rat (Sprague-Dawley) 10 M, 10 F | 1–2 weeks 5 days/week 6 hours/day (WB) | 0, 0.022, 0.11, 0.5 | LE, CS, BW, FI, HE, BC, GN, OW, HP | Hepatic Renal Immuno Neuro | 0.5 0.5 0.5 Other noncancer | 0.5 |  | Decreased food and water intake |\n| Jackson and Hardy 1986 |  |  |  |  |  |  |  |  |  |\n| 2 | Rat (Wistar) 5 M, 5 F | 1 hour (WB) | 0, 1.67, 2.38, 3.53, 6.25, 8.30 | LE, CS, BW, FI, WI, OW, GN | Death Bd wt | 1.67 |  | 3.69 | LC50 Decreased body weight at death or scheduled sacrifice (3-weeks post exposure) in males (41%) and females (26%) Abnormal respiratory pattern Decreased food consumption |\n| 2 | Rat (Wistar) 5 M, 5 F | 1 hour (WB) | 0, 1.67, 2.38, 3.53, 6.25, 8.30 | LE, CS, BW, FI, WI, OW, GN | Resp Other noncancer | 1.67 1.67 |  |  | LC50 Decreased body weight at death or scheduled sacrifice (3-weeks post exposure) in males (41%) and females (26%) Abnormal respiratory pattern Decreased food consumption |\n\n---\n\n**Table 2-1. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation\n(ppm)**\n\nAbnormal respiratory pattern\nDecreased food consumption\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Jackson and Hardy 1987 |  |  |  |  |  |  |  |  |  |\n| 3 | Rat (Wistar) 5 M, 5 F | 4 hours (WB) | 0, 1.68, 1.83, 3.31, 3.47 | LE, CS, BW, FI, WI, GN, OW | Death Bd wt |  |  | 2.9 1.68 M | LC50 23% decreased body weight at scheduled sacrifice (4 weeks post exposure) |\n| 3 | Rat (Wistar) 5 M, 5 F | 4 hours (WB) | 0, 1.68, 1.83, 3.31, 3.47 | LE, CS, BW, FI, WI, GN, OW | Resp Other noncancer | 1.68 F | 1.68 1.68 | 1.83 F | 24% decreased body weight at death or scheduled sacrifice (4 weeks post exposure) |\n| OxyChem 1972 |  |  |  |  |  |  |  |  |  |\n| 4 | Rat (Carworth CFE) 10 M | 4 hours (WB) | 176, 1,760 | LE, CS, GN | Death |  |  | 176 | 10/10 died within 48 hours |\n| Rand et al. 1982a |  |  |  |  |  |  |  |  |  |\n| 5 | Rat (Sprague-Dawley) 10 M, 10 F | 4 hours (WB) | 0.28, 1.4, 2.5, 3.1, 3.3, 3.4, 4, 5.8 | LE, CS, BW | Death |  |  | 3.5 F 1.6 M | LC50 LC50 |\n| 5 | Rat (Sprague-Dawley) 10 M, 10 F | 4 hours (WB) | 0.28, 1.4, 2.5, 3.1, 3.3, 3.4, 4, 5.8 | LE, CS, BW | Bd wt | 0.28 | 1.4 F | 1.4 M | 17% body weight loss 25% body weight loss |\n| 5 | Rat (Sprague-Dawley) 10 M, 10 F | 4 hours (WB) | 0.28, 1.4, 2.5, 3.1, 3.3, 3.4, 4, 5.8 | LE, CS, BW | Neuro | 0.28 | 1.4 | 5.8 | LOAEL: Sedation SLOAEL: Ataxia |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 6 | Rat 4 NS | 2 days 7 hours/day (WB) | 3.2 | LE, CS, GN | Death |  |  | 3.2 | 4/4 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 7 | Rat 4 NS | 3 days 7 hours/day (WB) | 1.4 | LE, CS, GN | Death |  |  | 1.4 | 3/4 died |\n\n---\n\n**Table 2-1. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation\n(ppm)**\n\n| Species |  |  |  |  |  |  |  |  |  |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Figure keya | No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 8 | Rat 4 NS | 2.6–3.6 hours (WB) | 1.4, 3.1, 7.1, 12.4, 12.7, 46.5, 56.9, 70.4 | LE, CS, GN | Death |  |  | 3.1 | 2/4 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 9 | Rat 4 NS | 7 hours (WB) | 1.5, 3.2, 6.7 | LE, CS, GN | Death |  |  | 3.2 | 3/4 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 10 | Rat 4 NS | 5 days 7 hours/day (WB) | 0.33, 1.0, 1.6 | LE, CS, GN | Death |  |  | 1 | 4/4 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 11 | Rat 4 NS | 0.25–1.25 hours (WB) | 1.4, 1.5, 3.1, 7.2, 13.0, 13.8, 19.4, 20.0, 20.2, 69.1, 69.2 | LE, CS, GN | Death |  |  | 7.2 | 2/4 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 12 | Rat 4 NS | 4 hours (WB) | 73.6 | LE, CS, GN | Death |  |  | 73.6 | 4/4 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 13 | Mouse 5 NS | 0.25–1.25 hours (WB) | 1.4, 1.5, 3.1, 7.2, 13.0, 13.8, 19.4, 20.0, 20.2, 69.1, 69.2 | LE, CS, GN | Death |  |  | 7.2 | 5/5 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 14 | Mouse 5 NS | 4 hours (WB) | 73.6 | LE, CS, GN | Death |  |  | 73.6 | 5/5 died |\n\n---\n\n**Table 2-1. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation\n(ppm)**\n\n| Species (strain) keya | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| 15 Mouse 5 NS | 2 days 7 hours/day (WB) | 3.2 | LE, CS, GN | Death |  |  | 3.2 | 4/5 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| 16 Mouse 5 NS | 3 days 7 hours/day (WB) | 1.4 | LE, CS, GN | Death |  |  | 1.4 | 5/5 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| 17 Mouse 5 NS | 7 hours (WB) | 1.5, 3.2, 6.7 | LE, CS, GN | Death |  |  | 1.5 | 4/5 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| 18 Mouse 5 NS | 2.6– 3.6 hours (WB) | 1.4, 3.1, 7.1, 12.4, 12.7, 46.5, 56.9, 70.4 | LE, CS, GN | Death |  |  | 3.1 | 4/5 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| 19 Mouse 5 NS | 5 days 7 hours/day (WB) | 0.33, 1.0, 1.6 | LE, CS, GN | Death |  |  | 1 | 4/5 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| 20 Rabbit 3 NS | 4 hours (WB) | 73.6 | LE, CS, GN | Death |  |  | 73.6 | 3/3 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| 21 Rabbit 3 NS | 3 days 7 hours/day (WB) | 1.4 | LE, CS, GN | Death |  |  | 1.4 | 3/3 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| 22 Rabbit 3 NS | 5 days 7 hours/day (WB) | 1, 1.6 | LE, CS, GN | Death |  |  | 1 | 3/3 died |\n\n---\n\n**Table 2-1. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation\n(ppm)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 23 | Rabbit 3 NS | 2.6–3.6 hours (WB) | 1.4, 3.1, 7.1, 12.4, 12.7, 46.5, 56.9, 70.4 | LE, CS, GN | Death |  |  | 1.4 | 2/3 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 24 | Rabbit 3 NS | 7 hours (WB) | 1.5, 3.2, 6.7 | LE, CS, GN | Death |  |  | 1.5 | 3/3 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 25 | Rabbit 3 NS | 0.25–1.25 hours (WB) | 1.4, 1.5, 3.1, 7.2, 13.0, 13.8, 19.4, 20.0, 20.2, 69.1, 69.2 | LE, CS, GN | Death |  |  | 3.1 | 2/3 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 26 | Rabbit 3 NS | 2 days 7 hours/day (WB) | 3.2 | LE, CS, GN | Death |  |  | 3.2 | 3/3 died |\n| INTERMEDIATE EXPOSURE |  |  |  |  |  |  |  |  |  |\n| Alexander et al. 1980b; Rand et al. 1982a, 1982b |  |  |  |  |  |  |  |  |  |\n| 27 | Monkey (Cynomolgus) 6 M, 6 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, HE, BC, UR, OP, GN, OW, HP, OF | Bd wt Resp Cardio Gastro Hemato Musc/skel Hepatic Renal Ocular Endocr Immuno | 0.2 0.2 0.2 0.2 0.2 0.2 |  |  |  |\n\n---\n\n**Table 2-1. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation\n(ppm)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n|  |  |  |  |  | Neuro | 0.2 |  |  |  |\n|  |  |  |  |  | Repro | 0.2 |  |  |  |\n|  |  |  |  |  | Other |  |  |  |  |\n|  |  |  |  |  | noncancer |  |  |  |  |\n| Alexander et al. 1980b; Huntingdon Research Centre 1980; Rand et al. 1982a, 1982b |  |  |  |  |  |  |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Bd wt | 0.2 |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Resp | 0.2 |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Cardio | 0.2 |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Gastro | 0.2 |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Hemat | 0.2 |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Musc/skel | 0.2 |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Hepatic | 0.2 |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Renal | 0.2 |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Ocular | 0.2 |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Endocr | 0.2 |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Immuno | 0.2 |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Neuro | 0.2 |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Repro | 0.2 |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Other |  |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | noncancer |  |  |  |  |\n\n---\n\n**Table 2-1. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation\n(ppm)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Clark 1981 |  |  |  |  |  |  |  |  |  |\n| 29 | Rat (Wistar) 18 M, 18 F | 30 weeks 5 days/week 6 hours/day (WB) | 0, 0.06, 0.14, 0.56 | LE, CS, BW, FI, WI, HE, BC, UR, GN, OW, HP | Death Bd wt Resp | 0.56 | 0.56 F | 0.56 M | 4/18 males and 2/18 females died |\n| 29 | Rat (Wistar) 18 M, 18 F | 30 weeks 5 days/week 6 hours/day (WB) | 0, 0.06, 0.14, 0.56 | LE, CS, BW, FI, WI, HE, BC, UR, GN, OW, HP | Resp | 0.14 | 0.56 F | 0.56 M | Females: perivascular/peribronchiolar inflammatory cell infiltration; sneezing Males: bronchiolar epithelial ulceration/thinning and perivascular/peribronchiolar inflammatory cell infiltration; sneezing |\n| 29 | Rat (Wistar) 18 M, 18 F | 30 weeks 5 days/week 6 hours/day (WB) | 0, 0.06, 0.14, 0.56 | LE, CS, BW, FI, WI, HE, BC, UR, GN, OW, HP | Cardio Gastro Hematoma | 0.56 0.56 F 0.06 M | 0.56 F 0.14 M |  | Decreased lymphocyte counts Increased red blood cell counts, hemoglobin, hematocrit, and neutrophil counts; decreased lymphocyte percentage |\n| 29 | Rat (Wistar) 18 M, 18 F | 30 weeks 5 days/week 6 hours/day (WB) | 0, 0.06, 0.14, 0.56 | LE, CS, BW, FI, WI, HE, BC, UR, GN, OW, HP | Musc/skel Hepatic Renal Dermal Ocular Endocr Immuno Neuro Repro | 0.56 0.56 0.56 0.56 0.56 0.56 |  |  |  |\n\n---\n\n**Table 2-1. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation\n(ppm)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n|  |  |  |  |  | Other noncancer | 0.56 |  |  |  |\n| NTP 1994 |  |  |  |  |  |  |  |  |  |\n| 30 | Rat (Fischer-344) 10 M, 10 F | 13 weeks 5 days/week 6 hours/day (WB) | 0, 0.039, 0.146, 0.385, 0.941, 2.065 | LE, CS, BW, HE, BC, GN, OW, HP | Death Bd wt Resp | 0.385 0.385 F 0.146b M | 0.385 M | 0.941 | 100% mortality during first 4 weeks |\n|  |  |  |  |  |  |  |  |  | Nasal squamous metaplasia and suppurative inflammation; suppurative and necrotizing inflammation of the bronchus/bronchiole; increased absolute and relative lung weights |\n|  |  |  |  |  |  |  |  | 0.941 | Increased respiration rate and mouth breathing; suppurative inflammation and hemorrhaging in the alveolus; necrotizing inflammation of the nose, larynx, trachea, and bronchus/bronchiole |\n|  |  |  |  |  | Cardio Gastro Hemato | 0.385 0.385 0.146 | 0.385 |  |  |\n|  |  |  |  |  | Musc/skel | 0.385 |  |  | Males: increased packed cell volume, hemoglobin, red blood cell count, and MCHC |\n|  |  |  |  |  | Hepatic | 0.385 |  |  |  |\n|  |  |  |  |  | Renal | 0.385 |  |  |  |\n|  |  |  |  |  | Endocr | 0.385 |  |  |  |\n|  |  |  |  |  | Immuno | 0.385 |  |  |  |\n|  |  |  |  |  | Neuro | 0.385 |  |  |  |\n|  |  |  |  |  | Repro | 0.385 |  |  |  |\n\n***DRAFT FOR PUBLIC COMMENT***\n\n---\n\n**Table 2-1. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation\n(ppm)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| NTP 1994 |  |  |  |  |  |  |  |  |  |\n| 31 | Rat (Fischer-344) 20 M, 20 F | 13 weeks 5 days/week 6 hours/day (WB) | 0, 0.039, 0.385, 2.065 | LE, HE, BC, UR | Death Hemato | 0.039 | 0.385 | 2.065 | 100% mortality Males: increased MCV; Females: increased MCV, packed cell volume, hemoglobin, and red blood cell count Increased AST |\n| 31 | Rat (Fischer-344) 20 M, 20 F | 13 weeks 5 days/week 6 hours/day (WB) | 0, 0.039, 0.385, 2.065 | LE, HE, BC, UR | Hepatic Renal | 0.385 2.065 | 2.065 | 2.065 | 100% mortality Males: increased MCV; Females: increased MCV, packed cell volume, hemoglobin, and red blood cell count Increased AST |\n| NTP 1994 |  |  |  |  |  |  |  |  |  |\n| 32 | Mouse (B6C3F1) 10 M | 42 weeks 5 days/week 6 hours/day (WB) | 0, 0.5 | LE, CS, BW, GN, OW, HP | Death Bd wt |  |  | 0.5 | 14% decreased survival at 45 weeks Decreased body weight (19%) and body weight gain (42%) at the end of the exposure period Suppurative inflammation of the nose, trachea, and lungs |\n| 32 | Mouse (B6C3F1) 10 M | 42 weeks 5 days/week 6 hours/day (WB) | 0, 0.5 | LE, CS, BW, GN, OW, HP | Resp |  | 0.5 | 0.5 | 14% decreased survival at 45 weeks Decreased body weight (19%) and body weight gain (42%) at the end of the exposure period Suppurative inflammation of the nose, trachea, and lungs |\n| 32 | Mouse (B6C3F1) 10 M | 42 weeks 5 days/week 6 hours/day (WB) | 0, 0.5 | LE, CS, BW, GN, OW, HP | Gastro Hepatic | 0.5 |  | 0.5 | 14% decreased survival at 45 weeks Decreased body weight (19%) and body weight gain (42%) at the end of the exposure period Suppurative inflammation of the nose, trachea, and lungs |\n| 32 | Mouse (B6C3F1) 10 M | 42 weeks 5 days/week 6 hours/day (WB) | 0, 0.5 | LE, CS, BW, GN, OW, HP | Renal | 0.5 |  | 0.5 | 14% decreased survival at 45 weeks Decreased body weight (19%) and body weight gain (42%) at the end of the exposure period Suppurative inflammation of the nose, trachea, and lungs |\n| 32 | Mouse (B6C3F1) 10 M | 42 weeks 5 days/week 6 hours/day (WB) | 0, 0.5 | LE, CS, BW, GN, OW, HP | Endocr Immuno | 0.5 |  | 0.5 | 14% decreased survival at 45 weeks Decreased body weight (19%) and body weight gain (42%) at the end of the exposure period Suppurative inflammation of the nose, trachea, and lungs |\n| 32 | Mouse (B6C3F1) 10 M | 42 weeks 5 days/week 6 hours/day (WB) | 0, 0.5 | LE, CS, BW, GN, OW, HP | Repro | 0.5 |  | 0.5 | 14% decreased survival at 45 weeks Decreased body weight (19%) and body weight gain (42%) at the end of the exposure period Suppurative inflammation of the nose, trachea, and lungs |\n| NTP 1994 |  |  |  |  |  |  |  |  |  |\n| 33 | Mouse (B6C3F1) 20 M, 20 F | 13 weeks 5 days/week 6 hours/day (WB) | 0, 0.039, 0.389, 2.142 | LE, HE, BC, UR | Death Hemato |  | 0.039 F 0.389 M | 2.142 | 100% mortality Increased MCHC Increased MCHC |\n| 33 | Mouse (B6C3F1) 20 M, 20 F | 13 weeks 5 days/week 6 hours/day (WB) | 0, 0.039, 0.389, 2.142 | LE, HE, BC, UR | Hepatic Renal | 0.039 M 2.142 2.142 | 0.039 F 0.389 M | 2.142 | 100% mortality Increased MCHC Increased MCHC |\n\n---\n\n**Table 2-1. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation\n(ppm)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| NTP 1994 |  |  |  |  |  |  |  |  |  |\n| 34 | Mouse (B6C3F1) 10 M | 26 weeks 5 days/week 6 hours/day (WB) | 0, 0.5 | LE, CS, BW, GN, OW, HP | Bd wt Resp | 0.5 | 0.5 |  | Nasal suppurative inflammation |\n| NTP 1994 |  |  |  |  |  |  |  |  |  |\n| 35 | Mouse (B6C3F1) 10 M | 33 weeks 5 days/week 6 hours/day (WB) | 0, 0.2 | LE, CS, BW, GN, OW, HP | Bd wt Resp Gastro Hepatic Renal Immuno Neuro Repro | 0.2 | 0.2 |  | Nasal suppurative inflammation |\n| NTP 1994 |  |  |  |  |  |  |  |  |  |\n| 36 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week 6 hours/day (WB) | 0, 0.039, 0.146, 0.389, 0.949, 2.142 | LE, CS, BW, HE, BC, OW, HP | Death |  |  | 0.949 F 0.389 M | 10/10 died 5/10 died |\n| 36 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week 6 hours/day (WB) | 0, 0.039, 0.146, 0.389, 0.949, 2.142 | LE, CS, BW, HE, BC, OW, HP | Bd wt Resp | 0.389 |  |  | Females: focal serous or suppurative inflammation of the nose Males: squamous metaplasia in the trachea, focal serous or suppurative inflammation of the nose |\n| 36 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week 6 hours/day (WB) | 0, 0.039, 0.146, 0.389, 0.949, 2.142 | LE, CS, BW, HE, BC, OW, HP | Cardio Gastro Hemato | 0.389 |  |  | Decreased MCV |\n| 36 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week 6 hours/day (WB) | 0, 0.039, 0.146, 0.389, 0.949, 2.142 | LE, CS, BW, HE, BC, OW, HP | Musc/skel | 0.389 |  |  |  |\n\n***DRAFT FOR PUBLIC COMMENT***\n\n---\n\n**Table 2-1. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation\n(ppm)**\n\n| Species Figure keya | Species (strain) No./group | Species Exposure parameters | Species Doses | Species Parameters monitored | Species Endpoint | Species NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n|  |  |  |  |  | Hepatic | 0.389 |  |  |  |\n|  |  |  |  |  | Renal | 0.389 |  |  |  |\n|  |  |  |  |  | Endocr | 0.389 |  |  |  |\n|  |  |  |  |  | Immuno | 0.389 |  |  |  |\n|  |  |  |  |  | Neuro | 0.389 |  |  |  |\n|  |  |  |  |  | Repro | 0.389 |  |  |  |\n| CHRONIC EXPOSURE |  |  |  |  |  |  |  |  |  |\n| NTP 1994 |  |  |  |  |  |  |  |  |  |\n| 37 | Rat (Fischer-344) 50 M, 50 F | 104 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, UR, GN, OW, HP | Bd wt | 0.2 |  |  |  |\n| 37 | Rat (Fischer-344) 50 M, 50 F | 104 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, UR, GN, OW, HP | Resp | 0.2 |  |  |  |\n| 37 | Rat (Fischer-344) 50 M, 50 F | 104 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, UR, GN, OW, HP | Cardio | 0.2 |  |  |  |\n| 37 | Rat (Fischer-344) 50 M, 50 F | 104 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, UR, GN, OW, HP | Gastro | 0.2 |  |  |  |\n| 37 | Rat (Fischer-344) 50 M, 50 F | 104 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, UR, GN, OW, HP | Hemat | 0.2 |  |  |  |\n| 37 | Rat (Fischer-344) 50 M, 50 F | 104 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, UR, GN, OW, HP | Musc/skel | 0.2 |  |  |  |\n| 37 | Rat (Fischer-344) 50 M, 50 F | 104 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, UR, GN, OW, HP | Hepatic | 0.2 |  |  |  |\n| 37 | Rat (Fischer-344) 50 M, 50 F | 104 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, UR, GN, OW, HP | Renal | 0.2 |  |  |  |\n| 37 | Rat (Fischer-344) 50 M, 50 F | 104 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, UR, GN, OW, HP | Dermal | 0.2 |  |  |  |\n| 37 | Rat (Fischer-344) 50 M, 50 F | 104 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, UR, GN, OW, HP | Endocr | 0.2 |  |  |  |\n| 37 | Rat (Fischer-344) 50 M, 50 F | 104 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, UR, GN, OW, HP | Immuno | 0.2 |  |  |  |\n| 37 | Rat (Fischer-344) 50 M, 50 F | 104 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, UR, GN, OW, HP | Neuro | 0.2 |  |  |  |\n| 37 | Rat (Fischer-344) 50 M, 50 F | 104 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, UR, GN, OW, HP | Repro | 0.2 |  |  |  |\n\n---\n\n**Table 2-1. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation\n(ppm)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| NTP 1994 |  |  |  |  |  |  |  |  |  |\n| 38 | Mouse (B6C3F1) 50 M, 50 F | 103 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, BW, GN, OW, HP | Death Bd wt Resp | 0.2 0.05c | 0.2 | 0.2 F | 57% mortality |\n| 38 | Mouse (B6C3F1) 50 M, 50 F | 103 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, BW, GN, OW, HP | Death Bd wt Resp | 0.2 0.05c | 0.2 | 0.2 F | Males: nasal suppurative inflammation, alveolar epithelium hyperplasia, and suppurative inflammation of the lung Females: nasal suppurative inflammation (BMCL10 for nasal suppurative inflammation in females = 0.0052 ppm)c |\n| 38 | Mouse (B6C3F1) 50 M, 50 F | 103 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, BW, GN, OW, HP | Cardio Gastro Hemat Muc/skel Hepatic Renal Dermal Endocr Immuno Neuro | 0.2 0.2 0.2 0.2 0.2 0.2 | 0.2 | 0.2 F | Males: nasal suppurative inflammation, alveolar epithelium hyperplasia, and suppurative inflammation of the lung Females: nasal suppurative inflammation (BMCL10 for nasal suppurative inflammation in females = 0.0052 ppm)c |\n\n---\n\n**Table 2-1. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation\n(ppm)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n|  |  |  |  |  | Repro | 0.01 F | 0.05 F | 0.2 F | LOAEL: Suppurative inflammation of the ovaries SLOAEL: Severe ovarian suppurative inflammation (associated with increased lethality) |\n|  |  |  |  |  |  | 0.2 M |  |  |  |\n\n<sup>a</sup>The number corresponds to entries in Figure 2-2; differences in levels of health effects and cancer effects between male and females are not indicated in \nFigure 2-2. Where such differences exist, only the levels of effect for the most sensitive sex are presented.\n\n$$\n1\\times10^{-4}\n$$\n\n<sup>b</sup>Used to derive a provisional intermediate-duration inhalation MRL of 1x10<sup>-4</sup> ppm based on a NOAEL of 0.146 ppm, which was converted into a NOAELHEC of \n0.00344 ppm and divided by an uncertainty factor of 30 (10 for human variability and 3 for animal to human extrapolation after dosimetric adjustment).\n<sup>c</sup>Used to derive a provisional chronic-duration inhalation MRL of 6x10<sup>-5</sup> ppm based on a BMCL10 of 0.052 ppm, which was converted into a BMCLHEC of \n0.0019 ppm and divided by an uncertainty factor of 30 (10 for human variability and 3 for animal to human extrapolation after dosimetric adjustment).\n\nGreen shading indicates the study selected for derivation of provisional inhalation MRLs.\n\nAST = aspartate aminotransferase; BC = blood chemistry; Bd wt or BW = body weight; BMCL = benchmark concentration lower confidence limit; BMCL10 = 95% \nlower confidence limit on the benchmark concentration (subscripts denote benchmark response: i.e., 10 = concentration associated with 10% extra risk); \nCardio = cardiovascular; CS = clinical signs; Endocr = endocrine; F = female(s); FI = food intake; Gastro = gastrointestinal; GN = gross necropsy; \nHE = hematology; HEC = human equivalent concentration; Hemato = hematological; HP = histopathology; Immuno = immunological; LC50 = median lethal \nconcentration; LE = lethality; LOAEL = lowest-observed-adverse-effect level; M = male(s); MCHC = mean corpuscular hemoglobin concentration; MCV = mean \ncorpuscular volume; MRL = Minimal Risk Level; Musc/skeletal = muscular/skeletal; Neuro = neurological; NOAEL = no-observed-adverse-effect level; NS = not \nspecified; OF = organ function; OP = ophthalmology; OW = organ weight; Repro = reproductive; Resp = respiratory; SLOAEL = serious lowest-observed-adverseeffect level; UR = urinalysis; (WB) = whole body; WI = water intake\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation**\nAcute (≤14 days)\n\n**Figure 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation Acute (≤14 days) - Death**\n\n| Category | Animal - LD50/LC50 (ppm) | Animal - NOAEL (ppm) | Animal - LOAEL (ppm) | Animal - SLOAEL (ppm) |\n| --- | --- | --- | --- | --- |\n| 1R |  |  |  | 0.45 |\n| 2R | 3.4 |  |  |  |\n| 3R | 2.6 |  |  |  |\n| 4R |  |  |  | 170 |\n| 5R | 1.6 |  |  |  |\n| 6R |  |  |  | 2.8 |\n| 7R |  |  | 1.4 |  |\n| 8R |  |  |  | 3.2 |\n| 9R |  |  |  | 2.8 |\n| 10R |  |  |  | 1.0 |\n| 11R |  |  |  | 7.0 |\n| 12R |  |  |  | 75 |\n| 13M |  |  |  | 7.5 |\n| 14M |  |  |  | 75 |\n| 15M |  |  |  | 3.2 |\n| 16M |  |  |  | 1.4 |\n| 17M |  |  |  | 1.5 |\n| 18M |  |  |  | 3.2 |\n| 19M |  |  |  | 1.0 |\n| 20H |  |  |  | 75 |\n| 21H |  |  |  | 1.4 |\n| 22H |  |  |  | 1.0 |\n| 23H |  |  |  | 1.4 |\n| 24H |  |  |  | 1.5 |\n| 25H |  |  |  | 3.2 |\n| 26H |  |  |  | 3.2 |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation**\nAcute (≤14 days)\n\n| Category | Body Weight Animal - LD50/LC50 (ppm) | Body Weight Animal - NOAEL (ppm) | Body Weight Animal - LOAEL (ppm) | Body Weight Animal - SLOAEL (ppm) | Respiratory Animal - LD50/LC50 (ppm) | Respiratory Animal - NOAEL (ppm) | Respiratory Animal - LOAEL (ppm) | Respiratory Animal - SLOAEL (ppm) | Cardiovascular Animal - LD50/LC50 (ppm) | Cardiovascular Animal - NOAEL (ppm) | Cardiovascular Animal - LOAEL (ppm) | Cardiovascular Animal - SLOAEL (ppm) | Hematological Animal - LD50/LC50 (ppm) | Hematological Animal - NOAEL (ppm) | Hematological Animal - LOAEL (ppm) | Hematological Animal - SLOAEL (ppm) |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| 1R |  | 0.12 |  | 0.5 |  | 0.12 |  | 0.5 |  | 0.5 |  |  |  | 0.12 |  | 0.5 |\n| 2R |  | 1.8 |  | 2.6 |  |  |  | 1.8 |  |  |  |  |  |  |  |  |\n| 3R |  |  |  | 1.8 |  |  |  | 1.8 |  |  |  |  |  |  |  |  |\n| 5R |  | 0.26 |  | 1.4 |  |  |  |  |  |  |  |  |  |  |  |  |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation**\nAcute (≤14 days)\n\n**Figure 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation Acute (≤14 days)**\n\n| Category | Animal - NOAEL (ppm) | Animal - LOAEL (ppm) | Animal - SLOAEL (ppm) |\n| --- | --- | --- | --- |\n| Hepatic | 0.5 |  |  |\n| Renal | 0.45 |  |  |\n| Immunological | 0.5 |  |  |\n| Neuological | 0.4 | 1.4 | 5.5 |\n| Other Noncancer | 0.12 | 0.45 | 1.7 |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation**\nIntermediate (15–364 days)\n\n**Figure 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation Intermediate (15–364 days)**\n\n| Category | Death Animal - NOAEL (ppm) | Death Animal - LOAEL (ppm) | Death Animal - SLOAEL (ppm) | Body Weight Animal - NOAEL (ppm) | Body Weight Animal - LOAEL (ppm) | Body Weight Animal - SLOAEL (ppm) | Respiratory Animal - NOAEL (ppm) | Respiratory Animal - LOAEL (ppm) | Respiratory Animal - SLOAEL (ppm) |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| 29R |  |  | 0.6 | 0.5 |  |  | 0.15 |  | 0.6 |\n| 30R |  |  | 1.0 | 0.4 |  |  | 0.15 | 0.45 | 1.0 |\n| 31R |  |  | 2.3 |  |  |  |  |  |  |\n| 32M |  |  | 0.55 |  | 0.5 |  |  | 0.5 |  |\n| 33M |  |  | 2.6 |  |  |  |  |  |  |\n| 36M |  |  | 0.4 | 0.45 |  |  | 0.15 | 0.45 |  |\n| 27K |  |  |  | 0.2 |  |  | 0.2 |  |  |\n| 28R |  |  |  | 0.2 |  |  | 0.2 |  |  |\n| 34M |  |  |  | 0.55 |  |  |  | 0.5 |  |\n| 35M |  |  |  | 0.2 |  |  |  | 0.2 |  |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation**\nIntermediate (15–364 days)\n\n**Figure 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation Intermediate (15–364 days)**\n\n| Category | Cardiovascular Animal - NOAEL (ppm) | Cardiovascular Animal - LOAEL (ppm) | Cardiovascular Animal - SLOAEL (ppm) | Gastrointestinal Animal - NOAEL (ppm) | Gastrointestinal Animal - LOAEL (ppm) | Gastrointestinal Animal - SLOAEL (ppm) | Hematological Animal - NOAEL (ppm) | Hematological Animal - LOAEL (ppm) | Hematological Animal - SLOAEL (ppm) |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| 27K | 0.22 |  |  | 0.22 |  |  | 0.22 |  |  |\n| 28R | 0.22 |  |  | 0.22 |  |  | 0.22 |  |  |\n| 29R | 0.55 |  |  | 0.55 |  |  | 0.060 | 0.15 |  |\n| 30R | 0.44 |  |  | 0.44 |  |  | 0.17 | 0.44 |  |\n| 36M | 0.44 |  |  | 0.44 |  |  | 0.17 | 0.44 |  |\n| 32M |  |  |  | 0.50 |  |  |  |  |  |\n| 35M |  |  |  | 0.22 |  |  |  |  |  |\n| 31R |  |  |  |  |  |  | 0.040 | 0.44 |  |\n| 33M |  |  |  |  |  |  |  | 0.044 |  |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation**\nIntermediate (15–364 days)\n\n**Figure 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation Intermediate (15–364 days)**\n\n| Category | Musculoskeletal Animal - NOAEL (ppm) | Musculoskeletal Animal - LOAEL (ppm) | Musculoskeletal Animal - SLOAEL (ppm) | Hepatic Animal - NOAEL (ppm) | Hepatic Animal - LOAEL (ppm) | Hepatic Animal - SLOAEL (ppm) | Renal Animal - NOAEL (ppm) | Renal Animal - LOAEL (ppm) | Renal Animal - SLOAEL (ppm) |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| 27K | 0.22 |  |  | 0.20 |  |  | 0.20 |  |  |\n| 28R | 0.20 |  |  | 0.22 |  |  | 0.20 |  |  |\n| 29R | 0.55 |  |  | 0.60 |  |  | 0.55 |  |  |\n| 30R | 0.44 |  |  | 0.40 |  |  | 0.40 |  |  |\n| 36M | 0.44 |  |  | 0.44 |  |  | 0.44 |  |  |\n| 31R |  |  |  | 0.44 |  |  | 2.2 |  |  |\n| 31R |  |  |  |  |  | 2.4 |  |  |  |\n| 32M |  |  |  | 0.55 |  |  | 0.60 |  |  |\n| 33M |  |  |  | 2.4 |  |  | 2.4 |  |  |\n| 35M |  |  |  | 0.20 |  |  | 0.20 |  |  |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation**\nIntermediate (15–364 days)\n\n**Figure 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation Intermediate (15–364 days)**\n\n| Category | Animal - NOAEL (ppm) | Animal - LOAEL (ppm) | Animal - SLOAEL (ppm) |\n| --- | --- | --- | --- |\n| Dermal 29R | 0.55 |  |  |\n| Ocular 27K | 0.20 |  |  |\n| Ocular 28R | 0.20 |  |  |\n| Ocular 29R | 0.55 |  |  |\n| Endocrine 27K | 0.20 |  |  |\n| Endocrine 28R | 0.20 |  |  |\n| Endocrine 29R | 0.60 |  |  |\n| Endocrine 30R | 0.40 |  |  |\n| Endocrine 32M | 0.50 |  |  |\n| Endocrine 36M | 0.40 |  |  |\n| Immunological 27K | 0.20 |  |  |\n| Immunological 28R | 0.20 |  |  |\n| Immunological 29R | 0.60 |  |  |\n| Immunological 30R | 0.40 |  |  |\n| Immunological 32M | 0.55 |  |  |\n| Immunological 35M | 0.20 |  |  |\n| Immunological 36M | 0.40 |  |  |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation**\nIntermediate (15–364 days)\n\n**Figure 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation Intermediate (15–364 days)**\n\n| Category | Neuropsychological Animal - NOAEL (ppm) | Neuropsychological Animal - LOAEL (ppm) | Neuropsychological Animal - SLOAEL (ppm) | Reproductive Animal - NOAEL (ppm) | Reproductive Animal - LOAEL (ppm) | Reproductive Animal - SLOAEL (ppm) | Other Noncancer Animal - NOAEL (ppm) | Other Noncancer Animal - LOAEL (ppm) | Other Noncancer Animal - SLOAEL (ppm) |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| 27K | 0.22 |  |  | 0.22 |  |  | 0.22 |  |  |\n| 28R | 0.22 |  |  | 0.22 |  |  | 0.22 |  |  |\n| 29R | 0.55 |  |  | 0.55 |  |  | 0.55 |  |  |\n| 30R | 0.44 |  |  | 0.44 |  |  |  |  |  |\n| 35M | 0.22 |  |  | 0.22 |  |  |  |  |  |\n| 36M | 0.44 |  |  | 0.44 |  |  |  |  |  |\n| 32M |  |  |  | 0.55 |  |  |  |  |  |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation**\nChronic (≥365 days)\n\n**Figure 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation Chronic (≥365 days)**\n\n| Category | R-Rat Animal - NOAEL (ppm) | R-Rat Animal - LOAEL (ppm) | R-Rat Animal - SLOAEL (ppm) | M-Mouse Animal - NOAEL (ppm) | M-Mouse Animal - LOAEL (ppm) | M-Mouse Animal - SLOAEL (ppm) | M-Mouse MRL for effect other than cancer (ppm) |\n| --- | --- | --- | --- | --- | --- | --- | --- |\n| Death |  |  |  |  |  | 0.22 |  |\n| Body Weight |  |  |  | 0.22 |  |  |  |\n| Respiratory | 0.22 |  |  |  | 0.055 | 0.22 | 0.006 |\n| Cardiovascular | 0.22 |  |  | 0.22 |  |  |  |\n| Gastrointestinal |  |  |  | 0.22 |  |  |  |\n| unlabelled 1 |  |  |  | 0.22 |  |  |  |\n\n---\n\n2.  HEALTH EFFECTS\n\n**Figure 2-2.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation**\nChronic (≥365 days)\n\n| Category | R-Rat (ppm) | M-Mouse (ppm) |\n| --- | --- | --- |\n| Hematological | 0.22 | 0.22 |\n| Musculoskeletal | 0.22 | 0.22 |\n| Hepatic | 0.22 | 0.22 |\n| Renal | 0.22 | 0.22 |\n| Dermal | 0.22 | 0.22 |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation**\nChronic (≥365 days)\n\n**Figure 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation Chronic (≥365 days)**\n\n| Category | Endocrine Animal - NOAEL (ppm) | Endocrine Animal - LOAEL (ppm) | Endocrine Animal - SLOAEL (ppm) | Immunological Animal - NOAEL (ppm) | Immunological Animal - LOAEL (ppm) | Immunological Animal - SLOAEL (ppm) | Neuological Animal - NOAEL (ppm) | Neuological Animal - LOAEL (ppm) | Neuological Animal - SLOAEL (ppm) | Reproductive Animal - NOAEL (ppm) | Reproductive Animal - LOAEL (ppm) | Reproductive Animal - SLOAEL (ppm) |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| 37R | 0.23 |  |  | 0.23 |  |  | 0.23 |  |  | 0.23 |  |  |\n| 38M | 0.23 |  |  | 0.23 |  |  | 0.23 |  |  | 0.011 | 0.055 | 0.23 |\n\n---\n\n**Table 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Oral\n(mg/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| ACUTE EXPOSURE |  |  |  |  |  |  |  |  |  |\n| Gardner 1986a |  |  |  |  |  |  |  |  |  |\n| 1 | Rat (CFY) 5 M, 5 F | Once (GO) | 1,260, 1,600, 2,000 | LE, CS, BW, GN | Death |  |  | 1,300 F 1,500 M | LD50 LD50 |\n| 1 | Rat (CFY) 5 M, 5 F | Once (GO) | 1,260, 1,600, 2,000 | LE, CS, BW, GN | Resp Gastro Neuro |  | 1,260 | 1,260 | Decreased respiratory rate Diarrhea Abnormal gait, lethargy |\n| OxyChem 1972 |  |  |  |  |  |  |  |  |  |\n| 2 | Rat (Spartan) 25 M, 25 F | Once (GO) | 315, 500, 794, 1,250, 1,984 | LE | Death |  |  | 530 F 630 M | LD50 LD50 |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 3 | Rat 9–11 M | Once (GO) | 280, 340, 420, 520, 620, 940, 1,400 | LE, CS, GN | Death |  |  | 505 | LD50 |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 4 | Rat 10 F | Once (GO) | 280, 940, 1,400, 2,100 | LE, CS, GN | Death |  |  | 940 | 9/10 died |\n| Chernoff and Kavlock 1982, 1983; Gray and Kavlock 1984; Gray et al. 1986 |  |  |  |  |  |  |  |  |  |\n| 5 | Mouse (CD-1) 16 F | 5 days GDs 8–12 (GO) | 0, 45 | BW, DX | Bd wt Develop | 45 |  |  |  |\n\n$$\n\\mathsf{L}\\mathsf{D}_{50}\n$$\n\nOffspring evaluated through PND 250 for postnatal viability, growth, locomotor activity, female sexual development, and reproductive function\n\n---\n\n**Table 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Oral\n(mg/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Dean 1977 |  |  |  |  |  |  |  |  |  |\n| 6 | Mouse (CD-1) 5 M, 5 F | Once (GO) | 21.5, 46.4, 100, 215, 464, 1,000, 2,150 | LE, CS, BW | Death Resp Gastro | 1,000 215 F 464 M 464 | 464 F 1,000 M 1,000 | 679 2,150 | LD50 Decreased respiratory rate Diarrhea Diarrhea Decreased limb tone in animals that died LOAEL: Hypoactivity SLOAEL: Ataxia |\n| 6 | Mouse (CD-1) 5 M, 5 F | Once (GO) | 21.5, 46.4, 100, 215, 464, 1,000, 2,150 | LE, CS, BW | Musc/skel | 215 | 464 | 1,000 | LOAEL: Hypoactivity SLOAEL: Ataxia |\n| Murray et al. 1980 |  |  |  |  |  |  |  |  |  |\n| 7 | Mouse (CF-1) NS F | 10 days GDs 6–15 (GO) | 0, 5, 25, 75 | LE, CS, BW, FI, WI, RX, DX | Bd wt Develop Other noncancer | 75 75 75 |  |  |  |\n| Murray et al. 1980 |  |  |  |  |  |  |  |  |  |\n| 8 | Mouse (CF-1) 5 F | 10 days GDs 6–15 (GO) | 0, 25, 75, 250, 500 | LE, CS, BW | Death |  |  | 250 | 3/5 dams died |\n| Murray et al. 1980 |  |  |  |  |  |  |  |  |  |\n| 9 | Rabbit (New Zealand) NS F | 13 days GDs 6–18 (GO) | 0, 5, 25, 75 | LE, CS, BW, RX, DX | Death Develop | 25 | 75 | 75 | Unspecified increased maternal death during pregnancy Increased proportion of fetuses with 13 ribs |\n| Murray et al. 1980 |  |  |  |  |  |  |  |  |  |\n| 10 | Rabbit (New Zealand) 5 F | 13 days GDs 6–18 (GO) | 0, 25, 75, 250, 500 | LE, CS, BW | Death |  |  | 250 | 4/5 does die |\n\n---\n\n**Table 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Oral\n(mg/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 11 | Rabbit 3 F | Once (GO) | 180, 280, 420, 620, 940 | LE, CS, GN | Death |  |  | 940 | 3/3 died |\n| INTERMEDIATE EXPOSURE |  |  |  |  |  |  |  |  |  |\n| Abdo et al. 1984; Velsicol 1981b |  |  |  |  |  |  |  |  |  |\n| 12 | Rat (Fischer-344) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 10, 19, 38, 75, 150 | LE, BW, GN, OW, HP | Death Bd wt | 38 F | 75 F | 150 M | 60% treatment-related mortality 15% decreased terminal body weight LOAEL: 13% decreased terminal body weight SLOAEL: 30% decreased terminal body weight Forestomach epithelial hyperplasia and focal inflammation (BMDL10 for combined incidence of forestomach lesions = 7.7 mg/kg/day)b |\n| 12 | Rat (Fischer-344) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 10, 19, 38, 75, 150 | LE, BW, GN, OW, HP | Resp Cardio Gastro | 150 150 19b | 38 |  |  |\n| 12 | Rat (Fischer-344) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 10, 19, 38, 75, 150 | LE, BW, GN, OW, HP | Hemato Musc/skel | 150 150 150 Renal | 38 |  | Toxic nephrosis |\n| 12 | Rat (Fischer-344) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 10, 19, 38, 75, 150 | LE, BW, GN, OW, HP | Dermal | 150 |  |  |  |\n| 12 | Rat (Fischer-344) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 10, 19, 38, 75, 150 | LE, BW, GN, OW, HP | Endocr | 150 |  |  |  |\n| 12 | Rat (Fischer-344) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 10, 19, 38, 75, 150 | LE, BW, GN, OW, HP | Immuno | 150 |  |  |  |\n| 12 | Rat (Fischer-344) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 10, 19, 38, 75, 150 | LE, BW, GN, OW, HP | Neuro | 150 |  |  |  |\n| 12 | Rat (Fischer-344) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 10, 19, 38, 75, 150 | LE, BW, GN, OW, HP | Repro | 150 |  |  |  |\n\n---\n\n**Table 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Oral\n(mg/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Abdo et al. 1984; Velsicol 1981a |  |  |  |  |  |  |  |  |  |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP | Death |  |  | 300 | 10/10 males died, 3/10 females died 11% decreased terminal body weight 13% decreased terminal body weight |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP | Bd wt | 75 M | 150 F | 300 | 10/10 males died, 3/10 females died 11% decreased terminal body weight 13% decreased terminal body weight |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP |  | 150 F | 300 F | 300 | 10/10 males died, 3/10 females died 11% decreased terminal body weight 13% decreased terminal body weight |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP | Resp | 300 |  |  |  |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP | Cardio | 300 |  |  |  |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP | Gastro | 38 | 75 |  | Focal inflammation and epithelial hyperplasia of the forestomach |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP | Hemato | 300 |  |  |  |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP | Musc/skel | 300 |  |  |  |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP | Hepatic | 300 |  |  |  |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP | Renal | 38 F | 75 F |  | Toxic nephrosis |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP |  | 150 M | 300 M |  | Acute tubular necrosis |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP | Dermal | 300 |  |  |  |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP | Endocr | 300 |  |  |  |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP | Immuno | 300 |  |  |  |\n\n---\n\n**Table 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Oral\n(mg/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n|  |  |  |  |  | Neuro Repro | 300 300 |  |  |  |\n\n<sup>a</sup>The number corresponds to entries in Figure 2-3; differences in levels of health effects between male and females are not indicated in Figure 2-3.  Where such \ndifferences exist, only the levels of effect for the most sensitive sex are presented.\n\n<sup>b</sup>Used to derive a provisional intermediate-duration oral MRL of 0.06 mg/kg/day based on a BMDL10 of 7.7 mg/kg/day, which was adjusted to continuous duration \nexposure to a BMDLADJ of 5.5 mg/kg/day and divided by an uncertainty factor of 100 (10 for human variability and 10 for animal to human extrapolation).  See \nAppendix A for more detailed information regarding the MRL.\n\nGreen shading indicates the study selected for derivation of the provisional oral MRL.\n\nADJ = adjusted; Bd wt or BW = body weight; BMDL = benchmark dose lower confidence limit; BMDL10 = 95% benchmark dose lower confidence limit (subscript \ndenotes benchmark response: i.e., 10 = dose associated with 10% extra risk); Cardio = cardiovascular; CS = clinical signs; Develop = developmental; \nDX = developmental toxicity; Endocr = endocrine; F = female(s); FI = food intake; Gastro = gastrointestinal; GD = gestation day; GN = gross necropsy; \n(GO) = gavage in oil; Hemato = hematological; HP = histopathology; Immuno = immunological; LD50 = median lethal dose; LE = lethality; LOAEL = lowestobserved-adverse-effect level; M = male(s); MRL = Minimal Risk Level; Musc/skeletal = muscular/skeletal; Neuro = neurological; NOAEL = no-observed-adverseeffect level; NS = not specified; OW = organ weight; PND = postnatal day; Repro = reproductive; Resp = respiratory; RX = reproductive function; \nSLOAEL = serious lowest-observed-adverse-effect level; WI = water intake\n\n---\n\n**Figure 2-3.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Oral**\nAcute (≤14 days)\n\n| Category | Animal - LD50/LC50 (mg/kg/day) | Animal - NOAEL (mg/kg/day) | Animal - LOAEL (mg/kg/day) | Animal - SLOAEL (mg/kg/day) |\n| --- | --- | --- | --- | --- |\n| 1R | 1300 |  |  |  |\n| 2R | 530 |  |  |  |\n| 3R | 500 |  |  |  |\n| 4R |  |  |  | 950 |\n| 6M | 660 |  |  |  |\n| 8M |  |  |  | 300 |\n| 9H |  |  |  | 75 |\n| 10H |  |  |  | 280 |\n| 11H |  |  |  | 950 |\n| 5M |  | 50 |  |  |\n| 7M |  | 80 |  |  |\n| 1R |  |  |  | 1200 |\n| 6M |  | 1000 |  | 2400 |\n\n---\n\n**Figure 2-3.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Oral**\nAcute (≤14 days)\n\n| Category | R-Rat (mg/kg/day) | M-Mouse (mg/kg/day) | H-Rabbit (mg/kg/day) |\n| --- | --- | --- | --- |\n| Animal - LD50/LC50 |  |  |  |\n| Animal - NOAEL |  | 130 |  |\n| Animal - LOAEL |  |  | 1300 |\n| Animal - SLOAEL |  |  | 1000 |\n\n---\n\n**Figure 2-3.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Oral**\nIntermediate (15–364 days)\n\n| Category | R-Rat Animal - NOAEL (mg/kg/day) | R-Rat Animal - LOAEL (mg/kg/day) | R-Rat Animal - SLOAEL (mg/kg/day) | M-Mouse Animal - NOAEL (mg/kg/day) | M-Mouse Animal - LOAEL (mg/kg/day) | M-Mouse Animal - SLOAEL (mg/kg/day) |\n| --- | --- | --- | --- | --- | --- | --- |\n| Death |  |  |  |  |  |  |\n| 12R |  |  | 150 |  |  |  |\n| 13M |  |  | 330 |  |  |  |\n| Body Weight |  |  |  |  |  |  |\n| 12R | 20 |  |  |  |  |  |\n| 12R |  | 40 |  |  |  |  |\n| 12R |  |  | 75 |  |  |  |\n| 13M |  | 80 |  |  |  |  |\n| 13M |  |  | 150 |  |  |  |\n| 13M |  |  | 160 |  |  |  |\n| Respiratory |  |  |  |  |  |  |\n| 12R | 160 |  |  |  |  |  |\n| 13M | 330 |  |  |  |  |  |\n| Cardiovascular |  |  |  |  |  |  |\n| 12R | 150 |  |  |  |  |  |\n| 13M | 330 |  |  |  |  |  |\n| Gastrointestinal |  |  |  |  |  |  |\n| 12R BMDL | 8.0 |  |  |  |  |  |\n| 12R | 20 |  |  |  |  |  |\n| 12R |  | 44 |  |  |  |  |\n| 13M | 40 |  |  |  |  |  |\n| 13M |  |  | 80 |  |  |  |\n\n---\n\n**Figure 2-3.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Oral**\nIntermediate (15–364 days)\n\n| Category | R-Rat Animal - NOAEL (mg/kg/day) | R-Rat Animal - LOAEL (mg/kg/day) | R-Rat Animal - SLOAEL (mg/kg/day) | M-Mouse Animal - NOAEL (mg/kg/day) | M-Mouse Animal - LOAEL (mg/kg/day) | M-Mouse Animal - SLOAEL (mg/kg/day) |\n| --- | --- | --- | --- | --- | --- | --- |\n| Hematological | 150 |  |  | 330 |  |  |\n| Musculoskeletal |  |  |  | 150 |  |  |\n| Hepatic |  |  |  | 150 |  |  |\n| Renal | 20 | 44 |  | 36 |  | 80 |\n| Dermal |  |  |  | 150 |  | 330 |\n\n---\n\n**Figure 2-3.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Oral**\nIntermediate (15–364 days)\n\n**Figure 2-3. Levels of Significant Exposure to Hexachlorocyclopentadiene – Oral Intermediate (15–364 days)**\n\n| Category | Animal - NOAEL (mg/kg/day) | Animal - LOAEL (mg/kg/day) | Animal - SLOAEL (mg/kg/day) |\n| --- | --- | --- | --- |\n| Endocrine 12R | 160 |  |  |\n| Endocrine 13M | 330 |  |  |\n| Immunological 12R | 160 |  |  |\n| Immunological 13M | 330 |  |  |\n| Neuological 12R | 160 |  |  |\n| Neuological 13M | 330 |  |  |\n| Reproductive 12R | 160 |  |  |\n| Reproductive 13M | 330 |  |  |\n\n---\n\n**Table 2-3. Levels of Significant Exposure to Hexachlorocyclopentadiene – Dermal**\n\n| Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| ACUTE EXPOSURE |  |  |  |  |  |  |  |  |\n| Kominsky et al. 1980 |  |  |  |  |  |  |  |  |\n| Human 154 M, 23 F | 3–15 days | ≤0.97 ppm | CS, BC | Dermal Ocular |  | 0.97 0.97 |  | Skin irritation Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Monkey 1 NS | Once | 0.001, 0.01, 0.1, 1, 10% (0.01 mL); 20, 40, 60, 90% (0.05 mL) | CS | Dermal | 10 | 20 |  | Skin discoloration and swelling |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Monkey 1 NS | 3 days Once/day | 10% | CS | Dermal |  |  | 10 | Skin irritation, necrosis, hemorrhaging |\n| Alexander et al. 1980a; Rand et al. 1982a |  |  |  |  |  |  |  |  |\n| Rat (Sprague-Dawley) 10 M, 10 F | 1–2 weeks 5 days/week 6 hours/day | 0, 0.022, 0.11, 0.5 ppm | CS | Ocular | 0.11 | 0.5 |  | Dark red eyes |\n| Gardner 1986b |  |  |  |  |  |  |  |  |\n| Rat (CFY) 5 M, 5 F | 24 hours | 1,600, 2,000, 3,200 mg/kg | LE, CS, BW, GN | Death |  |  | 3,100 F 2,600 M | LD50 LD50 |\n| Rat (CFY) 5 M, 5 F | 24 hours | 1,600, 2,000, 3,200 mg/kg | LE, CS, BW, GN | Dermal |  | 1,600 |  | Moderate to severe edema |\n| Jackson and Hardy 1986 |  |  |  |  |  |  |  |  |\n| Rat (Wistar) 5 M, 5 F | 1 hour | 0, 1.67, 2.38, 3.53, 6.25, 8.30 ppm | CS | Ocular |  | 1.67 |  | Total or partial closing of the eyes |\n| Jackson and Hardy 1987 |  |  |  |  |  |  |  |  |\n| Rat (Wistar) 5 M, 5 F | 4 hours | 0, 1.68, 1.83, 3.31, 3.47 ppm | CS | Ocular |  | 1.68 |  | Total or partial closing of the eyes |\n| Rand et al. 1982a |  |  |  |  |  |  |  |  |\n| Rat (Sprague-Dawley) 10 M, 10 F | 4 hours | 0.28, 1.4, 2.5, 3.1, 3.3, 3.4, 4, 5.8 ppm | CS | Ocular | 4 | 5.8 |  | Lacrimation |\n\n$$\n\\mathsf{L}\\mathsf{D}_{50}\n$$\n\n$$\n\\mathsf{L}\\mathsf{D}_{50}\n$$\n\n---\n\n**Table 2-3. Levels of Significant Exposure to Hexachlorocyclopentadiene – Dermal**\n\n| Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rat 4 NS | 5 days 7 hours/day | 0.33, 1, 1.6 ppm | CS | Ocular |  | 0.33 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rat 4 NS | 3 days 7 hours/day | 1.4 ppm | CS | Ocular |  | 1.4 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rat 4 NS | 4 hours | 73.6 ppm | CS | Ocular |  | 73.6 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rat 4 NS | 7 hours | 1.5, 3.2, 6.7 ppm | CS | Ocular |  | 1.5 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rat 4 NS | 2.6–3.6 hours | 1.4, 3.1, 7.1, 11.1, 12.7, 46.5, 56.9, 70.4 ppm | CS | Ocular |  | 1.4 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rat 3–4 NS | 0.25–1.25 hours | 1.4, 1.5, 3.1, 7.2, 13.0, 13.8, 19.4, 20.0, 20.2, 69.1, 69.2 ppm | CS | Ocular |  | 1.4 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rat 4 NS | 2 days 7 hours/day | 3.2 ppm | CS | Ocular |  | 3.2 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Mouse 4–5 NS | 0.25–1.25 hours | 1.4, 1.5, 3.1, 7.2, 13.0, 13.8, 19.4, 20.0, 20.2, 69.1, 69.2 ppm | CS | Ocular |  | 1.4 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Mouse 5 NS | 7 hours | 1.5, 3.2, 6.7 ppm | CS | Ocular |  | 1.5 |  | Eye irritation |\n\n---\n\n**Table 2-3. Levels of Significant Exposure to Hexachlorocyclopentadiene – Dermal**\n\n| Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Mouse 5 NS | 2.6–3.6 hours | 1.4, 3.1, 7.1, 12.4, 12.7, 46.5, 56.9, 70.4 ppm | CS | Ocular |  | 1.4 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Mouse 5 NS | 4 hours | 73.6 ppm | CS | Ocular |  | 73.6 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Mouse 5 NS | 2 days 7 hours/day | 3.2 ppm | CS | Ocular |  | 3.2 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Mouse 5 NS | 3 days 7 hours/day | 1.4 ppm | CS | Ocular |  | 1.4 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Mouse 5 NS | 5 days 7 hours/day | 0.33, 1.0, 1.6 ppm | CS | Ocular |  | 0.33 |  | Eye irritation |\n| OxyChem 1972 |  |  |  |  |  |  |  |  |\n| Rabbit (New Zealand) 3 M, 3 F | 4 hours | 0.5 mL | LE, CS | Death Dermal Neuro | 0.5 | 0.5 | 0.5 | 3/6 died Moderate to severe edema Ataxia and hypoactivity |\n| OxyChem 1972 |  |  |  |  |  |  |  |  |\n| Rabbit (New Zealand) 5 NS | 5 minutes | 0.1 mL | LE, CS | Death |  | 0.1 | 5/5 died within 9 days |  |\n| OxyChem 1972 |  |  |  |  |  |  |  |  |\n| Rabbit (New Zealand) 2 M, 2 F | Once | 200, 2,000 mg/kg | LE, CS, BW | Death |  | 200 M 2,000 F | 2/2 died within 14 days 2/2 died within 24 hours Dermal irritation and discoloration Hypoactivity |  |\n|  |  |  |  | Dermal Neuro | 200 200 M |  |  |  |\n\n---\n\n**Table 2-3. Levels of Significant Exposure to Hexachlorocyclopentadiene – Dermal**\n\n| Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| OxyChem 1972 |  |  |  |  |  |  |  |  |\n| Rabbit (New Zealand) 3 NS | 24 hours | 0.1 mL | LE, CS | Death Ocular |  |  | 0.1 0.1 | 3/3 died within 6 days Severe eye irritation and corrosion |\n| OxyChem 1992 |  |  |  |  |  |  |  |  |\n| Rabbit (New Zealand) 12 NS | 24 hours | 200 mg/kg | LE, CS | Death Dermal |  |  | 200 200 | 8/12 died Eschar formation |\n| OxyChem 1992 |  |  |  |  |  |  |  |  |\n| Rabbit (New Zealand) 6 NS | 4 hours | 0.5 mL | LE, CS | Dermal |  |  | 0.5 | Erythema, edema, necrosis |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rabbit 1–3 F | 24 hours | 430, 610, 1,020, 2,130, 6,130 mg/kg | LE, CS, GN | Death Dermal |  | 430 | 1020 | 2/3 died Skin irritation, discoloration, subcutaneous edema, acanthosis, epiulation, hyperkeratosis, chronic inflammation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rabbit 3 NS | 4 hours | 73.6 ppm | CS | Ocular |  | 73.6 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rabbit 3 NS | 2.6–3.6 hours | 1.4, 3.1, 7.1, 12.4, 12.7, 46.5, 56.9, 70.4 ppm | CS | Ocular |  | 1.4 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rabbit 3 NS | 7 hours | 1.5, 3.2, 6.7 ppm | CS | Ocular |  | 1.5 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rabbit 3 NS | 0.25–1.25 hours | 1.4, 1.5, 3.1, 7.2, 13.0, 13.8, 19.4, 20.0, 20.2, 69.1, 69.2 ppm | CS | Ocular |  | 1.4 |  | Eye irritation |\n\n---\n\n**Table 2-3. Levels of Significant Exposure to Hexachlorocyclopentadiene – Dermal**\n\n| Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rabbit 3 NS | 2 days 7 hours/day | 3.2 ppm | CS | Ocular |  | 3.2 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rabbit 3 NS | 3 days 7 hours/day | 1.4 ppm | CS | Ocular |  | 1.4 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rabbit 3 NS | 5 days 7 hours/day | 1, 1.6 ppm | CS | Ocular |  | 1 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Guinea pig 2 NS | Once | 0.01, 0.1, 1, 40, 60, 90% | CS | Dermal | 1 | 40 |  | Skin discoloration and irritation |\n| INTERMEDIATE EXPOSURE |  |  |  |  |  |  |  |  |\n| Alexander et al. 1980b; Rand et al. 1982a |  |  |  |  |  |  |  |  |\n| Monkey (Cynomolgus) 6 M, 6 F | 14 weeks 5 days/week 6 hours/day | 0, 0.01, 0.05, 0.2 ppm | CS | Ocular | 0.2 |  |  |  |\n| Alexander et al. 1980b; Rand et al. 1982a |  |  |  |  |  |  |  |  |\n| Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day | 0, 0.01, 0.05, 0.2 ppm | CS | Ocular | 0.01 | 0.05 |  | Dark red eyes |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rat 4 NS | 30 weeks 5 days/week 7 hours/day | 0.15 ppm | CS | Ocular | 0.15 |  |  |  |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rat 4 NS | 6 weeks 5 days/week 7 hours/day | 0.34 ppm | CS | Ocular |  | 0.34 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Mouse 5 NS | 30 weeks 5 days/week 7 hours/day | 0.15 ppm | CS | Ocular | 0.15 |  |  |  |\n\n***DRAFT FOR PUBLIC COMMENT***\n\n---\n\n**Table 2-3. Levels of Significant Exposure to Hexachlorocyclopentadiene – Dermal**\n\n| Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Mouse 5 NS | 6 weeks 5 days/week 7 hours/day (WB) | 0.34 ppm | CS | Ocular |  | 0.34 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rabbit 6 NS | 6 weeks 5 days/week 7 hours/day | 0.34 ppm | CS | Ocular |  | 0.34 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rabbit 2 NS | 30 weeks 5 days/week 7 hours/day | 0.15 ppm | CS | Ocular | 0.15 |  |  |  |\n\nBC = serum (blood) chemistry; BW = body weight; CS = clinical signs; F = female(s); GN = gross necropsy; LD50 = median lethal dose; LE = lethality; \nLOAEL = lowest-observed-adverse-effect level; M = male(s); Neuro = neurological; NOAEL = no-observed-adverse-effect level; NS = not specified; (WB) = wholebody exposure\n\n---\n\n###### 2.2 DEATH\n\nNo studies were located regarding mortality in humans after exposure to HCCPD.\n\nHCCPD induced death in experimental animals via the inhalation, oral, and dermal routes.  The lethality \nof HCCPD following inhalation exposures has been evaluated for acute-, intermediate-, and chronicduration studies.  Acute-duration inhalation exposures to HCCPD at 1.0–73.6 ppm were lethal to rats, \nmice, guinea pigs, and rabbits in a concentration- and exposure duration-related manner (Treon et al. \n1955).  For example, the concentrations that produced 50% fatalities in mice after 1-, 3.5-, and 7-hour \nexposures were 7.2, <3.1, and <1.5 ppm, respectively.  Species-specific differences were observed in the \nmortality data; the concentrations that produced 50% fatalities after 3.5-hour exposures were 7.1 ppm for \nguinea pigs, 3.1 ppm for rats, <3.1 ppm for mice, and <1.4 ppm for rabbits.  All 10 rats exposed to \n176 ppm HCCPD for 4 hours died within 48 hours of the exposure period (OxyChem 1972).  The 1- and \n4-hour inhalation LC50 values for rats are 3.69 ppm (Jackson and Hardy 1986) and 2.9 ppm (Jackson and \nHardy 1987), respectively.  Male rats appear to be more susceptible to HCCPD lethality than female rats; \nthe sex-specific 4-hour inhalation median lethal concentration (LC50) values are 1.6 ppm for males and \n3.5 ppm for females (Rand et al. 1982a).  With 2-week exposures to 0.5 ppm HCCPD, one rat of each sex \ndied, and nine male rats and one female rat were sacrificed in moribund condition by the end of the \nexposure period.  When the exposure duration was reduced to 5 days, three of five males and none of five\nfemales died at 0.5 ppm.  All animals exposed to ≤0.11 ppm survived until the scheduled sacrifice\n(Alexander et al. 1980a; Rand et al. 1982a).\n\n$$\n\\mathrm{LC}_{50}\n$$\n\n$$\n\\left(LC_{50}\\right)\n$$\n\nIn 13-week studies, all rats and mice exposed to ≥0.941 ppm HCCPD died during the exposure periods \n(NTP 1994).  As was observed after acute-duration inhalation exposures, mice appeared to be more \nsensitive to HCCPD-induced lethality; all mice exposed to 2.142 ppm died during the first week while \nrats exposed to 2.065 ppm survived for up to 3 weeks.  Additionally, no rat mortalities were observed at \n≤0.385 ppm, while 5 of 10 male mice died at 0.389 ppm.  NTP (1994) hypothesized that the sensitivity of \nmice to inhalation exposure was the result of HCCPD-induced inflammation of the breathing passages \nand the narrower diameter of the mouse air passages.  No treatment-related deaths were reported for rats \nor monkeys exposed to ≤0.2 ppm for 14 weeks (Alexander et al. 1980b; Rand et al. 1982a) and overall \nsurvival was not statistically significantly affected by HCCPD treatment in male mice exposed to 0.2 ppm \nfor 33 weeks or 0.5 ppm for 26 weeks (NTP 1994).  Although overall survival of male rats was not \naffected after exposure to 0.5 ppm for 42 weeks, survival in this group decreased 14% 3 weeks after \nexposure cessation (NTP 1994).  In a 30-week study, 22% of male rats exposed to 0.56 ppm died during\n\n$$\n\\leq0.385ppm\n$$ the exposure period (Clark 1981).  No mortality attributed to HCCPD was observed in rats exposed to \n0.06 or 0.14 ppm.\n\nSurvival of male and female rats and male mice chronically exposed to 0.01–0.2 ppm HCCPD for 2 years \nwas similar to controls.  Decreased survival was observed for female mice exposed to 0.2 ppm, but not at \nlower concentrations (NTP 1994).  Ovarian inflammation, possibly resulting from an infection, appeared \nto be the cause of premature deaths in female mice exposed to 0.2 ppm HCCPD.\n\nThe lethality of HCCPD in laboratory animals has been evaluated for acute- and intermediate-duration \noral exposures.  The oral median lethal dose (LD50) values were 505 mg/kg in male rats of an unspecified \nstrain (Treon et al. 1955), 630 and 530 mg/kg in male and female Spartan rats, respectively (OxyChem\n1972), and 1,500 and 1,300 mg/kg in male and female CFY rats, respectively (Gardner 1986a).  An oral\ndose of 940 mg/kg was lethal to ≥90% of the male and female rats (Treon et al. 1955).  Acute-duration \noral lethality data for species other than rats are more limited.  The oral LD50 value for male and female \nmice is 679 mg/kg (Dean 1977).  In rabbits, doses of 420, 620, and 940 mg/kg killed 0/3, 1/3, and \n3/3 animals, respectively (Treon et al. 1955).  In pregnant animals, several rabbits (exact number not \nidentified) did not survive 13 days of treatment with 75 mg/kg/day HCCPD on gestational days (GDs) 6–\n18 (Murray et al. 1980).  With intermediate-duration oral exposure, rats appeared to be more sensitive to \nHCCPD lethality than mice, a reverse of the sensitivity observed for inhalation exposures.  There were no \nmouse deaths following 13-week exposures to ≤150 mg/kg/day, but 6 of 10 male rat deaths at \n150 mg/kg/day were attributed to HCCPD treatment following 13 weeks of exposure (Abdo et al. 1984: \nVelsicol 1981a, 1981b).  All 10 male mice and 3 of 10 female mice died during the first 2 weeks of \nexposure to 300 mg/kg/day (Abdo et al. 1984; Velsicol 1981a).\n\n$$\n\\left(\\mathrm{LD}_{50}\\right)\n$$\n\n$$\n\\mathrm{LD}_{50}\n$$\n\n$$\n\\leqq150\n$$\n\nFor the dermal route, lethality of HCCPD in laboratory animals has only been evaluated for acuteduration exposures.  In rabbits administered topical applications of 200 mg/kg for 24 hours, deaths were \nreported in 2/2 males and 0/2 females (OxyChem 1972) and 8/12 rabbits of unspecified sex (OxyChem \n1992).  Dermal exposure to 2,000 mg/kg resulted in 100% mortality in male and female rabbits within \n24 hours (OxyChem 1972).  At lower doses, single dermal doses applied for 24 hours caused mortality in \n0/3, 1/3, and 2/3 rabbits at 430, 610, and 1,020 mg/kg, respectively (Treon et al. 1955).  In the multi-dose \nstudy by Treon et al. (1955), survival time was inversely proportional to the dose; rabbits survived 72, \n24–48, 20, and 17 hours after dermal dosing with 610, 1,020, 2,130, and 6,130 mg/kg, respectively.  None \nof the animals died with a dermal application of 430 mg/kg, although one rabbit was in poor condition \nand likely would have died had it not been sacrificed at 21 days.  In rats, the dermal LD50 values were\n\n$$\n\\mathrm{LD}_{50}\n$$\n\n---\n\n2,600 mg/kg in males and 3,100 mg/kg in females (Gardner 1986b).  These results suggest that rabbits are \nmore sensitive to HCCPD toxicity via the dermal route relative to rats.\n\nWhen 0.1 mL of HCCPD was instilled into the conjunctival sac of five rabbits for 5 minutes and then \nrinsed with water, the quantity of material absorbed was lethal to all the animals within 9 days (OxyChem\n1972).  When ocular rinsing was delayed until 24 hours post-instillation, all three rabbits administered\n0.1 mL of HCCPD died within 6 days.\n\n###### 2.3 BODY WEIGHT\n\nNo reports of body weight effects in humans after exposure to HCCPD were found.  The available data in \nlaboratory animals indicate that HCCPD produces body weight effects at sufficiently high inhalation and \noral exposure levels; no body weight data are available via the dermal route. In several of these studies, \nbody weight changes were associated with decreased food and/or water intake (see Section 2.18, Other \nNoncancer, for additional details).\n\nBody weight effects resulting from inhalation exposures to HCCPD have been assessed in acute-, \nintermediate-, and chronic-duration studies.  Inhalation exposures to sufficient HCCPD concentrations \nover acute and intermediate periods decrease body weights and/or suppress body weight gains.  A single \n1-hour exposure to HCCPD resulted in decreased body weights in rats during the 3-week post-exposure \nobservation period at concentrations ≥2.38 ppm; when animals that died prematurely and those sacrificed \nat the end of the observation period are combined, body weight decreases compared to control were 41% \nin males and 26% in females (Jackson and Hardy 1986).  A 4-hour exposure resulted in >20% decreases \nin body weight in male and female rats at ≥1.68 and 1.83 ppm, respectively, during the 4-week \nobservation period (Jackson and Hardy 1987).  In both studies by Jackson and Hardy (1986, 1987), body \nweight effects were associated with decreased food intake.  Similarly, after a 4-hour exposure to HCCPD, \nbody weight decreases of at least 25 and 17% relative to pre-exposure weights were observed for male \nand female rats, respectively, after exposures to 1.4–5.8 ppm; no food intake data were provided (Rand et \nal. 1982a).  With significantly decreased food intake, male and female rats exposed to 0.5 ppm HCCPD \nfor 1–2 weeks lost body weight; male body weights decreased 32% on day 10 and terminal female body \nweight decreased 29% (Alexander et al. 1980a; Rand et al. 1982a).\n\n$$\nt\\geqq1.68\n$$\n\nIn 13-week inhalation studies, terminal body weights remained within 10% of control values following \nexposure to HCCPD at concentrations up to 0.385 ppm in rats and 0.389 ppm in mice (NTP 1994).\n\n---\n\nSimilarly, no effects on body weight were observed in rats and monkeys exposed to ≤0.2 ppm HCCPD \nfor 14 weeks (Alexander et al. 1980b; Rand et al. 1982a).  Body weight decreased 19% and body weight \ngain decreased 42% in male mice exposed to 0.5 ppm for 42 weeks (NTP 1994).  No body weight deficits \nwere identified after exposure of male mice to 0.2 ppm for 33 weeks or to 0.5 ppm for 26 weeks (NTP \n1994).  Body weights remained within 10% of control values for male and female rats exposed to \n≤0.56 ppm for 30 weeks (Clark 1981), and in male and female mice and rats exposed to ≤0.2 ppm for \n2 years (NTP 1994).\n\nBody weight effects after oral exposure to HCCPD in experimental animals have been evaluated in acuteand intermediate-duration studies.  In intermediate-duration studies, sufficient oral dosing with HCCPD \ndecreased body weights and suppressed body weight gains.  Male and female rats and mice experienced \ndose-related decreased body weights and body weight gains when compared to controls after oral \nexposure to HCCPD for 13 weeks (Abdo et al. 1984; Velsicol 1981a, 1981b).  Male rats were affected \nmore than females, and rats were affected more than mice.  Terminal body weights in male rats decreased \n13–35% and overall body weight gains were reduced 21–58% at dose levels of ≥38 mg/kg/day. In female\nrats exposed to 75–150 mg/kg/day, terminal body weights were reduced 15–17% and overall body weight \ngains decreased 28–36%.  Terminal body weights in male mice were reduced 11% and overall body \nweight gains decreased 39% at 150 mg/kg/day.  In female mice, terminal body weights decreased 13% at \n300 mg/kg/day and overall body weight gains were reduced 22–44% at ≥150 mg/kg/day. Differences in \nterminal body weights and overall body weight gains were within 10% of control values for male rats at \n≤19 mg/kg/day, female rats at ≤38 mg/kg/day, and male and female mice at ≤75 mg/kg/day.  Maternal \nweight loss was observed in rabbits administered 75 mg/kg/day on GDs 6–18; the magnitude of weight \nloss was not reported (Murray et al. 1980).  No body weight effects were reported for rabbits dosed with \n≤25 mg/kg/day on GDs 6–18 or for mice dosed with ≤75 mg/kg/day on GDs 6–15.\n\n###### 2.4 RESPIRATORY\n\nThe data provide strong evidence that HCCPD produces portal-of-entry effects in the respiratory system \nfollowing inhalation exposures; no effects on the respiratory tract were observed following oral or dermal \nexposures to HCCPD.  Based upon systematic review (Appendix C), the respiratory system is a presumed \nhazard of HCCPD toxicity following inhalation exposure based on inadequate evidence in humans and a \nhigh level of evidence from laboratory animal studies.\n\n---\n\nThe available data on respiratory effects of HCCPD in humans are limited to reports of WWTP workers \nand cleanup crew members exposed to HCCPD for 3–15 days after an inadvertent industrial release of \nthis material into the sewage system (Kominsky et al. 1980; Morse et al. 1979).  Maximum atmospheric \nconcentrations for the treatment plant workers were unknown but were most likely >0.97 ppm, the \nmaximum concentration measured 4 days after compound identification (Morse et al. 1979).  The \nmaximum concentration recorded during cleanup was 19.2 ppm (Kominsky et al. 1980).  Symptoms of \ntracheobronchial irritation were reported by the treatment plant workers early in the exposure period.  \nThese symptoms were recounted by 39 of 145 (27%) employees who responded to a questionnaire shortly \nafter the exposure incident and by 16 of 177 (9%) employees who responded to a follow-up questionnaire \n6 weeks later (Morse et al. 1979).  Chest x-rays of 28 exposed workers were normal and tests of \npulmonary function were normal in a subset of 22 workers from this group (Kominsky et al. 1980).  \nMinor respiratory complaints included sore throat, cough, chest discomfort, and difficulty breathing.  \nThese effects were likely a consequence of the direct action of the HCCPD vapor on the mucous \nmembranes of the respiratory tract, rather than systemic effects due to exposure to HCCPD through the \nlungs.  One cleanup crew worker also reported respiratory difficulty when exposed for a few seconds to \n19.2 ppm HCCPD without protective equipment (Kominsky et al. 1980).  Chest discomfort persisted for \nseveral days in this individual.\n\nRespiratory effects induced by HCCPD in laboratory animals have been evaluated in acute-, \nintermediate-, and chronic-duration inhalation exposure studies.  Inhalation exposures to HCCPD \nproduced clinical signs of respiratory toxicity and/or irritation including abnormal respiratory pattern \n(irregular or exaggerated respiratory movements, fast or irregular respiration rate or pattern, rales and/or \nnoisy respiration, and/or gasping), labored respiration, sneezing, increased respiration rate, and/or mouth \nbreathing in rats exposed to 1.67 ppm for 1 hour (Jackson and Hardy 1986), 1.68 ppm for 4 hours \n(Jackson and Hardy 1987), 0.5 ppm for 1–2 weeks (Alexander et al. 1980a; Rand et al. 1982a), 0.56 ppm \nfor 30 weeks (Clark 1981), and ≥0.941 ppm for 13 weeks (NTP 1994).  No respiratory clinical signs were \nobserved in rats or monkeys exposed to 0.2 ppm for 14 weeks (Alexander et al. 1980b; Rand et al. \n1982a), mice exposed to ≤2.142 ppm for 13 weeks (NTP 1994), male mice exposed to 0.2 ppm for \n33 weeks or 0.5 ppm for 26 or 42 weeks (NTP 1994), or rats and mice exposed to ≤0.2 ppm for 2 years \n(NTP 1994).  Based on these data, it appears that rats are more susceptible to HCCPD-induced respiratory \nirritation effects than mice. Blood gas analysis, pulmonary ventilation, and lung mechanics were within \nnormal ranges in pulmonary function tests of monkeys exposed to ≤0.2 ppm HCCPD for 7 and 13 weeks \n(Alexander et al. 1980b; Rand et al. 1982a).\n\n---\n\nInhalation exposures to HCCPD vapor caused histopathological changes in the respiratory tracts of \nexperimental animals.  At nonlethal concentrations, these alterations were largely inflammatory or \nhyperplastic in nature, consistent with repetitive irritation at the portal of entry.  Inflammation of the \ntissues was followed by necrosis, exfoliation, and/or hemorrhage.  No histopathological examination was \nconducted, but gross necropsy of the lungs showed pale and swollen lungs in rats exposed to ≥1.68 ppm \nfor 4 hours; findings were associated with increased absolute and relative lung weights at ≥3.31 and \n1.83 ppm in male and female rats, respectively (Jackson and Hardy 1987).  Inflammation, hyperplasia, \nand epithelial erosion were identified in the lungs of rats exposed to HCCPD vapor at 0.5 ppm for 1–\n2 weeks; recovery was apparent 2 weeks after exposure ceased in surviving animals (Alexander et al. \n1980a; Rand et al. 1982a).  No histopathological changes were identified in respiratory tissues of rats\nexposed to ≤0.11 ppm in the same manner (Alexander et al. 1980a; Rand et al. 1982a) or in rats and \nmonkeys exposed to ≤0.2 ppm for 14 weeks (Alexander et al. 1980b; Rand et al. 1982a). Using electron \nmicroscopy, exposure-related increases in electron-lucent inclusions in club cells, formerly called Clara \ncells, were observed in rats exposed to 0.01–0.2 ppm for 14 weeks (Huntingdon Research Centre 1980; \nRand et al. 1982b); however, this findings is considered a biomarker of exposure rather than evidence of \ntoxicity due to the absence of histopathological findings or any other ultrastructural changes.  No \nexposure-related ultrastructural changes were observed in monkeys exposed to ≤0.2 ppm for 14 weeks\n(Rand et al. 1982b).  In a 30-week inhalation exposure study in rats, increased incidences of \nperivascular/peribronchiolar inflammatory cell infiltration were observed in males and females exposed to \n0.56 ppm; males exposed to this concentration also exhibited an increased incidence of bronchiolar \nepithelial thinning/ulceration (Clark 1981).  The incidences of bronchiolar epithelial hyperplasia, \nsloughing/loss, and edema also increased in male and female rats exposed to 0.56 ppm but did not reach \nstatistical significance.  Following a 14-week recovery period, no histopathological differences were \nidentified in the lungs of control and treated rats, indicating reversibility of these lesions.\n\n$$\nt_{0}\\geqq1.68\n$$\n\nIn 13-week studies, microscopic effects in the respiratory system produced by lethal HCCPD \nconcentrations included necrotizing inflammation of the nose, larynx, trachea, and bronchus/bronchiole \nand hemorrhaging of the alveolus in male and female rats exposed to 0.941–2.065 ppm; suppurative \ninflammation of the alveolus in male and female rats at 0.941 ppm; acute necrosis of the nose, larynx, \ntrachea, and lung epithelium and lung congestion in male and female mice at 2.142 ppm; tracheal \nsquamous metaplasia in male and female mice at 0.949 ppm; and suppurative inflammation of the nasal \nepithelium of male and female mice exposed to 0.949–2.142 ppm (NTP 1994).  Increased incidences of \nsuppurative inflammation and squamous metaplasia in the nose and necrotizing and suppurative \ninflammation of the bronchus/bronchiole were identified in male rats exposed to 0.385 ppm, increased incidences of nasal suppurative inflammation and tracheal squamous metaplasia were observed in male \nmice exposed to 0.389 ppm, and an increased incidence of nasal serous inflammation was present in \nfemale mice exposed to 0.389 ppm.  No statistically significant increases were identified for nonneoplastic lesions in the respiratory tract tissues of female rats exposed to ≤0.385 ppm, male rats exposed \nto 0.146 ppm, or male or female mice exposed to ≤0.146 ppm (NTP 1994).\n\nHistopathological findings in male and female mice exposed to 0.2 ppm for 2 years included nasal \nsuppurative inflammation characterized by accumulation of cellular debris, mucus, neutrophils, and fibrin \nin the nasal lumen and infiltration of mononuclear cells and neutrophils into the lamina propria (NTP \n1994).  After 2-year exposures, an increased incidence of squamous metaplasia of the larynx (minimal \nseverity) was identified in female rats at 0.01 and 0.2 ppm; the incidence at 0.05 ppm was also elevated \nbut was not statistically significantly different from the concurrent control incidence.  No treatmentrelated respiratory tract lesions were identified in male rats.  The toxicological relevance of the squamous \nmetaplasia was not clear to the NTP (1994) authors due to difficulties in obtaining consistent sections for \nanalysis and determination of the boundary between squamous and columnar epithelium.  Due to this, as \nwell as the lack of clear dose-response, a LOAEL determination for squamous metaplasia was not \nincluded in Table 2-1.\n\nTo examine the progression and permanence of non-neoplastic lesions in the respiratory tract, NTP \n(1994) conducted additional studies in male mice with the intent of evaluating the relative effects of \nconcentration and duration on development of these lesions.  In these studies, concentrations were 0 or \n0.2 ppm for 33 weeks and 0 or 0.5 ppm for 26 or 42 weeks.  Animals were sacrificed at interim \nevaluations after 27, 34, or 43 weeks or 15 months of exposure or were sacrificed after 2 years.  At the \nend of the exposure periods, the incidence of nasal suppurative inflammation increased in all treatment \ngroups and suppurative inflammation of the trachea and lungs and alveolar epithelial hyperplasia \nincreased in animals exposed to 0.5 ppm for 42 weeks.  The incidence of alveolar epithelial hyperplasia \nalso increased in male mice exposed to 0.5 ppm for 42 weeks.  An evaluation of the data indicated that \nboth concentration and duration of exposure influenced the development of these respiratory tract lesions; \nthe inflammation of the trachea and lungs was not observed unless the product of the concentration and \nduration was >20 or 21 ppm-weeks.\n\nIn the chronic-duration studies of rats and mice exposed to HCCPD for 2 years, accumulation of a \ngranular yellow-brown pigment was observed in the nasal epithelium in male and female rats and mice at \n≥0.01 ppm, tracheal epithelium of male and female mice at ≥0.01 ppm, bronchiole epithelium of female\n\n$$\n\\geqq0.01\n$$ rats at ≥0.01 ppm, and lung epithelium of male and female mice ≥0.05 ppm (NTP 1994).  At 0.2 ppm, \nminimal-to-mild tracheal, bronchiole, and peribronchiole pigmentation was observed in male rats and \nperibronchiole pigmentation was identified in female rats (NTP 1994).  The pigmentation incidence and \nseverity generally increased with concentration for each sex-species combination.  In male mice exposed \nto 0.2 ppm for 33 weeks or 0.5 ppm for 26 or 42 weeks and then maintained for up to 2 years, \npigmentation of the respiratory tract (nose, trachea, and/or lungs) was seen in the majority of exposed \nanimals and did not disappear following exposure cessation and evaluation at 2 years, indicating a lack of \nrecovery and physiological turnover of the pigment material.  The incidence and severity were similar \nafter 33, 66, and 104 weeks of exposure to 0.2 ppm HCCPD.  In the chronic-duration and additional \nstudies in male mice exposed to 0.2 ppm for 33 weeks and 0.5 ppm for 26 or 42 weeks, the pigmentation \ndid not co-occur with respiratory lesions and did not appear to be a precursor to more significant effects \n(i.e., did not indicate an initial phase in the progression of a disease state).  Results of several staining \nprocedures applied to the pigmented lung sections of rats and mice indicated the presence of reducing \nsubstances, but no further analytical identification was performed.  NTP (1994) indicated that the \npigmentation may be a unique response to HCCPD and could be due to lipid peroxidation.  Based on \nthese data, ATSDR concludes that it is more appropriate to characterize the pigmentation as a marker of \nexposure to HCCPD rather than an adverse effect attributable to HCCPD exposure.\n\nThe potential for oral exposure to HCCPD to induce respiratory effects has been evaluated in acute- and \nintermediate-duration studies.  In rats and mice administered lethal gavage doses of HCCPD, decreased \nrespiratory rates were observed prior to death (Dean 1977; Gardner 1986a); this clinical sign was likely a \nconsequence of significant morbidity prior to death rather than an effect of HCCPD on the respiratory \nsystem.  No gross or histopathological changes were identified in the nasal cavity, trachea, larynx, \nbronchi, or lungs of rats at doses ≤150 mg/kg/day or in mice at doses ≤300 mg/kg/day for 13 weeks \n(Abdo et al. 1984; Velsicol 1981a, 1981b).\n\nThe potential toxicological effects of HCCPD on the respiratory tract following dermal exposure were \nevaluated in one acute-duration dermal toxicity study.  A decreased rate of respiration was observed in \nrats administered topical doses ≥2,000 mg/kg for 24 hours (Gardner 1986b).  The animals appeared \nnormal 5–9 days after dosing and no gross pathological changes were identified in the lungs of animals \nthat survived to the scheduled sacrifice.\n\n---\n\n###### 2.5 CARDIOVASCULAR\n\nNo studies were located regarding cardiovascular effects in humans after exposure to HCCPD. Available\ndata from laboratory animals indicate that the cardiovascular system is not a sensitive toxicity target \nfollowing inhalation or oral exposure to HCCPD.\n\nThe cardiovascular system has been evaluated in experimental animals exposed to HCCPD via inhalation \nin acute-, intermediate-, and chronic-duration studies.  Diffuse degenerative changes were observed in the \nhearts of rats, mice, and rabbits that died following acute exposure to lethal concentrations of HCCPD \nranging from 0.3 to 66 ppm for 15 minutes to 2 weeks; incidence data were not provided, and findings \nwere potentially attributable to autolysis (Treon et al. 1955).  In another acute-duration study, there were \nno histopathological changes in the heart in rats exposed to concentrations up to 0.5 ppm after either 1 or \n2 weeks (Alexander et al. 1980a; Rand et al. 1982a).  In longer-term inhalation studies, there was no \nevidence for histopathological changes in the heart at intermediate-duration concentrations up to \n0.56 ppm in rats, 0.389 ppm in mice, or 0.2 ppm in monkeys (Alexander et al. 1980b; Clark 1981; NTP \n1994; Rand et al. 1982a) or chronic-duration concentrations up to 0.2 ppm in rats or mice (NTP 1994).\n\nPotential cardiovascular effects of HCCPD oral exposures in experimental animals were evaluated in \nacute- and intermediate-duration studies.  Single oral doses of 280–2,100 mg/kg caused degenerative \nchanges in the hearts of rats and rabbits, possibly due to tissue autolysis; incidence data were not provided\n(Treon et al. 1955).  In contrast, there were no gross or histopathological changes in the hearts of rats \nexposed to doses ≤150 mg/kg/day or mice exposed to doses ≤300 mg/kg/day for 13 weeks (Abdo et al. \n1984; Velsicol 1981a, 1981b).\n\nRabbits that died following single dermal doses of 610–6,130 mg/kg displayed degenerative changes in \nthe heart, possibly because of tissue autolysis; incidence data were not provided (Treon et al. 1955).\n\n###### 2.6 GASTROINTESTINAL\n\nThe data provide evidence that HCCPD produces portal-of-entry effects in the gastrointestinal system, \nspecifically the stomach, following oral exposures.  Data on adverse gastrointestinal effects following \ninhalation exposure are limited to clinical signs following accidental occupational exposure; no effects on \nthe gastrointestinal system were observed following dermal exposure to HCCPD.  Based upon systematic \nreview (Appendix C), the gastrointestinal system is a presumed hazard of HCCPD toxicity following oral exposure based on no route-specific data in humans and a high level of evidence from laboratory animal \nstudies.\n\nWWTP workers exposed to HCCPD for 3–15 days due to an inadvertent industrial release complained of \nnausea (22% of 177 workers) and abdominal cramps (prevalence not specified) (Kominsky et al. 1980; \nMorse et al. 1979).  One member of the cleanup crew who was exposed to 19.2 ppm for several seconds \nwithout protective equipment experienced nausea several minutes after the exposure (Kominsky et al. \n1980).  While classified as gastrointestinal in this profile, it is possible that nausea may be neurological in \norigin.\n\nGastrointestinal effects of HCCPD have been evaluated in laboratory animals following intermediate- and \nchronic-duration inhalation exposures.  No microscopic changes were seen in the stomach, esophagus, or \nintestines of monkeys, rats, or mice exposed to concentrations up to 0.2, 0.56, or 0.5 ppm, respectively, in\nintermediate-duration studies (Alexander et al. 1980b; Clark 1981; NTP 1994; Rand et al. 1982a), or rats \nor mice following chronic-duration exposure to concentrations up to 0.2 ppm (NTP 1994).  The \ngastrointestinal tract does not appear to be a sensitive target for HCCPD in animals following inhalation \nexposures.\n\nThe potential impact of HCCPD exposure on gastrointestinal tissues has been evaluated in acute- and \nintermediate-duration oral exposure studies in experimental animals.  Increased incidences of diarrhea \nwere observed in rats dosed with ≥1,260 mg/kg (Gardner 1986a) and female and male mice dosed with \n464 and 1,000 mg/kg, respectively (Dean 1977).  Acute necrotic lesions of the forestomach were noted in \nsome rats administered an oral dose of 280–2,100 mg/kg; incidence data were not provided (Treon et al. \n1955).  After 13-week exposures to HCCPD, increased incidences of forestomach epithelial hyperplasia \nwere observed in male and female rats at 38 mg/kg/day and male and female mice at 75 mg/kg/day (Abdo \net al. 1984; Velsicol 1981a, 1981b).  Increased incidences of focal inflammation in the forestomach were \nidentified in male and female rats at 38 mg/kg/day and male and female mice at 75 mg/kg/day.  The \nincidences and ranges of lesion severities were directly related to the dose.  No histopathological changes \nwere identified in the esophagus, duodenum, jejunum, ileum, or colon of males and females of either \nspecies.  These data suggest that rats are more sensitive to HCCPD-induced effects to the forestomach \nthan mice.  The presence of the forestomach lesions and lack of histopathological changes in other \nregions of the gastrointestinal tract suggests that the forestomach effects result from direct contact of \nthese tissues with HCCPD.\n\n---\n\n###### 2.7 HEMATOLOGICAL\n\nThe data indicate HCCPD may alter red blood cell hematology parameters following inhalation exposure \nwithout causing histopathological changes to bone marrow; no consistent effects were noted in white \nblood cell parameters following inhalation exposure and no effects on the hematological system were \nobserved in animals following oral exposures to HCCPD.  Data are not available via the dermal route.  \nBased upon systematic review (Appendix C), the hematological system, specifically red blood cell \nparameters, is a suspected hazard of HCCPD toxicity following inhalation exposure based on inadequate \ndata in humans and a moderate level of evidence from laboratory animal studies.  White blood cell effects \nare not classifiable as to the hazard to humans based on inadequate data in humans and animals.\n\nNo changes in blood counts were observed in workers exposed to HCCPD at a WWTP after an industrial \ndischarge of the material into the sewage system (Kominsky et al. 1980).\n\nThe potential hematological effects of HCCPD were evaluated in experimental animals exposed via \ninhalation after acute-, intermediate-, and chronic-duration exposures.  No effects on bone marrow \nhistopathology were reported in rats exposed to 0.5 ppm for 1–2 weeks (Alexander et al. 1980a; Rand et \nal. 1982a), rats and mice exposed to ≤0.385 and ≤0.389 ppm, respectively, for 13 weeks, or rats and mice \nexposed to ≤0.2 ppm for 2 years (Alexander et al. 1980b; NTP 1994; Rand et al. 1982a).  Across acuteand intermediate-duration multiple exposure studies, altered red blood cell hematology parameters were \nidentified in rats, particularly males, as seen in Table 2-4.\n\n**Table 2-4. LOAEL Values for Red Blood Cell Hematological Effects of Rats** \n**Exposed to HCCPD Vapor in Acute- and Intermediate-Duration Inhalation**\n**Studies**\n\n| Hematology parameter | Rand et al. 1982aa: 1–2 weeks | Rand et al. 1982aa: 1–2 weeks (recovery group) | NTP 1994: 13 weeks | NTP 1994: 13-week special hematology study | Clark 1981: 30 weeks |\n| --- | --- | --- | --- | --- | --- |\n| Males |  |  |  |  |  |\n| PCV | \\(\\uparrow (0.5^{{b}})\\) | ↔ | \\(\\uparrow (0.385)\\) | ↔ | - |\n| Hb | \\(\\uparrow (0.5)\\) | \\(\\uparrow (0.5)\\) | \\(\\uparrow (0.385)\\) | ↔ | \\(\\uparrow (0.14)\\) |\n| RBC | \\(\\uparrow (0.5)\\) | ↔ | \\(\\uparrow (0.385)\\) | ↔ | \\(\\uparrow (0.14)\\) |\n| MCV | ↔ | ↔ | ↔ | \\(\\uparrow (0.385)\\) | ↔ |\n| MCH | - | - | \\(\\uparrow (0.385)\\) | ↔ | ↔ |\n| MCHC | ↔ | \\(\\uparrow (0.5)\\) | ↔ | ↔ | ↔ |\n\n---\n\n**Table 2-4. LOAEL Values for Red Blood Cell Hematological Effects of Rats** \n**Exposed to HCCPD Vapor in Acute- and Intermediate-Duration Inhalation**\n**Studies**\n\n| Hematology parameter | Rand et al. 1982aa: 1–2 weeks | Rand et al. 1982aa: 1–2 weeks (recovery group) | NTP 1994: 13 weeks | NTP 1994: 13-week special hematology study | Clark 1981: 30 weeks |\n| --- | --- | --- | --- | --- | --- |\n| HCT | - | - | - | - | \\(\\uparrow\\) (0.14) |\n| Females |  |  |  |  |  |\n| PCV | \\(\\uparrow\\) (0.5) | ↔ | ↔ | \\(\\uparrow\\) (0.385) | - |\n| Hb | \\(\\uparrow\\) (0.5) | ↔ | ↔ | \\(\\uparrow\\) (0.385) | ↔ |\n| RBC | \\(\\uparrow\\) (0.5) | ↔ | \\(\\downarrow\\) (0.385) | \\(\\uparrow\\) (0.385) | ↔ |\n| MCV | ↔ | ↔ | \\(\\uparrow\\) (0.385) | \\(\\uparrow\\) (0.385) | ↔ |\n| MCH | - | - | ↔ | \\(\\uparrow\\) (0.385) | ↔ |\n| MCHC | ↔ | ↔ | ↔ | ↔ | ↔ |\n| HCT | - | - | - | - | ↔ |\n\n<sup>a</sup>Data are also available in the unpublished industry report by Alexander et al. (1980a).\n\n<sup>b</sup>LOAEL concentrations are in ppm.\n\n↑ = increased mean value; ↓ = decreased mean value; ↔ = no significant, dose-related change in mean value;\n\n– = not assessed; Hb = hemoglobin; HCT =hematocrit; MCH = mean cell hemoglobin; MCHC = mean cell\n\nhemoglobin concentration; MCV = mean cell volume; PCV = packed cell volume; RBC = red blood cell count\n\nThe most consistently observed effects were increased hemoglobin levels in male and female rats and \nincreased red blood cell counts in male rats.  Generally, effects were observed at concentrations \n≥0.14 ppm and had magnitudes of effect that were <10% of control values.  The exceptions are for the 1–\n2-week range-finding study (Alexander et al. 1980a; Rand et al. 1982a), where 20–30% increases in red \nblood cell parameters were identified at 0.5 ppm, a concentration that co-occurred with significantly \ndecreased water intake and produced significant mortality and morbidity (see Section 2.2).  Drinking \nwater intakes were not assessed in the NTP (1994) studies and were not affected by HCCPD exposure in \nthe Clark (1981) study (see Section 2.18).  While statistically significant altered hemoglobin, mean cell \nvolume (MCV), and mean cell hemoglobin concentration (MCHC) values were reported in rats following \na 14-week exposure at concentrations as low as 0.01 ppm, these changes were sporadically observed and\nwere not dose-responsive, and the magnitudes of effect were generally low (≤5%) (Alexander et al. \n1980b; Rand et al. 1982a).  Therefore, they were not considered to be biologically significant in this \nassessment and are not presented in Table 2-4.  For intermediate-duration exposures in rats, the NOAEL \nvalues were 0.039–0.146 ppm for the NTP (1994) 13-week studies and 0.06 ppm for the Clark (1981) \n30-week study.\n\n---\n\nRand et al. (1982a) postulated that these minor variances in hematological parameters were a \nconsequence of hemorrhagic lesions in the lungs and not a direct influence of HCCPD on hematopoiesis \nor red cell turnover.  Since the red blood cell hematology parameters were more consistently altered in \nmale rats than in female rats, this hypothesis correlates with the increased absolute and relative lung \nweights and more severe histopathological effects observed in the lungs of male rats in the 1–2-week\nRand et al. (1982a) study.  NTP (1994) suggested that the red blood cell hematology alterations were not \nattributable to HCCPD treatment due to the inconsistent dose-response and lack of correlation in the \nresults across sexes and between the core and special 13-week hematology studies.  While there are \ninconsistencies in the red blood cell parameter results obtained from the NTP (1994) studies, common \nalterations in hemoglobin levels and red blood cell counts across repeated inhalation exposure studies \nsuggest a consistent biological response to HCCPD.  In the absence of additional data and based on the \nlack of histopathological effects to bone marrow, ATSDR considers the altered red blood cell parameters \nto be plausibly related to respiratory tract damage resulting in compromised gas exchange.\n\nIn mice, the only consistent HCCPD treatment-related effect on red blood cell hematology parameters \nacross studies was decreased MCV in female mice after exposure to 0.389 ppm for 13 weeks in the core\nand special hematology studies (NTP 1994).  Other red blood cell effects were limited to increased \nMCHC in male mice at 0.389 ppm and in female mice at 0.039–0.389 ppm in the special 13-week \nhematology study.  The magnitudes of effect were within 5% of control values.  HCCPD treatmentrelated effects on other hematological parameters following inhalation exposures were limited to \ndecreased reticulocytes (40%) in female rats exposed to 0.385 ppm in the special hematology study (NTP \n1994); decreased total white blood cells (46%) and lymphocyte count (53%) in male rats, and increased \nneutrophil count (114%) in female rats exposed to 0.5 ppm for 1–2 weeks (Alexander et al. 1980a; Rand \net al. 1982a); and decreased percent lymphocytes (8–10%) and increased neutrophil count (27–36%) in \nmale rats exposed to ≥0.14 ppm and decreased lymphocyte count (16%) in female rats exposed to \n0.56 ppm for 30 weeks (Clark 1981).  No clear biological basis can be identified for these effects based \non the lack of consistency across studies.\n\nIn intermediate-duration oral exposure studies, no histopathological changes were identified in the bone \nmarrow of rats dosed with ≤150 mg/kg/day or mice dosed with ≤300 mg/kg/day for 13 weeks (Abdo et al. \n1984; Velsicol 1981a, 1981b).  Hematology parameters were not evaluated in this study.\n\n---\n\n###### 2.8 MUSCULOSKELETAL\n\nNo studies were located regarding musculoskeletal effects in humans after exposure to HCCPD.  \nAvailable inhalation and oral data in laboratory animals indicate the musculoskeletal system is not a \nsensitive target of toxicity following exposure to HCCPD; no dermal studies were identified.\n\nThe potential effect of HCCPD on musculoskeletal tissues has been evaluated in laboratory animals \nfollowing intermediate- and chronic-duration inhalation exposures and acute- and intermediate-duration \noral exposures.  HCCPD did not affect skeletal muscle of rats or monkeys exposed to up to 0.2 ppm for \n14 weeks (Alexander et al. 1980b; Rand et al. 1982a); femoral muscle, knee joint, or femur of male and \nfemale rats exposed to ≤0.56 ppm for 30 weeks (Clark 1981); bone histopathology of mice or rats \nexposed to ≤0.389 ppm for 13 weeks or ≤0.2 ppm for 2 years (NTP 1994).  Similarly, no \nhistopathological changes were identified in thigh muscle, rib (costochondral junction), or femur of rats \nexposed to ≤150 mg/kg/day or mice exposed to ≤300 mg/kg/day via gavage for 13 weeks (Abdo et al. \n1984; Velsicol 1981a, 1981b). In animals that died, decreased limb tone was observed in mice (prior to \ndeath) after a single exposure to 1,000 mg/kg via gavage (Dean 1977).\n\n###### 2.9 HEPATIC\n\nThe data indicate that the hepatic system is not a sensitive target of HCCPD toxicity.\n\nSerum markers of hepatotoxicity were evaluated in 97 cleanup workers exposed to HCCPD vapors at a \nWWTP because of an inadvertent industrial release (Kominsky et al. 1980).  Abnormal serum marker \nranges were identified for 18 of the 97 workers (19%); aspartate aminotransferase (AST) values were \nelevated for 12 workers, alkaline phosphatase (ALP) was elevated for 5 workers, and total bilirubin was \nelevated for 1 worker (Kominsky et al. 1980).  For 8 of the 97 cleanup crew members, these biochemical \nparameters were abnormal on more than one occasion, and 7 workers had values that were temporallyrelated to exposure conditions.  It should be noted that evaluations were not performed on unexposed \nworkers, and it is not known if the abnormal values observed in exposed workers differ from the \nunexposed local general population.\n\nRelative to a group of 35 controls, 73 male operators employed for an average of 8.2 years (range 0.5–\n23 years) in a plant producing chlorinated hydrocarbons, including HCCPD, showed no evidence of \nhepatotoxicity (Boogaard et al. 1993).  Clinical tests included measurement of alanine aminotransferase\n\n---\n\n(ALT), AST, ALP, total bilirubin, γ-glutamyltransferase (GGT), lactate dehydrogenase (LDH), and total \nbile acids.  Personal air sampling for HCCPD was performed on a subset of study participants but was not \nused to evaluate associations between HCCPD exposure and liver function values.\n\nThe hepatotoxic potential of HCCPD has been evaluated in laboratory animals following acute-, \nintermediate-, and chronic-duration inhalation exposures.  Mild-to-moderate hepatic tissue degeneration \nwas observed following acute-duration inhalation exposures to 0.34–73.6 ppm for 15 minutes to 5 days, \nand to intermediate-duration exposures to 0.34 ppm for 6 weeks or 0.15 ppm for 30 weeks; incidence data \nwere not provided (Treon et al. 1955).  Hepatic damage was more pronounced in the animals that died \nthan in those that survived and, thus, may have been, at least partially, the result of autolysis in moribund \nor dying animals.  An apparent dose-related increase in perivascular/peribiliary inflammatory cell \ninfiltrates in the liver was observed in female rats exposed to 0.06–0.56 ppm; however, incidences did not \ndiffer significantly from control and no hepatic lesions were observed in similarly exposed male rats \n(Clark 1981).  In other inhalation studies, no exposure-related hepatic lesions were seen following acuteduration exposure in rats to concentrations up to 0.5 ppm (Alexander et al. 1980a; Rand et al. 1982a); \nintermediate-duration exposure in monkeys, rats, or mice to concentrations up to 0.2, 0.385, or 0.5 ppm, \nrespectively (Alexander et al. 1980b; NTP 1994; Rand et al. 1982a); or chronic-duration exposure in rats \nor mice to concentrations up to 0.2 ppm (NTP 1994).\n\nNo consistent evidence of exposure-related changes in hepatic serum biochemistry or liver weight was \nobserved following inhalation exposure to HCCPD.  Serum concentrations of the biochemical parameters\nLDH, AST, ALP, and ALT in rats and mice were not influenced by inhalation exposure to HCCPD \nconcentrations ≤0.389 ppm for 13–14 weeks (Alexander et al. 1980b; NTP 1994; Rand et al. 1982a).  \nDuring the 13-week special hematology, clinical chemistry, and urinalysis study conducted in rats by \nNTP (1994), the highest concentration of 2.065 ppm caused elevated serum AST concentrations (1.7–\n7.6-fold) in male and female rats on days 4–16; however, this concentration was lethal to all the animals \nprior to the day 46 clinical evaluation, and a comparable increase was not observed in mice (NTP 1994).  \nRelative liver weights of rats were significantly reduced by 3–15% in males and females exposed to 0.01–\n0.2 ppm for 13 weeks, but the decreases were not dose-related (Alexander et al. 1980b; Rand et al. \n1982a).  No changes in liver weights were observed in rats or mice exposed to concentrations ≤0.389 ppm \nfor 13 weeks or ≤0.2 ppm for 2 years (NTP 1994).\n\nAcute- and intermediate-duration oral toxicity studies have evaluated the potential effects of HCCPD\nexposure on the liver.  High, acute-duration oral doses of HCCPD were associated with liver necrosis and tissue degeneration in rats (261–1,959 mg/kg) and rabbits (579–877 mg/kg); incidence data were not \nprovided (Treon et al. 1955).  HCCPD did not induce histopathological changes in hepatic tissues of rats \nand mice exposed to doses up to 150 and 300 mg/kg/day, respectively, via gavage for 13 weeks (Abdo et \nal. 1984; Velsicol 1981a, 1981b).\n\nThe potential for HCCPD to cause hepatotoxicity following dermal exposure was evaluated only for \nacute-duration exposures.  Rabbits exposed to single dermal doses of 401–5,719 mg/kg displayed necrosis \nof the liver; incidence data were not provided (Treon et al. 1955).  The study authors stated that \ndegenerative changes persisted even 21 days after the exposure period in surviving animals.\n\n###### 2.10 RENAL\n\nThe data indicate that the renal system is a potential target for HCCPD via the oral route; it does not \nappear to be a sensitive target for HCCPD via the inhalation or dermal routes.  Based upon systematic \nreview (Appendix C), the kidney is a presumed hazard of HCCPD toxicity following oral exposure based \non no data in humans and a high level of evidence from laboratory animal studies.\n\nUrine samples were collected from 41 workers exposed for 3–15 days to HCCPD at a WWTP as the \nresult of an inadvertent industrial release into the sewage system (Morse et al. 1979).  Proteinuria was \nidentified in 6 of 41 workers immediately after exposure but no abnormalities were detected 3 weeks \nlater.  Urinalysis parameters were normal in all 97 cleanup crew workers evaluated (Kominsky et al. \n1980).  It should be noted that urinalysis was not performed on unexposed workers, and it is not known if \nproteinuria values observed in exposed workers differ from the local general population.\n\nRelative to a group of 35 controls, 73 male operators employed for an average of 8.2 years in a plant \nproducing chlorinated hydrocarbons, including HCCPD, showed no evidence of damage to the renal \ntubules (Boogaard et al. 1993).  The investigations included measurement of urinary alanine \naminopeptidase, N-acetyl-β-D-glucosaminidase, and retinol binding protein.  Although total urinary \nprotein concentrations did not differ between the two groups, urinary albumin was significantly higher in \nthe exposed group.  The difference, however, was not related to time of employment, and there was no \ndifference in urinary albumin concentration in workers involved in the manufacture of HCCPD and those \ninvolved in the preparation of other chlorinated hydrocarbon.  Thus, the effect was not considered to be \ndue to the damage to the glomerulus caused by exposure to HCCPD.  Personal air sampling for HCCPD\n\n---\n\n2.  HEALTH EFFECTS\n\nwas performed on a subset of study participants but was not used to evaluate associations with renal \nfunction values.\n\nThe potential renal effects following inhalation exposure to HCCPD have been evaluated in laboratory \nanimals following acute, intermediate, and chronic durations.  Inhalation exposure of HCCPD caused \nrenal tubular necrosis in rats, mice, guinea pigs, and rabbits at 0.34–73.6 ppm for 15 minutes to 7 days, \n0.34 ppm for 6 weeks, and 0.15 ppm for 30 weeks; incidence data were not provided (Treon et al. 1955).  \nIn other inhalation studies, no significant, exposure-related renal lesions were seen following acuteduration exposure in rats to concentrations up to 0.5 ppm (Alexander et al. 1980a; Rand et al. 1982a); \nintermediate-duration exposure in monkeys, rats, or mice to concentrations up to 0.2, 0.56, or 0.5 ppm, \nrespectively (Alexander et al. 1980b; Clark 1981; NTP 1994; Rand et al. 1982a); or chronic-duration \nexposure in rats or mice to concentrations up to 0.2 ppm (NTP 1994).\n\nThe potential toxicological effects of HCCPD on the kidneys have been evaluated in laboratory animals \nin acute-and intermediate-duration oral studies.  Degenerative lesions in the kidney tubules resulted from \nsingle gavage doses of 261–1,959 mg/kg in rats and 579–877 mg/kg in rabbits; incidence data were not \nprovided (Treon et al. 1955).  Toxic nephrosis was observed in male and female rats exposed to \n≥38 mg/kg/day and female mice exposed to ≥75 mg/kg/day via gavage for 13 weeks (Abdo et al. 1984; \nVelsicol 1981a, 1981b). These lesions were located in the terminal sections of the proximal tubules of the \nrenal cortex and were characterized by mild dilation of the tubules and karyomegaly, cytomegaly, and \nanisokaryosis accompanied by cytoplasmic and nuclear vacuolization.  Additionally, brown granular \npigment debris protruded into the lumen.  In male mice, tubular necrosis was present in 70% of the male \nmice receiving the 300 mg/kg/day dose but not at lower doses; this lesion was morphologically distinct \nfrom the toxic nephrosis seen in the other animals and may have contributed to the early deaths observed \nat this dose level.  No renal histopathological effects were identified in male and female rats at\n≤19 mg/kg/day, female mice at ≤38 mg/kg/day, or male mice at ≤150 mg/kg/day (Abdo et al. 1984; \nVelsicol 1981a, 1981b).\n\nRabbits exposed to single dermal doses of 401–5,719 mg/kg displayed degeneration and necrosis of the \nkidney tubules; incidence data were not provided (Treon et al. 1955). The study authors stated that renal \neffects were still apparent 21 days after dosing in surviving animals.\n\n---\n\n2.  HEALTH EFFECTS\n\n###### 2.11 DERMAL\n\nHuman and animal data indicate HCCPD causes skin irritation following direct dermal contact with \nHCCPD liquid or vapor.\n\nAn unspecified percentage of 145 workers exposed to HCCPD vapors for 3–15 days at a WWTP as a \nresult of an inadvertent industrial release reported skin irritation, with five employees verified to exhibit\nvisible signs of skin irritation (Morse et al. 1979).  In a subsequent publication, 21% of 177 employees \nwith usable medical questionnaire responses reported skin irritation following HCCPD release and prior \nto plant closure; 10% of the 177 employees reported experiencing skin irritation approximately 6 weeks \nlater (Kominsky et al. 1980).\n\nIn acute-duration dermal toxicity studies, topical application of HCCPD in either its pure form or in \nsolution appears to have a pronounced effect upon the epidermis of experimental animals.  Generally, \nHCCPD initially causes edema that progressed to hardening or encrustation at the application site \n(Gardner 1986b; OxyChem 1972; Treon et al. 1955).  In a series of studies, severe irritation and skin \nnecrosis were observed in a monkey administered 0.05 mL of a 10% (v/v) solution for 3 days; necrotic, \nhardened, encrusted, and discolored skin was identified following application of Ultrasene solutions \ncontaining ≥40% HCCPD to guinea pigs; and subcutaneous edema and local discoloration that progressed \nto encrustation and fissuring were observed after a dermal dose of ≥430 mg/kg was applied to rabbit skin; \nincidence data were not provided (Treon et al. 1955).  The lesions generally healed with time in the \nsurviving animals.  Thirteen months after exposure, the monkey’s treated skin was scarred and hairless.  \nNo evidence of dermal effects was identified in a monkey administered 0.01 mL of Ultrasene solutions \ncontaining up to 10% HCCPD, but application of 0.05 mL of solutions containing ≥20% HCCPD caused \nthe skin to become discolored and swell.  No evidence of skin irritation was observed in guinea pigs after \ndermal doses of 0.05 mL of Ultrasene solutions containing ≤1% HCCPD (Treon et al. 1955).  Eschar \nformation was noted after dermal application of 200 mg/kg HCCPD to rabbits (OxyChem 1992).  Results \nof standard dermal irritation tests indicated that 0.5 mL HCCPD produced slight to severe edema and \nnecrosis at the application sites (OxyChem 1972, 1992).\n\nThe potential effects of systemic HCCPD exposure on skin histopathology of laboratory animals were \nevaluated in intermediate- and chronic-duration inhalation studies and intermediate-duration oral studies.  \nNo histopathological changes were identified in the skin (specific location not identified) of male or \nfemale rats exposed to concentrations ≤0.56 ppm for 30 weeks (Clark 1981) or in male or female rats and mice exposed to concentrations ≤0.2 ppm for 2 years (NTP 1994).  Additionally, no histopathological \nchanges were identified in skin (specific location not identified) of rats and mice at gavage doses up to \n150 or 300 mg/kg/day, respectively, for 13 weeks (Abdo et al. 1984; Velsicol 1981a, 1981b).\n\n###### 2.12 OCULAR\n\nHuman and animal data indicate that direct ocular contact with HCCPD vapor may produce ocular \nirritation at sufficiently high concentrations.\n\nEye irritation was one of the major symptoms reported by sewage treatment plant workers exposed to \nHCCPD vapors for 3–15 days at a WWTP because of an inadvertent industrial release (Kominsky et al. \n1980; Morse et al. 1979).  From the 145 individuals who responded to a questionnaire immediately after \nexposure occurred, 85 (59%) complained of eye irritation (Morse et al. 1979).  In a follow-up \nquestionnaire 6 weeks later, 9% of 177 respondents were still experiencing ocular irritation (Kominsky et \nal. 1980; Morse et al. 1979).  Tearing and redness of the eyes were present in five individuals on the day \nof exposure.\n\nEye irritation, as evidenced by lacrimation, was also observed in animals exposed to HCCPD vapors for \nup to 7 hours (Jackson and Hardy 1986, 1987; OxyChem 1972; Rand et al. 1982a; Treon et al. 1955).  \nPartially or completely closed eyes were identified in rats exposed to ≥1.67 ppm for 1 hour (Jackson and \nHardy 1986) and ≥1.68 ppm for 4 hours (Jackson and Hardy 1987).  Direct ocular exposure to HCCPD\nvapors most likely contributed to these effects.  Irritation of the eyes or eyelids was observed for rats, \nmice, guinea pigs, and rabbits following single exposures to HCCPD concentrations as low as 1.0 ppm \nand multiple exposures to concentrations as low as 0.33 ppm for up to 6 weeks; ocular irritation was not \nobserved in any species exposed to 0.15 ppm for up to 30 weeks (Treon et al. 1955).  Lacrimation was \nevident in rats exposed to 5.8 ppm HCCPD for 4 hours and dark red eyes were observed in rats exposed \nto 0.5 ppm for 5–10 days and ≥0.05 ppm for 14 weeks (Alexander et al. 1980a, 1980b; Rand et al. 1982a).  \nNo clinical signs of eye irritation were noted in monkeys exposed to HCCPD vapor at concentrations up \nto 0.2 ppm for 14 weeks (Alexander et al. 1980b; Rand et al. 1982a).  No ophthalmological or\nhistopathological changes were identified in the ocular tissues of rats or monkeys exposed to \nconcentrations up to 0.2 ppm for 14 weeks (Alexander et al. 1980b; Rand et al. 1982a).  HCCPD \nexposure did not cause histopathological changes in the eyes of rats exposed to concentrations up to \n0.56 ppm for 30 weeks (Clark 1981).\n\n---\n\nSevere eye irritation was produced when 0.1 mL of HCCPD was placed in the conjunctival eye sac for \n5 minutes and then rinsed with water (OxyChem 1972).  Corrosion of the ocular tissues occurred when \nthe material was left in place for 24 hours prior to rinsing (OxyChem 1972).\n\n###### 2.13 ENDOCRINE\n\n2.13  ENDOCRINE\n\nNo reports of changes in human endocrine parameters or organs after exposure to HCCPD were found. \nBased on available data in laboratory animals, HCCPD does not produce histopathological changes to \nendocrine organs.  Insufficient data are available to assess the potential effects of HCCPD exposure on \nendocrine function, including endocrine hormone levels.\n\nPotential histopathological and organ weight effects in endocrine organs have been evaluated in \nlaboratory animals following acute-, intermediate-, and chronic-duration inhalation exposure to HCCPD.  \nDegenerative changes in the adrenal glands of rats, mice, guinea pigs, and rabbits were observed after \nexposures to concentrations of 0.34–73.6 ppm for periods of 15 minutes to 1 week, 0.34 ppm for 6 weeks, \nand 0.15 ppm for 30 weeks; incidence data were not provided (Treon et al. 1955).  Due to the high \nmortality observed at these concentrations, these changes may have been the result of tissue autolysis in \nmoribund or dying animals.  Effects on the adrenal, thyroid, parathyroid, pancreas, and pituitary glands \nfollowing inhalation exposure of male mice to 0.039–0.389 ppm HCCPD for 13 weeks were limited to \nincreased relative adrenal weights; no histopathological changes were noted in these organs in treated \nmale mice and no effects on adrenal, thyroid, parathyroid, pancreas, or pituitary gland weights or\nhistopathology were observed in female mice exposed to ≤0.389 and male and female rats exposed to \n≤0.385 ppm for 13 weeks (NTP 1994).  The biological significance of these adrenal weight changes\ncannot be assessed quantitatively in the absence of hormone product measurements or concurrent \nhistopathological findings.  There were no organ weight or histopathological changes in the adrenal \nglands, pancreas, thyroid, parathyroid gland, and/or pituitary gland identified in male and female rats and \nmonkeys exposed for 14 weeks at ≤0.2 ppm (Alexander et al. 1980b; Rand et al. 1982a), in male and \nfemale rats after 30-week exposures to ≤0.56 ppm (Clark 1981), or in rats and mice following 2-year \nexposures to ≤0.2 ppm (NTP 1994).  Additionally, no effects on the adrenal glands were identified in \nmale mice exposed to 0.5 ppm for 26–42 weeks (NTP 1994).\n\n$$\n\\leq0.385ppm\n$$\n\nPotential effects of HCCPD on endocrine organ weight and histology have also been evaluated in \nlaboratory animals following acute- and intermediate-duration oral exposures and acute-duration dermal \nexposures.  Degenerative changes in the adrenal tissues resulted from exposure to single oral doses of\n\n---\n\n280–2,100 mg/kg in rats and 620–940 mg/kg in rabbits; these changes may have resulted from tissue \nautolysis in moribund or dying animals, but no incidence data were reported (Treon et al. 1955).  There \nwere no histopathological changes in the adrenals, thyroid, parathyroid, or pituitary glands in 13-week \nstudies at gavage doses up to 150 mg/kg/day in rats and 300 mg/kg/day in mice (Abdo et al. 1984; \nVelsicol 1981a, 1981b).  Rabbits that were dermally exposed to HCCPD (430–6,130 mg/kg) had \ndegenerative changes of the adrenal glands that were still apparent in survivors 21 days after exposure; \nincidence data were not provided (Treon et al. 1955).\n\nNo data were identified evaluating endocrine function following *in vivo* exposure to HCCPD; however, \nlimited *in vitro* screening data are available.  HCCPD exhibited statistically significant radioactive iodide \nuptake inhibition in a ToxCast high-throughput screening assay (Wang et al. 2019).  Iodide uptake is the \nfirst step in thyroid hormone biosynthesis.\n\n###### 2.14 IMMUNOLOGICAL\n\n2.14  IMMUNOLOGICAL\n\nNo studies were located regarding immunological effects in humans after exposure to HCCPD. Based on \navailable data in laboratory animals, HCCPD does not cause histopathological alterations to \nimmunological organs.  However, no studies evaluating immune function following exposure to HCCPD \nwere identified.\n\nPotential effects of HCCPD on immune organ weight and histology have also been evaluated in acute-, \nintermediate-, and chronic-duration inhalation exposure studies and intermediate-duration oral exposure \nstudies in laboratory animals.  No exposure-related changes were identified in these studies.  There were \nno histopathological changes in the spleen of rats exposed to ≤0.5 ppm for 1–2 weeks (Alexander et al. \n1980a; Rand et al. 1982a).  In intermediate-duration studies, no histopathological changes were identified \nin immune organs (spleen, thymus, and/or lymph nodes) of monkeys, rats, or mice to concentrations up to \n0.2, 0.56, or 0.5 ppm, respectively (Alexander et al. 1980b; Clark 1981; NTP 1994; Rand et al. 1982a).  \nSimilarly, no histopathological effects were observed in immune organs of rats or mice exposed to \n≤0.2 ppm for 2 years (NTP 1994).  In a 13-week oral study, no treatment-related histopathological \nfindings were identified in the mandibular and mesenteric lymph nodes, thymus, or spleen at gavage \ndoses up to 150 mg/kg/day in rats or 300 mg/kg/day in mice (Abdo et al. 1984; Velsicol 1981a, 1981b).\n\n---\n\n2.  HEALTH EFFECTS\n\n###### 2.15 NEUROLOGICAL\n\n2.15  NEUROLOGICAL\n\nBased on available data, HCCPD does not cause histopathological alterations in the nervous system.  \nEvaluation of neurological function is limited to clinical signs of toxicity; therefore, insufficient data are \navailable to assess the potential effect of HCCPD exposure on neurological function, including behavior.\n\nAmong sewage treatment plant workers exposed to HCCPD at a WWTP because of an inadvertent \nindustrial release, headaches were self-reported by 65 of 145 workers (45%) after exposure for 3–15 days \n(Morse et al. 1979).  Six weeks later, 32 of 177 workers (18%) responding to a questionnaire were still \nexperiencing headaches (Kominsky et al. 1980). No studies were located regarding neurological effects \nin humans after oral or dermal exposure to HCCPD.\n\nNeurological clinical signs of toxicity and nervous system histopathology were evaluated in acute-, \nintermediate-, and chronic-duration inhalation exposure studies.  Rats and mice exposed to concentrations \nof 0.385–2.142 ppm HCCPD were described as listless after 1–3 weeks of exposure (NTP 1994).  \nIncidence data for clinical signs were not provided, so it is unclear how many animals exhibited this effect \nor how frequently; however, the study authors did note that listlessness was observed earlier during the \nexposure period with higher HCCPD concentrations.  Some rats, mice, guinea pigs, and rabbits exposed \nto high lethal concentrations of HCCPD (≥46.5 ppm) by acute-duration inhalation experienced tremors; \nincidence data were not provided (Treon et al. 1955).  At necropsy, diffuse degenerative changes in the \nbrain were observed in all rats, mice, guinea pigs, and rabbits after exposures to 0.34–73.6 ppm for \nperiods of 15 minutes to 1 week, 0.34 ppm for 6 weeks, and 0.15 ppm for 30 weeks; incidence data were \nnot provided (Treon et al. 1955).  These degenerative changes may have been the result of tissue \nautolysis.  In contrast, there were no histopathological changes in the brains of rats exposed to 0.5 ppm \nfor 1–2 weeks (Alexander et al. 1980a; Rand et al. 1982a), male mice exposed to 0.2 ppm for 33 weeks \n(NTP 1994), or rats and mice exposed to ≤0.389 ppm for 13 weeks or ≤0.2 ppm for 2 years (NTP 1994).  \nSimilarly, no histopathological changes were observed in the brains or sciatic nerve of rats or monkeys \nexposed to ≤0.2 ppm for 14 weeks (Alexander et al. 1980b; Rand et al. 1982a) or in brain, spinal cord, or \nsciatic or posterior tibial nerves of rats exposed to ≤0.56 ppm for 30 weeks (Clark 1981).\n\nThe potential neurotoxicity of HCCPD has been evaluated in acute- and intermediate-duration oral \nexposure studies.  Clinical signs of neurotoxicity were observed following acute-duration gavage \nexposure in mice, including hypoactivity at 464 mg/kg and ataxia at 1,000 mg/kg, a dose associated with \nlethality (Dean 1977).  Similarly, all rats exposed once to ≥1,260 mg/kg via gavage exhibited abnormal gait (high stepping, waddling) and lethargy (Gardner 1986a).  Single oral doses ≥180 mg/kg caused \nlethargy in rats and rabbits in the period “immediately after exposure” (Treon et al. 1955).  During \npostmortem examination of tissues, degenerative lesions of the brain were observed in the rats and rabbits \nthat succumbed to exposure and in the rats that survived to the scheduled sacrifice; incidence data were \nnot provided.  No histopathological lesions of the brain, sciatic nerve, or spinal cord were noted in rats or \nmice exposed to gavage doses up to 150 or 300 mg/kg/day, respectively, for 13 weeks (Abdo et al. 1984; \nVelsicol 1981a, 1981b). These data suggest that brain lesions occur only with exposures to high oral \ndoses of HCCPD.\n\nRabbits exposed to single dermal doses of HCCPD (430–6,130 mg/kg) displayed degenerative changes in \nthe brain at necropsy; incidence data were not provided (Treon et al. 1955).  These changes were still \napparent 21 days after exposure in surviving animals.  Ataxia, hypoactivity, and a depressed breathing \npattern have been observed in rabbits at lethal dermal doses of HCCPD (OxyChem 1972).\n\n###### 2.16 REPRODUCTIVE\n\n2.16  REPRODUCTIVE\n\nNo studies were located regarding reproductive effects in humans after exposure to HCCPD.  The \navailable animal data do not indicate that HCCPD causes histopathological alterations to reproductive \norgans.  However, insufficient data are available to thoroughly assess the potential for toxicity to the \nreproductive system, as no studies evaluating reproductive function following inhalation, oral, or dermal \nexposure to HCCPD were identified.\n\nThe potential effects of HCCPD on reproductive organ weight and histology have been evaluated in \nexperimental animals exposed by inhalation for intermediate and chronic durations.  The sole effect on \nreproductive organs identified with HCCPD treatment is an increased incidence of ovarian suppurative \ninflammation in female mice exposed to HCCPD at 0.05–0.2 ppm for 2 years; no histopathological \nchanges were identified in the uterus (NTP 1994).  While this lesion is clearly adverse, as it was the \nsuspected cause of increased mortality at 0.2 ppm, the causal relationship between HCCPD exposure and \nlesion development is unclear.  The study authors noted that lesions were similar to those observed in \nother NTP studies attributed to stress-related susceptibility to utero-ovarian infection by *Klebsiella* \nspecies (NTP 1994).  In contrast, no treatment-related histopathological lesions of the female (ovaries and \nuterus) or male (testes, prostate, and/or seminal vesicle) reproductive organs were identified in monkeys, \nrats, or mice exposed to concentrations up to 0.2, 0.385, or 0.389 ppm for 13–14 weeks (Alexander et al. \n1980b; NTP 1994; Rand et al. 1982a); male mice exposed to 0.2 ppm for 33 weeks or 0.5 ppm for\n\n---\n\n42 weeks (NTP 1994); rats exposed to ≤0.56 ppm for 30 weeks (Clark 1981); or rats or male mice \nexposed to ≤0.2 ppm for 2 years (NTP 1994).\n\n$$\n\\leqq0.56\n$$\n\nThe potential effects of HCCPD on reproductive organ weight and histology have also been evaluated in \nlaboratory animals following intermediate-duration oral exposure.  HCCPD did not cause treatmentrelated effects on the testes, seminal vesicles, prostate, ovaries, or uterus in rats or mice exposed to doses \nup to 150 or 300 mg/kg/day, respectively, via gavage for 13 weeks (Abdo et al. 1984; Velsicol 1981a, \n1981b).\n\nNo data were identified evaluating reproductive function following inhalation, oral, or dermal exposure to \nHCCPD; however, limited screening data are available.  Although it exhibited some estrogen receptor \nbinding affinity in a recombinant human estrogen receptor α (hERα) binding assay, HCCPD did not \nexhibit estrogenic or anti-estrogenic activity in an immature uterotrophic assay in female rats following \nsubcutaneous injection (Akahori et al. 2008).  No anti-androgenic activity was detected for HCCPD in \nChinese hamster ovary (CHO) cells transfected with human androgen receptor (hAR) in an androgenresponsive luciferase reporter assay (Roy et al. 2004).\n\n###### 2.17 DEVELOPMENTAL\n\n2.17  DEVELOPMENTAL\n\nNo studies were located regarding developmental effects in humans after exposure to HCCPD.  Animal \ndata are available only via the oral route and are too limited to assess whether or not the developing \norganism is a target of HCCPD toxicity at doses below those associated with maternal toxicity.\n\nHCCPD was not embryotoxic, fetotoxic, or teratogenic in mice following maternal exposure to gavage \ndoses up to 75 mg/kg/day during GDs 6–15 (Murray et al. 1980).  In rabbits, a dose-dependent increase in \nthe incidence of 13 ribs was identified in the offspring of does exposed to 75 mg/kg/day via gavage \nduring GDs 6–18; nonstatistically significant increases were also identified at 5 and 25 mg/kg/day.  No \nother evidence of embryotoxicity, fetotoxicity, or teratogenicity was identified in rabbits (Murray et al. \n1980).  The natural variation in the number of ribs for rabbits is 12–13.  It should be noted that the \ncompound was not maternally toxic in mice, but maternal mortalities and weight loss were observed in \nrabbits at 75 mg/kg/day (numbers affected and magnitude of effect not specified).\n\nA screening study was performed to evaluate prenatal and postnatal development of mice exposed to \nHCCPD during gestation.  Mice born to dams administered 45 mg/kg/day HCCPD via gavage during\n\n---\n\nGDs 8–12 did not exhibit evidence of developmental toxicity when evaluated on postnatal days (PNDs) 1 \nand 3 (Chernoff and Kavlock 1982, 1983).  When the offspring were evaluated over a 250-day postnatal \nperiod (including through puberty and breeding), there were no adverse effects on postnatal viability, \ngrowth, locomotor activity, sexual development (percent vaginal patency at day 30), or reproductive \nfunction (Gray and Kavlock 1984; Gray et al. 1986).\n\n###### 2.18 OTHER NONCANCER\n\n2.18  OTHER NONCANCER\n\nNo studies were located regarding other noncancer effects in humans after exposure to HCCPD.\n\nOther noncancer effects of HCCPD identified in experimental animals are limited to food and water \nintake.  During the first few days of the post-exposure observation periods, decreased food and water \nintake were observed in rats exposed for 1 hour to ≥1.67 ppm (Jackson and Hardy 1986) and rats exposed \nfor 4 hours to ≥1.68 ppm (Jackson and Hardy 1987); these concentrations were associated with overt \nsigns of toxicity during exposure (e.g., abnormal respiratory pattern).  After a 1–2-week exposure to \nHCCPD, male and female rats exposed to 0.5 ppm had decreased food and water intake (Alexander et al. \n1980a; Rand et al. 1982a).  All males exposed to 0.5 ppm died or were sacrificed in moribund condition \nby the end of the exposure period.  Minor decreases in food intake were also observed for male rats \nexposed to 0.11 ppm without meaningful changes to body weight; the biological significance of this \nfinding is uncertain.  Food intake was not affected in rats or monkeys and water intake was not affected in \nrats exposed to ≤0.2 ppm for 14 weeks (Alexander et al. 1980b; Rand et al. 1982a).  In a 30-week study, \nno treatment-related deficits were identified for male or female rats regarding food or water intake\nfollowing exposure to ≤0.56 ppm (Clark 1981). No treatment-related effects were observed for food and \nwater intake of pregnant mice administered gavage doses of HCCPD at ≤75 mg/kg/day on GDs 6–15 \n(Murray et al. 1980).  Where deficits in food and/or water intake were observed after exposure to \nHCCPD, these effects were likely the result of nonspecific toxicity following exposures to high \nconcentrations of an irritating/corrosive chemical.\n\n$$\n\\mathrm{to}\\geq1.67\\mathrm{ppm}\n$$\n\n$$\nt0\\geq1.68\n$$\n\n$$\nt o\\leqq0.2\n$$\n\n$$\n0.56ppm\n$$\n\n###### 2.19 CANCER\n\nNo studies were located regarding cancer in humans following exposure to HCCPD.\n\nThe carcinogenicity of HCCPD has been evaluated in 2-year rodent bioassays in which male and female \nrats and mice were exposed to concentrations up to 0.2 ppm for 104 weeks (NTP 1994).  There were no statistically significant increases in tumor incidence in rats or mice.  There was a slight increase in the \nincidence of adenomas of the pituitary pars distalis in male rats at 0.2 ppm and in thyroid follicle cell \nadenomas in female mice at 0.05 ppm, but, since the incidences were similar to the historical control \nmeans, were within the historical control range, or did not exhibit a dose-dependency, NTP (1994) did not \nconsider these tumors to be related to HCCPD exposure.  In male mice exposed to 0.5 ppm for 26 or \n42 weeks, then evaluated at 105 weeks, the incidence of alveolar/bronchiolar carcinomas was \nsignificantly increased but was within the historical range for the laboratory (NTP 1994).  Thus, \nalveolar/bronchiolar carcinomas may n", 'pages': None, 'truncated': True, 'extraction': 'firecrawl-public-document-markdown', 'request_id': 'f55ece8d-03a0-45b7-b220-29efe5d1d238', 'source_url': 'https://downloads.regulations.gov/ATSDR-2026-0133-0003/attachment_1.pdf', 'observed_at': '2026-10-04T00:40:37.145404+00:00', 'content_hash': '063c002435b7a13b9144e8da7119795794d56ee2e0ab2fe90a88e51b9525c505'}, 'title': 'Draft Tox Profile for Hexachlorocyclopentadiene', 'check_failed': False}, {'url': 'https://downloads.regulations.gov/ATSDR-2026-0133-0003/content.pdf', 'body': {'text': "## Toxicological Profile for Hexachlorocyclopentadiene (HCCPD)\nDraft for Public Comment\nOctober 2026\n\nU.S. Department of Health and Human Services\nAgency for Toxic Substances and Disease Registry\n\n---\n\n## DISCLAIMER\n\nUse of trade names is for identification only and does not imply endorsement by the Agency for Toxic \nSubstances and Disease Registry, the Public Health Service, or the U.S. Department of Health and Human \nServices.\n\nThis information is distributed solely for the purpose of pre-dissemination for public comment under \napplicable information quality guidelines.  It has not been formally disseminated by the Agency for Toxic \nSubstances and Disease Registry.  It does not represent and should not be construed to represent any \nagency determination or policy.\n\n---\n\n## FOREWORD\n\nThis toxicological profile is prepared in accordance with guidelines developed by the Agency for Toxic \nSubstances and Disease Registry (ATSDR) and the Environmental Protection Agency (EPA).  The \noriginal guidelines were published in the *Federal Register* on April 17, 1987.  Each profile will be revised \nand republished as necessary.\n\nThe ATSDR toxicological profile succinctly characterizes the toxicologic and adverse health effects \ninformation for these toxic substances described therein.  Each peer-reviewed profile identifies and \nreviews the key literature that describes a substance's toxicologic properties.  Other pertinent literature is \nalso presented but is described in less detail than the key studies.  The profile is not intended to be an \nexhaustive document; however, more comprehensive sources of specialty information are referenced.\n\nThe focus of the profiles is on health and toxicologic information; therefore, each toxicological profile \nbegins with a relevance to public health discussion which would allow a public health professional to \nmake a real-time determination of whether the presence of a particular substance in the environment \nposes a potential threat to human health.  The adequacy of information to determine a substance's health \neffects is described in a health effects summary.  Data needs that are of significance to the protection of \npublic health are identified by ATSDR.\n\nEach profile includes the following:\n\n(A) The examination, summary, and interpretation of available toxicologic information and \nepidemiologic evaluations on a toxic substance to ascertain the levels of significant \nhuman exposure for the substance due to associated acute-, intermediate-, and chronicduration exposures;\n\n(B) A determination of whether adequate information on the health effects of each substance \nis available or in the process of development to determine the levels of exposure that \npresent a significant risk to human health due to acute-, intermediate-, and chronicduration exposures; and\n\n(C) Where appropriate, identification of toxicologic testing needed to identify the types or \nlevels of exposure that may present significant risk of adverse health effects in humans.\n\nThe principal audiences for the toxicological profiles are health professionals at the Federal, State, and \nlocal levels; interested private sector organizations and groups; and members of the public.  ATSDR plans \nto revise these documents in response to public comments and as additional data become available.  \nTherefore, we encourage comments that will make the toxicological profile series of the greatest use.\n\nElectronic comments may be submitted via: www.regulations.gov. Follow the on-line instructions for \nsubmitting comments.\n\nWritten comments may also be sent to:\n\nAgency for Toxic Substances and Disease Registry\n\nOffice of Innovation and Analytics\n\nToxicology Section\n\n1600 Clifton Road, N.E.\n\nMail Stop S106-5\n\nAtlanta, Georgia 30329-4027\n\n---\n\nThe toxicological profiles are developed under the Comprehensive Environmental Response, \nCompensation, and Liability Act of 1980, as amended (CERCLA or Superfund).  CERCLA \nSection 104(i)(1) directs the Administrator of ATSDR to “…effectuate and implement the health-related \nauthorities” of the statute.  This includes the preparation of toxicological profiles for hazardous \nsubstances most commonly found at facilities on the CERCLA National Priorities List (NPL) and that \npose the most significant potential threat to human health, as determined by ATSDR and the EPA.  \nSection 104(i)(3) of CERCLA, as amended, directs the Administrator of ATSDR to prepare a \ntoxicological profile for each substance on the list.  In addition, ATSDR has the authority to prepare \ntoxicological profiles for substances not found at sites on the NPL, in an effort to “…establish and \nmaintain inventory of literature, research, and studies on the health effects of toxic substances” under \nCERCLA Section 104(i)(1)(B), to respond to requests for consultation under Section 104(i)(4), and as \notherwise necessary to support the site-specific response actions conducted by ATSDR.\n\nThis profile reflects ATSDR’s assessment of all relevant toxicologic testing and information that has been \npeer-reviewed.  Staffs of the Centers for Disease Control and Prevention and other Federal scientists have \nalso reviewed the profile.  In addition, this profile has been peer-reviewed by a nongovernmental panel \nand is being made available for public review.  Final responsibility for the contents and views expressed \nin this toxicological profile resides with ATSDR.\n\nChristopher M. Reh, Ph.D. \nAssociate Director, \nAgency for Toxic Substances and Disease Registry \nCenters for Disease Control and Prevention\n\n---\n\n**VERSION HISTORY**\n\n| Date | Description |\n| --- | --- |\n| October 2026 | Draft for public comment toxicological profile released |\n| July 1999 | Final toxicological profile released |\n\n---\n\n# CONTRIBUTORS & REVIEWERS\n\n# CHEMICAL MANAGER TEAM\n\nGaston Casillas, Ph.D. (Lead)\nFahim Atif, Ph.D.\nJennifer Przybyla, Ph.D.\nNickolette Roney, M.P.H.\nBrittany Szafran, D.V.M., Ph.D., D.A.B.T.\n\nZach Guerrette, Ph.D., D.A.B.T.\nChristina Coley, M.S.\nLisa Ingerman, Ph.D., D.A.B.T.\nKimberly Zaccaria, Ph.D., D.A.B.T.\nMario Citra, Ph.D.\n\nATSDR, Office of Innovation and Analytics, \nToxicology Section, Atlanta, GA\n\nSRC, Inc., North Syracuse, NY\n\n### REVIEWERS\n\n#### Interagency Minimal Risk Level Workgroup:\n\nIncludes ATSDR; National Center for Environmental Health (NCEH); U.S. Environmental Protection \nAgency (EPA); National Toxicology Program (NTP).\n\n#### Additional reviews for science and/or policy:\n\nATSDR, Office of Community Health Hazard Assessment; ATSDR, Office of Capacity Development \nand Applied Prevention Science; ATSDR, Office of Science; NCEH, Division of Laboratory Sciences; \nNCEH, Division of Environmental Health Science and Practice; EPA, Office of Research and \nDevelopment; EPA, Office of Water.\n\n### PEER REVIEWERS\n\n1. David Dorman, D.V.M., Ph.D., D.A.B.V.T., D.A.B.T.; Professor of Toxicology; North Carolina \nState University; College of Veterinary Medicine; Department of Molecular Biomedical \nSciences; Raleigh, North Carolina\n\n2. Slawo Lomnicki, Ph.D.; Assistant Professor of Environmental Sciences; Louisiana State \nUniversity, Chemistry Department; LSU Superfund Research Materials Core leader; Baton \nRouge, Louisiana\n\n3. Deborah A. Slechta, Ph.D., M.A.; University of Rochester; Professor - Department of \nEnvironmental Medicine (SMD); Professor - Department of Neuroscience (SMD) -– Joint; \nProfessor - Department of Public Health Sciences (SMD) - Joint; Rochester, New York\n\nThese experts collectively have knowledge of toxicology, chemistry, and/or health effects.  All reviewers \nwere selected in conformity with Section 104(I)(13) of the Comprehensive Environmental Response, \nCompensation, and Liability Act, as amended.\n\nATSDR scientists review peer reviewers’ comments and determine whether changes will be made to the \nprofile based on comments.  The peer reviewers’ comments and responses to these comments are part of \nthe administrative record for this compound.\n\nThe listing of peer reviewers should not be understood to imply their approval of the profile's final \ncontent.  The responsibility for the content of this profile lies with ATSDR.\n\n---\n\n## CONTENTS\n\nDISCLAIMER .............................................................................................................................................. ii\nFOREWORD ............................................................................................................................................... iii\nVERSION HISTORY ................................................................................................................................... v\nCONTRIBUTORS & REVIEWERS ........................................................................................................... vi\nCONTENTS ................................................................................................................................................ vii\nLIST OF FIGURES ..................................................................................................................................... ix\nLIST OF TABLES ........................................................................................................................................ x\nCHAPTER 1. RELEVANCE TO PUBLIC HEALTH ................................................................................. 1\n1.1 OVERVIEW AND U.S. EXPOSURES ......................................................................................... 1\n1.2 SUMMARY OF HEALTH EFFECTS........................................................................................... 1\n1.3 MINIMAL RISK LEVELS (MRLs) .............................................................................................. 6\nCHAPTER 2. HEALTH EFFECTS ............................................................................................................ 10\n2.1 INTRODUCTION ........................................................................................................................ 10\n2.2 DEATH ........................................................................................................................................ 55\n2.3 BODY WEIGHT .......................................................................................................................... 57\n2.4 RESPIRATORY .......................................................................................................................... 58\n2.5 CARDIOVASCULAR ................................................................................................................. 63\n2.6 GASTROINTESTINAL ............................................................................................................... 63\n2.7 HEMATOLOGICAL ................................................................................................................... 65\n2.8 MUSCULOSKELETAL .............................................................................................................. 68\n2.9 HEPATIC ..................................................................................................................................... 68\n2.10 RENAL ........................................................................................................................................ 70\n2.11 DERMAL ..................................................................................................................................... 72\n2.12 OCULAR ..................................................................................................................................... 73\n2.13 ENDOCRINE ............................................................................................................................... 74\n2.14 IMMUNOLOGICAL ................................................................................................................... 75\n2.15 NEUROLOGICAL....................................................................................................................... 76\n2.16 REPRODUCTIVE ....................................................................................................................... 77\n2.17 DEVELOPMENTAL ................................................................................................................... 78\n2.18 OTHER NONCANCER ............................................................................................................... 79\n2.19 CANCER ...................................................................................................................................... 79\n2.20 GENOTOXICITY ........................................................................................................................ 80\n2.21 MECHANISM OF ACTION ....................................................................................................... 82\nCHAPTER 3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, \nCHEMICAL INTERACTIONS ........................................................................................... 84\n3.1 TOXICOKINETICS..................................................................................................................... 84\n3.1.1 Absorption ............................................................................................................................. 84\n3.1.2 Distribution ........................................................................................................................... 86\n3.1.3 Metabolism ............................................................................................................................ 88\n3.1.4 Excretion ............................................................................................................................... 90\n3.1.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models ............. 92\n3.1.6 Animal-to-Human Extrapolations ......................................................................................... 93\n3.2 CHILDREN AND OTHER POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE ..... 93\n3.3 BIOMARKERS OF EXPOSURE AND EFFECT ....................................................................... 95\n\n---\n\n3.3.1 Biomarkers of Exposure ........................................................................................................ 95\n3.3.2 Biomarkers of Effect ............................................................................................................. 96\n3.4 INTERACTIONS WITH OTHER CHEMICALS ....................................................................... 97\nCHAPTER 4. CHEMICAL AND PHYSICAL INFORMATION ............................................................. 98\n4.1 CHEMICAL IDENTITY ............................................................................................................. 98\n4.2 PHYSICAL AND CHEMICAL PROPERTIES .......................................................................... 98\nCHAPTER 5. POTENTIAL FOR HUMAN EXPOSURE ....................................................................... 100\n5.1 OVERVIEW .............................................................................................................................. 100\n5.2 PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL ................................................ 101\n5.2.1 Production ........................................................................................................................... 101\n5.2.2 Import/Export ...................................................................................................................... 103\n5.2.3 Use ...................................................................................................................................... 103\n5.2.4 Disposal ............................................................................................................................... 104\n5.3 RELEASES TO THE ENVIRONMENT ................................................................................... 104\n5.3.1 Air ....................................................................................................................................... 105\n5.3.2 Water ................................................................................................................................... 107\n5.3.3 Soil ...................................................................................................................................... 108\n5.4 ENVIRONMENTAL FATE ...................................................................................................... 109\n5.4.1 Transport and Partitioning ................................................................................................... 109\n5.4.2 Transformation and Degradation ........................................................................................ 112\n5.5 LEVELS IN THE ENVIRONMENT ......................................................................................... 116\n5.5.1 Air ....................................................................................................................................... 117\n5.5.2 Water ................................................................................................................................... 118\n5.5.3 Sediment and Soil ............................................................................................................... 122\n5.5.4 Other Media ........................................................................................................................ 123\n5.6 GENERAL POPULATION EXPOSURE.................................................................................. 124\n5.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES .............................................. 125\nCHAPTER 6. ADEQUACY OF THE DATABASE ................................................................................ 126\n6.1 EXISTING INFORMATION ON HEALTH EFFECTS ........................................................... 126\n6.2 IDENTIFICATION OF DATA NEEDS .................................................................................... 126\n6.3 ONGOING STUDIES ................................................................................................................ 135\nCHAPTER 7. REGULATIONS AND GUIDELINES ............................................................................. 136\nCHAPTER 8. REFERENCES .................................................................................................................. 138\nAPPENDICES\nAPPENDIX A.  ATSDR MINIMAL RISK LEVEL WORKSHEETS .................................................... A-1 \nAPPENDIX B. LITERATURE SEARCH FRAMEWORK FOR HCCPD ............................................. B-1 \nAPPENDIX C. FRAMEWORK FOR ATSDR’S SYSTEMATIC REVIEW OF HEALTH EFFECTS \nDATA FOR HCCPD ...................................................................................................... C-1 \nAPPENDIX D.  USER’S GUIDE ............................................................................................................. D-1 \nAPPENDIX E.  QUICK REFERENCE FOR HEALTH CARE PROVIDERS ....................................... E-1 \nAPPENDIX F.  GLOSSARY .................................................................................................................... F-1 \nAPPENDIX G.  ACRONYMS, ABBREVIATIONS, AND SYMBOLS................................................. G-1\n\n---\n\n## LIST OF FIGURES\n\n1-1.  Health Effects Found in Animals Following Inhalation Exposure to HCCPD .................................... 3\n1-2.  Health Effects Found in Animals Following Oral Exposure to HCCPD .............................................. 4\n1-3.  Summary of Sensitive Targets of HCCPD – Inhalation ....................................................................... 7\n1-4.  Summary of Sensitive Targets of HCCPD – Oral ................................................................................ 8\n2-1.  Overview of the Number of Studies Examining HCCPD Health Effects .......................................... 14\n2-2.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation ..................................... 28\n2-3.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Oral .............................................. 44\n5-1.  Number of NPL Sites with Hexachlorocyclopentadiene Contamination ......................................... 100\n5-2.  Transformation of Hexachlorocyclopentadiene ................................................................................ 113\n6-1.  Summary of Existing Health Effects Studies on HCCPD by Route and Endpoint .......................... 127\n\n---\n\n## LIST OF TABLES\n\n1-1.  Provisional Minimal Risk Levels (MRLs) for HCCPD ........................................................................ 9\n2-1.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation ..................................... 15\n2-2.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Oral .............................................. 39\n2-3.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Dermal ......................................... 49\n2-4.  LOAEL Values for Red Blood Cell Hematological Effects of Rats Exposed to HCCPD \nVapor in Acute- and Intermediate-Duration Inhalation  Studies ........................................................ 65\n2-5.  Genotoxicity of Hexachlorocyclopentadiene *In Vivo* ......................................................................... 81\n2-6.  Genotoxicity of Hexachlorocyclopentadiene *In Vitro* ........................................................................ 81\n4-1.  Chemical Identity of Hexachlorocyclopentadiene .............................................................................. 98\n4-2.  Physical and Chemical Properties of Hexachlorocyclopentadiene ..................................................... 98\n5-1.  Facilities that Produce, Process, or Use Hexachlorocyclopentadiene .............................................. 102\n5-2.  Summary of National Aggregate Volumes Reported to U.S. Environmental Protection \nAgency (EPA) Chemical Data  Reporting (CDR) ............................................................................ 103\n5-3.  Releases to the Environment from Facilities that Produce, Process, or Use \nHexachlorocyclopentadiene .............................................................................................................. 105\n5-4.  Summary of Releases to the Environment from the Emissions Inventory System (EIS) \nGateway Emission Sectors in 2020 .................................................................................................. 106\n5-5.  Summary of Releases to the Environment from the Emissions Inventory System (EIS) \nGateway Emission Sectors in 2021 .................................................................................................. 107\n5-6.  Lowest Limit of Detection Based on Standards ............................................................................... 117\n5-7.  Summary of Environmental Levels of HCCPD ............................................................................... 117\n5-*8.*  Summary of Water Monitoring Data for Hexachlorocyclopentadiene Across the \nUnited States ..................................................................................................................................... 119\n7-1.  Regulations and Guidelines Applicable to Hexachlorocyclopentadiene .......................................... 136\n\n---\n\n# CHAPTER 1. RELEVANCE TO PUBLIC HEALTH\n\n###### 1.1 OVERVIEW AND U.S. EXPOSURES\n\nHexachlorocyclopentadiene (HCCPD) is a highly volatile, reactive liquid.  HCCPD is an anthropogenic \nchemical that has entered the environment primarily because of its use in the production of chlorinated \npesticides and flame-retardant chemicals.  Restriction of pesticides synthesized from HCCPD has \ndecreased the possibility of exposure to HCCPD and pesticide residues among most members of the \ngeneral population.  Exposure to materials containing HCCPD at hazardous waste sites is still possible.\n\nThe potential for persistence of HCCPD in the environment is low.  Due to its high vapor pressure, \nHCCPD is most likely released to the environment through volatilization, especially from surface waters \nand soils.  The main degradation processes expected include photolysis and photooxidation, hydrolysis, \nand, to a lesser extent, biodegradation.  HCCPD in the air is expected to degrade with estimated half-lives \nranging from 5 hours to <1 day, which limits its potential for long-range transport. HCCPD in water is \nexpected to degrade rapidly, with half-lives for photolysis of ~2–4 minutes and half-lives for hydrolysis \nof ~3–5.45 days.\n\nOccupational exposure to HCCPD is most likely to occur via inhalation and dermal routes.  The general \npopulation may be exposed to HCCPD through inhalation of air contaminated with this chemical and \ningestion of drinking water contaminated with this chemical.\n\n###### 1.2 SUMMARY OF HEALTH EFFECTS\n\nInformation on the noncancer toxicity of HCCPD in humans is limited to reports by wastewater treatment \nplant (WWTP) workers and cleanup crew members exposed after an inadvertent industrial release.  No \noccupational studies evaluating health effects in workers exposed during regular manufacture or use of \nHCCPD are available.  Additionally, no observational epidemiological studies of workers or the public \nare available for HCCPD.  Further information on the noncancer toxicity of HCCPD comes from \ninhalation and oral studies in animals.  Data following dermal exposure are very limited in humans and \nanimals.\n\nIn laboratory animals, evaluation of available dose-response data by route and duration indicates that \nsensitive noncancer targets of HCCPD toxicity are respiratory and hematological effects following inhalation exposure (Figure 1-1).  Ovarian inflammation was noted in mice following chronic-duration \ninhalation exposure; however, the causal relationship between the effect and HCCPD exposure could not \nbe determined due to apparent association with stress-induced susceptibility to an infection in the mouse \ncolony (see Section 2.16).  Due to this, female reproductive (ovarian) effects were not considered as \npotential sensitive effects or included in Figure 1-1.  The oral database is very limited; the only potential \ntargets identified below doses associated with lethality include the gastrointestinal tract and kidney \n(Figure 1-2). General toxicity (decreased body weight) was also observed at similar doses.  A systematic \nreview of sensitive target organs/systems by exposure route resulted in the following hazard identification \nconclusions:\n\n• Respiratory effects are a presumed health effect for humans following inhalation exposure.\n\n• Gastrointestinal effects are a presumed health effect for humans following oral exposure.\n\n• Hematological (red blood cell) effects are suspected health effects for humans following \ninhalation exposure; white blood cell effects are not classifiable as to the hazard to humans.\n\n• Renal effects are a presumed health effect for humans following oral exposure.\n\n**_Respiratory Effects (Inhalation Route)._**  The respiratory tract is sensitive to HCCPD toxicity after \ninhalation exposure; findings are attributed to compound reactivity upon contact with respiratory tissues \nat the portal of entry.  WWTP workers and cleanup crew members reported respiratory symptoms \nincluding coughing, nose and throat irritation, and difficulty breathing following inhalation of HCCPD \nvapors from an inadvertent industrial discharge (Kominsky et al. 1980; Morse et al. 1979).  Acuteduration inhalation exposure studies in animals identified increased or labored respiration or abnormal \nrespiratory patterns at concentrations ≥0.5 ppm (Alexander et al. 1980a; Jackson and Hardy 1986, 1987; \nRand et al. 1982a).  Sneezing and altered respiratory rates/patterns were observed in rodents at \nintermediate-duration exposures of ≥0.56 ppm (Clark 1981; NTP 1994).  Histopathological evaluation \nidentified changes to the nasal, tracheobronchial, and/or pulmonary epithelium in rats and mice at \n≥0.385 and ≥0.2 ppm, respectively; these changes consisted of inflammation (suppurative or necrotizing) \nor metaplasia at nonlethal concentrations (Clark 1981; NTP 1994) and hemorrhaging or necrosis at lethal \nconcentrations (NTP 1994).  Nasal and pulmonary lesions were observed in mice exposed to 0.2 ppm \nHCCPD for 2 years, while no lesions were observed in rats under the same exposure conditions (NTP \n1994).\n\n$$\n\\geq0.385and\\geq0.2\n$$\n\n---\n\n**Figure 1-1.  Health Effects Found in Animals Following Inhalation Exposure to** \n**HCCPD**\n\n**Concentration (ppm)**\n\n**≥1.4**\n\n**Effects in Animals**\n\n**Acute:**  Neurobehavioral effects\n\n**Intermediate:**  Hepatic effects\n\n**0.5**\n\n**Acute:**  Death, respiratory lesions, altered hematology parameters, \ndecreased body weight, decreased food and water intake\n\n**Intermediate:**  Decreased body weight\n\n**0.389**\n\n**Intermediate:**  Death\n\n**0.2**\n\n**0.039**\n\n**Intermediate:**  Respiratory lesions\n\n**Chronic:**  Death, respiratory lesions\n\n**Intermediate:**  Altered red blood cell parameters\n\n1x10<sup>-4</sup> ppm\n6x10<sup>-5</sup> ppm\n\n**Provisional Intermediate MRL**\n**Provisional Chronic MRL**\n\n---\n\n**Figure 1-2.  Health Effects Found in Animals Following Oral Exposure to HCCPD**\n\nDose (mg/kg/day) Effects in Animals\n≥464 Acute:  Gastrointestinal, neurological, respiratory, and musculoskeletal  \neffects \n150 Intermediate:  Death\n75 Acute:  Death, developmental effects\n38 Intermediate:  Gastrointestinal and renal lesions, decreased body \nweight\n0.06 mg/kg/day Provisional Intermediate MRL\n\n**_Gastrointestinal Effects (Oral Route)._** The gastrointestinal tract is sensitive to HCCPD after oral \nexposure; findings are attributed to compound reactivity upon contact with gastrointestinal tissues at the \nportal of entry.  No human data are available evaluating potential gastrointestinal effects of HCCPD \nfollowing oral exposure.  Diarrhea was reported in rodents administered single oral doses of ≥464 mg/kg \n(Dean 1977; Gardner 1986a); this effect was not reported at lower doses in intermediate-duration studies \nup to 150 mg/kg/day in rats or 300 mg/kg/day in mice (Abdo et al. 1984).  In the only available \nintermediate-duration oral study in animals, focal inflammation and epithelial hyperplasia of the \nforestomach were observed in rats and mice exposed to ≥38 and ≥75 mg/kg/day, respectively (Abdo et al.\n1984).  While humans lack a forestomach, analogous lesions could occur in the proximate portions of the \nhuman gastrointestinal tract, including oral, pharyngeal, and/or esophageal tissues, due to portal-of-entry \nreactivity following oral exposure to HCCPD.\n\n**_Hematological Effects (Inhalation Route)._**  No changes in blood counts were observed in workers \nexposed to HCCPD at a WWTP following an inadvertent industrial discharge (Kominsky et al. 1980).  \nAlterations in red blood cell parameters, primarily elevated red blood cell counts and hemoglobin levels, were reported in rats following acute- and intermediate-duration inhalation exposure to HCCPD at \nconcentrations of 0.5 and ≥0.14 ppm, respectively (Clark 1981; NTP 1994; Rand et al. 1982a); similar \nfindings were observed in mice at intermediate-duration inhalation concentrations ≥0.039 ppm (NTP \n1994).  Based on the absence of histopathological changes to bone marrow, observed red blood cell \neffects have been hypothesized to be a compensatory response to hemorrhagic damage to the lungs \nfollowing inhalation exposure rather than direct effects on hematopoiesis (Rand et al. 1982a).  However,\nrats showed sex-specific findings (females were less sensitive), and there were inconsistencies between \nthe main 13-week (comprehensive) study and the 13-week specialized hematological study conducted by \nNTP (1994).  In mice, findings were limited and inconsistent with respect to alterations in red blood cell \nparameters after exposure for 13–42 weeks (NTP 1994).  Additionally, no hematological effects were \nobserved in the 2-year inhalation studies in rats or mice at concentrations up to 2 ppm (NTP 1994).  No \nconsistent effects on white blood cell parameters were observed with inhalation exposures in animal \nstudies (Clark 1981; NTP 1994; Rand et al. 1982a).\n\n**_Renal Effects (Oral Route)._** No human data are available to assess the potential for HCCPD to cause \nrenal toxicity.  In the only available oral study in animals evaluating the kidney, HCCPD produced toxic \nnephrosis in male and female rats at ≥38 mg/kg/day and in female mice at ≥75 mg/kg/day (Abdo et al. \n1984).  Toxic nephrosis was not identified in male mice, but acute tubular necrosis was identified in male \nmice exposed to 300 mg/kg/day. Available toxicokinetic data indicate that HCCPD and/or its metabolites \ndistribute to the kidneys in both rats and mice after oral dosing; however, the highest distribution is to the \nkidney in the rat and to the liver in the mouse (Dorough and Ranieri 1984).  This observed difference in \ndistribution may explain the observed species sensitivity.\n\n**_Cancer Effects._**  There were no data from studies in humans pertaining to the carcinogenicity of HCCPD.  \nThe National Toxicology Program (NTP) conducted 2-year bioassays of HCCPD in mice and rats and \nconcluded that it is not a carcinogen in either species (NTP 1994).  Although the incidence of \nalveolar/bronchiolar carcinomas was significantly increased in male mice exposed to 0.5 ppm for 26 or \n42 weeks and evaluated at 2 years, the incidence was within the historical range for the laboratory and \nwas not elevated in animals exposed to 0.2 ppm for 2 years. There was also a slight increase in the \nincidence of adenomas of the pituitary pars distalis in male rats and thyroid follicle cell adenomas in \nfemale mice, but these tumors were not considered to be exposure-related since the incidences were \nsimilar to the historical control means, were within the historical control range, or did not exhibit a dosedependency.  Based on these results, the U.S. Environmental Protection Agency (EPA) determined that \nHCCPD is not likely to be a human carcinogen by the inhalation route (IRIS 2003).  The International\n\n---\n\nAgency for Research on Cancer (IARC) has not evaluated the carcinogenicity of HCCPD (IARC 2025).  \nThe U.S. Department of Health and Human Services (HHS) has not evaluated a cancer classification \ncategory for HCCPD (NTP 2021).\n\n###### 1.3 MINIMAL RISK LEVELS (MRLs)\n\nAs illustrated in Figure 1-3, available inhalation data for HCCPD suggest that the respiratory and \nhematological systems are the most sensitive targets for toxicity. The inhalation database was considered \nadequate for derivation of provisional intermediate- and chronic-duration MRLs.  As discussed in \nSection 1.2, ovarian effects observed in the chronic-duration mouse study were not considered as \npotential sensitive effects due to potential confounding by a utero-ovarian infection (see Appendix A for \ndetails).  Therefore, female reproductive effects are not included in Figure 1-3.\n\nAs illustrated in Figure 1-4, gastrointestinal, renal, and body weight effects appear to be the most \nsensitive targets of HCCPD toxicity following oral exposure. The oral database was considered adequate \nfor derivation of a provisional intermediate-duration MRL for HCCPD.  The acute- and chronic-duration \noral data were insufficient for deriving MRLs.\n\nThe provisional MRL values are summarized in Table 1-1 and discussed in greater detail in Appendix A.\n\n---\n\n**Figure 1-3.  Summary of Sensitive Targets of HCCPD – Inhalation**\n\n**Available data indicate that the hematological and respiratory systems are the most sensitive \ntargets of HCCPD inhalation exposure.**\n\nNumbers in circles are the lowest LOAELs for all health effects in animals. No reliable dose response \ndata were available for humans.\n\n**Acute (ppm)**\n\n| Category | Acute (ppm) | Intermediate (ppm) | Chronic (ppm) |\n| --- | --- | --- | --- |\n| Death | 0.5 | 0.389 | 0.2 |\n| Body weight | 0.5 |  |  |\n| Respiratory | 0.5 | 0.2 | 0.2 |\n| Hematological | 0.5 | 0.039 |  |\n| Other noncancer | 0.5 |  |  |\n\n---\n\n**Figure 1-4. Summary of Sensitive Targets of HCCPD – Oral**\n\n**Available data indicate that the gastrointestinal tract, renal system, and body weight are the most\nsensitive targets of HCCPD oral exposure.**\nNumbers in circles are the lowest LOAELs for all health effects in animals. \nNo reliable dose response data were available for humans.\n\n## Acute (mg/kg/day)\n\n| Category | Lowest LOAEL (mg/kg/day) |\n| --- | --- |\n| Death (Acute) | 75 |\n| Developmental (Acute) | 75 |\n| Gastrointestinal (Acute) | 464 |\n| Neuological (Acute) | 464 |\n| Body weight (Intermediate) | 38 |\n| Gastrointestinal (Intermediate) | 38 |\n| Renal (Intermediate) | 38 |\n| Death (Intermediate) | 150 |\n\n---\n\nTable 1-1. Provisional Minimal Risk Levels (MRLs) for HCCPD<sup>a</sup>\n\n| Exposure route | Exposure duration | Provisional MRL | Critical effect | POD type | POD value | Uncertainty/modifying factor | Reference |\n| --- | --- | --- | --- | --- | --- | --- | --- |\n| Inhalation | Acute | None | - | - | - | - | - |\n| Inhalation | Intermediate | 1 × 10-4 ppm (1 × 10-3 mg/m3) | Nasal suppurative inflammation in rats | NOAELHEC | 0.00344 ppm | UF: 30 | NTP 1994 |\n| Inhalation | Chronic | 6 × 10-5 ppm (7 × 10-4 mg/m3) | Nasal suppurative inflammation in mice | BMCLHEC | 0.0019 ppm | UF: 30 | NTP 1994 |\n| Oral | Acute | None | - | - | - | - | - |\n| Oral | Intermediate | 0.06 mg/kg/day | Combined incidence of forestomach epithelial hyperplasia and focal inflammation in rats | BMDLADJ | 5.5 mg/kg/day | UF: 100 | Abdo et al. 1984: Velsicol 1981b |\n| Oral | Chronic | None | - | - | - | - | - |\n\n$$\n1\\times10^{-4}ppm\n$$\n\n$$\n(1\\times10^{-3}mg/m^3)\n$$\n\n$$\n6\\times10^{-5}ppm\n$$\n\n$$\n(7\\times10^{-4}mg/m^3)\n$$\n\n<sup>a</sup>See Appendix A for additional information.\n\nADJ = adjusted for intermittent exposure; BMCL = benchmark concentration lower confidence limit; BMDL = benchmark dose lower confidence limit;\n\nHEC = human equivalent concentration; NOAEL = no-observed-adverse-effect level; POD = point of departure; UF = uncertainty factor\n\n---\n\n# CHAPTER 2. HEALTH EFFECTS\n\n###### 2.1 INTRODUCTION\n\nThe primary purpose of this chapter is to provide public health officials, physicians, toxicologists, and \nother interested individuals and groups with an overall perspective on the toxicology of HCCPD.  It \ncontains descriptions and evaluations of toxicological studies and epidemiological investigations and \nprovides conclusions, where possible, on the relevance of toxicity and toxicokinetic data to public health.  \nWhen available, mechanisms of action are discussed along with the health effects data; toxicokinetic \nmechanistic data are discussed in Section 3.1.\n\nA glossary and list of acronyms, abbreviations, and symbols can be found at the end of this profile.\n\nTo help public health professionals and others address the needs of persons living or working near hazardous \nwaste sites, the information in this section is organized by health effects.  These data are discussed in terms \nof route of exposure (inhalation, oral, and dermal) and three exposure periods:  acute (≤14 days), \nintermediate (15–364 days), and chronic (≥365 days).\n\nAs discussed in Appendix B, a literature search was conducted to identify relevant studies examining health \neffect endpoints.  Figure 2-1 provides an overview of the database of studies in humans or experimental \nanimals included in this chapter of the profile.  These studies evaluate the potential health effects associated \nwith inhalation, oral, or dermal exposure to HCCPD, but may not be inclusive of the entire body of literature.  \nA systematic review of the scientific evidence of the health effects associated with exposure to HCCPD was \nalso conducted; the results of this review are presented in Appendix C.\n\nHuman and animal inhalation studies are presented in Table 2-1 and Figure 2-2, animal oral studies are \npresented in Table 2-2 and Figure 2-3, and human and animal dermal studies are presented in Table 2-3.  \nDue to the limited nature of the database, several older studies lacking quantitative data reporting are \nincluded in Chapter 2 to provide data potentially relevant for hazard identification; however, data that are \nonly reported qualitatively (i.e., histopathological data lacking incidence data) are not included in \nTables 2-1, 2-2, or 2-3.\n\nLevels of significant exposure (LSEs) for each route and duration are presented in tables and illustrated in \nfigures.  The points in the figures showing no-observed-adverse-effect levels (NOAELs) or lowest- observed-adverse-effect levels (LOAELs) reflect the actual doses (levels of exposure) used in the studies.  \nEffects have been classified into “less serious LOAELs” or “serious LOAELs (SLOAELs).”  “Serious” \neffects are those that evoke failure in a biological system and can lead to morbidity or mortality (e.g., \nacute respiratory distress or death).  “Less serious” effects are those that are not expected to cause \nsignificant dysfunction or death, or those whose significance to the organism is not entirely clear.  \nATSDR acknowledges that a considerable amount of judgment may be required in establishing whether \nan endpoint should be classified as a NOAEL, “less serious” LOAEL, or “serious” LOAEL, and that in \nsome cases, there will be insufficient data to decide whether the effect is indicative of significant \ndysfunction.  However, the Agency has established guidelines and policies that are used to classify these \nendpoints.  ATSDR believes that there is sufficient merit in this approach to warrant an attempt at \ndistinguishing between “less serious” and “serious” effects.  The distinction between “less serious” effects \nand “serious” effects is considered to be important because it helps the users of the profiles to identify \nlevels of exposure at which major health effects start to appear.  LOAELs or NOAELs should also help in \ndetermining whether or not the effects vary with dose and/or duration, and place into perspective the \npossible significance of these effects to human health.\n\nA User's Guide has been provided at the end of this profile (see Appendix C).  This guide should aid in \nthe interpretation of the tables and figures for LSEs and MRLs.\n\nThe health effects of HCCPD have been evaluated in 2 human studies and 68 animal studies.  As \nillustrated in Figure 2-1, most of the health effect data come from dermal and inhalation studies in \nanimals.  In both human and animal studies, the ocular effects observed in HCCPD inhalation studies are \nlikely attributable to direct contact with HCCPD vapors.  Therefore, ocular effects from inhalation studies \nare counted as dermal exposure in Figure 2-1 and are listed in the dermal LSE table.\n\nThe available human studies were predominantly focused on evaluation of dermal, ocular, and respiratory \neffects in WWTP workers and cleanup crew members following an inadvertent industrial release of \nHCCPD.  For these studies, exposure was evaluated as HCCPD vapor levels in air.\n\nFor animal data, inhalation and oral studies are available for most health effects.  Acute-, intermediate-, \nand chronic-duration studies are available for the inhalation route, while only acute- and intermediateduration studies are available for the oral route.  The dermal animal database is mostly limited to ocular \nand dermal effects, largely following exposure to HCCPD vapor.  The most examined endpoints in \nanimal studies were death, respiratory, hepatic, renal, and ocular.\n\n---\n\nA systematic review was conducted on potential targets of HCCPD exposure, which included respiratory \nand hematological effects for inhalation exposure and gastrointestinal and renal effects following oral \nexposure (see Appendix C for details).\n\n• **Respiratory Effects.** Respiratory effects are a presumed health effect associated with HCCPD \nexposure via inhalation based on inadequate evidence in humans and a high level of evidence in \nanimals.  WWTP workers and cleanup crew members reported respiratory symptoms including \ncoughing and respiratory tract irritation after exposure to HCCPD vapors following an \ninadvertent industrial release.  Several animal studies have reported altered respiratory patterns \nfollowing single or repeated exposures to HCCPD.  Upon histopathological examination, \nnonneoplastic lesions of the nasal, tracheobronchial, and pulmonary regions were consistently \nobserved in mice and rats exposed for intermediate durations to concentrations ≥0.2 or \n≥0.385 ppm, respectively.  Chronic-duration exposure to 0.2 ppm resulted in similar lesions in \nmice, but not rats.  Observed lesions (suppurative, serous, or necrotizing inflammation; epithelial \nhyperplasia) are consistent with chronic irritation at the portal of entry.\n\n• **Gastrointestinal Effects.** Gastrointestinal effects are a presumed health effect associated with \nHCCPD exposure via oral exposure based on no human data and a high level of evidence in \nanimal studies.  Diarrhea was reported in rodents following exposure to high acute doses \n≥464 mg/kg.  Forestomach lesions (epithelial hyperplasia and focal inflammation) were observed \nin rats and mice following intermediate-duration exposures of ≥38 and ≥75 mg/kg/day, \nrespectively.  Although humans lack a forestomach, effects associated with HCCPD are \nconsistent with chronic irritation at the portal of entry.  Thus, the upper gastrointestinal tract is\npresumably vulnerable to toxicity following oral exposure to HCCPD.\n\n• **Hematological Effects.** Hematological effects, specifically red blood cell parameters, are a \nsuspected health effect associated with HCCPD exposure via inhalation based on inadequate data \nin humans and a moderate level of evidence in animals.  No changes in blood counts were \nobserved in WWTP workers after exposure to HCCPD vapors following an inadvertent industrial \nrelease.  Several acute- and intermediate-duration inhalation studies reported altered red blood \ncell parameters (e.g., increased hemoglobin, red blood cell counts, and packed cell volume) at \nconcentrations as low as 0.14 and 0.039 ppm in rats and mice, respectively; however, these \nfindings were not consistent across sexes or species nor were they reproducible in targeted \nanalyses by the same researchers.  Observed red blood cell effects may be attributable to\ncompromised gas exchange following tissue damage to the respiratory tract, as no evidence of \nbone marrow hyperplasia was observed in rodents following repeated inhalation exposure to \nHCCPD. White blood cell effects are not classifiable as to the hazard to humans based on no data \nin humans and inadequate evidence in animals.  Available studies did not find consistent evidence \nof alterations in white blood cell parameters in rats or mice following intermediate- or chronicduration inhalation exposure to HCCPD.\n\n• **Renal Effects.** Renal effects are a presumed health effect associated with oral exposure to\nHCCPD based on no human data and a high level of evidence in animal studies.  Renal lesions, \nspecifically toxic nephrosis, were observed in rats and mice following intermediate-duration \nexposures to ≥38 and ≥75 mg/kg/day, respectively. Acute tubular necrosis was observed in male \nmice at a higher dose (300 mg/kg/day).  Available toxicokinetic data indicate that HCCPD and/or\n\n---\n\n###### 2. HEALTH EFFECTS\n\nits metabolites distribute to the kidneys of both rats and mice after oral dosing; however, it will \naccumulate to a higher degree in rats.\n\n---\n\n**Figure 2-1.  Overview of the Number of Studies Examining HCCPD Health Effects***\n\n**Most studies examined the potential death, respiratory, neurological, renal, hepatic, and ocular effects of HCCPD**\nFewer studies evaluated health effects in **humans** than **animals** (counts represent studies examining endpoint)\n\n| Category | Number of studies |\n| --- | --- |\n| Death | 57 |\n| Body weight | 18 |\n| Respiratory | 44 |\n| Cardiovascular | 35 |\n| Gastrointestinal | 16 |\n| Hematological | 13 |\n| Musculoskeletal | 10 |\n| Hepatic | 39 |\n| Renal | 39 |\n| Dermal | 16 |\n| Ocular | 39 |\n| Endocrine | 35 |\n| Immunological | 12 |\n| Neurolgical | 41 |\n| Reproductive | 11 |\n| Developmental | 3 |\n| Other Noncancer | 7 |\n| Cancer | 5 |\n\n**Exposure Route**\n\n| Category | Share of studies (%) |\n| --- | --- |\n| Inhalation | 40 |\n| Oral | 13 |\n| Dermal | 47 |\n\n**Exposure Duration**\n\n| Category | Share of studies (%) |\n| --- | --- |\n| Chronic | 2 |\n| Acute | 78 |\n| Intermediate | 20 |\n\n*Includes studies discussed in Chapter 2.  A total of 70 studies (including those finding no effect) have examined toxicity; most studies examined multiple \nendpoints.\n\n---\n\n**Table 2-1. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation\n(ppm)**\n\n| Species (strain) keya | No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| ACUTE EXPOSURE |  |  |  |  |  |  |  |  |  |\n| Alexander et al. 1980a; Rand et al. 1982a |  |  |  |  |  |  |  |  |  |\n| 1 | Rat (Sprague-Dawley) 10 M, 10 F | 1–2 weeks 5 days/week 6 hours/day (WB) | 0, 0.022, 0.11, 0.5 | LE, CS, BW, FI, HE, BC, GN, OW, HP | Death Bd wt | 0.11 |  | 0.5 M | 10/10 died or were sacrificed in moribund condition Decreased terminal body weight in females (29%) and males (32%) Labored respiration; increased absolute lung weight; bronchiole inflammation, hyperplasia, and epithelial erosion |\n| 1 | Rat (Sprague-Dawley) 10 M, 10 F | 1–2 weeks 5 days/week 6 hours/day (WB) | 0, 0.022, 0.11, 0.5 | LE, CS, BW, FI, HE, BC, GN, OW, HP | Resp | 0.11 |  | 0.5 | 10/10 died or were sacrificed in moribund condition Decreased terminal body weight in females (29%) and males (32%) Labored respiration; increased absolute lung weight; bronchiole inflammation, hyperplasia, and epithelial erosion |\n| 1 | Rat (Sprague-Dawley) 10 M, 10 F | 1–2 weeks 5 days/week 6 hours/day (WB) | 0, 0.022, 0.11, 0.5 | LE, CS, BW, FI, HE, BC, GN, OW, HP | Cardio Hematoc | 0.5 0.11 | 0.5 | 0.5 | Males: total white blood cell and lymphocyte counts reduced Females: neutrophils increased Both: red blood cell count, packed cell volume, and hemoglobin increased |\n| 1 | Rat (Sprague-Dawley) 10 M, 10 F | 1–2 weeks 5 days/week 6 hours/day (WB) | 0, 0.022, 0.11, 0.5 | LE, CS, BW, FI, HE, BC, GN, OW, HP | Hepatic Renal Immuno Neuro | 0.5 0.5 0.5 Other noncancer | 0.5 |  | Decreased food and water intake |\n| Jackson and Hardy 1986 |  |  |  |  |  |  |  |  |  |\n| 2 | Rat (Wistar) 5 M, 5 F | 1 hour (WB) | 0, 1.67, 2.38, 3.53, 6.25, 8.30 | LE, CS, BW, FI, WI, OW, GN | Death Bd wt | 1.67 |  | 3.69 | LC50 Decreased body weight at death or scheduled sacrifice (3-weeks post exposure) in males (41%) and females (26%) Abnormal respiratory pattern Decreased food consumption |\n| 2 | Rat (Wistar) 5 M, 5 F | 1 hour (WB) | 0, 1.67, 2.38, 3.53, 6.25, 8.30 | LE, CS, BW, FI, WI, OW, GN | Resp Other noncancer | 1.67 1.67 |  |  | LC50 Decreased body weight at death or scheduled sacrifice (3-weeks post exposure) in males (41%) and females (26%) Abnormal respiratory pattern Decreased food consumption |\n\n---\n\n**Table 2-1. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation\n(ppm)**\n\nAbnormal respiratory pattern\nDecreased food consumption\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Jackson and Hardy 1987 |  |  |  |  |  |  |  |  |  |\n| 3 | Rat (Wistar) 5 M, 5 F | 4 hours (WB) | 0, 1.68, 1.83, 3.31, 3.47 | LE, CS, BW, FI, WI, GN, OW | Death Bd wt |  |  | 2.9 1.68 M | LC50 23% decreased body weight at scheduled sacrifice (4 weeks post exposure) |\n| 3 | Rat (Wistar) 5 M, 5 F | 4 hours (WB) | 0, 1.68, 1.83, 3.31, 3.47 | LE, CS, BW, FI, WI, GN, OW | Resp Other noncancer | 1.68 F | 1.68 1.68 | 1.83 F | 24% decreased body weight at death or scheduled sacrifice (4 weeks post exposure) |\n| OxyChem 1972 |  |  |  |  |  |  |  |  |  |\n| 4 | Rat (Carworth CFE) 10 M | 4 hours (WB) | 176, 1,760 | LE, CS, GN | Death |  |  | 176 | 10/10 died within 48 hours |\n| Rand et al. 1982a |  |  |  |  |  |  |  |  |  |\n| 5 | Rat (Sprague-Dawley) 10 M, 10 F | 4 hours (WB) | 0.28, 1.4, 2.5, 3.1, 3.3, 3.4, 4, 5.8 | LE, CS, BW | Death |  |  | 3.5 F 1.6 M | LC50 LC50 |\n| 5 | Rat (Sprague-Dawley) 10 M, 10 F | 4 hours (WB) | 0.28, 1.4, 2.5, 3.1, 3.3, 3.4, 4, 5.8 | LE, CS, BW | Bd wt | 0.28 | 1.4 F | 1.4 M | 17% body weight loss 25% body weight loss |\n| 5 | Rat (Sprague-Dawley) 10 M, 10 F | 4 hours (WB) | 0.28, 1.4, 2.5, 3.1, 3.3, 3.4, 4, 5.8 | LE, CS, BW | Neuro | 0.28 | 1.4 | 5.8 | LOAEL: Sedation SLOAEL: Ataxia |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 6 | Rat 4 NS | 2 days 7 hours/day (WB) | 3.2 | LE, CS, GN | Death |  |  | 3.2 | 4/4 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 7 | Rat 4 NS | 3 days 7 hours/day (WB) | 1.4 | LE, CS, GN | Death |  |  | 1.4 | 3/4 died |\n\n---\n\n**Table 2-1. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation\n(ppm)**\n\n| Species |  |  |  |  |  |  |  |  |  |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Figure keya | No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 8 | Rat 4 NS | 2.6–3.6 hours (WB) | 1.4, 3.1, 7.1, 12.4, 12.7, 46.5, 56.9, 70.4 | LE, CS, GN | Death |  |  | 3.1 | 2/4 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 9 | Rat 4 NS | 7 hours (WB) | 1.5, 3.2, 6.7 | LE, CS, GN | Death |  |  | 3.2 | 3/4 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 10 | Rat 4 NS | 5 days 7 hours/day (WB) | 0.33, 1.0, 1.6 | LE, CS, GN | Death |  |  | 1 | 4/4 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 11 | Rat 4 NS | 0.25–1.25 hours (WB) | 1.4, 1.5, 3.1, 7.2, 13.0, 13.8, 19.4, 20.0, 20.2, 69.1, 69.2 | LE, CS, GN | Death |  |  | 7.2 | 2/4 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 12 | Rat 4 NS | 4 hours (WB) | 73.6 | LE, CS, GN | Death |  |  | 73.6 | 4/4 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 13 | Mouse 5 NS | 0.25–1.25 hours (WB) | 1.4, 1.5, 3.1, 7.2, 13.0, 13.8, 19.4, 20.0, 20.2, 69.1, 69.2 | LE, CS, GN | Death |  |  | 7.2 | 5/5 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 14 | Mouse 5 NS | 4 hours (WB) | 73.6 | LE, CS, GN | Death |  |  | 73.6 | 5/5 died |\n\n---\n\n**Table 2-1. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation\n(ppm)**\n\n| Species (strain) keya | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| 15 Mouse 5 NS | 2 days 7 hours/day (WB) | 3.2 | LE, CS, GN | Death |  |  | 3.2 | 4/5 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| 16 Mouse 5 NS | 3 days 7 hours/day (WB) | 1.4 | LE, CS, GN | Death |  |  | 1.4 | 5/5 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| 17 Mouse 5 NS | 7 hours (WB) | 1.5, 3.2, 6.7 | LE, CS, GN | Death |  |  | 1.5 | 4/5 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| 18 Mouse 5 NS | 2.6– 3.6 hours (WB) | 1.4, 3.1, 7.1, 12.4, 12.7, 46.5, 56.9, 70.4 | LE, CS, GN | Death |  |  | 3.1 | 4/5 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| 19 Mouse 5 NS | 5 days 7 hours/day (WB) | 0.33, 1.0, 1.6 | LE, CS, GN | Death |  |  | 1 | 4/5 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| 20 Rabbit 3 NS | 4 hours (WB) | 73.6 | LE, CS, GN | Death |  |  | 73.6 | 3/3 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| 21 Rabbit 3 NS | 3 days 7 hours/day (WB) | 1.4 | LE, CS, GN | Death |  |  | 1.4 | 3/3 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| 22 Rabbit 3 NS | 5 days 7 hours/day (WB) | 1, 1.6 | LE, CS, GN | Death |  |  | 1 | 3/3 died |\n\n---\n\n**Table 2-1. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation\n(ppm)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 23 | Rabbit 3 NS | 2.6–3.6 hours (WB) | 1.4, 3.1, 7.1, 12.4, 12.7, 46.5, 56.9, 70.4 | LE, CS, GN | Death |  |  | 1.4 | 2/3 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 24 | Rabbit 3 NS | 7 hours (WB) | 1.5, 3.2, 6.7 | LE, CS, GN | Death |  |  | 1.5 | 3/3 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 25 | Rabbit 3 NS | 0.25–1.25 hours (WB) | 1.4, 1.5, 3.1, 7.2, 13.0, 13.8, 19.4, 20.0, 20.2, 69.1, 69.2 | LE, CS, GN | Death |  |  | 3.1 | 2/3 died |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 26 | Rabbit 3 NS | 2 days 7 hours/day (WB) | 3.2 | LE, CS, GN | Death |  |  | 3.2 | 3/3 died |\n| INTERMEDIATE EXPOSURE |  |  |  |  |  |  |  |  |  |\n| Alexander et al. 1980b; Rand et al. 1982a, 1982b |  |  |  |  |  |  |  |  |  |\n| 27 | Monkey (Cynomolgus) 6 M, 6 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, HE, BC, UR, OP, GN, OW, HP, OF | Bd wt Resp Cardio Gastro Hemato Musc/skel Hepatic Renal Ocular Endocr Immuno | 0.2 0.2 0.2 0.2 0.2 0.2 |  |  |  |\n\n---\n\n**Table 2-1. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation\n(ppm)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n|  |  |  |  |  | Neuro | 0.2 |  |  |  |\n|  |  |  |  |  | Repro | 0.2 |  |  |  |\n|  |  |  |  |  | Other |  |  |  |  |\n|  |  |  |  |  | noncancer |  |  |  |  |\n| Alexander et al. 1980b; Huntingdon Research Centre 1980; Rand et al. 1982a, 1982b |  |  |  |  |  |  |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Bd wt | 0.2 |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Resp | 0.2 |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Cardio | 0.2 |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Gastro | 0.2 |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Hemat | 0.2 |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Musc/skel | 0.2 |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Hepatic | 0.2 |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Renal | 0.2 |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Ocular | 0.2 |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Endocr | 0.2 |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Immuno | 0.2 |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Neuro | 0.2 |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Repro | 0.2 |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | Other |  |  |  |  |\n| 28 | Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, FI, WI, HE, BC, UR, OP, GN, OW, HP | noncancer |  |  |  |  |\n\n---\n\n**Table 2-1. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation\n(ppm)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Clark 1981 |  |  |  |  |  |  |  |  |  |\n| 29 | Rat (Wistar) 18 M, 18 F | 30 weeks 5 days/week 6 hours/day (WB) | 0, 0.06, 0.14, 0.56 | LE, CS, BW, FI, WI, HE, BC, UR, GN, OW, HP | Death Bd wt Resp | 0.56 | 0.56 F | 0.56 M | 4/18 males and 2/18 females died |\n| 29 | Rat (Wistar) 18 M, 18 F | 30 weeks 5 days/week 6 hours/day (WB) | 0, 0.06, 0.14, 0.56 | LE, CS, BW, FI, WI, HE, BC, UR, GN, OW, HP | Resp | 0.14 | 0.56 F | 0.56 M | Females: perivascular/peribronchiolar inflammatory cell infiltration; sneezing Males: bronchiolar epithelial ulceration/thinning and perivascular/peribronchiolar inflammatory cell infiltration; sneezing |\n| 29 | Rat (Wistar) 18 M, 18 F | 30 weeks 5 days/week 6 hours/day (WB) | 0, 0.06, 0.14, 0.56 | LE, CS, BW, FI, WI, HE, BC, UR, GN, OW, HP | Cardio Gastro Hematoma | 0.56 0.56 F 0.06 M | 0.56 F 0.14 M |  | Decreased lymphocyte counts Increased red blood cell counts, hemoglobin, hematocrit, and neutrophil counts; decreased lymphocyte percentage |\n| 29 | Rat (Wistar) 18 M, 18 F | 30 weeks 5 days/week 6 hours/day (WB) | 0, 0.06, 0.14, 0.56 | LE, CS, BW, FI, WI, HE, BC, UR, GN, OW, HP | Musc/skel Hepatic Renal Dermal Ocular Endocr Immuno Neuro Repro | 0.56 0.56 0.56 0.56 0.56 0.56 |  |  |  |\n\n---\n\n**Table 2-1. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation\n(ppm)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n|  |  |  |  |  | Other noncancer | 0.56 |  |  |  |\n| NTP 1994 |  |  |  |  |  |  |  |  |  |\n| 30 | Rat (Fischer-344) 10 M, 10 F | 13 weeks 5 days/week 6 hours/day (WB) | 0, 0.039, 0.146, 0.385, 0.941, 2.065 | LE, CS, BW, HE, BC, GN, OW, HP | Death Bd wt Resp | 0.385 0.385 F 0.146b M | 0.385 M | 0.941 | 100% mortality during first 4 weeks |\n|  |  |  |  |  |  |  |  |  | Nasal squamous metaplasia and suppurative inflammation; suppurative and necrotizing inflammation of the bronchus/bronchiole; increased absolute and relative lung weights |\n|  |  |  |  |  |  |  |  | 0.941 | Increased respiration rate and mouth breathing; suppurative inflammation and hemorrhaging in the alveolus; necrotizing inflammation of the nose, larynx, trachea, and bronchus/bronchiole |\n|  |  |  |  |  | Cardio Gastro Hemato | 0.385 0.385 0.146 | 0.385 |  |  |\n|  |  |  |  |  | Musc/skel | 0.385 |  |  | Males: increased packed cell volume, hemoglobin, red blood cell count, and MCHC |\n|  |  |  |  |  | Hepatic | 0.385 |  |  |  |\n|  |  |  |  |  | Renal | 0.385 |  |  |  |\n|  |  |  |  |  | Endocr | 0.385 |  |  |  |\n|  |  |  |  |  | Immuno | 0.385 |  |  |  |\n|  |  |  |  |  | Neuro | 0.385 |  |  |  |\n|  |  |  |  |  | Repro | 0.385 |  |  |  |\n\n***DRAFT FOR PUBLIC COMMENT***\n\n---\n\n**Table 2-1. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation\n(ppm)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| NTP 1994 |  |  |  |  |  |  |  |  |  |\n| 31 | Rat (Fischer-344) 20 M, 20 F | 13 weeks 5 days/week 6 hours/day (WB) | 0, 0.039, 0.385, 2.065 | LE, HE, BC, UR | Death Hemato | 0.039 | 0.385 | 2.065 | 100% mortality Males: increased MCV; Females: increased MCV, packed cell volume, hemoglobin, and red blood cell count Increased AST |\n| 31 | Rat (Fischer-344) 20 M, 20 F | 13 weeks 5 days/week 6 hours/day (WB) | 0, 0.039, 0.385, 2.065 | LE, HE, BC, UR | Hepatic Renal | 0.385 2.065 | 2.065 | 2.065 | 100% mortality Males: increased MCV; Females: increased MCV, packed cell volume, hemoglobin, and red blood cell count Increased AST |\n| NTP 1994 |  |  |  |  |  |  |  |  |  |\n| 32 | Mouse (B6C3F1) 10 M | 42 weeks 5 days/week 6 hours/day (WB) | 0, 0.5 | LE, CS, BW, GN, OW, HP | Death Bd wt |  |  | 0.5 | 14% decreased survival at 45 weeks Decreased body weight (19%) and body weight gain (42%) at the end of the exposure period Suppurative inflammation of the nose, trachea, and lungs |\n| 32 | Mouse (B6C3F1) 10 M | 42 weeks 5 days/week 6 hours/day (WB) | 0, 0.5 | LE, CS, BW, GN, OW, HP | Resp |  | 0.5 | 0.5 | 14% decreased survival at 45 weeks Decreased body weight (19%) and body weight gain (42%) at the end of the exposure period Suppurative inflammation of the nose, trachea, and lungs |\n| 32 | Mouse (B6C3F1) 10 M | 42 weeks 5 days/week 6 hours/day (WB) | 0, 0.5 | LE, CS, BW, GN, OW, HP | Gastro Hepatic | 0.5 |  | 0.5 | 14% decreased survival at 45 weeks Decreased body weight (19%) and body weight gain (42%) at the end of the exposure period Suppurative inflammation of the nose, trachea, and lungs |\n| 32 | Mouse (B6C3F1) 10 M | 42 weeks 5 days/week 6 hours/day (WB) | 0, 0.5 | LE, CS, BW, GN, OW, HP | Renal | 0.5 |  | 0.5 | 14% decreased survival at 45 weeks Decreased body weight (19%) and body weight gain (42%) at the end of the exposure period Suppurative inflammation of the nose, trachea, and lungs |\n| 32 | Mouse (B6C3F1) 10 M | 42 weeks 5 days/week 6 hours/day (WB) | 0, 0.5 | LE, CS, BW, GN, OW, HP | Endocr Immuno | 0.5 |  | 0.5 | 14% decreased survival at 45 weeks Decreased body weight (19%) and body weight gain (42%) at the end of the exposure period Suppurative inflammation of the nose, trachea, and lungs |\n| 32 | Mouse (B6C3F1) 10 M | 42 weeks 5 days/week 6 hours/day (WB) | 0, 0.5 | LE, CS, BW, GN, OW, HP | Repro | 0.5 |  | 0.5 | 14% decreased survival at 45 weeks Decreased body weight (19%) and body weight gain (42%) at the end of the exposure period Suppurative inflammation of the nose, trachea, and lungs |\n| NTP 1994 |  |  |  |  |  |  |  |  |  |\n| 33 | Mouse (B6C3F1) 20 M, 20 F | 13 weeks 5 days/week 6 hours/day (WB) | 0, 0.039, 0.389, 2.142 | LE, HE, BC, UR | Death Hemato |  | 0.039 F 0.389 M | 2.142 | 100% mortality Increased MCHC Increased MCHC |\n| 33 | Mouse (B6C3F1) 20 M, 20 F | 13 weeks 5 days/week 6 hours/day (WB) | 0, 0.039, 0.389, 2.142 | LE, HE, BC, UR | Hepatic Renal | 0.039 M 2.142 2.142 | 0.039 F 0.389 M | 2.142 | 100% mortality Increased MCHC Increased MCHC |\n\n---\n\n**Table 2-1. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation\n(ppm)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| NTP 1994 |  |  |  |  |  |  |  |  |  |\n| 34 | Mouse (B6C3F1) 10 M | 26 weeks 5 days/week 6 hours/day (WB) | 0, 0.5 | LE, CS, BW, GN, OW, HP | Bd wt Resp | 0.5 | 0.5 |  | Nasal suppurative inflammation |\n| NTP 1994 |  |  |  |  |  |  |  |  |  |\n| 35 | Mouse (B6C3F1) 10 M | 33 weeks 5 days/week 6 hours/day (WB) | 0, 0.2 | LE, CS, BW, GN, OW, HP | Bd wt Resp Gastro Hepatic Renal Immuno Neuro Repro | 0.2 | 0.2 |  | Nasal suppurative inflammation |\n| NTP 1994 |  |  |  |  |  |  |  |  |  |\n| 36 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week 6 hours/day (WB) | 0, 0.039, 0.146, 0.389, 0.949, 2.142 | LE, CS, BW, HE, BC, OW, HP | Death |  |  | 0.949 F 0.389 M | 10/10 died 5/10 died |\n| 36 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week 6 hours/day (WB) | 0, 0.039, 0.146, 0.389, 0.949, 2.142 | LE, CS, BW, HE, BC, OW, HP | Bd wt Resp | 0.389 |  |  | Females: focal serous or suppurative inflammation of the nose Males: squamous metaplasia in the trachea, focal serous or suppurative inflammation of the nose |\n| 36 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week 6 hours/day (WB) | 0, 0.039, 0.146, 0.389, 0.949, 2.142 | LE, CS, BW, HE, BC, OW, HP | Cardio Gastro Hemato | 0.389 |  |  | Decreased MCV |\n| 36 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week 6 hours/day (WB) | 0, 0.039, 0.146, 0.389, 0.949, 2.142 | LE, CS, BW, HE, BC, OW, HP | Musc/skel | 0.389 |  |  |  |\n\n***DRAFT FOR PUBLIC COMMENT***\n\n---\n\n**Table 2-1. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation\n(ppm)**\n\n| Species Figure keya | Species (strain) No./group | Species Exposure parameters | Species Doses | Species Parameters monitored | Species Endpoint | Species NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n|  |  |  |  |  | Hepatic | 0.389 |  |  |  |\n|  |  |  |  |  | Renal | 0.389 |  |  |  |\n|  |  |  |  |  | Endocr | 0.389 |  |  |  |\n|  |  |  |  |  | Immuno | 0.389 |  |  |  |\n|  |  |  |  |  | Neuro | 0.389 |  |  |  |\n|  |  |  |  |  | Repro | 0.389 |  |  |  |\n| CHRONIC EXPOSURE |  |  |  |  |  |  |  |  |  |\n| NTP 1994 |  |  |  |  |  |  |  |  |  |\n| 37 | Rat (Fischer-344) 50 M, 50 F | 104 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, UR, GN, OW, HP | Bd wt | 0.2 |  |  |  |\n| 37 | Rat (Fischer-344) 50 M, 50 F | 104 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, UR, GN, OW, HP | Resp | 0.2 |  |  |  |\n| 37 | Rat (Fischer-344) 50 M, 50 F | 104 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, UR, GN, OW, HP | Cardio | 0.2 |  |  |  |\n| 37 | Rat (Fischer-344) 50 M, 50 F | 104 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, UR, GN, OW, HP | Gastro | 0.2 |  |  |  |\n| 37 | Rat (Fischer-344) 50 M, 50 F | 104 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, UR, GN, OW, HP | Hemat | 0.2 |  |  |  |\n| 37 | Rat (Fischer-344) 50 M, 50 F | 104 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, UR, GN, OW, HP | Musc/skel | 0.2 |  |  |  |\n| 37 | Rat (Fischer-344) 50 M, 50 F | 104 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, UR, GN, OW, HP | Hepatic | 0.2 |  |  |  |\n| 37 | Rat (Fischer-344) 50 M, 50 F | 104 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, UR, GN, OW, HP | Renal | 0.2 |  |  |  |\n| 37 | Rat (Fischer-344) 50 M, 50 F | 104 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, UR, GN, OW, HP | Dermal | 0.2 |  |  |  |\n| 37 | Rat (Fischer-344) 50 M, 50 F | 104 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, UR, GN, OW, HP | Endocr | 0.2 |  |  |  |\n| 37 | Rat (Fischer-344) 50 M, 50 F | 104 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, UR, GN, OW, HP | Immuno | 0.2 |  |  |  |\n| 37 | Rat (Fischer-344) 50 M, 50 F | 104 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, UR, GN, OW, HP | Neuro | 0.2 |  |  |  |\n| 37 | Rat (Fischer-344) 50 M, 50 F | 104 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, CS, BW, UR, GN, OW, HP | Repro | 0.2 |  |  |  |\n\n---\n\n**Table 2-1. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation\n(ppm)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| NTP 1994 |  |  |  |  |  |  |  |  |  |\n| 38 | Mouse (B6C3F1) 50 M, 50 F | 103 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, BW, GN, OW, HP | Death Bd wt Resp | 0.2 0.05c | 0.2 | 0.2 F | 57% mortality |\n| 38 | Mouse (B6C3F1) 50 M, 50 F | 103 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, BW, GN, OW, HP | Death Bd wt Resp | 0.2 0.05c | 0.2 | 0.2 F | Males: nasal suppurative inflammation, alveolar epithelium hyperplasia, and suppurative inflammation of the lung Females: nasal suppurative inflammation (BMCL10 for nasal suppurative inflammation in females = 0.0052 ppm)c |\n| 38 | Mouse (B6C3F1) 50 M, 50 F | 103 weeks 5 days/week 6 hours/day (WB) | 0, 0.01, 0.05, 0.2 | LE, BW, GN, OW, HP | Cardio Gastro Hemat Muc/skel Hepatic Renal Dermal Endocr Immuno Neuro | 0.2 0.2 0.2 0.2 0.2 0.2 | 0.2 | 0.2 F | Males: nasal suppurative inflammation, alveolar epithelium hyperplasia, and suppurative inflammation of the lung Females: nasal suppurative inflammation (BMCL10 for nasal suppurative inflammation in females = 0.0052 ppm)c |\n\n---\n\n**Table 2-1. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation\n(ppm)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n|  |  |  |  |  | Repro | 0.01 F | 0.05 F | 0.2 F | LOAEL: Suppurative inflammation of the ovaries SLOAEL: Severe ovarian suppurative inflammation (associated with increased lethality) |\n|  |  |  |  |  |  | 0.2 M |  |  |  |\n\n<sup>a</sup>The number corresponds to entries in Figure 2-2; differences in levels of health effects and cancer effects between male and females are not indicated in \nFigure 2-2. Where such differences exist, only the levels of effect for the most sensitive sex are presented.\n\n$$\n1\\times10^{-4}\n$$\n\n<sup>b</sup>Used to derive a provisional intermediate-duration inhalation MRL of 1x10<sup>-4</sup> ppm based on a NOAEL of 0.146 ppm, which was converted into a NOAELHEC of \n0.00344 ppm and divided by an uncertainty factor of 30 (10 for human variability and 3 for animal to human extrapolation after dosimetric adjustment).\n<sup>c</sup>Used to derive a provisional chronic-duration inhalation MRL of 6x10<sup>-5</sup> ppm based on a BMCL10 of 0.052 ppm, which was converted into a BMCLHEC of \n0.0019 ppm and divided by an uncertainty factor of 30 (10 for human variability and 3 for animal to human extrapolation after dosimetric adjustment).\n\nGreen shading indicates the study selected for derivation of provisional inhalation MRLs.\n\nAST = aspartate aminotransferase; BC = blood chemistry; Bd wt or BW = body weight; BMCL = benchmark concentration lower confidence limit; BMCL10 = 95% \nlower confidence limit on the benchmark concentration (subscripts denote benchmark response: i.e., 10 = concentration associated with 10% extra risk); \nCardio = cardiovascular; CS = clinical signs; Endocr = endocrine; F = female(s); FI = food intake; Gastro = gastrointestinal; GN = gross necropsy; \nHE = hematology; HEC = human equivalent concentration; Hemato = hematological; HP = histopathology; Immuno = immunological; LC50 = median lethal \nconcentration; LE = lethality; LOAEL = lowest-observed-adverse-effect level; M = male(s); MCHC = mean corpuscular hemoglobin concentration; MCV = mean \ncorpuscular volume; MRL = Minimal Risk Level; Musc/skeletal = muscular/skeletal; Neuro = neurological; NOAEL = no-observed-adverse-effect level; NS = not \nspecified; OF = organ function; OP = ophthalmology; OW = organ weight; Repro = reproductive; Resp = respiratory; SLOAEL = serious lowest-observed-adverseeffect level; UR = urinalysis; (WB) = whole body; WI = water intake\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation**\nAcute (≤14 days)\n\n**Figure 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation Acute (≤14 days) - Death**\n\n| Category | Animal - LD50/LC50 (ppm) | Animal - NOAEL (ppm) | Animal - LOAEL (ppm) | Animal - SLOAEL (ppm) |\n| --- | --- | --- | --- | --- |\n| 1R |  |  |  | 0.45 |\n| 2R | 3.4 |  |  |  |\n| 3R | 2.6 |  |  |  |\n| 4R |  |  |  | 170 |\n| 5R | 1.6 |  |  |  |\n| 6R |  |  |  | 2.8 |\n| 7R |  |  | 1.4 |  |\n| 8R |  |  |  | 3.2 |\n| 9R |  |  |  | 2.8 |\n| 10R |  |  |  | 1.0 |\n| 11R |  |  |  | 7.0 |\n| 12R |  |  |  | 75 |\n| 13M |  |  |  | 7.5 |\n| 14M |  |  |  | 75 |\n| 15M |  |  |  | 3.2 |\n| 16M |  |  |  | 1.4 |\n| 17M |  |  |  | 1.5 |\n| 18M |  |  |  | 3.2 |\n| 19M |  |  |  | 1.0 |\n| 20H |  |  |  | 75 |\n| 21H |  |  |  | 1.4 |\n| 22H |  |  |  | 1.0 |\n| 23H |  |  |  | 1.4 |\n| 24H |  |  |  | 1.5 |\n| 25H |  |  |  | 3.2 |\n| 26H |  |  |  | 3.2 |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation**\nAcute (≤14 days)\n\n| Category | Body Weight Animal - LD50/LC50 (ppm) | Body Weight Animal - NOAEL (ppm) | Body Weight Animal - LOAEL (ppm) | Body Weight Animal - SLOAEL (ppm) | Respiratory Animal - LD50/LC50 (ppm) | Respiratory Animal - NOAEL (ppm) | Respiratory Animal - LOAEL (ppm) | Respiratory Animal - SLOAEL (ppm) | Cardiovascular Animal - LD50/LC50 (ppm) | Cardiovascular Animal - NOAEL (ppm) | Cardiovascular Animal - LOAEL (ppm) | Cardiovascular Animal - SLOAEL (ppm) | Hematological Animal - LD50/LC50 (ppm) | Hematological Animal - NOAEL (ppm) | Hematological Animal - LOAEL (ppm) | Hematological Animal - SLOAEL (ppm) |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| 1R |  | 0.12 |  | 0.5 |  | 0.12 |  | 0.5 |  | 0.5 |  |  |  | 0.12 |  | 0.5 |\n| 2R |  | 1.8 |  | 2.6 |  |  |  | 1.8 |  |  |  |  |  |  |  |  |\n| 3R |  |  |  | 1.8 |  |  |  | 1.8 |  |  |  |  |  |  |  |  |\n| 5R |  | 0.26 |  | 1.4 |  |  |  |  |  |  |  |  |  |  |  |  |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation**\nAcute (≤14 days)\n\n**Figure 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation Acute (≤14 days)**\n\n| Category | Animal - NOAEL (ppm) | Animal - LOAEL (ppm) | Animal - SLOAEL (ppm) |\n| --- | --- | --- | --- |\n| Hepatic | 0.5 |  |  |\n| Renal | 0.45 |  |  |\n| Immunological | 0.5 |  |  |\n| Neuological | 0.4 | 1.4 | 5.5 |\n| Other Noncancer | 0.12 | 0.45 | 1.7 |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation**\nIntermediate (15–364 days)\n\n**Figure 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation Intermediate (15–364 days)**\n\n| Category | Death Animal - NOAEL (ppm) | Death Animal - LOAEL (ppm) | Death Animal - SLOAEL (ppm) | Body Weight Animal - NOAEL (ppm) | Body Weight Animal - LOAEL (ppm) | Body Weight Animal - SLOAEL (ppm) | Respiratory Animal - NOAEL (ppm) | Respiratory Animal - LOAEL (ppm) | Respiratory Animal - SLOAEL (ppm) |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| 29R |  |  | 0.6 | 0.5 |  |  | 0.15 |  | 0.6 |\n| 30R |  |  | 1.0 | 0.4 |  |  | 0.15 | 0.45 | 1.0 |\n| 31R |  |  | 2.3 |  |  |  |  |  |  |\n| 32M |  |  | 0.55 |  | 0.5 |  |  | 0.5 |  |\n| 33M |  |  | 2.6 |  |  |  |  |  |  |\n| 36M |  |  | 0.4 | 0.45 |  |  | 0.15 | 0.45 |  |\n| 27K |  |  |  | 0.2 |  |  | 0.2 |  |  |\n| 28R |  |  |  | 0.2 |  |  | 0.2 |  |  |\n| 34M |  |  |  | 0.55 |  |  |  | 0.5 |  |\n| 35M |  |  |  | 0.2 |  |  |  | 0.2 |  |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation**\nIntermediate (15–364 days)\n\n**Figure 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation Intermediate (15–364 days)**\n\n| Category | Cardiovascular Animal - NOAEL (ppm) | Cardiovascular Animal - LOAEL (ppm) | Cardiovascular Animal - SLOAEL (ppm) | Gastrointestinal Animal - NOAEL (ppm) | Gastrointestinal Animal - LOAEL (ppm) | Gastrointestinal Animal - SLOAEL (ppm) | Hematological Animal - NOAEL (ppm) | Hematological Animal - LOAEL (ppm) | Hematological Animal - SLOAEL (ppm) |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| 27K | 0.22 |  |  | 0.22 |  |  | 0.22 |  |  |\n| 28R | 0.22 |  |  | 0.22 |  |  | 0.22 |  |  |\n| 29R | 0.55 |  |  | 0.55 |  |  | 0.060 | 0.15 |  |\n| 30R | 0.44 |  |  | 0.44 |  |  | 0.17 | 0.44 |  |\n| 36M | 0.44 |  |  | 0.44 |  |  | 0.17 | 0.44 |  |\n| 32M |  |  |  | 0.50 |  |  |  |  |  |\n| 35M |  |  |  | 0.22 |  |  |  |  |  |\n| 31R |  |  |  |  |  |  | 0.040 | 0.44 |  |\n| 33M |  |  |  |  |  |  |  | 0.044 |  |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation**\nIntermediate (15–364 days)\n\n**Figure 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation Intermediate (15–364 days)**\n\n| Category | Musculoskeletal Animal - NOAEL (ppm) | Musculoskeletal Animal - LOAEL (ppm) | Musculoskeletal Animal - SLOAEL (ppm) | Hepatic Animal - NOAEL (ppm) | Hepatic Animal - LOAEL (ppm) | Hepatic Animal - SLOAEL (ppm) | Renal Animal - NOAEL (ppm) | Renal Animal - LOAEL (ppm) | Renal Animal - SLOAEL (ppm) |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| 27K | 0.22 |  |  | 0.20 |  |  | 0.20 |  |  |\n| 28R | 0.20 |  |  | 0.22 |  |  | 0.20 |  |  |\n| 29R | 0.55 |  |  | 0.60 |  |  | 0.55 |  |  |\n| 30R | 0.44 |  |  | 0.40 |  |  | 0.40 |  |  |\n| 36M | 0.44 |  |  | 0.44 |  |  | 0.44 |  |  |\n| 31R |  |  |  | 0.44 |  |  | 2.2 |  |  |\n| 31R |  |  |  |  |  | 2.4 |  |  |  |\n| 32M |  |  |  | 0.55 |  |  | 0.60 |  |  |\n| 33M |  |  |  | 2.4 |  |  | 2.4 |  |  |\n| 35M |  |  |  | 0.20 |  |  | 0.20 |  |  |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation**\nIntermediate (15–364 days)\n\n**Figure 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation Intermediate (15–364 days)**\n\n| Category | Animal - NOAEL (ppm) | Animal - LOAEL (ppm) | Animal - SLOAEL (ppm) |\n| --- | --- | --- | --- |\n| Dermal 29R | 0.55 |  |  |\n| Ocular 27K | 0.20 |  |  |\n| Ocular 28R | 0.20 |  |  |\n| Ocular 29R | 0.55 |  |  |\n| Endocrine 27K | 0.20 |  |  |\n| Endocrine 28R | 0.20 |  |  |\n| Endocrine 29R | 0.60 |  |  |\n| Endocrine 30R | 0.40 |  |  |\n| Endocrine 32M | 0.50 |  |  |\n| Endocrine 36M | 0.40 |  |  |\n| Immunological 27K | 0.20 |  |  |\n| Immunological 28R | 0.20 |  |  |\n| Immunological 29R | 0.60 |  |  |\n| Immunological 30R | 0.40 |  |  |\n| Immunological 32M | 0.55 |  |  |\n| Immunological 35M | 0.20 |  |  |\n| Immunological 36M | 0.40 |  |  |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation**\nIntermediate (15–364 days)\n\n**Figure 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation Intermediate (15–364 days)**\n\n| Category | Neuropsychological Animal - NOAEL (ppm) | Neuropsychological Animal - LOAEL (ppm) | Neuropsychological Animal - SLOAEL (ppm) | Reproductive Animal - NOAEL (ppm) | Reproductive Animal - LOAEL (ppm) | Reproductive Animal - SLOAEL (ppm) | Other Noncancer Animal - NOAEL (ppm) | Other Noncancer Animal - LOAEL (ppm) | Other Noncancer Animal - SLOAEL (ppm) |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| 27K | 0.22 |  |  | 0.22 |  |  | 0.22 |  |  |\n| 28R | 0.22 |  |  | 0.22 |  |  | 0.22 |  |  |\n| 29R | 0.55 |  |  | 0.55 |  |  | 0.55 |  |  |\n| 30R | 0.44 |  |  | 0.44 |  |  |  |  |  |\n| 35M | 0.22 |  |  | 0.22 |  |  |  |  |  |\n| 36M | 0.44 |  |  | 0.44 |  |  |  |  |  |\n| 32M |  |  |  | 0.55 |  |  |  |  |  |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation**\nChronic (≥365 days)\n\n**Figure 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation Chronic (≥365 days)**\n\n| Category | R-Rat Animal - NOAEL (ppm) | R-Rat Animal - LOAEL (ppm) | R-Rat Animal - SLOAEL (ppm) | M-Mouse Animal - NOAEL (ppm) | M-Mouse Animal - LOAEL (ppm) | M-Mouse Animal - SLOAEL (ppm) | M-Mouse MRL for effect other than cancer (ppm) |\n| --- | --- | --- | --- | --- | --- | --- | --- |\n| Death |  |  |  |  |  | 0.22 |  |\n| Body Weight |  |  |  | 0.22 |  |  |  |\n| Respiratory | 0.22 |  |  |  | 0.055 | 0.22 | 0.006 |\n| Cardiovascular | 0.22 |  |  | 0.22 |  |  |  |\n| Gastrointestinal |  |  |  | 0.22 |  |  |  |\n| unlabelled 1 |  |  |  | 0.22 |  |  |  |\n\n---\n\n2.  HEALTH EFFECTS\n\n**Figure 2-2.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation**\nChronic (≥365 days)\n\n| Category | R-Rat (ppm) | M-Mouse (ppm) |\n| --- | --- | --- |\n| Hematological | 0.22 | 0.22 |\n| Musculoskeletal | 0.22 | 0.22 |\n| Hepatic | 0.22 | 0.22 |\n| Renal | 0.22 | 0.22 |\n| Dermal | 0.22 | 0.22 |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation**\nChronic (≥365 days)\n\n**Figure 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Inhalation Chronic (≥365 days)**\n\n| Category | Endocrine Animal - NOAEL (ppm) | Endocrine Animal - LOAEL (ppm) | Endocrine Animal - SLOAEL (ppm) | Immunological Animal - NOAEL (ppm) | Immunological Animal - LOAEL (ppm) | Immunological Animal - SLOAEL (ppm) | Neuological Animal - NOAEL (ppm) | Neuological Animal - LOAEL (ppm) | Neuological Animal - SLOAEL (ppm) | Reproductive Animal - NOAEL (ppm) | Reproductive Animal - LOAEL (ppm) | Reproductive Animal - SLOAEL (ppm) |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| 37R | 0.23 |  |  | 0.23 |  |  | 0.23 |  |  | 0.23 |  |  |\n| 38M | 0.23 |  |  | 0.23 |  |  | 0.23 |  |  | 0.011 | 0.055 | 0.23 |\n\n---\n\n**Table 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Oral\n(mg/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| ACUTE EXPOSURE |  |  |  |  |  |  |  |  |  |\n| Gardner 1986a |  |  |  |  |  |  |  |  |  |\n| 1 | Rat (CFY) 5 M, 5 F | Once (GO) | 1,260, 1,600, 2,000 | LE, CS, BW, GN | Death |  |  | 1,300 F 1,500 M | LD50 LD50 |\n| 1 | Rat (CFY) 5 M, 5 F | Once (GO) | 1,260, 1,600, 2,000 | LE, CS, BW, GN | Resp Gastro Neuro |  | 1,260 | 1,260 | Decreased respiratory rate Diarrhea Abnormal gait, lethargy |\n| OxyChem 1972 |  |  |  |  |  |  |  |  |  |\n| 2 | Rat (Spartan) 25 M, 25 F | Once (GO) | 315, 500, 794, 1,250, 1,984 | LE | Death |  |  | 530 F 630 M | LD50 LD50 |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 3 | Rat 9–11 M | Once (GO) | 280, 340, 420, 520, 620, 940, 1,400 | LE, CS, GN | Death |  |  | 505 | LD50 |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 4 | Rat 10 F | Once (GO) | 280, 940, 1,400, 2,100 | LE, CS, GN | Death |  |  | 940 | 9/10 died |\n| Chernoff and Kavlock 1982, 1983; Gray and Kavlock 1984; Gray et al. 1986 |  |  |  |  |  |  |  |  |  |\n| 5 | Mouse (CD-1) 16 F | 5 days GDs 8–12 (GO) | 0, 45 | BW, DX | Bd wt Develop | 45 |  |  |  |\n\n$$\n\\mathsf{L}\\mathsf{D}_{50}\n$$\n\nOffspring evaluated through PND 250 for postnatal viability, growth, locomotor activity, female sexual development, and reproductive function\n\n---\n\n**Table 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Oral\n(mg/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Dean 1977 |  |  |  |  |  |  |  |  |  |\n| 6 | Mouse (CD-1) 5 M, 5 F | Once (GO) | 21.5, 46.4, 100, 215, 464, 1,000, 2,150 | LE, CS, BW | Death Resp Gastro | 1,000 215 F 464 M 464 | 464 F 1,000 M 1,000 | 679 2,150 | LD50 Decreased respiratory rate Diarrhea Diarrhea Decreased limb tone in animals that died LOAEL: Hypoactivity SLOAEL: Ataxia |\n| 6 | Mouse (CD-1) 5 M, 5 F | Once (GO) | 21.5, 46.4, 100, 215, 464, 1,000, 2,150 | LE, CS, BW | Musc/skel | 215 | 464 | 1,000 | LOAEL: Hypoactivity SLOAEL: Ataxia |\n| Murray et al. 1980 |  |  |  |  |  |  |  |  |  |\n| 7 | Mouse (CF-1) NS F | 10 days GDs 6–15 (GO) | 0, 5, 25, 75 | LE, CS, BW, FI, WI, RX, DX | Bd wt Develop Other noncancer | 75 75 75 |  |  |  |\n| Murray et al. 1980 |  |  |  |  |  |  |  |  |  |\n| 8 | Mouse (CF-1) 5 F | 10 days GDs 6–15 (GO) | 0, 25, 75, 250, 500 | LE, CS, BW | Death |  |  | 250 | 3/5 dams died |\n| Murray et al. 1980 |  |  |  |  |  |  |  |  |  |\n| 9 | Rabbit (New Zealand) NS F | 13 days GDs 6–18 (GO) | 0, 5, 25, 75 | LE, CS, BW, RX, DX | Death Develop | 25 | 75 | 75 | Unspecified increased maternal death during pregnancy Increased proportion of fetuses with 13 ribs |\n| Murray et al. 1980 |  |  |  |  |  |  |  |  |  |\n| 10 | Rabbit (New Zealand) 5 F | 13 days GDs 6–18 (GO) | 0, 25, 75, 250, 500 | LE, CS, BW | Death |  |  | 250 | 4/5 does die |\n\n---\n\n**Table 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Oral\n(mg/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |  |\n| 11 | Rabbit 3 F | Once (GO) | 180, 280, 420, 620, 940 | LE, CS, GN | Death |  |  | 940 | 3/3 died |\n| INTERMEDIATE EXPOSURE |  |  |  |  |  |  |  |  |  |\n| Abdo et al. 1984; Velsicol 1981b |  |  |  |  |  |  |  |  |  |\n| 12 | Rat (Fischer-344) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 10, 19, 38, 75, 150 | LE, BW, GN, OW, HP | Death Bd wt | 38 F | 75 F | 150 M | 60% treatment-related mortality 15% decreased terminal body weight LOAEL: 13% decreased terminal body weight SLOAEL: 30% decreased terminal body weight Forestomach epithelial hyperplasia and focal inflammation (BMDL10 for combined incidence of forestomach lesions = 7.7 mg/kg/day)b |\n| 12 | Rat (Fischer-344) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 10, 19, 38, 75, 150 | LE, BW, GN, OW, HP | Resp Cardio Gastro | 150 150 19b | 38 |  |  |\n| 12 | Rat (Fischer-344) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 10, 19, 38, 75, 150 | LE, BW, GN, OW, HP | Hemato Musc/skel | 150 150 150 Renal | 38 |  | Toxic nephrosis |\n| 12 | Rat (Fischer-344) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 10, 19, 38, 75, 150 | LE, BW, GN, OW, HP | Dermal | 150 |  |  |  |\n| 12 | Rat (Fischer-344) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 10, 19, 38, 75, 150 | LE, BW, GN, OW, HP | Endocr | 150 |  |  |  |\n| 12 | Rat (Fischer-344) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 10, 19, 38, 75, 150 | LE, BW, GN, OW, HP | Immuno | 150 |  |  |  |\n| 12 | Rat (Fischer-344) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 10, 19, 38, 75, 150 | LE, BW, GN, OW, HP | Neuro | 150 |  |  |  |\n| 12 | Rat (Fischer-344) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 10, 19, 38, 75, 150 | LE, BW, GN, OW, HP | Repro | 150 |  |  |  |\n\n---\n\n**Table 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Oral\n(mg/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Abdo et al. 1984; Velsicol 1981a |  |  |  |  |  |  |  |  |  |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP | Death |  |  | 300 | 10/10 males died, 3/10 females died 11% decreased terminal body weight 13% decreased terminal body weight |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP | Bd wt | 75 M | 150 F | 300 | 10/10 males died, 3/10 females died 11% decreased terminal body weight 13% decreased terminal body weight |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP |  | 150 F | 300 F | 300 | 10/10 males died, 3/10 females died 11% decreased terminal body weight 13% decreased terminal body weight |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP | Resp | 300 |  |  |  |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP | Cardio | 300 |  |  |  |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP | Gastro | 38 | 75 |  | Focal inflammation and epithelial hyperplasia of the forestomach |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP | Hemato | 300 |  |  |  |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP | Musc/skel | 300 |  |  |  |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP | Hepatic | 300 |  |  |  |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP | Renal | 38 F | 75 F |  | Toxic nephrosis |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP |  | 150 M | 300 M |  | Acute tubular necrosis |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP | Dermal | 300 |  |  |  |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP | Endocr | 300 |  |  |  |\n| 13 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week (GO) | 0, 19, 38, 75, 150, 300 | LE, BW, GN, OW, HP | Immuno | 300 |  |  |  |\n\n---\n\n**Table 2-2. Levels of Significant Exposure to Hexachlorocyclopentadiene – Oral\n(mg/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n|  |  |  |  |  | Neuro Repro | 300 300 |  |  |  |\n\n<sup>a</sup>The number corresponds to entries in Figure 2-3; differences in levels of health effects between male and females are not indicated in Figure 2-3.  Where such \ndifferences exist, only the levels of effect for the most sensitive sex are presented.\n\n<sup>b</sup>Used to derive a provisional intermediate-duration oral MRL of 0.06 mg/kg/day based on a BMDL10 of 7.7 mg/kg/day, which was adjusted to continuous duration \nexposure to a BMDLADJ of 5.5 mg/kg/day and divided by an uncertainty factor of 100 (10 for human variability and 10 for animal to human extrapolation).  See \nAppendix A for more detailed information regarding the MRL.\n\nGreen shading indicates the study selected for derivation of the provisional oral MRL.\n\nADJ = adjusted; Bd wt or BW = body weight; BMDL = benchmark dose lower confidence limit; BMDL10 = 95% benchmark dose lower confidence limit (subscript \ndenotes benchmark response: i.e., 10 = dose associated with 10% extra risk); Cardio = cardiovascular; CS = clinical signs; Develop = developmental; \nDX = developmental toxicity; Endocr = endocrine; F = female(s); FI = food intake; Gastro = gastrointestinal; GD = gestation day; GN = gross necropsy; \n(GO) = gavage in oil; Hemato = hematological; HP = histopathology; Immuno = immunological; LD50 = median lethal dose; LE = lethality; LOAEL = lowestobserved-adverse-effect level; M = male(s); MRL = Minimal Risk Level; Musc/skeletal = muscular/skeletal; Neuro = neurological; NOAEL = no-observed-adverseeffect level; NS = not specified; OW = organ weight; PND = postnatal day; Repro = reproductive; Resp = respiratory; RX = reproductive function; \nSLOAEL = serious lowest-observed-adverse-effect level; WI = water intake\n\n---\n\n**Figure 2-3.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Oral**\nAcute (≤14 days)\n\n| Category | Animal - LD50/LC50 (mg/kg/day) | Animal - NOAEL (mg/kg/day) | Animal - LOAEL (mg/kg/day) | Animal - SLOAEL (mg/kg/day) |\n| --- | --- | --- | --- | --- |\n| 1R | 1300 |  |  |  |\n| 2R | 530 |  |  |  |\n| 3R | 500 |  |  |  |\n| 4R |  |  |  | 950 |\n| 6M | 660 |  |  |  |\n| 8M |  |  |  | 300 |\n| 9H |  |  |  | 75 |\n| 10H |  |  |  | 280 |\n| 11H |  |  |  | 950 |\n| 5M |  | 50 |  |  |\n| 7M |  | 80 |  |  |\n| 1R |  |  |  | 1200 |\n| 6M |  | 1000 |  | 2400 |\n\n---\n\n**Figure 2-3.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Oral**\nAcute (≤14 days)\n\n| Category | R-Rat (mg/kg/day) | M-Mouse (mg/kg/day) | H-Rabbit (mg/kg/day) |\n| --- | --- | --- | --- |\n| Animal - LD50/LC50 |  |  |  |\n| Animal - NOAEL |  | 130 |  |\n| Animal - LOAEL |  |  | 1300 |\n| Animal - SLOAEL |  |  | 1000 |\n\n---\n\n**Figure 2-3.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Oral**\nIntermediate (15–364 days)\n\n| Category | R-Rat Animal - NOAEL (mg/kg/day) | R-Rat Animal - LOAEL (mg/kg/day) | R-Rat Animal - SLOAEL (mg/kg/day) | M-Mouse Animal - NOAEL (mg/kg/day) | M-Mouse Animal - LOAEL (mg/kg/day) | M-Mouse Animal - SLOAEL (mg/kg/day) |\n| --- | --- | --- | --- | --- | --- | --- |\n| Death |  |  |  |  |  |  |\n| 12R |  |  | 150 |  |  |  |\n| 13M |  |  | 330 |  |  |  |\n| Body Weight |  |  |  |  |  |  |\n| 12R | 20 |  |  |  |  |  |\n| 12R |  | 40 |  |  |  |  |\n| 12R |  |  | 75 |  |  |  |\n| 13M |  | 80 |  |  |  |  |\n| 13M |  |  | 150 |  |  |  |\n| 13M |  |  | 160 |  |  |  |\n| Respiratory |  |  |  |  |  |  |\n| 12R | 160 |  |  |  |  |  |\n| 13M | 330 |  |  |  |  |  |\n| Cardiovascular |  |  |  |  |  |  |\n| 12R | 150 |  |  |  |  |  |\n| 13M | 330 |  |  |  |  |  |\n| Gastrointestinal |  |  |  |  |  |  |\n| 12R BMDL | 8.0 |  |  |  |  |  |\n| 12R | 20 |  |  |  |  |  |\n| 12R |  | 44 |  |  |  |  |\n| 13M | 40 |  |  |  |  |  |\n| 13M |  |  | 80 |  |  |  |\n\n---\n\n**Figure 2-3.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Oral**\nIntermediate (15–364 days)\n\n| Category | R-Rat Animal - NOAEL (mg/kg/day) | R-Rat Animal - LOAEL (mg/kg/day) | R-Rat Animal - SLOAEL (mg/kg/day) | M-Mouse Animal - NOAEL (mg/kg/day) | M-Mouse Animal - LOAEL (mg/kg/day) | M-Mouse Animal - SLOAEL (mg/kg/day) |\n| --- | --- | --- | --- | --- | --- | --- |\n| Hematological | 150 |  |  | 330 |  |  |\n| Musculoskeletal |  |  |  | 150 |  |  |\n| Hepatic |  |  |  | 150 |  |  |\n| Renal | 20 | 44 |  | 36 |  | 80 |\n| Dermal |  |  |  | 150 |  | 330 |\n\n---\n\n**Figure 2-3.  Levels of Significant Exposure to Hexachlorocyclopentadiene – Oral**\nIntermediate (15–364 days)\n\n**Figure 2-3. Levels of Significant Exposure to Hexachlorocyclopentadiene – Oral Intermediate (15–364 days)**\n\n| Category | Animal - NOAEL (mg/kg/day) | Animal - LOAEL (mg/kg/day) | Animal - SLOAEL (mg/kg/day) |\n| --- | --- | --- | --- |\n| Endocrine 12R | 160 |  |  |\n| Endocrine 13M | 330 |  |  |\n| Immunological 12R | 160 |  |  |\n| Immunological 13M | 330 |  |  |\n| Neuological 12R | 160 |  |  |\n| Neuological 13M | 330 |  |  |\n| Reproductive 12R | 160 |  |  |\n| Reproductive 13M | 330 |  |  |\n\n---\n\n**Table 2-3. Levels of Significant Exposure to Hexachlorocyclopentadiene – Dermal**\n\n| Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| ACUTE EXPOSURE |  |  |  |  |  |  |  |  |\n| Kominsky et al. 1980 |  |  |  |  |  |  |  |  |\n| Human 154 M, 23 F | 3–15 days | ≤0.97 ppm | CS, BC | Dermal Ocular |  | 0.97 0.97 |  | Skin irritation Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Monkey 1 NS | Once | 0.001, 0.01, 0.1, 1, 10% (0.01 mL); 20, 40, 60, 90% (0.05 mL) | CS | Dermal | 10 | 20 |  | Skin discoloration and swelling |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Monkey 1 NS | 3 days Once/day | 10% | CS | Dermal |  |  | 10 | Skin irritation, necrosis, hemorrhaging |\n| Alexander et al. 1980a; Rand et al. 1982a |  |  |  |  |  |  |  |  |\n| Rat (Sprague-Dawley) 10 M, 10 F | 1–2 weeks 5 days/week 6 hours/day | 0, 0.022, 0.11, 0.5 ppm | CS | Ocular | 0.11 | 0.5 |  | Dark red eyes |\n| Gardner 1986b |  |  |  |  |  |  |  |  |\n| Rat (CFY) 5 M, 5 F | 24 hours | 1,600, 2,000, 3,200 mg/kg | LE, CS, BW, GN | Death |  |  | 3,100 F 2,600 M | LD50 LD50 |\n| Rat (CFY) 5 M, 5 F | 24 hours | 1,600, 2,000, 3,200 mg/kg | LE, CS, BW, GN | Dermal |  | 1,600 |  | Moderate to severe edema |\n| Jackson and Hardy 1986 |  |  |  |  |  |  |  |  |\n| Rat (Wistar) 5 M, 5 F | 1 hour | 0, 1.67, 2.38, 3.53, 6.25, 8.30 ppm | CS | Ocular |  | 1.67 |  | Total or partial closing of the eyes |\n| Jackson and Hardy 1987 |  |  |  |  |  |  |  |  |\n| Rat (Wistar) 5 M, 5 F | 4 hours | 0, 1.68, 1.83, 3.31, 3.47 ppm | CS | Ocular |  | 1.68 |  | Total or partial closing of the eyes |\n| Rand et al. 1982a |  |  |  |  |  |  |  |  |\n| Rat (Sprague-Dawley) 10 M, 10 F | 4 hours | 0.28, 1.4, 2.5, 3.1, 3.3, 3.4, 4, 5.8 ppm | CS | Ocular | 4 | 5.8 |  | Lacrimation |\n\n$$\n\\mathsf{L}\\mathsf{D}_{50}\n$$\n\n$$\n\\mathsf{L}\\mathsf{D}_{50}\n$$\n\n---\n\n**Table 2-3. Levels of Significant Exposure to Hexachlorocyclopentadiene – Dermal**\n\n| Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rat 4 NS | 5 days 7 hours/day | 0.33, 1, 1.6 ppm | CS | Ocular |  | 0.33 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rat 4 NS | 3 days 7 hours/day | 1.4 ppm | CS | Ocular |  | 1.4 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rat 4 NS | 4 hours | 73.6 ppm | CS | Ocular |  | 73.6 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rat 4 NS | 7 hours | 1.5, 3.2, 6.7 ppm | CS | Ocular |  | 1.5 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rat 4 NS | 2.6–3.6 hours | 1.4, 3.1, 7.1, 11.1, 12.7, 46.5, 56.9, 70.4 ppm | CS | Ocular |  | 1.4 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rat 3–4 NS | 0.25–1.25 hours | 1.4, 1.5, 3.1, 7.2, 13.0, 13.8, 19.4, 20.0, 20.2, 69.1, 69.2 ppm | CS | Ocular |  | 1.4 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rat 4 NS | 2 days 7 hours/day | 3.2 ppm | CS | Ocular |  | 3.2 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Mouse 4–5 NS | 0.25–1.25 hours | 1.4, 1.5, 3.1, 7.2, 13.0, 13.8, 19.4, 20.0, 20.2, 69.1, 69.2 ppm | CS | Ocular |  | 1.4 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Mouse 5 NS | 7 hours | 1.5, 3.2, 6.7 ppm | CS | Ocular |  | 1.5 |  | Eye irritation |\n\n---\n\n**Table 2-3. Levels of Significant Exposure to Hexachlorocyclopentadiene – Dermal**\n\n| Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Mouse 5 NS | 2.6–3.6 hours | 1.4, 3.1, 7.1, 12.4, 12.7, 46.5, 56.9, 70.4 ppm | CS | Ocular |  | 1.4 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Mouse 5 NS | 4 hours | 73.6 ppm | CS | Ocular |  | 73.6 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Mouse 5 NS | 2 days 7 hours/day | 3.2 ppm | CS | Ocular |  | 3.2 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Mouse 5 NS | 3 days 7 hours/day | 1.4 ppm | CS | Ocular |  | 1.4 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Mouse 5 NS | 5 days 7 hours/day | 0.33, 1.0, 1.6 ppm | CS | Ocular |  | 0.33 |  | Eye irritation |\n| OxyChem 1972 |  |  |  |  |  |  |  |  |\n| Rabbit (New Zealand) 3 M, 3 F | 4 hours | 0.5 mL | LE, CS | Death Dermal Neuro | 0.5 | 0.5 | 0.5 | 3/6 died Moderate to severe edema Ataxia and hypoactivity |\n| OxyChem 1972 |  |  |  |  |  |  |  |  |\n| Rabbit (New Zealand) 5 NS | 5 minutes | 0.1 mL | LE, CS | Death |  | 0.1 | 5/5 died within 9 days |  |\n| OxyChem 1972 |  |  |  |  |  |  |  |  |\n| Rabbit (New Zealand) 2 M, 2 F | Once | 200, 2,000 mg/kg | LE, CS, BW | Death |  | 200 M 2,000 F | 2/2 died within 14 days 2/2 died within 24 hours Dermal irritation and discoloration Hypoactivity |  |\n|  |  |  |  | Dermal Neuro | 200 200 M |  |  |  |\n\n---\n\n**Table 2-3. Levels of Significant Exposure to Hexachlorocyclopentadiene – Dermal**\n\n| Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| OxyChem 1972 |  |  |  |  |  |  |  |  |\n| Rabbit (New Zealand) 3 NS | 24 hours | 0.1 mL | LE, CS | Death Ocular |  |  | 0.1 0.1 | 3/3 died within 6 days Severe eye irritation and corrosion |\n| OxyChem 1992 |  |  |  |  |  |  |  |  |\n| Rabbit (New Zealand) 12 NS | 24 hours | 200 mg/kg | LE, CS | Death Dermal |  |  | 200 200 | 8/12 died Eschar formation |\n| OxyChem 1992 |  |  |  |  |  |  |  |  |\n| Rabbit (New Zealand) 6 NS | 4 hours | 0.5 mL | LE, CS | Dermal |  |  | 0.5 | Erythema, edema, necrosis |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rabbit 1–3 F | 24 hours | 430, 610, 1,020, 2,130, 6,130 mg/kg | LE, CS, GN | Death Dermal |  | 430 | 1020 | 2/3 died Skin irritation, discoloration, subcutaneous edema, acanthosis, epiulation, hyperkeratosis, chronic inflammation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rabbit 3 NS | 4 hours | 73.6 ppm | CS | Ocular |  | 73.6 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rabbit 3 NS | 2.6–3.6 hours | 1.4, 3.1, 7.1, 12.4, 12.7, 46.5, 56.9, 70.4 ppm | CS | Ocular |  | 1.4 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rabbit 3 NS | 7 hours | 1.5, 3.2, 6.7 ppm | CS | Ocular |  | 1.5 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rabbit 3 NS | 0.25–1.25 hours | 1.4, 1.5, 3.1, 7.2, 13.0, 13.8, 19.4, 20.0, 20.2, 69.1, 69.2 ppm | CS | Ocular |  | 1.4 |  | Eye irritation |\n\n---\n\n**Table 2-3. Levels of Significant Exposure to Hexachlorocyclopentadiene – Dermal**\n\n| Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rabbit 3 NS | 2 days 7 hours/day | 3.2 ppm | CS | Ocular |  | 3.2 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rabbit 3 NS | 3 days 7 hours/day | 1.4 ppm | CS | Ocular |  | 1.4 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rabbit 3 NS | 5 days 7 hours/day | 1, 1.6 ppm | CS | Ocular |  | 1 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Guinea pig 2 NS | Once | 0.01, 0.1, 1, 40, 60, 90% | CS | Dermal | 1 | 40 |  | Skin discoloration and irritation |\n| INTERMEDIATE EXPOSURE |  |  |  |  |  |  |  |  |\n| Alexander et al. 1980b; Rand et al. 1982a |  |  |  |  |  |  |  |  |\n| Monkey (Cynomolgus) 6 M, 6 F | 14 weeks 5 days/week 6 hours/day | 0, 0.01, 0.05, 0.2 ppm | CS | Ocular | 0.2 |  |  |  |\n| Alexander et al. 1980b; Rand et al. 1982a |  |  |  |  |  |  |  |  |\n| Rat (Sprague-Dawley) 40 M, 40 F | 14 weeks 5 days/week 6 hours/day | 0, 0.01, 0.05, 0.2 ppm | CS | Ocular | 0.01 | 0.05 |  | Dark red eyes |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rat 4 NS | 30 weeks 5 days/week 7 hours/day | 0.15 ppm | CS | Ocular | 0.15 |  |  |  |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rat 4 NS | 6 weeks 5 days/week 7 hours/day | 0.34 ppm | CS | Ocular |  | 0.34 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Mouse 5 NS | 30 weeks 5 days/week 7 hours/day | 0.15 ppm | CS | Ocular | 0.15 |  |  |  |\n\n***DRAFT FOR PUBLIC COMMENT***\n\n---\n\n**Table 2-3. Levels of Significant Exposure to Hexachlorocyclopentadiene – Dermal**\n\n| Species (strain) No./group | Exposure parameters | Doses | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Mouse 5 NS | 6 weeks 5 days/week 7 hours/day (WB) | 0.34 ppm | CS | Ocular |  | 0.34 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rabbit 6 NS | 6 weeks 5 days/week 7 hours/day | 0.34 ppm | CS | Ocular |  | 0.34 |  | Eye irritation |\n| Treon et al. 1955 |  |  |  |  |  |  |  |  |\n| Rabbit 2 NS | 30 weeks 5 days/week 7 hours/day | 0.15 ppm | CS | Ocular | 0.15 |  |  |  |\n\nBC = serum (blood) chemistry; BW = body weight; CS = clinical signs; F = female(s); GN = gross necropsy; LD50 = median lethal dose; LE = lethality; \nLOAEL = lowest-observed-adverse-effect level; M = male(s); Neuro = neurological; NOAEL = no-observed-adverse-effect level; NS = not specified; (WB) = wholebody exposure\n\n---\n\n###### 2.2 DEATH\n\nNo studies were located regarding mortality in humans after exposure to HCCPD.\n\nHCCPD induced death in experimental animals via the inhalation, oral, and dermal routes.  The lethality \nof HCCPD following inhalation exposures has been evaluated for acute-, intermediate-, and chronicduration studies.  Acute-duration inhalation exposures to HCCPD at 1.0–73.6 ppm were lethal to rats, \nmice, guinea pigs, and rabbits in a concentration- and exposure duration-related manner (Treon et al. \n1955).  For example, the concentrations that produced 50% fatalities in mice after 1-, 3.5-, and 7-hour \nexposures were 7.2, <3.1, and <1.5 ppm, respectively.  Species-specific differences were observed in the \nmortality data; the concentrations that produced 50% fatalities after 3.5-hour exposures were 7.1 ppm for \nguinea pigs, 3.1 ppm for rats, <3.1 ppm for mice, and <1.4 ppm for rabbits.  All 10 rats exposed to \n176 ppm HCCPD for 4 hours died within 48 hours of the exposure period (OxyChem 1972).  The 1- and \n4-hour inhalation LC50 values for rats are 3.69 ppm (Jackson and Hardy 1986) and 2.9 ppm (Jackson and \nHardy 1987), respectively.  Male rats appear to be more susceptible to HCCPD lethality than female rats; \nthe sex-specific 4-hour inhalation median lethal concentration (LC50) values are 1.6 ppm for males and \n3.5 ppm for females (Rand et al. 1982a).  With 2-week exposures to 0.5 ppm HCCPD, one rat of each sex \ndied, and nine male rats and one female rat were sacrificed in moribund condition by the end of the \nexposure period.  When the exposure duration was reduced to 5 days, three of five males and none of five\nfemales died at 0.5 ppm.  All animals exposed to ≤0.11 ppm survived until the scheduled sacrifice\n(Alexander et al. 1980a; Rand et al. 1982a).\n\n$$\n\\mathrm{LC}_{50}\n$$\n\n$$\n\\left(LC_{50}\\right)\n$$\n\nIn 13-week studies, all rats and mice exposed to ≥0.941 ppm HCCPD died during the exposure periods \n(NTP 1994).  As was observed after acute-duration inhalation exposures, mice appeared to be more \nsensitive to HCCPD-induced lethality; all mice exposed to 2.142 ppm died during the first week while \nrats exposed to 2.065 ppm survived for up to 3 weeks.  Additionally, no rat mortalities were observed at \n≤0.385 ppm, while 5 of 10 male mice died at 0.389 ppm.  NTP (1994) hypothesized that the sensitivity of \nmice to inhalation exposure was the result of HCCPD-induced inflammation of the breathing passages \nand the narrower diameter of the mouse air passages.  No treatment-related deaths were reported for rats \nor monkeys exposed to ≤0.2 ppm for 14 weeks (Alexander et al. 1980b; Rand et al. 1982a) and overall \nsurvival was not statistically significantly affected by HCCPD treatment in male mice exposed to 0.2 ppm \nfor 33 weeks or 0.5 ppm for 26 weeks (NTP 1994).  Although overall survival of male rats was not \naffected after exposure to 0.5 ppm for 42 weeks, survival in this group decreased 14% 3 weeks after \nexposure cessation (NTP 1994).  In a 30-week study, 22% of male rats exposed to 0.56 ppm died during\n\n$$\n\\leq0.385ppm\n$$ the exposure period (Clark 1981).  No mortality attributed to HCCPD was observed in rats exposed to \n0.06 or 0.14 ppm.\n\nSurvival of male and female rats and male mice chronically exposed to 0.01–0.2 ppm HCCPD for 2 years \nwas similar to controls.  Decreased survival was observed for female mice exposed to 0.2 ppm, but not at \nlower concentrations (NTP 1994).  Ovarian inflammation, possibly resulting from an infection, appeared \nto be the cause of premature deaths in female mice exposed to 0.2 ppm HCCPD.\n\nThe lethality of HCCPD in laboratory animals has been evaluated for acute- and intermediate-duration \noral exposures.  The oral median lethal dose (LD50) values were 505 mg/kg in male rats of an unspecified \nstrain (Treon et al. 1955), 630 and 530 mg/kg in male and female Spartan rats, respectively (OxyChem\n1972), and 1,500 and 1,300 mg/kg in male and female CFY rats, respectively (Gardner 1986a).  An oral\ndose of 940 mg/kg was lethal to ≥90% of the male and female rats (Treon et al. 1955).  Acute-duration \noral lethality data for species other than rats are more limited.  The oral LD50 value for male and female \nmice is 679 mg/kg (Dean 1977).  In rabbits, doses of 420, 620, and 940 mg/kg killed 0/3, 1/3, and \n3/3 animals, respectively (Treon et al. 1955).  In pregnant animals, several rabbits (exact number not \nidentified) did not survive 13 days of treatment with 75 mg/kg/day HCCPD on gestational days (GDs) 6–\n18 (Murray et al. 1980).  With intermediate-duration oral exposure, rats appeared to be more sensitive to \nHCCPD lethality than mice, a reverse of the sensitivity observed for inhalation exposures.  There were no \nmouse deaths following 13-week exposures to ≤150 mg/kg/day, but 6 of 10 male rat deaths at \n150 mg/kg/day were attributed to HCCPD treatment following 13 weeks of exposure (Abdo et al. 1984: \nVelsicol 1981a, 1981b).  All 10 male mice and 3 of 10 female mice died during the first 2 weeks of \nexposure to 300 mg/kg/day (Abdo et al. 1984; Velsicol 1981a).\n\n$$\n\\left(\\mathrm{LD}_{50}\\right)\n$$\n\n$$\n\\mathrm{LD}_{50}\n$$\n\n$$\n\\leqq150\n$$\n\nFor the dermal route, lethality of HCCPD in laboratory animals has only been evaluated for acuteduration exposures.  In rabbits administered topical applications of 200 mg/kg for 24 hours, deaths were \nreported in 2/2 males and 0/2 females (OxyChem 1972) and 8/12 rabbits of unspecified sex (OxyChem \n1992).  Dermal exposure to 2,000 mg/kg resulted in 100% mortality in male and female rabbits within \n24 hours (OxyChem 1972).  At lower doses, single dermal doses applied for 24 hours caused mortality in \n0/3, 1/3, and 2/3 rabbits at 430, 610, and 1,020 mg/kg, respectively (Treon et al. 1955).  In the multi-dose \nstudy by Treon et al. (1955), survival time was inversely proportional to the dose; rabbits survived 72, \n24–48, 20, and 17 hours after dermal dosing with 610, 1,020, 2,130, and 6,130 mg/kg, respectively.  None \nof the animals died with a dermal application of 430 mg/kg, although one rabbit was in poor condition \nand likely would have died had it not been sacrificed at 21 days.  In rats, the dermal LD50 values were\n\n$$\n\\mathrm{LD}_{50}\n$$\n\n---\n\n2,600 mg/kg in males and 3,100 mg/kg in females (Gardner 1986b).  These results suggest that rabbits are \nmore sensitive to HCCPD toxicity via the dermal route relative to rats.\n\nWhen 0.1 mL of HCCPD was instilled into the conjunctival sac of five rabbits for 5 minutes and then \nrinsed with water, the quantity of material absorbed was lethal to all the animals within 9 days (OxyChem\n1972).  When ocular rinsing was delayed until 24 hours post-instillation, all three rabbits administered\n0.1 mL of HCCPD died within 6 days.\n\n###### 2.3 BODY WEIGHT\n\nNo reports of body weight effects in humans after exposure to HCCPD were found.  The available data in \nlaboratory animals indicate that HCCPD produces body weight effects at sufficiently high inhalation and \noral exposure levels; no body weight data are available via the dermal route. In several of these studies, \nbody weight changes were associated with decreased food and/or water intake (see Section 2.18, Other \nNoncancer, for additional details).\n\nBody weight effects resulting from inhalation exposures to HCCPD have been assessed in acute-, \nintermediate-, and chronic-duration studies.  Inhalation exposures to sufficient HCCPD concentrations \nover acute and intermediate periods decrease body weights and/or suppress body weight gains.  A single \n1-hour exposure to HCCPD resulted in decreased body weights in rats during the 3-week post-exposure \nobservation period at concentrations ≥2.38 ppm; when animals that died prematurely and those sacrificed \nat the end of the observation period are combined, body weight decreases compared to control were 41% \nin males and 26% in females (Jackson and Hardy 1986).  A 4-hour exposure resulted in >20% decreases \nin body weight in male and female rats at ≥1.68 and 1.83 ppm, respectively, during the 4-week \nobservation period (Jackson and Hardy 1987).  In both studies by Jackson and Hardy (1986, 1987), body \nweight effects were associated with decreased food intake.  Similarly, after a 4-hour exposure to HCCPD, \nbody weight decreases of at least 25 and 17% relative to pre-exposure weights were observed for male \nand female rats, respectively, after exposures to 1.4–5.8 ppm; no food intake data were provided (Rand et \nal. 1982a).  With significantly decreased food intake, male and female rats exposed to 0.5 ppm HCCPD \nfor 1–2 weeks lost body weight; male body weights decreased 32% on day 10 and terminal female body \nweight decreased 29% (Alexander et al. 1980a; Rand et al. 1982a).\n\n$$\nt\\geqq1.68\n$$\n\nIn 13-week inhalation studies, terminal body weights remained within 10% of control values following \nexposure to HCCPD at concentrations up to 0.385 ppm in rats and 0.389 ppm in mice (NTP 1994).\n\n---\n\nSimilarly, no effects on body weight were observed in rats and monkeys exposed to ≤0.2 ppm HCCPD \nfor 14 weeks (Alexander et al. 1980b; Rand et al. 1982a).  Body weight decreased 19% and body weight \ngain decreased 42% in male mice exposed to 0.5 ppm for 42 weeks (NTP 1994).  No body weight deficits \nwere identified after exposure of male mice to 0.2 ppm for 33 weeks or to 0.5 ppm for 26 weeks (NTP \n1994).  Body weights remained within 10% of control values for male and female rats exposed to \n≤0.56 ppm for 30 weeks (Clark 1981), and in male and female mice and rats exposed to ≤0.2 ppm for \n2 years (NTP 1994).\n\nBody weight effects after oral exposure to HCCPD in experimental animals have been evaluated in acuteand intermediate-duration studies.  In intermediate-duration studies, sufficient oral dosing with HCCPD \ndecreased body weights and suppressed body weight gains.  Male and female rats and mice experienced \ndose-related decreased body weights and body weight gains when compared to controls after oral \nexposure to HCCPD for 13 weeks (Abdo et al. 1984; Velsicol 1981a, 1981b).  Male rats were affected \nmore than females, and rats were affected more than mice.  Terminal body weights in male rats decreased \n13–35% and overall body weight gains were reduced 21–58% at dose levels of ≥38 mg/kg/day. In female\nrats exposed to 75–150 mg/kg/day, terminal body weights were reduced 15–17% and overall body weight \ngains decreased 28–36%.  Terminal body weights in male mice were reduced 11% and overall body \nweight gains decreased 39% at 150 mg/kg/day.  In female mice, terminal body weights decreased 13% at \n300 mg/kg/day and overall body weight gains were reduced 22–44% at ≥150 mg/kg/day. Differences in \nterminal body weights and overall body weight gains were within 10% of control values for male rats at \n≤19 mg/kg/day, female rats at ≤38 mg/kg/day, and male and female mice at ≤75 mg/kg/day.  Maternal \nweight loss was observed in rabbits administered 75 mg/kg/day on GDs 6–18; the magnitude of weight \nloss was not reported (Murray et al. 1980).  No body weight effects were reported for rabbits dosed with \n≤25 mg/kg/day on GDs 6–18 or for mice dosed with ≤75 mg/kg/day on GDs 6–15.\n\n###### 2.4 RESPIRATORY\n\nThe data provide strong evidence that HCCPD produces portal-of-entry effects in the respiratory system \nfollowing inhalation exposures; no effects on the respiratory tract were observed following oral or dermal \nexposures to HCCPD.  Based upon systematic review (Appendix C), the respiratory system is a presumed \nhazard of HCCPD toxicity following inhalation exposure based on inadequate evidence in humans and a \nhigh level of evidence from laboratory animal studies.\n\n---\n\nThe available data on respiratory effects of HCCPD in humans are limited to reports of WWTP workers \nand cleanup crew members exposed to HCCPD for 3–15 days after an inadvertent industrial release of \nthis material into the sewage system (Kominsky et al. 1980; Morse et al. 1979).  Maximum atmospheric \nconcentrations for the treatment plant workers were unknown but were most likely >0.97 ppm, the \nmaximum concentration measured 4 days after compound identification (Morse et al. 1979).  The \nmaximum concentration recorded during cleanup was 19.2 ppm (Kominsky et al. 1980).  Symptoms of \ntracheobronchial irritation were reported by the treatment plant workers early in the exposure period.  \nThese symptoms were recounted by 39 of 145 (27%) employees who responded to a questionnaire shortly \nafter the exposure incident and by 16 of 177 (9%) employees who responded to a follow-up questionnaire \n6 weeks later (Morse et al. 1979).  Chest x-rays of 28 exposed workers were normal and tests of \npulmonary function were normal in a subset of 22 workers from this group (Kominsky et al. 1980).  \nMinor respiratory complaints included sore throat, cough, chest discomfort, and difficulty breathing.  \nThese effects were likely a consequence of the direct action of the HCCPD vapor on the mucous \nmembranes of the respiratory tract, rather than systemic effects due to exposure to HCCPD through the \nlungs.  One cleanup crew worker also reported respiratory difficulty when exposed for a few seconds to \n19.2 ppm HCCPD without protective equipment (Kominsky et al. 1980).  Chest discomfort persisted for \nseveral days in this individual.\n\nRespiratory effects induced by HCCPD in laboratory animals have been evaluated in acute-, \nintermediate-, and chronic-duration inhalation exposure studies.  Inhalation exposures to HCCPD \nproduced clinical signs of respiratory toxicity and/or irritation including abnormal respiratory pattern \n(irregular or exaggerated respiratory movements, fast or irregular respiration rate or pattern, rales and/or \nnoisy respiration, and/or gasping), labored respiration, sneezing, increased respiration rate, and/or mouth \nbreathing in rats exposed to 1.67 ppm for 1 hour (Jackson and Hardy 1986), 1.68 ppm for 4 hours \n(Jackson and Hardy 1987), 0.5 ppm for 1–2 weeks (Alexander et al. 1980a; Rand et al. 1982a), 0.56 ppm \nfor 30 weeks (Clark 1981), and ≥0.941 ppm for 13 weeks (NTP 1994).  No respiratory clinical signs were \nobserved in rats or monkeys exposed to 0.2 ppm for 14 weeks (Alexander et al. 1980b; Rand et al. \n1982a), mice exposed to ≤2.142 ppm for 13 weeks (NTP 1994), male mice exposed to 0.2 ppm for \n33 weeks or 0.5 ppm for 26 or 42 weeks (NTP 1994), or rats and mice exposed to ≤0.2 ppm for 2 years \n(NTP 1994).  Based on these data, it appears that rats are more susceptible to HCCPD-induced respiratory \nirritation effects than mice. Blood gas analysis, pulmonary ventilation, and lung mechanics were within \nnormal ranges in pulmonary function tests of monkeys exposed to ≤0.2 ppm HCCPD for 7 and 13 weeks \n(Alexander et al. 1980b; Rand et al. 1982a).\n\n---\n\nInhalation exposures to HCCPD vapor caused histopathological changes in the respiratory tracts of \nexperimental animals.  At nonlethal concentrations, these alterations were largely inflammatory or \nhyperplastic in nature, consistent with repetitive irritation at the portal of entry.  Inflammation of the \ntissues was followed by necrosis, exfoliation, and/or hemorrhage.  No histopathological examination was \nconducted, but gross necropsy of the lungs showed pale and swollen lungs in rats exposed to ≥1.68 ppm \nfor 4 hours; findings were associated with increased absolute and relative lung weights at ≥3.31 and \n1.83 ppm in male and female rats, respectively (Jackson and Hardy 1987).  Inflammation, hyperplasia, \nand epithelial erosion were identified in the lungs of rats exposed to HCCPD vapor at 0.5 ppm for 1–\n2 weeks; recovery was apparent 2 weeks after exposure ceased in surviving animals (Alexander et al. \n1980a; Rand et al. 1982a).  No histopathological changes were identified in respiratory tissues of rats\nexposed to ≤0.11 ppm in the same manner (Alexander et al. 1980a; Rand et al. 1982a) or in rats and \nmonkeys exposed to ≤0.2 ppm for 14 weeks (Alexander et al. 1980b; Rand et al. 1982a). Using electron \nmicroscopy, exposure-related increases in electron-lucent inclusions in club cells, formerly called Clara \ncells, were observed in rats exposed to 0.01–0.2 ppm for 14 weeks (Huntingdon Research Centre 1980; \nRand et al. 1982b); however, this findings is considered a biomarker of exposure rather than evidence of \ntoxicity due to the absence of histopathological findings or any other ultrastructural changes.  No \nexposure-related ultrastructural changes were observed in monkeys exposed to ≤0.2 ppm for 14 weeks\n(Rand et al. 1982b).  In a 30-week inhalation exposure study in rats, increased incidences of \nperivascular/peribronchiolar inflammatory cell infiltration were observed in males and females exposed to \n0.56 ppm; males exposed to this concentration also exhibited an increased incidence of bronchiolar \nepithelial thinning/ulceration (Clark 1981).  The incidences of bronchiolar epithelial hyperplasia, \nsloughing/loss, and edema also increased in male and female rats exposed to 0.56 ppm but did not reach \nstatistical significance.  Following a 14-week recovery period, no histopathological differences were \nidentified in the lungs of control and treated rats, indicating reversibility of these lesions.\n\n$$\nt_{0}\\geqq1.68\n$$\n\nIn 13-week studies, microscopic effects in the respiratory system produced by lethal HCCPD \nconcentrations included necrotizing inflammation of the nose, larynx, trachea, and bronchus/bronchiole \nand hemorrhaging of the alveolus in male and female rats exposed to 0.941–2.065 ppm; suppurative \ninflammation of the alveolus in male and female rats at 0.941 ppm; acute necrosis of the nose, larynx, \ntrachea, and lung epithelium and lung congestion in male and female mice at 2.142 ppm; tracheal \nsquamous metaplasia in male and female mice at 0.949 ppm; and suppurative inflammation of the nasal \nepithelium of male and female mice exposed to 0.949–2.142 ppm (NTP 1994).  Increased incidences of \nsuppurative inflammation and squamous metaplasia in the nose and necrotizing and suppurative \ninflammation of the bronchus/bronchiole were identified in male rats exposed to 0.385 ppm, increased incidences of nasal suppurative inflammation and tracheal squamous metaplasia were observed in male \nmice exposed to 0.389 ppm, and an increased incidence of nasal serous inflammation was present in \nfemale mice exposed to 0.389 ppm.  No statistically significant increases were identified for nonneoplastic lesions in the respiratory tract tissues of female rats exposed to ≤0.385 ppm, male rats exposed \nto 0.146 ppm, or male or female mice exposed to ≤0.146 ppm (NTP 1994).\n\nHistopathological findings in male and female mice exposed to 0.2 ppm for 2 years included nasal \nsuppurative inflammation characterized by accumulation of cellular debris, mucus, neutrophils, and fibrin \nin the nasal lumen and infiltration of mononuclear cells and neutrophils into the lamina propria (NTP \n1994).  After 2-year exposures, an increased incidence of squamous metaplasia of the larynx (minimal \nseverity) was identified in female rats at 0.01 and 0.2 ppm; the incidence at 0.05 ppm was also elevated \nbut was not statistically significantly different from the concurrent control incidence.  No treatmentrelated respiratory tract lesions were identified in male rats.  The toxicological relevance of the squamous \nmetaplasia was not clear to the NTP (1994) authors due to difficulties in obtaining consistent sections for \nanalysis and determination of the boundary between squamous and columnar epithelium.  Due to this, as \nwell as the lack of clear dose-response, a LOAEL determination for squamous metaplasia was not \nincluded in Table 2-1.\n\nTo examine the progression and permanence of non-neoplastic lesions in the respiratory tract, NTP \n(1994) conducted additional studies in male mice with the intent of evaluating the relative effects of \nconcentration and duration on development of these lesions.  In these studies, concentrations were 0 or \n0.2 ppm for 33 weeks and 0 or 0.5 ppm for 26 or 42 weeks.  Animals were sacrificed at interim \nevaluations after 27, 34, or 43 weeks or 15 months of exposure or were sacrificed after 2 years.  At the \nend of the exposure periods, the incidence of nasal suppurative inflammation increased in all treatment \ngroups and suppurative inflammation of the trachea and lungs and alveolar epithelial hyperplasia \nincreased in animals exposed to 0.5 ppm for 42 weeks.  The incidence of alveolar epithelial hyperplasia \nalso increased in male mice exposed to 0.5 ppm for 42 weeks.  An evaluation of the data indicated that \nboth concentration and duration of exposure influenced the development of these respiratory tract lesions; \nthe inflammation of the trachea and lungs was not observed unless the product of the concentration and \nduration was >20 or 21 ppm-weeks.\n\nIn the chronic-duration studies of rats and mice exposed to HCCPD for 2 years, accumulation of a \ngranular yellow-brown pigment was observed in the nasal epithelium in male and female rats and mice at \n≥0.01 ppm, tracheal epithelium of male and female mice at ≥0.01 ppm, bronchiole epithelium of female\n\n$$\n\\geqq0.01\n$$ rats at ≥0.01 ppm, and lung epithelium of male and female mice ≥0.05 ppm (NTP 1994).  At 0.2 ppm, \nminimal-to-mild tracheal, bronchiole, and peribronchiole pigmentation was observed in male rats and \nperibronchiole pigmentation was identified in female rats (NTP 1994).  The pigmentation incidence and \nseverity generally increased with concentration for each sex-species combination.  In male mice exposed \nto 0.2 ppm for 33 weeks or 0.5 ppm for 26 or 42 weeks and then maintained for up to 2 years, \npigmentation of the respiratory tract (nose, trachea, and/or lungs) was seen in the majority of exposed \nanimals and did not disappear following exposure cessation and evaluation at 2 years, indicating a lack of \nrecovery and physiological turnover of the pigment material.  The incidence and severity were similar \nafter 33, 66, and 104 weeks of exposure to 0.2 ppm HCCPD.  In the chronic-duration and additional \nstudies in male mice exposed to 0.2 ppm for 33 weeks and 0.5 ppm for 26 or 42 weeks, the pigmentation \ndid not co-occur with respiratory lesions and did not appear to be a precursor to more significant effects \n(i.e., did not indicate an initial phase in the progression of a disease state).  Results of several staining \nprocedures applied to the pigmented lung sections of rats and mice indicated the presence of reducing \nsubstances, but no further analytical identification was performed.  NTP (1994) indicated that the \npigmentation may be a unique response to HCCPD and could be due to lipid peroxidation.  Based on \nthese data, ATSDR concludes that it is more appropriate to characterize the pigmentation as a marker of \nexposure to HCCPD rather than an adverse effect attributable to HCCPD exposure.\n\nThe potential for oral exposure to HCCPD to induce respiratory effects has been evaluated in acute- and \nintermediate-duration studies.  In rats and mice administered lethal gavage doses of HCCPD, decreased \nrespiratory rates were observed prior to death (Dean 1977; Gardner 1986a); this clinical sign was likely a \nconsequence of significant morbidity prior to death rather than an effect of HCCPD on the respiratory \nsystem.  No gross or histopathological changes were identified in the nasal cavity, trachea, larynx, \nbronchi, or lungs of rats at doses ≤150 mg/kg/day or in mice at doses ≤300 mg/kg/day for 13 weeks \n(Abdo et al. 1984; Velsicol 1981a, 1981b).\n\nThe potential toxicological effects of HCCPD on the respiratory tract following dermal exposure were \nevaluated in one acute-duration dermal toxicity study.  A decreased rate of respiration was observed in \nrats administered topical doses ≥2,000 mg/kg for 24 hours (Gardner 1986b).  The animals appeared \nnormal 5–9 days after dosing and no gross pathological changes were identified in the lungs of animals \nthat survived to the scheduled sacrifice.\n\n---\n\n###### 2.5 CARDIOVASCULAR\n\nNo studies were located regarding cardiovascular effects in humans after exposure to HCCPD. Available\ndata from laboratory animals indicate that the cardiovascular system is not a sensitive toxicity target \nfollowing inhalation or oral exposure to HCCPD.\n\nThe cardiovascular system has been evaluated in experimental animals exposed to HCCPD via inhalation \nin acute-, intermediate-, and chronic-duration studies.  Diffuse degenerative changes were observed in the \nhearts of rats, mice, and rabbits that died following acute exposure to lethal concentrations of HCCPD \nranging from 0.3 to 66 ppm for 15 minutes to 2 weeks; incidence data were not provided, and findings \nwere potentially attributable to autolysis (Treon et al. 1955).  In another acute-duration study, there were \nno histopathological changes in the heart in rats exposed to concentrations up to 0.5 ppm after either 1 or \n2 weeks (Alexander et al. 1980a; Rand et al. 1982a).  In longer-term inhalation studies, there was no \nevidence for histopathological changes in the heart at intermediate-duration concentrations up to \n0.56 ppm in rats, 0.389 ppm in mice, or 0.2 ppm in monkeys (Alexander et al. 1980b; Clark 1981; NTP \n1994; Rand et al. 1982a) or chronic-duration concentrations up to 0.2 ppm in rats or mice (NTP 1994).\n\nPotential cardiovascular effects of HCCPD oral exposures in experimental animals were evaluated in \nacute- and intermediate-duration studies.  Single oral doses of 280–2,100 mg/kg caused degenerative \nchanges in the hearts of rats and rabbits, possibly due to tissue autolysis; incidence data were not provided\n(Treon et al. 1955).  In contrast, there were no gross or histopathological changes in the hearts of rats \nexposed to doses ≤150 mg/kg/day or mice exposed to doses ≤300 mg/kg/day for 13 weeks (Abdo et al. \n1984; Velsicol 1981a, 1981b).\n\nRabbits that died following single dermal doses of 610–6,130 mg/kg displayed degenerative changes in \nthe heart, possibly because of tissue autolysis; incidence data were not provided (Treon et al. 1955).\n\n###### 2.6 GASTROINTESTINAL\n\nThe data provide evidence that HCCPD produces portal-of-entry effects in the gastrointestinal system, \nspecifically the stomach, following oral exposures.  Data on adverse gastrointestinal effects following \ninhalation exposure are limited to clinical signs following accidental occupational exposure; no effects on \nthe gastrointestinal system were observed following dermal exposure to HCCPD.  Based upon systematic \nreview (Appendix C), the gastrointestinal system is a presumed hazard of HCCPD toxicity following oral exposure based on no route-specific data in humans and a high level of evidence from laboratory animal \nstudies.\n\nWWTP workers exposed to HCCPD for 3–15 days due to an inadvertent industrial release complained of \nnausea (22% of 177 workers) and abdominal cramps (prevalence not specified) (Kominsky et al. 1980; \nMorse et al. 1979).  One member of the cleanup crew who was exposed to 19.2 ppm for several seconds \nwithout protective equipment experienced nausea several minutes after the exposure (Kominsky et al. \n1980).  While classified as gastrointestinal in this profile, it is possible that nausea may be neurological in \norigin.\n\nGastrointestinal effects of HCCPD have been evaluated in laboratory animals following intermediate- and \nchronic-duration inhalation exposures.  No microscopic changes were seen in the stomach, esophagus, or \nintestines of monkeys, rats, or mice exposed to concentrations up to 0.2, 0.56, or 0.5 ppm, respectively, in\nintermediate-duration studies (Alexander et al. 1980b; Clark 1981; NTP 1994; Rand et al. 1982a), or rats \nor mice following chronic-duration exposure to concentrations up to 0.2 ppm (NTP 1994).  The \ngastrointestinal tract does not appear to be a sensitive target for HCCPD in animals following inhalation \nexposures.\n\nThe potential impact of HCCPD exposure on gastrointestinal tissues has been evaluated in acute- and \nintermediate-duration oral exposure studies in experimental animals.  Increased incidences of diarrhea \nwere observed in rats dosed with ≥1,260 mg/kg (Gardner 1986a) and female and male mice dosed with \n464 and 1,000 mg/kg, respectively (Dean 1977).  Acute necrotic lesions of the forestomach were noted in \nsome rats administered an oral dose of 280–2,100 mg/kg; incidence data were not provided (Treon et al. \n1955).  After 13-week exposures to HCCPD, increased incidences of forestomach epithelial hyperplasia \nwere observed in male and female rats at 38 mg/kg/day and male and female mice at 75 mg/kg/day (Abdo \net al. 1984; Velsicol 1981a, 1981b).  Increased incidences of focal inflammation in the forestomach were \nidentified in male and female rats at 38 mg/kg/day and male and female mice at 75 mg/kg/day.  The \nincidences and ranges of lesion severities were directly related to the dose.  No histopathological changes \nwere identified in the esophagus, duodenum, jejunum, ileum, or colon of males and females of either \nspecies.  These data suggest that rats are more sensitive to HCCPD-induced effects to the forestomach \nthan mice.  The presence of the forestomach lesions and lack of histopathological changes in other \nregions of the gastrointestinal tract suggests that the forestomach effects result from direct contact of \nthese tissues with HCCPD.\n\n---\n\n###### 2.7 HEMATOLOGICAL\n\nThe data indicate HCCPD may alter red blood cell hematology parameters following inhalation exposure \nwithout causing histopathological changes to bone marrow; no consistent effects were noted in white \nblood cell parameters following inhalation exposure and no effects on the hematological system were \nobserved in animals following oral exposures to HCCPD.  Data are not available via the dermal route.  \nBased upon systematic review (Appendix C), the hematological system, specifically red blood cell \nparameters, is a suspected hazard of HCCPD toxicity following inhalation exposure based on inadequate \ndata in humans and a moderate level of evidence from laboratory animal studies.  White blood cell effects \nare not classifiable as to the hazard to humans based on inadequate data in humans and animals.\n\nNo changes in blood counts were observed in workers exposed to HCCPD at a WWTP after an industrial \ndischarge of the material into the sewage system (Kominsky et al. 1980).\n\nThe potential hematological effects of HCCPD were evaluated in experimental animals exposed via \ninhalation after acute-, intermediate-, and chronic-duration exposures.  No effects on bone marrow \nhistopathology were reported in rats exposed to 0.5 ppm for 1–2 weeks (Alexander et al. 1980a; Rand et \nal. 1982a), rats and mice exposed to ≤0.385 and ≤0.389 ppm, respectively, for 13 weeks, or rats and mice \nexposed to ≤0.2 ppm for 2 years (Alexander et al. 1980b; NTP 1994; Rand et al. 1982a).  Across acuteand intermediate-duration multiple exposure studies, altered red blood cell hematology parameters were \nidentified in rats, particularly males, as seen in Table 2-4.\n\n**Table 2-4. LOAEL Values for Red Blood Cell Hematological Effects of Rats** \n**Exposed to HCCPD Vapor in Acute- and Intermediate-Duration Inhalation**\n**Studies**\n\n| Hematology parameter | Rand et al. 1982aa: 1–2 weeks | Rand et al. 1982aa: 1–2 weeks (recovery group) | NTP 1994: 13 weeks | NTP 1994: 13-week special hematology study | Clark 1981: 30 weeks |\n| --- | --- | --- | --- | --- | --- |\n| Males |  |  |  |  |  |\n| PCV | \\(\\uparrow (0.5^{{b}})\\) | ↔ | \\(\\uparrow (0.385)\\) | ↔ | - |\n| Hb | \\(\\uparrow (0.5)\\) | \\(\\uparrow (0.5)\\) | \\(\\uparrow (0.385)\\) | ↔ | \\(\\uparrow (0.14)\\) |\n| RBC | \\(\\uparrow (0.5)\\) | ↔ | \\(\\uparrow (0.385)\\) | ↔ | \\(\\uparrow (0.14)\\) |\n| MCV | ↔ | ↔ | ↔ | \\(\\uparrow (0.385)\\) | ↔ |\n| MCH | - | - | \\(\\uparrow (0.385)\\) | ↔ | ↔ |\n| MCHC | ↔ | \\(\\uparrow (0.5)\\) | ↔ | ↔ | ↔ |\n\n---\n\n**Table 2-4. LOAEL Values for Red Blood Cell Hematological Effects of Rats** \n**Exposed to HCCPD Vapor in Acute- and Intermediate-Duration Inhalation**\n**Studies**\n\n| Hematology parameter | Rand et al. 1982aa: 1–2 weeks | Rand et al. 1982aa: 1–2 weeks (recovery group) | NTP 1994: 13 weeks | NTP 1994: 13-week special hematology study | Clark 1981: 30 weeks |\n| --- | --- | --- | --- | --- | --- |\n| HCT | - | - | - | - | \\(\\uparrow\\) (0.14) |\n| Females |  |  |  |  |  |\n| PCV | \\(\\uparrow\\) (0.5) | ↔ | ↔ | \\(\\uparrow\\) (0.385) | - |\n| Hb | \\(\\uparrow\\) (0.5) | ↔ | ↔ | \\(\\uparrow\\) (0.385) | ↔ |\n| RBC | \\(\\uparrow\\) (0.5) | ↔ | \\(\\downarrow\\) (0.385) | \\(\\uparrow\\) (0.385) | ↔ |\n| MCV | ↔ | ↔ | \\(\\uparrow\\) (0.385) | \\(\\uparrow\\) (0.385) | ↔ |\n| MCH | - | - | ↔ | \\(\\uparrow\\) (0.385) | ↔ |\n| MCHC | ↔ | ↔ | ↔ | ↔ | ↔ |\n| HCT | - | - | - | - | ↔ |\n\n<sup>a</sup>Data are also available in the unpublished industry report by Alexander et al. (1980a).\n\n<sup>b</sup>LOAEL concentrations are in ppm.\n\n↑ = increased mean value; ↓ = decreased mean value; ↔ = no significant, dose-related change in mean value;\n\n– = not assessed; Hb = hemoglobin; HCT =hematocrit; MCH = mean cell hemoglobin; MCHC = mean cell\n\nhemoglobin concentration; MCV = mean cell volume; PCV = packed cell volume; RBC = red blood cell count\n\nThe most consistently observed effects were increased hemoglobin levels in male and female rats and \nincreased red blood cell counts in male rats.  Generally, effects were observed at concentrations \n≥0.14 ppm and had magnitudes of effect that were <10% of control values.  The exceptions are for the 1–\n2-week range-finding study (Alexander et al. 1980a; Rand et al. 1982a), where 20–30% increases in red \nblood cell parameters were identified at 0.5 ppm, a concentration that co-occurred with significantly \ndecreased water intake and produced significant mortality and morbidity (see Section 2.2).  Drinking \nwater intakes were not assessed in the NTP (1994) studies and were not affected by HCCPD exposure in \nthe Clark (1981) study (see Section 2.18).  While statistically significant altered hemoglobin, mean cell \nvolume (MCV), and mean cell hemoglobin concentration (MCHC) values were reported in rats following \na 14-week exposure at concentrations as low as 0.01 ppm, these changes were sporadically observed and\nwere not dose-responsive, and the magnitudes of effect were generally low (≤5%) (Alexander et al. \n1980b; Rand et al. 1982a).  Therefore, they were not considered to be biologically significant in this \nassessment and are not presented in Table 2-4.  For intermediate-duration exposures in rats, the NOAEL \nvalues were 0.039–0.146 ppm for the NTP (1994) 13-week studies and 0.06 ppm for the Clark (1981) \n30-week study.\n\n---\n\nRand et al. (1982a) postulated that these minor variances in hematological parameters were a \nconsequence of hemorrhagic lesions in the lungs and not a direct influence of HCCPD on hematopoiesis \nor red cell turnover.  Since the red blood cell hematology parameters were more consistently altered in \nmale rats than in female rats, this hypothesis correlates with the increased absolute and relative lung \nweights and more severe histopathological effects observed in the lungs of male rats in the 1–2-week\nRand et al. (1982a) study.  NTP (1994) suggested that the red blood cell hematology alterations were not \nattributable to HCCPD treatment due to the inconsistent dose-response and lack of correlation in the \nresults across sexes and between the core and special 13-week hematology studies.  While there are \ninconsistencies in the red blood cell parameter results obtained from the NTP (1994) studies, common \nalterations in hemoglobin levels and red blood cell counts across repeated inhalation exposure studies \nsuggest a consistent biological response to HCCPD.  In the absence of additional data and based on the \nlack of histopathological effects to bone marrow, ATSDR considers the altered red blood cell parameters \nto be plausibly related to respiratory tract damage resulting in compromised gas exchange.\n\nIn mice, the only consistent HCCPD treatment-related effect on red blood cell hematology parameters \nacross studies was decreased MCV in female mice after exposure to 0.389 ppm for 13 weeks in the core\nand special hematology studies (NTP 1994).  Other red blood cell effects were limited to increased \nMCHC in male mice at 0.389 ppm and in female mice at 0.039–0.389 ppm in the special 13-week \nhematology study.  The magnitudes of effect were within 5% of control values.  HCCPD treatmentrelated effects on other hematological parameters following inhalation exposures were limited to \ndecreased reticulocytes (40%) in female rats exposed to 0.385 ppm in the special hematology study (NTP \n1994); decreased total white blood cells (46%) and lymphocyte count (53%) in male rats, and increased \nneutrophil count (114%) in female rats exposed to 0.5 ppm for 1–2 weeks (Alexander et al. 1980a; Rand \net al. 1982a); and decreased percent lymphocytes (8–10%) and increased neutrophil count (27–36%) in \nmale rats exposed to ≥0.14 ppm and decreased lymphocyte count (16%) in female rats exposed to \n0.56 ppm for 30 weeks (Clark 1981).  No clear biological basis can be identified for these effects based \non the lack of consistency across studies.\n\nIn intermediate-duration oral exposure studies, no histopathological changes were identified in the bone \nmarrow of rats dosed with ≤150 mg/kg/day or mice dosed with ≤300 mg/kg/day for 13 weeks (Abdo et al. \n1984; Velsicol 1981a, 1981b).  Hematology parameters were not evaluated in this study.\n\n---\n\n###### 2.8 MUSCULOSKELETAL\n\nNo studies were located regarding musculoskeletal effects in humans after exposure to HCCPD.  \nAvailable inhalation and oral data in laboratory animals indicate the musculoskeletal system is not a \nsensitive target of toxicity following exposure to HCCPD; no dermal studies were identified.\n\nThe potential effect of HCCPD on musculoskeletal tissues has been evaluated in laboratory animals \nfollowing intermediate- and chronic-duration inhalation exposures and acute- and intermediate-duration \noral exposures.  HCCPD did not affect skeletal muscle of rats or monkeys exposed to up to 0.2 ppm for \n14 weeks (Alexander et al. 1980b; Rand et al. 1982a); femoral muscle, knee joint, or femur of male and \nfemale rats exposed to ≤0.56 ppm for 30 weeks (Clark 1981); bone histopathology of mice or rats \nexposed to ≤0.389 ppm for 13 weeks or ≤0.2 ppm for 2 years (NTP 1994).  Similarly, no \nhistopathological changes were identified in thigh muscle, rib (costochondral junction), or femur of rats \nexposed to ≤150 mg/kg/day or mice exposed to ≤300 mg/kg/day via gavage for 13 weeks (Abdo et al. \n1984; Velsicol 1981a, 1981b). In animals that died, decreased limb tone was observed in mice (prior to \ndeath) after a single exposure to 1,000 mg/kg via gavage (Dean 1977).\n\n###### 2.9 HEPATIC\n\nThe data indicate that the hepatic system is not a sensitive target of HCCPD toxicity.\n\nSerum markers of hepatotoxicity were evaluated in 97 cleanup workers exposed to HCCPD vapors at a \nWWTP because of an inadvertent industrial release (Kominsky et al. 1980).  Abnormal serum marker \nranges were identified for 18 of the 97 workers (19%); aspartate aminotransferase (AST) values were \nelevated for 12 workers, alkaline phosphatase (ALP) was elevated for 5 workers, and total bilirubin was \nelevated for 1 worker (Kominsky et al. 1980).  For 8 of the 97 cleanup crew members, these biochemical \nparameters were abnormal on more than one occasion, and 7 workers had values that were temporallyrelated to exposure conditions.  It should be noted that evaluations were not performed on unexposed \nworkers, and it is not known if the abnormal values observed in exposed workers differ from the \nunexposed local general population.\n\nRelative to a group of 35 controls, 73 male operators employed for an average of 8.2 years (range 0.5–\n23 years) in a plant producing chlorinated hydrocarbons, including HCCPD, showed no evidence of \nhepatotoxicity (Boogaard et al. 1993).  Clinical tests included measurement of alanine aminotransferase\n\n---\n\n(ALT), AST, ALP, total bilirubin, γ-glutamyltransferase (GGT), lactate dehydrogenase (LDH), and total \nbile acids.  Personal air sampling for HCCPD was performed on a subset of study participants but was not \nused to evaluate associations between HCCPD exposure and liver function values.\n\nThe hepatotoxic potential of HCCPD has been evaluated in laboratory animals following acute-, \nintermediate-, and chronic-duration inhalation exposures.  Mild-to-moderate hepatic tissue degeneration \nwas observed following acute-duration inhalation exposures to 0.34–73.6 ppm for 15 minutes to 5 days, \nand to intermediate-duration exposures to 0.34 ppm for 6 weeks or 0.15 ppm for 30 weeks; incidence data \nwere not provided (Treon et al. 1955).  Hepatic damage was more pronounced in the animals that died \nthan in those that survived and, thus, may have been, at least partially, the result of autolysis in moribund \nor dying animals.  An apparent dose-related increase in perivascular/peribiliary inflammatory cell \ninfiltrates in the liver was observed in female rats exposed to 0.06–0.56 ppm; however, incidences did not \ndiffer significantly from control and no hepatic lesions were observed in similarly exposed male rats \n(Clark 1981).  In other inhalation studies, no exposure-related hepatic lesions were seen following acuteduration exposure in rats to concentrations up to 0.5 ppm (Alexander et al. 1980a; Rand et al. 1982a); \nintermediate-duration exposure in monkeys, rats, or mice to concentrations up to 0.2, 0.385, or 0.5 ppm, \nrespectively (Alexander et al. 1980b; NTP 1994; Rand et al. 1982a); or chronic-duration exposure in rats \nor mice to concentrations up to 0.2 ppm (NTP 1994).\n\nNo consistent evidence of exposure-related changes in hepatic serum biochemistry or liver weight was \nobserved following inhalation exposure to HCCPD.  Serum concentrations of the biochemical parameters\nLDH, AST, ALP, and ALT in rats and mice were not influenced by inhalation exposure to HCCPD \nconcentrations ≤0.389 ppm for 13–14 weeks (Alexander et al. 1980b; NTP 1994; Rand et al. 1982a).  \nDuring the 13-week special hematology, clinical chemistry, and urinalysis study conducted in rats by \nNTP (1994), the highest concentration of 2.065 ppm caused elevated serum AST concentrations (1.7–\n7.6-fold) in male and female rats on days 4–16; however, this concentration was lethal to all the animals \nprior to the day 46 clinical evaluation, and a comparable increase was not observed in mice (NTP 1994).  \nRelative liver weights of rats were significantly reduced by 3–15% in males and females exposed to 0.01–\n0.2 ppm for 13 weeks, but the decreases were not dose-related (Alexander et al. 1980b; Rand et al. \n1982a).  No changes in liver weights were observed in rats or mice exposed to concentrations ≤0.389 ppm \nfor 13 weeks or ≤0.2 ppm for 2 years (NTP 1994).\n\nAcute- and intermediate-duration oral toxicity studies have evaluated the potential effects of HCCPD\nexposure on the liver.  High, acute-duration oral doses of HCCPD were associated with liver necrosis and tissue degeneration in rats (261–1,959 mg/kg) and rabbits (579–877 mg/kg); incidence data were not \nprovided (Treon et al. 1955).  HCCPD did not induce histopathological changes in hepatic tissues of rats \nand mice exposed to doses up to 150 and 300 mg/kg/day, respectively, via gavage for 13 weeks (Abdo et \nal. 1984; Velsicol 1981a, 1981b).\n\nThe potential for HCCPD to cause hepatotoxicity following dermal exposure was evaluated only for \nacute-duration exposures.  Rabbits exposed to single dermal doses of 401–5,719 mg/kg displayed necrosis \nof the liver; incidence data were not provided (Treon et al. 1955).  The study authors stated that \ndegenerative changes persisted even 21 days after the exposure period in surviving animals.\n\n###### 2.10 RENAL\n\nThe data indicate that the renal system is a potential target for HCCPD via the oral route; it does not \nappear to be a sensitive target for HCCPD via the inhalation or dermal routes.  Based upon systematic \nreview (Appendix C), the kidney is a presumed hazard of HCCPD toxicity following oral exposure based \non no data in humans and a high level of evidence from laboratory animal studies.\n\nUrine samples were collected from 41 workers exposed for 3–15 days to HCCPD at a WWTP as the \nresult of an inadvertent industrial release into the sewage system (Morse et al. 1979).  Proteinuria was \nidentified in 6 of 41 workers immediately after exposure but no abnormalities were detected 3 weeks \nlater.  Urinalysis parameters were normal in all 97 cleanup crew workers evaluated (Kominsky et al. \n1980).  It should be noted that urinalysis was not performed on unexposed workers, and it is not known if \nproteinuria values observed in exposed workers differ from the local general population.\n\nRelative to a group of 35 controls, 73 male operators employed for an average of 8.2 years in a plant \nproducing chlorinated hydrocarbons, including HCCPD, showed no evidence of damage to the renal \ntubules (Boogaard et al. 1993).  The investigations included measurement of urinary alanine \naminopeptidase, N-acetyl-β-D-glucosaminidase, and retinol binding protein.  Although total urinary \nprotein concentrations did not differ between the two groups, urinary albumin was significantly higher in \nthe exposed group.  The difference, however, was not related to time of employment, and there was no \ndifference in urinary albumin concentration in workers involved in the manufacture of HCCPD and those \ninvolved in the preparation of other chlorinated hydrocarbon.  Thus, the effect was not considered to be \ndue to the damage to the glomerulus caused by exposure to HCCPD.  Personal air sampling for HCCPD\n\n---\n\n2.  HEALTH EFFECTS\n\nwas performed on a subset of study participants but was not used to evaluate associations with renal \nfunction values.\n\nThe potential renal effects following inhalation exposure to HCCPD have been evaluated in laboratory \nanimals following acute, intermediate, and chronic durations.  Inhalation exposure of HCCPD caused \nrenal tubular necrosis in rats, mice, guinea pigs, and rabbits at 0.34–73.6 ppm for 15 minutes to 7 days, \n0.34 ppm for 6 weeks, and 0.15 ppm for 30 weeks; incidence data were not provided (Treon et al. 1955).  \nIn other inhalation studies, no significant, exposure-related renal lesions were seen following acuteduration exposure in rats to concentrations up to 0.5 ppm (Alexander et al. 1980a; Rand et al. 1982a); \nintermediate-duration exposure in monkeys, rats, or mice to concentrations up to 0.2, 0.56, or 0.5 ppm, \nrespectively (Alexander et al. 1980b; Clark 1981; NTP 1994; Rand et al. 1982a); or chronic-duration \nexposure in rats or mice to concentrations up to 0.2 ppm (NTP 1994).\n\nThe potential toxicological effects of HCCPD on the kidneys have been evaluated in laboratory animals \nin acute-and intermediate-duration oral studies.  Degenerative lesions in the kidney tubules resulted from \nsingle gavage doses of 261–1,959 mg/kg in rats and 579–877 mg/kg in rabbits; incidence data were not \nprovided (Treon et al. 1955).  Toxic nephrosis was observed in male and female rats exposed to \n≥38 mg/kg/day and female mice exposed to ≥75 mg/kg/day via gavage for 13 weeks (Abdo et al. 1984; \nVelsicol 1981a, 1981b). These lesions were located in the terminal sections of the proximal tubules of the \nrenal cortex and were characterized by mild dilation of the tubules and karyomegaly, cytomegaly, and \nanisokaryosis accompanied by cytoplasmic and nuclear vacuolization.  Additionally, brown granular \npigment debris protruded into the lumen.  In male mice, tubular necrosis was present in 70% of the male \nmice receiving the 300 mg/kg/day dose but not at lower doses; this lesion was morphologically distinct \nfrom the toxic nephrosis seen in the other animals and may have contributed to the early deaths observed \nat this dose level.  No renal histopathological effects were identified in male and female rats at\n≤19 mg/kg/day, female mice at ≤38 mg/kg/day, or male mice at ≤150 mg/kg/day (Abdo et al. 1984; \nVelsicol 1981a, 1981b).\n\nRabbits exposed to single dermal doses of 401–5,719 mg/kg displayed degeneration and necrosis of the \nkidney tubules; incidence data were not provided (Treon et al. 1955). The study authors stated that renal \neffects were still apparent 21 days after dosing in surviving animals.\n\n---\n\n2.  HEALTH EFFECTS\n\n###### 2.11 DERMAL\n\nHuman and animal data indicate HCCPD causes skin irritation following direct dermal contact with \nHCCPD liquid or vapor.\n\nAn unspecified percentage of 145 workers exposed to HCCPD vapors for 3–15 days at a WWTP as a \nresult of an inadvertent industrial release reported skin irritation, with five employees verified to exhibit\nvisible signs of skin irritation (Morse et al. 1979).  In a subsequent publication, 21% of 177 employees \nwith usable medical questionnaire responses reported skin irritation following HCCPD release and prior \nto plant closure; 10% of the 177 employees reported experiencing skin irritation approximately 6 weeks \nlater (Kominsky et al. 1980).\n\nIn acute-duration dermal toxicity studies, topical application of HCCPD in either its pure form or in \nsolution appears to have a pronounced effect upon the epidermis of experimental animals.  Generally, \nHCCPD initially causes edema that progressed to hardening or encrustation at the application site \n(Gardner 1986b; OxyChem 1972; Treon et al. 1955).  In a series of studies, severe irritation and skin \nnecrosis were observed in a monkey administered 0.05 mL of a 10% (v/v) solution for 3 days; necrotic, \nhardened, encrusted, and discolored skin was identified following application of Ultrasene solutions \ncontaining ≥40% HCCPD to guinea pigs; and subcutaneous edema and local discoloration that progressed \nto encrustation and fissuring were observed after a dermal dose of ≥430 mg/kg was applied to rabbit skin; \nincidence data were not provided (Treon et al. 1955).  The lesions generally healed with time in the \nsurviving animals.  Thirteen months after exposure, the monkey’s treated skin was scarred and hairless.  \nNo evidence of dermal effects was identified in a monkey administered 0.01 mL of Ultrasene solutions \ncontaining up to 10% HCCPD, but application of 0.05 mL of solutions containing ≥20% HCCPD caused \nthe skin to become discolored and swell.  No evidence of skin irritation was observed in guinea pigs after \ndermal doses of 0.05 mL of Ultrasene solutions containing ≤1% HCCPD (Treon et al. 1955).  Eschar \nformation was noted after dermal application of 200 mg/kg HCCPD to rabbits (OxyChem 1992).  Results \nof standard dermal irritation tests indicated that 0.5 mL HCCPD produced slight to severe edema and \nnecrosis at the application sites (OxyChem 1972, 1992).\n\nThe potential effects of systemic HCCPD exposure on skin histopathology of laboratory animals were \nevaluated in intermediate- and chronic-duration inhalation studies and intermediate-duration oral studies.  \nNo histopathological changes were identified in the skin (specific location not identified) of male or \nfemale rats exposed to concentrations ≤0.56 ppm for 30 weeks (Clark 1981) or in male or female rats and mice exposed to concentrations ≤0.2 ppm for 2 years (NTP 1994).  Additionally, no histopathological \nchanges were identified in skin (specific location not identified) of rats and mice at gavage doses up to \n150 or 300 mg/kg/day, respectively, for 13 weeks (Abdo et al. 1984; Velsicol 1981a, 1981b).\n\n###### 2.12 OCULAR\n\nHuman and animal data indicate that direct ocular contact with HCCPD vapor may produce ocular \nirritation at sufficiently high concentrations.\n\nEye irritation was one of the major symptoms reported by sewage treatment plant workers exposed to \nHCCPD vapors for 3–15 days at a WWTP because of an inadvertent industrial release (Kominsky et al. \n1980; Morse et al. 1979).  From the 145 individuals who responded to a questionnaire immediately after \nexposure occurred, 85 (59%) complained of eye irritation (Morse et al. 1979).  In a follow-up \nquestionnaire 6 weeks later, 9% of 177 respondents were still experiencing ocular irritation (Kominsky et \nal. 1980; Morse et al. 1979).  Tearing and redness of the eyes were present in five individuals on the day \nof exposure.\n\nEye irritation, as evidenced by lacrimation, was also observed in animals exposed to HCCPD vapors for \nup to 7 hours (Jackson and Hardy 1986, 1987; OxyChem 1972; Rand et al. 1982a; Treon et al. 1955).  \nPartially or completely closed eyes were identified in rats exposed to ≥1.67 ppm for 1 hour (Jackson and \nHardy 1986) and ≥1.68 ppm for 4 hours (Jackson and Hardy 1987).  Direct ocular exposure to HCCPD\nvapors most likely contributed to these effects.  Irritation of the eyes or eyelids was observed for rats, \nmice, guinea pigs, and rabbits following single exposures to HCCPD concentrations as low as 1.0 ppm \nand multiple exposures to concentrations as low as 0.33 ppm for up to 6 weeks; ocular irritation was not \nobserved in any species exposed to 0.15 ppm for up to 30 weeks (Treon et al. 1955).  Lacrimation was \nevident in rats exposed to 5.8 ppm HCCPD for 4 hours and dark red eyes were observed in rats exposed \nto 0.5 ppm for 5–10 days and ≥0.05 ppm for 14 weeks (Alexander et al. 1980a, 1980b; Rand et al. 1982a).  \nNo clinical signs of eye irritation were noted in monkeys exposed to HCCPD vapor at concentrations up \nto 0.2 ppm for 14 weeks (Alexander et al. 1980b; Rand et al. 1982a).  No ophthalmological or\nhistopathological changes were identified in the ocular tissues of rats or monkeys exposed to \nconcentrations up to 0.2 ppm for 14 weeks (Alexander et al. 1980b; Rand et al. 1982a).  HCCPD \nexposure did not cause histopathological changes in the eyes of rats exposed to concentrations up to \n0.56 ppm for 30 weeks (Clark 1981).\n\n---\n\nSevere eye irritation was produced when 0.1 mL of HCCPD was placed in the conjunctival eye sac for \n5 minutes and then rinsed with water (OxyChem 1972).  Corrosion of the ocular tissues occurred when \nthe material was left in place for 24 hours prior to rinsing (OxyChem 1972).\n\n###### 2.13 ENDOCRINE\n\n2.13  ENDOCRINE\n\nNo reports of changes in human endocrine parameters or organs after exposure to HCCPD were found. \nBased on available data in laboratory animals, HCCPD does not produce histopathological changes to \nendocrine organs.  Insufficient data are available to assess the potential effects of HCCPD exposure on \nendocrine function, including endocrine hormone levels.\n\nPotential histopathological and organ weight effects in endocrine organs have been evaluated in \nlaboratory animals following acute-, intermediate-, and chronic-duration inhalation exposure to HCCPD.  \nDegenerative changes in the adrenal glands of rats, mice, guinea pigs, and rabbits were observed after \nexposures to concentrations of 0.34–73.6 ppm for periods of 15 minutes to 1 week, 0.34 ppm for 6 weeks, \nand 0.15 ppm for 30 weeks; incidence data were not provided (Treon et al. 1955).  Due to the high \nmortality observed at these concentrations, these changes may have been the result of tissue autolysis in \nmoribund or dying animals.  Effects on the adrenal, thyroid, parathyroid, pancreas, and pituitary glands \nfollowing inhalation exposure of male mice to 0.039–0.389 ppm HCCPD for 13 weeks were limited to \nincreased relative adrenal weights; no histopathological changes were noted in these organs in treated \nmale mice and no effects on adrenal, thyroid, parathyroid, pancreas, or pituitary gland weights or\nhistopathology were observed in female mice exposed to ≤0.389 and male and female rats exposed to \n≤0.385 ppm for 13 weeks (NTP 1994).  The biological significance of these adrenal weight changes\ncannot be assessed quantitatively in the absence of hormone product measurements or concurrent \nhistopathological findings.  There were no organ weight or histopathological changes in the adrenal \nglands, pancreas, thyroid, parathyroid gland, and/or pituitary gland identified in male and female rats and \nmonkeys exposed for 14 weeks at ≤0.2 ppm (Alexander et al. 1980b; Rand et al. 1982a), in male and \nfemale rats after 30-week exposures to ≤0.56 ppm (Clark 1981), or in rats and mice following 2-year \nexposures to ≤0.2 ppm (NTP 1994).  Additionally, no effects on the adrenal glands were identified in \nmale mice exposed to 0.5 ppm for 26–42 weeks (NTP 1994).\n\n$$\n\\leq0.385ppm\n$$\n\nPotential effects of HCCPD on endocrine organ weight and histology have also been evaluated in \nlaboratory animals following acute- and intermediate-duration oral exposures and acute-duration dermal \nexposures.  Degenerative changes in the adrenal tissues resulted from exposure to single oral doses of\n\n---\n\n280–2,100 mg/kg in rats and 620–940 mg/kg in rabbits; these changes may have resulted from tissue \nautolysis in moribund or dying animals, but no incidence data were reported (Treon et al. 1955).  There \nwere no histopathological changes in the adrenals, thyroid, parathyroid, or pituitary glands in 13-week \nstudies at gavage doses up to 150 mg/kg/day in rats and 300 mg/kg/day in mice (Abdo et al. 1984; \nVelsicol 1981a, 1981b).  Rabbits that were dermally exposed to HCCPD (430–6,130 mg/kg) had \ndegenerative changes of the adrenal glands that were still apparent in survivors 21 days after exposure; \nincidence data were not provided (Treon et al. 1955).\n\nNo data were identified evaluating endocrine function following *in vivo* exposure to HCCPD; however, \nlimited *in vitro* screening data are available.  HCCPD exhibited statistically significant radioactive iodide \nuptake inhibition in a ToxCast high-throughput screening assay (Wang et al. 2019).  Iodide uptake is the \nfirst step in thyroid hormone biosynthesis.\n\n###### 2.14 IMMUNOLOGICAL\n\n2.14  IMMUNOLOGICAL\n\nNo studies were located regarding immunological effects in humans after exposure to HCCPD. Based on \navailable data in laboratory animals, HCCPD does not cause histopathological alterations to \nimmunological organs.  However, no studies evaluating immune function following exposure to HCCPD \nwere identified.\n\nPotential effects of HCCPD on immune organ weight and histology have also been evaluated in acute-, \nintermediate-, and chronic-duration inhalation exposure studies and intermediate-duration oral exposure \nstudies in laboratory animals.  No exposure-related changes were identified in these studies.  There were \nno histopathological changes in the spleen of rats exposed to ≤0.5 ppm for 1–2 weeks (Alexander et al. \n1980a; Rand et al. 1982a).  In intermediate-duration studies, no histopathological changes were identified \nin immune organs (spleen, thymus, and/or lymph nodes) of monkeys, rats, or mice to concentrations up to \n0.2, 0.56, or 0.5 ppm, respectively (Alexander et al. 1980b; Clark 1981; NTP 1994; Rand et al. 1982a).  \nSimilarly, no histopathological effects were observed in immune organs of rats or mice exposed to \n≤0.2 ppm for 2 years (NTP 1994).  In a 13-week oral study, no treatment-related histopathological \nfindings were identified in the mandibular and mesenteric lymph nodes, thymus, or spleen at gavage \ndoses up to 150 mg/kg/day in rats or 300 mg/kg/day in mice (Abdo et al. 1984; Velsicol 1981a, 1981b).\n\n---\n\n2.  HEALTH EFFECTS\n\n###### 2.15 NEUROLOGICAL\n\n2.15  NEUROLOGICAL\n\nBased on available data, HCCPD does not cause histopathological alterations in the nervous system.  \nEvaluation of neurological function is limited to clinical signs of toxicity; therefore, insufficient data are \navailable to assess the potential effect of HCCPD exposure on neurological function, including behavior.\n\nAmong sewage treatment plant workers exposed to HCCPD at a WWTP because of an inadvertent \nindustrial release, headaches were self-reported by 65 of 145 workers (45%) after exposure for 3–15 days \n(Morse et al. 1979).  Six weeks later, 32 of 177 workers (18%) responding to a questionnaire were still \nexperiencing headaches (Kominsky et al. 1980). No studies were located regarding neurological effects \nin humans after oral or dermal exposure to HCCPD.\n\nNeurological clinical signs of toxicity and nervous system histopathology were evaluated in acute-, \nintermediate-, and chronic-duration inhalation exposure studies.  Rats and mice exposed to concentrations \nof 0.385–2.142 ppm HCCPD were described as listless after 1–3 weeks of exposure (NTP 1994).  \nIncidence data for clinical signs were not provided, so it is unclear how many animals exhibited this effect \nor how frequently; however, the study authors did note that listlessness was observed earlier during the \nexposure period with higher HCCPD concentrations.  Some rats, mice, guinea pigs, and rabbits exposed \nto high lethal concentrations of HCCPD (≥46.5 ppm) by acute-duration inhalation experienced tremors; \nincidence data were not provided (Treon et al. 1955).  At necropsy, diffuse degenerative changes in the \nbrain were observed in all rats, mice, guinea pigs, and rabbits after exposures to 0.34–73.6 ppm for \nperiods of 15 minutes to 1 week, 0.34 ppm for 6 weeks, and 0.15 ppm for 30 weeks; incidence data were \nnot provided (Treon et al. 1955).  These degenerative changes may have been the result of tissue \nautolysis.  In contrast, there were no histopathological changes in the brains of rats exposed to 0.5 ppm \nfor 1–2 weeks (Alexander et al. 1980a; Rand et al. 1982a), male mice exposed to 0.2 ppm for 33 weeks \n(NTP 1994), or rats and mice exposed to ≤0.389 ppm for 13 weeks or ≤0.2 ppm for 2 years (NTP 1994).  \nSimilarly, no histopathological changes were observed in the brains or sciatic nerve of rats or monkeys \nexposed to ≤0.2 ppm for 14 weeks (Alexander et al. 1980b; Rand et al. 1982a) or in brain, spinal cord, or \nsciatic or posterior tibial nerves of rats exposed to ≤0.56 ppm for 30 weeks (Clark 1981).\n\nThe potential neurotoxicity of HCCPD has been evaluated in acute- and intermediate-duration oral \nexposure studies.  Clinical signs of neurotoxicity were observed following acute-duration gavage \nexposure in mice, including hypoactivity at 464 mg/kg and ataxia at 1,000 mg/kg, a dose associated with \nlethality (Dean 1977).  Similarly, all rats exposed once to ≥1,260 mg/kg via gavage exhibited abnormal gait (high stepping, waddling) and lethargy (Gardner 1986a).  Single oral doses ≥180 mg/kg caused \nlethargy in rats and rabbits in the period “immediately after exposure” (Treon et al. 1955).  During \npostmortem examination of tissues, degenerative lesions of the brain were observed in the rats and rabbits \nthat succumbed to exposure and in the rats that survived to the scheduled sacrifice; incidence data were \nnot provided.  No histopathological lesions of the brain, sciatic nerve, or spinal cord were noted in rats or \nmice exposed to gavage doses up to 150 or 300 mg/kg/day, respectively, for 13 weeks (Abdo et al. 1984; \nVelsicol 1981a, 1981b). These data suggest that brain lesions occur only with exposures to high oral \ndoses of HCCPD.\n\nRabbits exposed to single dermal doses of HCCPD (430–6,130 mg/kg) displayed degenerative changes in \nthe brain at necropsy; incidence data were not provided (Treon et al. 1955).  These changes were still \napparent 21 days after exposure in surviving animals.  Ataxia, hypoactivity, and a depressed breathing \npattern have been observed in rabbits at lethal dermal doses of HCCPD (OxyChem 1972).\n\n###### 2.16 REPRODUCTIVE\n\n2.16  REPRODUCTIVE\n\nNo studies were located regarding reproductive effects in humans after exposure to HCCPD.  The \navailable animal data do not indicate that HCCPD causes histopathological alterations to reproductive \norgans.  However, insufficient data are available to thoroughly assess the potential for toxicity to the \nreproductive system, as no studies evaluating reproductive function following inhalation, oral, or dermal \nexposure to HCCPD were identified.\n\nThe potential effects of HCCPD on reproductive organ weight and histology have been evaluated in \nexperimental animals exposed by inhalation for intermediate and chronic durations.  The sole effect on \nreproductive organs identified with HCCPD treatment is an increased incidence of ovarian suppurative \ninflammation in female mice exposed to HCCPD at 0.05–0.2 ppm for 2 years; no histopathological \nchanges were identified in the uterus (NTP 1994).  While this lesion is clearly adverse, as it was the \nsuspected cause of increased mortality at 0.2 ppm, the causal relationship between HCCPD exposure and \nlesion development is unclear.  The study authors noted that lesions were similar to those observed in \nother NTP studies attributed to stress-related susceptibility to utero-ovarian infection by *Klebsiella* \nspecies (NTP 1994).  In contrast, no treatment-related histopathological lesions of the female (ovaries and \nuterus) or male (testes, prostate, and/or seminal vesicle) reproductive organs were identified in monkeys, \nrats, or mice exposed to concentrations up to 0.2, 0.385, or 0.389 ppm for 13–14 weeks (Alexander et al. \n1980b; NTP 1994; Rand et al. 1982a); male mice exposed to 0.2 ppm for 33 weeks or 0.5 ppm for\n\n---\n\n42 weeks (NTP 1994); rats exposed to ≤0.56 ppm for 30 weeks (Clark 1981); or rats or male mice \nexposed to ≤0.2 ppm for 2 years (NTP 1994).\n\n$$\n\\leqq0.56\n$$\n\nThe potential effects of HCCPD on reproductive organ weight and histology have also been evaluated in \nlaboratory animals following intermediate-duration oral exposure.  HCCPD did not cause treatmentrelated effects on the testes, seminal vesicles, prostate, ovaries, or uterus in rats or mice exposed to doses \nup to 150 or 300 mg/kg/day, respectively, via gavage for 13 weeks (Abdo et al. 1984; Velsicol 1981a, \n1981b).\n\nNo data were identified evaluating reproductive function following inhalation, oral, or dermal exposure to \nHCCPD; however, limited screening data are available.  Although it exhibited some estrogen receptor \nbinding affinity in a recombinant human estrogen receptor α (hERα) binding assay, HCCPD did not \nexhibit estrogenic or anti-estrogenic activity in an immature uterotrophic assay in female rats following \nsubcutaneous injection (Akahori et al. 2008).  No anti-androgenic activity was detected for HCCPD in \nChinese hamster ovary (CHO) cells transfected with human androgen receptor (hAR) in an androgenresponsive luciferase reporter assay (Roy et al. 2004).\n\n###### 2.17 DEVELOPMENTAL\n\n2.17  DEVELOPMENTAL\n\nNo studies were located regarding developmental effects in humans after exposure to HCCPD.  Animal \ndata are available only via the oral route and are too limited to assess whether or not the developing \norganism is a target of HCCPD toxicity at doses below those associated with maternal toxicity.\n\nHCCPD was not embryotoxic, fetotoxic, or teratogenic in mice following maternal exposure to gavage \ndoses up to 75 mg/kg/day during GDs 6–15 (Murray et al. 1980).  In rabbits, a dose-dependent increase in \nthe incidence of 13 ribs was identified in the offspring of does exposed to 75 mg/kg/day via gavage \nduring GDs 6–18; nonstatistically significant increases were also identified at 5 and 25 mg/kg/day.  No \nother evidence of embryotoxicity, fetotoxicity, or teratogenicity was identified in rabbits (Murray et al. \n1980).  The natural variation in the number of ribs for rabbits is 12–13.  It should be noted that the \ncompound was not maternally toxic in mice, but maternal mortalities and weight loss were observed in \nrabbits at 75 mg/kg/day (numbers affected and magnitude of effect not specified).\n\nA screening study was performed to evaluate prenatal and postnatal development of mice exposed to \nHCCPD during gestation.  Mice born to dams administered 45 mg/kg/day HCCPD via gavage during\n\n---\n\nGDs 8–12 did not exhibit evidence of developmental toxicity when evaluated on postnatal days (PNDs) 1 \nand 3 (Chernoff and Kavlock 1982, 1983).  When the offspring were evaluated over a 250-day postnatal \nperiod (including through puberty and breeding), there were no adverse effects on postnatal viability, \ngrowth, locomotor activity, sexual development (percent vaginal patency at day 30), or reproductive \nfunction (Gray and Kavlock 1984; Gray et al. 1986).\n\n###### 2.18 OTHER NONCANCER\n\n2.18  OTHER NONCANCER\n\nNo studies were located regarding other noncancer effects in humans after exposure to HCCPD.\n\nOther noncancer effects of HCCPD identified in experimental animals are limited to food and water \nintake.  During the first few days of the post-exposure observation periods, decreased food and water \nintake were observed in rats exposed for 1 hour to ≥1.67 ppm (Jackson and Hardy 1986) and rats exposed \nfor 4 hours to ≥1.68 ppm (Jackson and Hardy 1987); these concentrations were associated with overt \nsigns of toxicity during exposure (e.g., abnormal respiratory pattern).  After a 1–2-week exposure to \nHCCPD, male and female rats exposed to 0.5 ppm had decreased food and water intake (Alexander et al. \n1980a; Rand et al. 1982a).  All males exposed to 0.5 ppm died or were sacrificed in moribund condition \nby the end of the exposure period.  Minor decreases in food intake were also observed for male rats \nexposed to 0.11 ppm without meaningful changes to body weight; the biological significance of this \nfinding is uncertain.  Food intake was not affected in rats or monkeys and water intake was not affected in \nrats exposed to ≤0.2 ppm for 14 weeks (Alexander et al. 1980b; Rand et al. 1982a).  In a 30-week study, \nno treatment-related deficits were identified for male or female rats regarding food or water intake\nfollowing exposure to ≤0.56 ppm (Clark 1981). No treatment-related effects were observed for food and \nwater intake of pregnant mice administered gavage doses of HCCPD at ≤75 mg/kg/day on GDs 6–15 \n(Murray et al. 1980).  Where deficits in food and/or water intake were observed after exposure to \nHCCPD, these effects were likely the result of nonspecific toxicity following exposures to high \nconcentrations of an irritating/corrosive chemical.\n\n$$\n\\mathrm{to}\\geq1.67\\mathrm{ppm}\n$$\n\n$$\nt0\\geq1.68\n$$\n\n$$\nt o\\leqq0.2\n$$\n\n$$\n0.56ppm\n$$\n\n###### 2.19 CANCER\n\nNo studies were located regarding cancer in humans following exposure to HCCPD.\n\nThe carcinogenicity of HCCPD has been evaluated in 2-year rodent bioassays in which male and female \nrats and mice were exposed to concentrations up to 0.2 ppm for 104 weeks (NTP 1994).  There were no statistically significant increases in tumor incidence in rats or mice.  There was a slight increase in the \nincidence of adenomas of the pituitary pars distalis in male rats at 0.2 ppm and in thyroid follicle cell \nadenomas in female mice at 0.05 ppm, but, since the incidences were similar to the historical control \nmeans, were within the historical control range, or did not exhibit a dose-dependency, NTP (1994) did not \nconsider these tumors to be related to HCCPD exposure.  In male mice exposed to 0.5 ppm for 26 or \n42 weeks, then evaluated at 105 weeks, the incidence of alveolar/bronchiolar carcinomas was \nsignificantly increased but was within the historical range for the laboratory (NTP 1994).  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Oct. 4, 2026, 12:20 a.m.: effective_date, abstract, document_body, attachments changed since Oct. 3, 2026, 8:03 p.m..

{'abstract': None, 'attachments': None, 'document_body': None, 'effective_date': None}

{'abstract': '', 'attachments': [{'url': 'https://downloads.regulations.gov/ATSDR-2026-0133-0003/attachment_1.pdf', 'title': 'Draft Tox Profile for Hexachlorocyclopentadiene'}, {'url': 'https://downloads.regulations.gov/ATSDR-2026-0133-0003/content.pdf', 'title': 'pdf'}], 'document_body': '', 'effective_date': ''}

Collection history starts with our observations; it is not complete legislative amendment history.

Oct. 5, 2026, 9:21 a.m.: attachments changed since Oct. 4, 2026, 12:40 a.m..

{'attachments': [{'url': 'https://downloads.regulations.gov/ATSDR-2026-0133-0002/attachment_1.pdf', 'body': {'text': '## Toxicological Profile for Cadmium\nDraft for Public Comment\nOctober 2026\n\nATSDR\nU.S. Department of Health and Human Services\nAgency for Toxic Substances and Disease Registry\n\nCS274127-A\n\n---\n\n## DISCLAIMER\n\nUse of trade names is for identification only and does not imply endorsement by the Agency for Toxic \nSubstances and Disease Registry, the Public Health Service, or the U.S. Department of Health and Human \nServices.\n\nThis information is distributed solely for the purpose of pre-dissemination for public comment under \napplicable information quality guidelines.  It has not been formally disseminated by the Agency for Toxic \nSubstances and Disease Registry.  It does not represent and should not be construed to represent any \nagency determination or policy.\n\n---\n\n## FOREWORD\n\nThis toxicological profile is prepared in accordance with guidelines developed by the Agency for Toxic \nSubstances and Disease Registry (ATSDR) and the Environmental Protection Agency (EPA).  The \noriginal guidelines were published in the *Federal Register* on April 17, 1987.  Each profile will be revised \nand republished as necessary.\n\nThe ATSDR toxicological profile succinctly characterizes the toxicologic and adverse health effects \ninformation for these toxic substances described therein.  Each peer-reviewed profile identifies and \nreviews the key literature that describes a substance\'s toxicologic properties.  Other pertinent literature is \nalso presented but is described in less detail than the key studies.  The profile is not intended to be an \nexhaustive document; however, more comprehensive sources of specialty information are referenced.\n\nThe focus of the profiles is on health and toxicologic information; therefore, each toxicological profile \nbegins with a relevance to public health discussion which would allow a public health professional to \nmake a real-time determination of whether the presence of a particular substance in the environment \nposes a potential threat to human health.  The adequacy of information to determine a substance\'s health \neffects is described in a health effects summary.  Data needs that are of significance to the protection of \npublic health are identified by ATSDR.\n\nEach profile includes the following:\n\n(A) The examination, summary, and interpretation of available toxicologic information and \nepidemiologic evaluations on a toxic substance to ascertain the levels of significant \nhuman exposure for the substance due to associated acute-, intermediate-, and chronicduration exposures;\n\n(B) A determination of whether adequate information on the health effects of each substance \nis available or in the process of development to determine the levels of exposure that \npresent a significant risk to human health due to acute-, intermediate-, and chronicduration exposures; and\n\n(C) Where appropriate, identification of toxicologic testing needed to identify the types or \nlevels of exposure that may present significant risk of adverse health effects in humans.\n\nThe principal audiences for the toxicological profiles are health professionals at the Federal, State, and \nlocal levels; interested private sector organizations and groups; and members of the public.  ATSDR plans \nto revise these documents in response to public comments and as additional data become available.  \nTherefore, we encourage comments that will make the toxicological profile series of the greatest use.\n\nElectronic comments may be submitted via: www.regulations.gov. Follow the on-line instructions for \nsubmitting comments.\n\nWritten comments may also be sent to:\n\nWritten comments may also be sent to:  Agency for Toxic Substances and Disease Registry\n\nOffice of Innovation and Analytics\n\nToxicology Section\n\n1600 Clifton Road, N.E.\n\nMail Stop S106-5\n\nAtlanta, Georgia 30329-4027\n\n---\n\nThe toxicological profiles are developed under the Comprehensive Environmental Response, \nCompensation, and Liability Act of 1980, as amended (CERCLA or Superfund).  CERCLA \nSection 104(i)(1) directs the Administrator of ATSDR to “…effectuate and implement the health-related \nauthorities” of the statute.  This includes the preparation of toxicological profiles for hazardous \nsubstances most commonly found at facilities on the CERCLA National Priorities List (NPL) and that \npose the most significant potential threat to human health, as determined by ATSDR and the EPA.  \nSection 104(i)(3) of CERCLA, as amended, directs the Administrator of ATSDR to prepare a \ntoxicological profile for each substance on the list.  In addition, ATSDR has the authority to prepare \ntoxicological profiles for substances not found at sites on the NPL, in an effort to “…establish and \nmaintain inventory of literature, research, and studies on the health effects of toxic substances” under \nCERCLA Section 104(i)(1)(B), to respond to requests for consultation under Section 104(i)(4), and as \notherwise necessary to support the site-specific response actions conducted by ATSDR.\n\nThis profile reflects ATSDR’s assessment of all relevant toxicologic testing and information that has been \npeer-reviewed.  Staffs of the Centers for Disease Control and Prevention and other Federal scientists have \nalso reviewed the profile.  In addition, this profile has been peer-reviewed by a nongovernmental panel \nand is being made available for public review.  Final responsibility for the contents and views expressed \nin this toxicological profile resides with ATSDR.\n\nChristopher M. Reh, Ph.D. \nAssociate Director,\nAgency for Toxic Substances and Disease Registry \nCenters for Disease Control and Prevention\n\n---\n\n**VERSION HISTORY**\n\n| Date | Description |\n| --- | --- |\n| October 2026 | Draft for public comment toxicological profile released |\n| September 2012 | Final toxicological profile released |\n| July 1999 | Final toxicological profile released |\n| April 1993 | Final toxicological profile released |\n| March 1989 | Final toxicological profile released |\n\n---\n\n# CONTRIBUTORS & REVIEWERS\n\n# CHEMICAL MANAGER TEAM\n\nBrittany Szafran, D.V.M, Ph.D., D.A.B.T. (lead)\nCustodio Muianga, M.P.H., Ph.D., C.H.M.M.\nMohammad Shoeb, Ph.D.\nBreanna Alman, M.P.H.\nFranco Scinicariello, M.D., M.P.H.\n\nKimberly Zaccaria, Ph.D., D.A.B.T.\nFrances Belmonte, Ph.D., D.A.B.T.\nHeather Carlson-Lynch, M.S., D.A.B.T.\nMario Citra, Ph.D.\nGary L. Diamond, Ph.D.\nZach Guerrette, Ph.D., D.A.B.T\nDeborah M. Herber, Ph.D.\nClaire Heit, Ph.D.\nLisa Ingerman, Ph.D., D.A.B.T.\nConnor McGuire, Ph.D.\nJennifer Rhoades, B.S.\n\nATSDR, Office of Innovation and Analytics, \nToxicology Section, Atlanta, GA\n\nSRC, Inc., North Syracuse, NY\n\n## REVIEWERS\n\n## Interagency Minimal Risk Level Workgroup:\n\nIncludes ATSDR; National Center for Environmental Health (NCEH); U.S. Environmental Protection \nAgency (EPA); National Toxicology Program (NTP).\n\n## Additional reviews for science and/or policy:\n\nATSDR, Office of Community Health Hazard Assessment; ATSDR, Office of Capacity Development \nand Applied Prevention Science; ATSDR, Office of Science; NCEH, Division of Laboratory Sciences; \nNCEH, Division of Environmental Health Science and Practice; National Institute for Occupational \nSafety and Health (NIOSH); EPA, Office of Research and Development; EPA, Office of Water.\n\n## PEER REVIEWERS\n\n1. Kristen Upson, Ph.D., M.P.H.; Associate Professor of Epidemiology and Biostatistics; Michigan \nState University; Department of Epidemiology and Biostatistics; 909 Wilson Road Room B601; \nEast Lansing, MI\n\n2. Zahir Shaikh, Ph.D.; Professor Emeritus and Former Founding Director of RI-INBRE; The \nUniversity of Rhode Island, College of Pharmacy; Kingston, RI\n\n3. Curtis D. Klaassen, M.S., Ph.D., FATS, FAASLD, FASPET; Director of the Mid-America \nToxicology Course; Previously University Distinguished Professor and Chair at The University \nof Kansas School of Medicine; Kansas City, KS (retired)\n\nThese experts collectively have knowledge of toxicology, chemistry, and/or health effects.  All reviewers \nwere selected in conformity with Section 104(I)(13) of the Comprehensive Environmental Response, \nCompensation, and Liability Act, as amended.\n\n---\n\nATSDR scientists review peer reviewers’ comments and determine whether changes will be made to the \nprofile based on comments.  The peer reviewers’ comments and responses to these comments are part of \nthe administrative record for this compound.\n\nThe listing of peer reviewers should not be understood to imply their approval of the profile\'s final \ncontent.  The responsibility for the content of this profile lies with ATSDR.\n\n---\n\n## CONTENTS\n\nDISCLAIMER .............................................................................................................................................. ii\nFOREWORD ............................................................................................................................................... iii\nVERSION HISTORY ................................................................................................................................... v\nCONTRIBUTORS & REVIEWERS ........................................................................................................... vi\nCONTENTS ............................................................................................................................................... viii\nLIST OF FIGURES ...................................................................................................................................... x\nLIST OF TABLES ....................................................................................................................................... xi\nCHAPTER 1. RELEVANCE TO PUBLIC HEALTH ................................................................................. 1\n1.1 OVERVIEW AND U.S. EXPOSURES ......................................................................................... 1\n1.2 SUMMARY OF HEALTH EFFECTS........................................................................................... 2\n1.3 MINIMAL RISK LEVELS (MRLs) .............................................................................................. 8\nCHAPTER 2. HEALTH EFFECTS ............................................................................................................ 12\n2.1 INTRODUCTION ........................................................................................................................ 12\n2.2 DEATH ........................................................................................................................................ 92\n2.3 BODY WEIGHT .......................................................................................................................... 99\n2.4 RESPIRATORY ........................................................................................................................ 104\n2.5 CARDIOVASCULAR ............................................................................................................... 113\n2.6 GASTROINTESTINAL ............................................................................................................. 124\n2.7 HEMATOLOGICAL ................................................................................................................. 125\n2.8 MUSCULOSKELETAL ............................................................................................................ 131\n2.9 HEPATIC ................................................................................................................................... 143\n2.10 RENAL ...................................................................................................................................... 151\n2.11 DERMAL ................................................................................................................................... 171\n2.12 OCULAR ................................................................................................................................... 172\n2.13 ENDOCRINE ............................................................................................................................. 172\n2.14 IMMUNOLOGICAL ................................................................................................................. 182\n2.15 NEUROLOGICAL..................................................................................................................... 189\n2.16 REPRODUCTIVE ..................................................................................................................... 196\n2.17 DEVELOPMENTAL ................................................................................................................. 213\n2.18 OTHER NONCANCER ............................................................................................................. 239\n2.19 CANCER .................................................................................................................................... 241\n2.20 GENOTOXICITY ...................................................................................................................... 256\n2.21 MECHANISMS OF ACTION ................................................................................................... 266\nCHAPTER 3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, \nCHEMICAL INTERACTIONS ......................................................................................... 269\n3.1 TOXICOKINETICS................................................................................................................... 269\n3.1.1 Absorption ........................................................................................................................... 269\n3.1.2 Distribution ......................................................................................................................... 274\n3.1.3 Metabolism .......................................................................................................................... 277\n3.1.4 Excretion ............................................................................................................................. 278\n3.1.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models ........... 278\n3.1.6 Animal-to-Human Extrapolations ....................................................................................... 285\n3.2 CHILDREN AND OTHER POPULATIONS THAT ARE UNUSUALLY \nSUSCEPTIBLE .......................................................................................................................... 286\n\n---\n\n3.3 BIOMARKERS OF EXPOSURE AND EFFECT ..................................................................... 290\n3.3.1 Biomarkers of Exposure ...................................................................................................... 291\n3.3.2 Biomarkers of Effect ........................................................................................................... 294\n3.4 INTERACTIONS WITH OTHER CHEMICALS ..................................................................... 297\nCHAPTER 4. CHEMICAL AND PHYSICAL INFORMATION ........................................................... 303\n4.1 CHEMICAL IDENTITY ........................................................................................................... 303\n4.2 PHYSICAL AND CHEMICAL PROPERTIES ........................................................................ 304\nCHAPTER 5. POTENTIAL FOR HUMAN EXPOSURE ....................................................................... 307\n5.1 OVERVIEW .............................................................................................................................. 307\n5.2 PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL ................................................ 310\n5.2.1 Production ........................................................................................................................... 310\n5.2.2 Import/Export ...................................................................................................................... 313\n5.2.3 Use ...................................................................................................................................... 314\n5.2.4 Disposal ............................................................................................................................... 314\n5.3 RELEASES TO THE ENVIRONMENT ................................................................................... 315\n5.3.1 Air ....................................................................................................................................... 315\n5.3.2 Water ................................................................................................................................... 319\n5.3.3 Soil ...................................................................................................................................... 320\n5.4 ENVIRONMENTAL FATE ...................................................................................................... 321\n5.4.1 Transport and Partitioning ................................................................................................... 321\n5.4.2 Transformation and Degradation ........................................................................................ 325\n5.5 LEVELS IN THE ENVIRONMENT ......................................................................................... 326\n5.5.1 Air ....................................................................................................................................... 327\n5.5.2 Water ................................................................................................................................... 328\n5.5.3 Sediment and Soil ............................................................................................................... 330\n5.5.4 Other Media ........................................................................................................................ 332\n5.6 GENERAL POPULATION EXPOSURE.................................................................................. 335\n5.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES .............................................. 362\nCHAPTER 6. ADEQUACY OF THE DATABASE ................................................................................ 363\n6.1 EXISTING INFORMATION ON HEALTH EFFECTS ........................................................... 363\n6.2 IDENTIFICATION OF DATA NEEDS .................................................................................... 365\n6.3 ONGOING STUDIES ................................................................................................................ 372\nCHAPTER 7. REGULATIONS AND GUIDELINES ............................................................................. 376\nCHAPTER 8. REFERENCES .................................................................................................................. 380\nAPPENDICES\nAPPENDIX A.  ATSDR MINIMAL RISK LEVEL WORKSHEETS .................................................... A-1 \nAPPENDIX B.  LITERATURE SEARCH FRAMEWORK FOR CADMIUM ...................................... B-1 \nAPPENDIX C.  FRAMEWORK FOR ATSDR’S SYSTEMATIC REVIEW OF HEALTH EFFECTS \nDATA FOR CADMIUM ................................................................................................ C-1 \nAPPENDIX D.  USER’S GUIDE ............................................................................................................. D-1 \nAPPENDIX E.  QUICK REFERENCE FOR HEALTH CARE PROVIDERS ....................................... E-1 \nAPPENDIX F.  GLOSSARY .................................................................................................................... F-1 \nAPPENDIX G.  ACRONYMS, ABBREVIATIONS, AND SYMBOLS................................................. G-1\n\n---\n\n## LIST OF FIGURES\n\n1-1.  Health Effects Found in Animals Following Inhalation Exposure to Cadmium .................................. 4\n1-2.  Health Effects Found in Animals Following Oral Exposure to Cadmium ........................................... 5\n1-3.  Summary of Sensitive Targets of Cadmium – Inhalation ..................................................................... 9\n1-4.  Summary of Sensitive Targets of Cadmium – Oral ............................................................................ 10\n2-1.  Overview of the Number of Studies Examining Cadmium Health Effects ........................................ 17\n2-2.  Levels of Significant Exposure to Cadmium – Inhalation .................................................................. 33\n2-3.  Levels of Significant Exposure to Cadmium – Oral ........................................................................... 72\n3-1.  Structure of Kjellström-Nordberg Cadmium Biokinetic Model ....................................................... 280\n3-2.  Structure of Diamond and Klotzbach Cadmium Biokinetics Model ................................................ 283\n5-1.  Number of NPL Sites with Cadmium Contamination ...................................................................... 307\n6-1.  Summary of Existing Health Effects Studies on Cadmium by Route and Endpoint ........................ 364\n\n---\n\n## LIST OF TABLES\n\n1-1.  Minimal Risk Levels (MRLs) for Cadmium ...................................................................................... 11\n2-1.  Levels of Significant Exposure to Cadmium – Inhalation .................................................................. 18\n2-2.  Levels of Significant Exposure to Cadmium – Oral ........................................................................... 41\n2-3.  Levels of Significant Exposure to Cadmium – Dermal ...................................................................... 90\n2-4.  Results of Meta-Analyses Evaluating Exposure to Cadmium and Mortality Endpoints .................... 93\n2-5.  Studies Included in Meta-Analyses Evaluating Exposure to Cadmium and Mortality \nEndpoints ............................................................................................................................................ 94\n2-6.  Results of General Population Studies Evaluating Urinary Cadmium Levels and All-Cause \nMortality ............................................................................................................................................. 94\n2-7.  Results of Meta-Analysis Evaluating Exposure to Cadmium and Respiratory Endpoints ............... 106\n2-8.  Results of Epidemiological Studies Evaluating Urinary Cadmium Levels and Respiratory \nEffects ............................................................................................................................................... 108\n2-9.  Results of Meta-Analyses Evaluating Exposure to Cadmium and Cardiovascular Endpoints ......... 113\n2-10.  Studies Included in Meta-Analyses Evaluating Exposure to Cadmium and Cardiovascular \nEndpoints ........................................................................................................................................ 116\n2-11.  Results of General Population Studies Evaluating Urinary Cadmium Levels and Blood \nPressure or Hypertension ................................................................................................................ 118\n2-12.  Results of General Population Studies Evaluating Urinary Cadmium Levels and \nCardiovascular Disease-Related Effects ......................................................................................... 122\n2-13.  Results of General Population Epidemiological Studies Evaluating Urinary Cadmium \nLevels and Hematological Effects .................................................................................................. 126\n2-14.  Results of Meta-Analyses Evaluating Exposure to Cadmium and Skeletal Endpoints .................. 132\n2-15.  Studies Included in Meta Analyses Evaluating Exposure to Cadmium and Skeletal \nEndpoints ........................................................................................................................................ 133\n2-16.  Results of General Population Epidemiological Studies Evaluating Urinary Cadmium \nLevels and Musculoskeletal Effects ............................................................................................... 136\n2-17.  Results of Meta-Analyses Evaluating Exposure to Cadmium and Serum Lipids .......................... 143\n2-18.  Studies Included in Meta-Analyses Evaluating Exposure to Cadmium and Serum Lipids ............ 144\n2-19.  Results of General Population Studies Evaluating Urinary Cadmium Levels and Blood \nLipid Levels .................................................................................................................................... 145\n\n---\n\n2-20.  Results of General Population Studies Evaluating Exposure to Urinary Cadmium Levels \nand Hepatic Disease and Clinical Chemistry ................................................................................. 147\n2-21.  Results of Occupational Studies Evaluating Urine Cadmium Levels and Renal Outcomes .......... 154\n2-22.  Results of Meta-Analyses Evaluating Exposure to Cadmium and Renal Endpoints ...................... 157\n2-23.  Studies Included in Meta-Analyses Evaluating Exposure to Cadmium and Renal Endpoints ....... 158\n2-24.  Results of Epidemiological Studies of General Populations Evaluating Urine Cadmium \nLevels and Renal Effects ................................................................................................................ 161\n2-25.  Results of Meta-Analysis Evaluating Exposure to Cadmium and Thyroid Endpoints ................... 173\n2-26.  Results of General Population Studies Evaluating Urinary Cadmium Levels and Thyroid \nEffects ............................................................................................................................................. 174\n2-27.  Results of Meta-Analyses Evaluating Exposure to Cadmium and Diabetes Endpoints ................. 175\n2-28.  Studies Included in Meta Analyses Evaluating Exposure to Cadmium and Diabetes \nEndpoints ........................................................................................................................................ 177\n2-29.  Results of Epidemiological Studies Evaluating Exposure to Cadmium and Diabetes-\nRelated Effects ................................................................................................................................ 179\n2-30.  Results of Epidemiological Studies Evaluating Urinary Cadmium Levels and \nImmunological Effects ................................................................................................................... 182\n2-31.  Results of Meta-Analyses Evaluating Exposure to Cadmium and Neurological Endpoints .......... 190\n2-32.  Studies Included in Meta-Analyses Evaluating Exposure to Cadmium and Neurological \nEndpoints ........................................................................................................................................ 191\n2-33.  Results of General Population Studies Evaluating Exposure to Urinary Cadmium and \nNeurological Effects ....................................................................................................................... 192\n2-34.  Results of Meta-Analyses Evaluating Exposure to Cadmium and Male Reproductive \nEndpoints ........................................................................................................................................ 196\n2-35.  Studies Included in Meta-Analyses Evaluating Exposure to Cadmium and Male \nReproductive Endpoints ................................................................................................................. 197\n2-36.  Results of General Population Studies Evaluating Urinary Cadmium Levels and \nReproductive Effects in Men .......................................................................................................... 199\n2-37.  Results of Meta-Analyses Evaluating Exposure to Cadmium and Female Reproductive \nEndpoints ........................................................................................................................................ 202\n2-38.  Studies Included in Meta-Analyses Evaluating Exposure to Cadmium and Female \nReproductive Endpoints ................................................................................................................. 203\n2-39.  Results of General Population Studies Evaluating Urinary Cadmium Levels and \nReproductive Effects in Women..................................................................................................... 204\n\n---\n\n2-40.  Results of Meta-Analyses Evaluating Exposure to Cadmium and Neurodevelopmental \nEndpoints ........................................................................................................................................ 213\n2-41.  Studies Included in Meta-Analyses Evaluating Exposure to Cadmium and \nNeurodevelopmental Endpoints ..................................................................................................... 214\n2-42.  Results of General Population Studies Evaluating Exposure to Cadmium and \nNeurodevelopmental Effects .......................................................................................................... 217\n2-43.  Results of General Population Studies Evaluating Urinary Cadmium Levels and Growth \nand Metabolism During Infancy, Childhood, and Adolescence ..................................................... 228\n2-44.  Results of General Population Studies Evaluating Urinary Cadmium Levels and \nReproductive Developmental Effects ............................................................................................. 233\n2-45.  Results of Meta-Analyses Evaluating Exposure to Cadmium and Metabolic Syndrome \nEndpoints ........................................................................................................................................ 240\n2-46.  Studies Included in Meta Analyses Evaluating Exposure to Cadmium and Metabolic \nSyndrome Endpoints ...................................................................................................................... 240\n2-47.  Results of Meta-Analyses Evaluating Exposure to Cadmium and Cancer ..................................... 242\n2-48.  Studies Included in Meta-Analyses Evaluating Exposure to Cadmium and Cancer ...................... 245\n2-49.  Results of Epidemiological Studies Evaluating Exposure to Cadmium and Cancer ...................... 250\n2-50.  Genotoxicity of Cadmium *In Vivo* .................................................................................................. 257\n2-51.  Genotoxicity of Cadmium *In Vitro* ................................................................................................. 259\n4-1.  Chemical Identity of Cadmium and Compounds ............................................................................. 303\n4-2.  Physical and Chemical Properties of Cadmium and Compounds .................................................... 304\n5-1.  Facilities that Produce, Process, or Use Cadmium ........................................................................... 310\n5-2.  Facilities that Produce, Process, or Use Cadmium Compounds ....................................................... 311\n5-3.  Releases to the Environment from Facilities that Produce, Process, or Use Cadmium .................... 316\n5-4.  Releases to the Environment from Facilities that Produce, Process, or Use Cadmium \nCompounds ....................................................................................................................................... 317\n5-5.  Lowest Limit of Detection Based on Standards ............................................................................... 326\n5-6.  Summary of Environmental Levels of Cadmium ............................................................................. 327\n5-7.  Range of Arithmetic Means for Cadmium from the AQS ................................................................ 327\n5-8.  Total Cadmium Levels in Groundwater and Surface Water in U.S. Samples Collected in \n2022–2024 ........................................................................................................................................ 329\n5-9.  Total Cadmium Levels in Ambient Sediment Collected in 2022–2024 ........................................... 331\n\n---\n\n5-10.  Mean Concentrations of Cadmium for FDA’s Total Diet Study Market Baskets 2006-1\nthrough 2008-4 ............................................................................................................................... 333\n5-11.  Geometric Mean and Selected Percentile Blood Concentrations (μg/L) of Cadmium in the\nU.S. Population, 1999–2018 ........................................................................................................... 336\n5-12.  Geometric Mean and Selected Percentile Urine Concentrations (Creatinine Corrected)\n(μg/g Creatinine) of Cadmium in the U.S. Population, 1999––2018 ............................................. 343\n5-13.  Geometric Mean and Selected Percentile Urine Concentrations (μg/L) of Cadmium in the\nU.S. Population, 1999–2018 ........................................................................................................... 350\n5-14.  Blood Cadmium Concentrations, Geometric Means, Adjusted Proportional Change in\nMeans, and 95<sup>th</sup> Percentiles in New York City Adults in Population \nSubgroups....................................................................................................................................... 357\n5-15.  Occupations with Potential Exposure to Cadmium and Cadmium Compounds ............................ 361\n6-1.  Ongoing Studies on Cadmium .......................................................................................................... 372\n7-1.  Regulations and Guidelines Applicable to Cadmium ....................................................................... 376\n\n---\n\n## CHAPTER 1. RELEVANCE TO PUBLIC HEALTH\n\n### 1.1 OVERVIEW AND U.S. EXPOSURES\n\nCadmium (Cd) occurs in the earth’s crust at a concentration of roughly 0.1–0.5 ppm and is commonly \nassociated with zinc, lead, and copper ores.  It is also a natural constituent of ocean water with average \nlevels between <5 and 110 ng/L, with higher levels reported near coastal areas and in marine phosphates \nand phosphorites (Morrow 2010).  The cadmium concentration of natural surface water and groundwater \nis usually <1 μg/L (Elinder 1985a, 1992).  Surface soil concentrations will depend on several factors such \nas its mobility, natural geochemistry, and magnitude of contamination from sources such as fertilizers and \natmospheric deposition.  Natural emissions of cadmium to the environment can result from volcanic \neruptions, forest fires, generation of sea salt aerosols, or other natural phenomena (EPA 1985; Morrow \n2010; Shevchenko et al. 2003).\n\n$$\n<1\\;\\mu g/L\n$$\n\nIn the environment, cadmium exists in only one oxidation state (Cd<sup>+2</sup>) and does not undergo oxidationreduction reactions.  In surface water and groundwater, cadmium can exist as the hydrated ion or as ionic \ncomplexes with other inorganic or organic substances.  Soluble forms of cadmium can migrate in water.  \nInsoluble forms of cadmium will settle and adsorb to sediments.  Cadmium’s fate in soil depends on \nseveral factors such as pH of the soil and availability of organic matter.  Generally, cadmium will bind \nstrongly to organic matter and this will, for the most part, immobilize it (Autier and White 2004).  \nHowever, cadmium’s behavior in soil will vary depending on the environmental conditions.  It is not \nlikely that cadmium will undergo significant transformation in the atmosphere (EPA 1980).  It will exist \nin particulate form and sometimes vapor form (emitted from high-temperature processes) where it will \nundergo atmospheric transport and eventually deposit onto soils and surface waters.\n\n$$\n\\left(\\mathrm{Cd^{+2}}\\right)\n$$\n\nNon-ferrous metal mining and refining, manufacture and application of phosphate fertilizers, fossil fuel \ncombustion, and waste incineration and disposal are the main anthropogenic sources of cadmium in the \nenvironment.  Except for those who live near cadmium-emitting industries, inhalation of cadmium in the \nambient air may occur but is not a major source of exposure.  Similarly, cadmium exposure through the \ndrinking water supply is of minor concern for the majority of the U.S. population.  However, water \nsources near cadmium-emitting industries, both with historic and current operations, have shown a \nmarked elevation of cadmium in water sediments and aquatic organisms (Angelo et al. 2007; Arnason and \nFletcher 2003; Brumbaugh et al. 2005; Mason et al. 2000; Paulson 1997).  Concentrations of cadmium in these polluted waters have ranged from <1.0 to 77 μg/L.  Cadmium from polluted soil and water can \naccumulate in plants and organisms, thus entering the food supply (Morrow 2010).\n\n$$\n7 7 \\mu \\mathrm {g} / \\mathrm {L}\n$$\n\nIn the United States, the largest source of cadmium exposure for nonsmoking adults and children is \nthrough dietary intake (NTP 2005).  The average daily intake of cadmium for children and adults \n(≥2 years of age) in the United States was estimated as 4.63 µg/day (Kim et al. 2019).  In general, leafy \nvegetables such as lettuce and spinach and staples such as potatoes and grains contain relatively high \nvalues of cadmium.  Peanuts, soybeans, and sunflower seeds have naturally high levels of cadmium \n(Morrow 2010).  Shellfish and organ meats (liver and kidney) also have relatively high concentrations of \ncadmium (Elinder 1985a).\n\nMean values of cadmium in the blood and urine of the U.S. population were reported in the National \nHealth and Nutrition Examination Survey (NHANES) 1999–2018 (CDC 2024).  Blood cadmium tends to \nreflect recent exposures, and urinary cadmium reflects cumulative cadmium exposure and body burden \n(particularly, kidney cadmium levels).  The geometric mean blood cadmium levels for the total population \n(≥1 year of age) have decreased nearly 50% from survey years 1999–2000 (0.412 µg/L) to survey years \n2017–2018 (0.241 µg/L).\n\n$$\n1999-2000\\left(0.412\\ \\mu g/L\\right)\n$$\n\n$$\n2017-2018\\left(0.241\\ \\mu g/L\\right)\n$$\n\nSmoking greatly increases exposure to cadmium, as tobacco leaves naturally accumulate high amounts of \ncadmium (Morrow 2010).  It has been estimated that tobacco smokers are exposed to 0.5–2.0 μg \ncadmium per cigarette, and about 10% is inhaled when smoked (Morrow 2010; Nordberg et al. 2015; \nNTP 2005).  A geometric mean blood cadmium level for a heavy smoker has been reported as high as \n1.58 μg/L (McKelvey et al. 2007), compared to the estimated national mean of 0.295 μg/L for all adults\n≥20 years of age, based on survey years 2017–2018 (CDC 2024).  Nonsmokers may also be exposed to \ncadmium in cigarettes via second-hand smoke.\n\n$$\n1. 5 8 \\mu \\mathrm {g} / \\mathrm {L}\n$$\n\n### 1.2 SUMMARY OF HEALTH EFFECTS\n\nSince the early 1950s, when the hazards of occupational cadmium exposure were recognized (Friberg \n1950), a large amount of information has been generated concerning the toxic effects of cadmium \nexposure in humans and laboratory animals.  Toxicological properties of cadmium are similar for the \nseveral different salts and oxides of cadmium that have been investigated, although differences in \nabsorption and distribution lead to different effect levels.  For inhalation exposure, particle size and \nsolubility in biological fluids (in contrast to solubility in water) appear to be the more important determinants of the toxicokinetics (Hirano et al. 1989a, 1989b; Oldiges and Glaser 1986; Rusch et al. \n1986).  For oral exposure, most experimental studies have used soluble cadmium, which exists as the Cd<sup>+2</sup>\nion regardless of the initial salt.  Absorption appears to be similar for cadmium ion and cadmium \ncomplexed with proteins in food, except for a few specific types of foods such as Bluff oysters and seal \nmeat.  Also, poorly soluble cadmium pigments may be absorbed to a lesser extent than soluble cadmium \nion (ILZRO 1977; Oldiges and Glaser 1986).\n\nThe database on the toxicity of cadmium in humans and animals following inhalation or oral exposure is \nextensive.  Target organs are similar among species and, in general, toxicokinetics following systemic \nabsorption from the gastrointestinal and respiratory tracts are similar.  Most of the human data involve \nevaluation of health effects associated with chronic-duration exposure in occupational studies, \ncommunity-based studies of populations living in cadmium-polluted areas, or epidemiological studies in \nthe general population.  When adequate exposure characterization is available, human studies generally \nreport exposure levels in terms of an internal biomarker of exposure (e.g., urinary cadmium).  Numerous \nstudies have conducted dose-response analyses between urinary cadmium levels and biomarkers of renal \ndysfunction (see Section 2.10); similar rigorous dose-response analyses are not available for other targets \nof toxicity in humans.  In animals, evaluation of available dose-response data by route and duration \nindicates that sensitive noncancer targets of cadmium toxicity are respiratory and neurodevelopmental \neffects following inhalation exposure (Figure 1-1) and renal, skeletal, and neurodevelopmental effects \nfollowing oral exposure (Figure 1-2).\n\nA systematic review of these sensitive noncancer endpoints resulted in the following hazard identification \nconclusions:\n\n• Respiratory effects are a known effect for humans following inhalation exposure.\n\n• Skeletal effects are a known effect for humans.\n\n• Renal effects are a known effect for humans.\n\n• Neurodevelopmental effects are a presumed effect for humans.\n\n---\n\n**Figure 1-1.  Health Effects Found in Animals Following Inhalation Exposure to** \n**Cadmium**\n\nConcentration (mg Cd/m<sup>3</sup>) Effects in Animals\n>8 Acute:  Mortality; clinical signs of neurotoxicity, female reproductive effects\n0.9-1.7 Acute:  Decreased body weight\nIntermediate:  Male and female reproductive effects\n0.19-0.4 Acute:  Developmental and immune effects\n0.05-0.1 Acute:  Respiratory effects\nIntermediate:  Death\n0.02-0.03 Intermediate:  Respiratory and neurodevelopmental effects\nChronic:  Cancer, mortality\n1x10<sup>-4</sup> mg Cd/m<sup>3</sup> Provisional Chronic MRL (based on human data and exposure levels predicted from biomarkers)\n\nCd = cadmium; MRL = minimal risk level\n\n---\n\n**Figure 1-2.  Health Effects Found in Animals Following Oral Exposure to** \n**Cadmium**\n\n## Dose (mg Cd/kg/day)\n\n## Effects in Animals\n\n**Acute:**  Death; hepatic, gastrointestinal, neurological, and male \nreproductive effects\n\n**5.28-15**\n\n**Intermediate:**  Death\n\n**Chronic:**  Hematological effects\n\n**Acute:**  Hematological effects; altered reproductive development\n\n**0.6-3.13**\n\n**Intermediate:**  Gastrointestinal effects\n\n**Chronic:**  Decreased body weight\n\n**Acute:**  Renal and developmental effects, decreased body weight\n\n**0.2-0.4**\n\n**Intermediate:**  Renal, hepatic, hematological, and male and female \nreproductive effects; increased blood pressure; decreased body weight\n\n**Chronic:**  Renal and neurological effects; cancer\n\n**0.04-0.08**\n\n**Intermediate:**  Skeletal, neurological, respiratory, and immunological \neffects; decreased birth weight and altered reproductive development\n\n## 0.002 mg Cd/kg/day 3x10<sup>-4</sup> mg Cd/kg/day\n\n3x10 -4 mg Cd/kg/day\n\n**Intermediate:**  Neurodevelopmental and endocrine effects\n\n**Chronic:**  Skeletal effects\n\n**Provisional Acute MRL**\n\n**Provisional Chronic MRL (based on human data and exposure levels predicted from biomarkers)**\n\nCd = cadmium; MRL = minimal risk level\n\n---\n\n**_Respiratory Effects._** A meta-analysis of 12 studies reported an association between chronic-duration \ninhalation exposure to cadmium and reduced forced expiratory volume in the first second to forced vital \ncapacity (FEV1/FVC), which is indicative of an increased risk of chronic obstructive pulmonary disease \n(Wang et al. 2024a).  A limited number of occupational studies not included in the meta-analysis also \nreported associations between impaired lung function and urinary cadmium levels in workers (Moitra et \nal. 2013, 2015; Zhou et al. 2022).  These findings are supported by occupational case reports of clinical \nsigns of respiratory distress and pulmonary damage after acute-duration exposure to fatal concentrations \n(Beton et al. 1966; Townshend 1982).  In animal acute- and intermediate-duration inhalation studies, the \nrespiratory tract is the most sensitive target of toxicity in animals (NTP 1995).  Available studies \nconsistently report histopathological and inflammatory reactions in the respiratory tract of multiple \nspecies; in studies that provide quantitative data, findings are clearly concentration-related \n(see Section 2.4).\n\n**_Skeletal Effects._** Cadmium-associated bone effects were first described in 1955 in the Jinzu River Basin, \na cadmium-contaminated area in Japan, following the development of a bone disease called Itai-Itai\n("ouch-ouch") disease, characterized by multiple fractures of the long bones, osteomalacia, and \nosteoporosis in combination with proteinuria (Järup et al. 1998; Nordberg et al. 1997; Shigematsu 1984).  \nFour meta-analyses evaluating 41 unique references confirm the association between cadmium exposure \nand adverse bone effects, including fractures, osteoporosis, and decreased bone mineral density (Cheng et \nal. 2016; Kunioka et al. 2022; Li et al. 2021; Qing et al. 2021), as do several studies published since the \nmeta-analyses (Lv et al. 2021; Wang et al. 2021a; Xie et al. 2023a, 2023b).  Occupational case studies \nindicate that calcium deficiency, osteoporosis, or osteomalacia can develop in some workers after longterm occupational exposure to high levels of cadmium (Adams et al. 1969; Blainey et al. 1980; Bonnell \n1955; Kazantzis 1979; Scott et al. 1980).  In rodents, decreases in bone mineralization, bone mineral \ndensity, and mechanical properties have been consistently observed following oral exposure to cadmium \nchloride (see Section 2.8).  While bone effects may be secondary to cadmium-associated renal damage \n(Bhattacharyya et al. 2023; Shevchenko et al. 2021; Zhang et al. 2020a), there is also evidence for a direct \neffect of cadmium on bone, and acceleration of bone resorption can occur in the absence of renal \ndysfunction (Reyes-Hinojosa et al. 2019; Shevchenko et al. 2021; Zhang et al. 2020a).\n\n**_Renal Effects._** The kidney is a well-established target of cadmium toxicity in humans following \noccupational or dietary exposure.  Available meta-analyses consistently reported associations between \none or more biomarkers of cadmium exposure and risk of proteinuria, urolithiasis, chronic kidney disease, \nhyperuricemia, renal cytotoxicity, and low glomerular filtration rate (GFR) (Chen et al. 2024; Doccioli et al. 2024; Gu et al. 2022; Jalili et al. 2021; Liu et al. 2016a; Woo et al. 2015; Zhu et al. 2024a).  These \nfindings are supported by several studies conducted since the meta-analyses were published (see \nSection 2.10).  In animals, there is no evidence for renal effects in acute- and intermediate-duration \ninhalation studies; however, exposure duration and concentration may not have been enough to reach the \ncritical kidney concentration to induce renal effects and chronic-duration inhalation studies evaluating \nrenal toxicity were not identified.  In oral studies, some studies reported adverse changes in sensitive \nbiomarkers of kidney damage, such as a β2-microglobulin (β2M) or N-acetyl-β-d-glucosaminidase \n(NAG) (Bernard et al. 1992; Liu et al. 2019; Wan et al. 2022).  However, other studies did not find this \neffect at similar or higher doses (Wang et al. 2014).  Similar inconsistencies were observed for serum \nclinical chemistry values and histopathological findings (see Section 2.10).\n\n**_Neurodevelopmental Effects._** While several general population studies are available, findings are mixed.  \nAvailable meta-analysis reported mixed conclusions regarding the potential association between cadmium \nexposure and autism spectrum disorder (ASD) (Ding et al. 2023; Dou et al. 2023; Ramazani et al. 2024; \nSaghazadeh and Rezaei 2017; Sulaiman et al. 2020) and did not find an association with attention deficit \nhyperactivity disorder (ADHD) (Dimitrov et al. 2023).  Some studies reported associations between \ncadmium exposure and decreased measures of cognitive development in children and adolescents (Gustin \net al. 2018; Kippler et al. 2016; Rodríguez-Barranco et al. 2014; Zhou et al. 2020); however, other studies \ndid not support this finding (Forns et al. 2014; Lucchini et al. 2019; Pan et al. 2018; Yang et al. 2020).  \nNo consistent findings were observed regarding potential associations between cadmium exposure and \nneurobehavioral or neurosensory evaluations during childhood or adolescence (see Section 2.17).  In \ncontrast, available animal studies collectively indicate that developmental cadmium exposure can cause \nalterations in sensorimotor function (including nerve conduction) and activity, socioemotional behavior, \nand learning and memory in rodents; however, the timing and duration of exposure and assessment \ninfluence findings (see Section 2.17).\n\n**_Cancer Effects._** The carcinogenicity of cadmium has been studied extensively in humans in studies \ninvolving workers and general populations and in animals after inhalation or oral exposures.  The \nInternational Agency for Research on Cancer (IARC) classified cadmium and cadmium compounds as \ncarcinogenic to humans (Group 1) based on sufficient evidence in humans for the carcinogenicity of \ncadmium and cadmium compounds, sufficient evidence in animals for the carcinogenicity of cadmium \ncompounds, and limited evidence in animals for the carcinogenicity of cadmium metal (IARC \n2012).  Similarly, the Department of Health and Human Services (HHS) classified cadmium and \ncadmium compounds as substances known to be human carcinogens based on sufficient evidence of carcinogenicity in humans, including epidemiological and mechanistic studies (NTP 2021).  In 1989, the \nU.S. Environmental Protection Agency (EPA) classified cadmium as a probable human carcinogen by \ninhalation (Group B1) based on limited evidence in humans and sufficient evidence in animals (IRIS \n1989).\n\n### 1.3 MINIMAL RISK LEVELS (MRLs)\n\nMRLs for inhalation and oral exposures to cadmium were derived.  As presented in Figure 1-3, the most \nsensitive effects following inhalation exposure to cadmium are respiratory and developmental \n(specifically neurodevelopmental effects) following acute- and intermediate-duration exposure and renal \nfollowing chronic-duration exposure.  A provisional chronic-duration inhalation MRL was derived based \non renal effects in humans; the inhalation database was considered inadequate for the derivation of acuteor intermediate-duration MRLs.  The lack of renal toxicity at shorter durations in animal inhalation\nstudies is attributed to inadequate exposure duration to meet the critical renal burden required to elicit \nadverse renal effects.  The relationship between renal and urinary cadmium appears to be nearly linear at \nchronic-duration intakes and kidney burdens that do not produce nephrotoxicity (i.e., elimination halftime is independent of dose).  However, at high kidney cadmium burdens, associated with renal damage \n(>50 μg Cd/g cortex), the elimination half-time increases with increasing severity of renal damage.  \nLinearity in the dose-urinary excretion relationship also does not appear to apply following an acuteduration, high exposure to cadmium.  Multicompartment, physiologically based pharmacokinetic (PBPK) \nmodels (described in detail in Section 3.1.5) can be used to estimate cadmium intakes (inhalation and oral \nexposure) associated with a given urinary cadmium level and/or kidney cadmium burden.  These models \nhave been extensively evaluated for predicting dose-kidney-urinary cadmium relationships within the \nlinear range of the dose-urinary cadmium relationship, and PBPK modeling was used in the derivation of \nthe provisional inhalation chronic-duration MRL.\n\nAs presented in Figure 1-4, the most sensitive effects following oral exposure are renal, developmental \n(specifically neurodevelopmental), and skeletal effects.  Provisional acute- and chronic-duration oral \nMRLs were derived based on renal effects in animals and humans, respectively; the oral database was \nconsidered inadequate for the derivation an intermediate-duration oral MRL.  As discussed for the provisional chronic-duration inhalation MRL, PBPK modeling was used in the derivation of the \nprovisional oral chronic-duration MRL.\n\nMRLs derived for both the inhalation and oral exposure routes for cadmium are summarized in Table 1-1\nand are discussed in greater detail in Appendix A.\n\n**Figure 1-3.  Summary of Sensitive Targets of Cadmium – Inhalation**\n\n**Available data indicate that the respiratory system and developing nervous system are the most \nsensitive targets following acute- and intermediate-duration exposure and the renal system is the \nmost sensitive target following chronic-duration exposure to cadmium via inhalation.**\n\nNumbers in circles are the lowest lowest-observed-adverse-effect levels (LOAELs) for all health effects in \nanimals and the number in the triangle is the point of departure (POD) for the chronic-duration inhalation \nMRL based on human data.*\n\n**Acute (mg Cd/m³ )**\n\n| Category | Acute (mg Cd/m³) | Intermediate (mg Cd/m³) | Chronic (mg Cd/m³) |\n| --- | --- | --- | --- |\n| Respiratory | 0.081 | 0.021 |  |\n| Immunological | 0.19 |  |  |\n| Developmental | 0.4 | 0.02 |  |\n| Hematological |  | 0.052 |  |\n| Body weight |  | 0.052 | 0.03 |\n| Renal |  |  | 0.00106 |\n| Death |  |  | 0.03 |\n\n*See Table 2-1 for animal studies identifying the LOAELs in circles.  The value of 0.00106 mg Cd/m<sup>3</sup> represented by \nthe triangle (human data) is the renal POD used for the provisional chronic-duration MRL; the value represents the \nlower 95% confidence limit on the weighted median of the urinary cadmium level associated with a 10% extra risk \nassociated with low-molecular weight proteinuria in 17 datasets from 11 human studies (see Appendix A for details).\n\n---\n\n## Figure 1-4. Summary of Sensitive Targets of Cadmium – Oral\n\n**Available data indicate that the renal, skeletal, and developing nervous system are the most \nsensitive targets of cadmium oral exposure.**\n\nNumbers in circles are the lowest lowest-observed-adverse-effect levels (LOAELs) for all health effects in \nanimals and the number in the triangle is the point of departure (POD) for the chronic-duration oral MRL \nbased on human data.*\n\n**Acute (mg Cd/kg/day)**\n\n| Category | LOAEL (mg Cd/kg/day) |\n| --- | --- |\n| Acute - Renal | 2 |\n| Acute - Body weight | 2 |\n| Acute - Developmental | 3.13 |\n| Intermediate - Developmental | 0.04 |\n| Intermediate - Endocrine | 0.053 |\n| Intermediate - Musculoskeletal | 0.2 |\n| Chronic - Renal (POD) | 0.00076 |\n| Chronic - Musculoskeletal | 0.08 |\n| Chronic - Renal | 2.301 |\n| Chronic - Cancer | 2.3 |\n\n*See Table 2-2 for animal studies identifying the LOAELs in circles.  The value of 7.60x10<sup>-4</sup> mg Cd/kg/day \nrepresented by a triangle (human data) is the renal POD used for the provisional chronic-duration MRL; the value \nrepresents the lower 95% confidence limit on the weighted median of the urinary cadmium level associated with a \n10% extra risk associated with low-molecular weight proteinuria in 17 datasets from 11 human studies \n(see Appendix A for details).\n\n$$\n7.60\\times10^{-4}\n$$\n\n---\n\n**Table 1-1.**\n\n**Minimal Risk Levels (MRLs) for Cadmium**\n\n| Exposure route | Exposure duration | Provisional MRL | Critical effect (species) | POD type | POD value | Uncertainty/modifying factor | Reference |\n| --- | --- | --- | --- | --- | --- | --- | --- |\n| Inhalation | Acute | None | - | - | - | - | - |\n| Inhalation | Intermediate | None | - | - | - | - | - |\n| Inhalation | Chronic | 1 × 10-4 mg CD/m3 | LMW proteinuria (humans) | 95% LCL of weighted median of UC10 from 17 datasets | 0.00106 mg Cd/m3 | UF: 3 MF: 3 | Weighted median from 17 datasetsb |\n| Oral | Acute | 0.002 mg Cd/kg/day | Total and LMW proteinuria; increased serum BUN (rats) | LOAEL | 2 mg Cd/kg/day | UF: 1,000 | Wan et al. 2022 |\n| Oral | Intermediate | None | - | - | - | - | - |\n| Oral | Chronic | 3 × 10-4 mg CD/kg/day | LMW proteinuria (humans) | 95% LCL of weighted median of UC10 from 17 datasets | 7.60 × 10-4 mg Cd/kg/day | UF: 3 | Weighted median from 17 datasetsb |\n\n<sup>a</sup>See Appendix A for additional information.\n\n<sup>b</sup>17 datasets from 3 occupational cohorts (Järup and Elinder 1994; Lei et al. 2007; Shao et al. 2007) and 8 general population cohorts (Buchet et al. 1990; Hong et \nal. 2004; Järup et al. 2000; Kobayashi et al. 2008; Suwazono et al. 2006; Uno et al. 2005; Wu et al. 2001; Zhang et al. 2016a).\n\nBUN = blood urea nitrogen; LCL = lower confidence limit; LMW = low molecular weight; LOAEL = lowest-observed-adverse-effect level; MF = modifying factor; \nPOD = point of departure; UC10 = urinary concentration associated with 10% extra risk; UF = uncertainty factor\n\n---\n\n## CHAPTER 2. HEALTH EFFECTS\n\n### 2.1 INTRODUCTION\n\nThe primary purpose of this chapter is to provide public health officials, physicians, toxicologists, and \nother interested individuals and groups with an overall perspective on the toxicology of cadmium.  It \ncontains descriptions and evaluations of toxicological studies and epidemiological investigations and \nprovides conclusions, where possible, on the relevance of toxicity and toxicokinetic data to public health.  \nWhen available, mechanisms of action specific to target organs are discussed along with the health effects \ndata, while general mechanisms of action are discussed in Section 2.21; toxicokinetic mechanistic data are \ndiscussed in Section 3.1.\n\nA glossary and list of acronyms, abbreviations, and symbols can be found at the end of this profile.\n\nTo help public health professionals and others address the needs of persons living or working near hazardous \nwaste sites, the information in this section is organized by health effect.  These data are discussed in terms of \nroute of exposure (inhalation, oral, and dermal) and three exposure periods:  acute (≤14 days), intermediate \n(15–364 days), and chronic (≥365 days).\n\nAs discussed in Appendix B, a literature search was conducted to identify relevant studies examining health \neffect endpoints.  Figure 2-1 provides an overview of the database of studies in humans or experimental \nanimals included in this chapter of the profile.  These studies evaluate the potential health effects associated \nwith inhalation, oral, or dermal exposure to cadmium, but may not be inclusive of the entire body of \nliterature.  As discussed in *Prioritization of Human Data* in Appendix B, the epidemiological database for \ncadmium is extensive, including thousands of primary studies and dozens of meta-analyses of available \nstudies.  To focus the profile review and discussion on the weight-of-evidence, recent evidence, and most \nrelevant data for hazard identification, ATSDR focused the discussion in Chapter 2 on meta-analyses \nconducted within the past 15 years.  To supplement discussion, any epidemiological study published since \nthe most recent meta-analysis for an endpoint was included if it provided: (1) reliable and reported estimates \nof cadmium exposure (measured levels in air or via urinary cadmium levels, as this is the most reliable \nbiomarker [see Section 3.3.1]); (2) analysis of potential confounders of the measures of association; and \n(3) appropriate statistical analysis.  For endpoints without a published meta-analysis, any study meeting these \ninclusion criteria were included, regardless of publication date.  Studies were excluded if they did not \nprovide quantitative evidence for associations, relied on semi-quantitative measures of exposure (e.g., food frequency questionnaires), or evaluated cadmium exposure from medical implants.  Exceptions to the above \ncriteria included studies reporting rare effects, inclusion of select older studies to provide historical context \n(e.g., Itai-Itai disease in the Jinzu River Basin region of Japan, early case reports and investigations of \nworkers exposed to cadmium that established targets of toxicity, etc.), and studies that fill data gaps (e.g., \nlower quality occupational studies in less-studied organ systems/tissues). The animal database for cadmium \nis also extensive.  As discussed in *Prioritization of Animal Data* in Appendix B, animal studies evaluating \nadverse effects were prioritized for efficient review.  Since cadmium is a well-established model of renal \ntoxicity, there are hundreds of studies describing administration of cadmium via oral or other routes (e.g., \nintraperitoneal) at known toxic doses to evaluate potential interventions to rescue (or prevent) renal toxicity \nor other cadmium-associated adverse effects at higher exposure levels.  Studies of this nature were excluded \nfrom the profile, as they do not inform dose-response effects at low, environmentally-relevant \ndoses. Similarly, acute- and intermediate-duration oral studies in rats or mice utilizing only one cadmium \ndose group were excluded due to lack of dose-response data; exceptions were made for acute-lethality \nstudies or studies addressing data-poor endpoints (e.g., lipid homeostasis studies).  All chronic-duration oral \nstudies and all inhalation and dermal studies of adequate quality were included in the profile.  A systematic \nreview of the scientific evidence of the most sensitive health effects associated with exposure to cadmium\nwas also conducted; the results of this review are presented in Appendix C.\n\nHuman and animal inhalation studies are presented together in Table 2-1 and Figure 2-2 and human and \nanimal oral studies are presented in Table 2-2 and Figure 2-3; limited dermal data were identified for \ncadmium and are presented in Table 2-3.\n\nLevels of significant exposure (LSEs) for each route and duration are presented in tables and illustrated in \nfigures.  The points in the figures showing no-observed-adverse-effect levels (NOAELs) or lowestobserved-adverse-effect levels (LOAELs) reflect the actual doses (levels of exposure) used in the studies.  \nEffects have been classified into “less serious LOAELs” or “serious LOAELs (SLOAELs).”  “Serious” \neffects are those that evoke failure in a biological system and can lead to morbidity or mortality (e.g., \nacute respiratory distress or death).  “Less serious” effects are those that are not expected to cause \nsignificant dysfunction or death, or those whose significance to the organism is not entirely clear.  \nATSDR acknowledges that a considerable amount of judgment may be required in establishing whether \nan endpoint should be classified as a NOAEL, “less serious” LOAEL, or “serious” LOAEL, and that in \nsome cases, there will be insufficient data to decide whether the effect is indicative of significant \ndysfunction.  However, the Agency has established guidelines and policies that are used to classify these \nendpoints.  ATSDR believes that there is sufficient merit in this approach to warrant an attempt at distinguishing between “less serious” and “serious” effects.  The distinction between “less serious” effects \nand “serious” effects is considered to be important because it helps the users of the profiles to identify \nlevels of exposure at which major health effects start to appear.  LOAELs or NOAELs should also help in \ndetermining whether or not the effects vary with dose and/or duration, and place into perspective the \npossible significance of these effects to human health.  Levels of exposure associated with cancer (Cancer \nEffect Levels, CELs) of cadmium are indicated in Tables 2-1 and 2-2 and Figures 2-2 and 2-3.\n\nA User\'s Guide has been provided at the end of this profile (see Appendix D).  This guide should aid in \nthe interpretation of the tables and figures for LSEs and MRLs.\n\nThis section provides information regarding potential adverse health effects of cadmium and cadmium \ncompounds.  To appropriately compare doses following exposures to various cadmium compounds, \ninhalation exposures are expressed throughout the profile as mg Cd/m<sup>3</sup> and oral exposures are expressed as \nmg Cd/kg/day, when possible.  This allows for evaluation of relative toxicities and determination of whether \ncertain chemical properties (e.g., solubility) impact toxicity.  When available, information pertaining to \nrelative toxicity of different cadmium compounds is discussed throughout Chapter 2.\n\nThe health effects of cadmium and cadmium compounds have been extensively evaluated in human and \nanimal studies.  As discussed above, due to the vast amount of available data, studies were prioritized for \ninclusion in Chapter 2 based on criteria defined in Appendix B.  A total of 69 meta-analyses of human \ndata were included.  An additional 219 human studies and 192 animal studies meeting inclusion criteria \nwere identified.  Most of the human data involve evaluation of health effects associated with chronicduration exposure in occupational studies, community-based studies of populations living in cadmiumpolluted areas, or epidemiological studies in the general population.  For workers, the predominant \nexposure route is inhalation; however, some gastrointestinal tract exposure may also occur when dust is \nremoved from the lungs by mucociliary clearance and subsequently swallowed, or by ingestion of dust on \nhands, cigarettes, or food (Adamsson et al. 1979).  For the nonsmoking general population, dietary \nexposure to cadmium is the most likely route of exposure (Kim et al. 2018; Nordberg et al. 2018; Zhu et \nal. 2024a).  However, since cadmium is present in tobacco leaves, tobacco smoking can contribute \nsignificantly to cadmium exposure in general populations (Diamond and Klotzbach 2025; Ellis et al. \n1979; Friis et al. 1998).  Therefore, both occupational and general population studies are classified as \nmulti-route exposure in Figure 2-1.  In animal studies, most of the health effects data in animals come \nfrom oral exposure studies (Figure 2-1).\n\n---\n\nHuman studies are available for nearly every organ system, with the predominant focus on renal, cancer, \ndevelopmental, musculoskeletal, and cardiovascular endpoints.  Animal studies predominantly focused on \nrespiratory endpoints following inhalation exposure and examined a comprehensive set of endpoints \nfollowing oral exposure.  For oral studies, the most well-studied effects include body weight, developmental, \nand reproductive endpoints.  Data from dermal exposure are very limited.\n\nAs outlined in Chapter 1, the most sensitive effects following exposure to cadmium appear to be respiratory, \nrenal, and neurodevelopmental following inhalation exposure and renal, skeletal, and neurodevelopmental \nfollowing oral exposure.  A systematic review was conducted on the available human and animal studies for \nthese endpoints.  The information in these studies indicates the following on the potential targets of cadmium\ntoxicity:\n\n• **Respiratory Endpoints.**  Respiratory effects are a known effect of cadmium toxicity following \ninhalation exposure based on a low level of evidence in human occupational studies, a high level \nof evidence in laboratory animal inhalation studies, and other relevant data including a metaanalysis, occupational case reports, and a plausible mechanism of action.  In humans, \noccupational exposure has been associated with respiratory irritation and impaired respiratory \nfunction.  In animals, inhalation exposure is consistently associated with inflammatory changes in \nthe lung and upper and lower respiratory tract lesions with increasing concentration and duration \nin multiple species.\n\n• **Skeletal Endpoints.**  Adverse effects on the skeletal system (e.g., decreased bone density, \nstrength, and mineralization) are a known effect of cadmium toxicity based on a moderate level of \nevidence from human epidemiological studies, a high level of evidence from laboratory animals, \nand other relevant data including several meta-analyses, older studies and case reports of high \ndietary or occupational exposure, and plausible mechanisms of action.  In humans, cadmium \nexposure is associated with adverse bone effects, including fractures, osteoporosis, and decreased \nbone mineral density.  Bone effects associated with cadmium exposure were first described in \ncadmium-contaminated communities in Japan with high dietary intake; the disease called Itai-Itai \n(“ouch-ouch”) disease was characterized by multiple fractures of the long bones, osteomalacia, \nand osteoporosis.  Bone effects have been confirmed in animal studies following oral exposure; \nthese endpoints have not been assessed following inhalation exposure in animals.\n\n• **Renal Endpoints.** Renal effects are a known effect of cadmium toxicity based on a high level of \nevidence from human epidemiological studies, a moderate level of evidence in laboratory animal \ninhalation studies, and other relevant data including several meta-analyses and a well-defined \nmechanism of action. The kidney has been a well-established target of cadmium toxicity in \nhumans following occupational and dietary exposure for decades.  Several studies have \ndeveloped dose-response analyses of sensitive biomarkers of cadmium exposure and renal \ntoxicity (e.g., urinary cadmium levels and low molecular weight [LMW] proteinuria).  Data in \nanimals following inhalation exposure are inadequate.  While findings in multi-dose oral studies \nin animals meeting inclusion criteria are mixed, several studies reported alterations in biomarkers \nof renal functions (e.g., LMW proteinuria, serum blood urea nitrogen [BUN]) and \nhistopathological changes.\n\n---\n\n## 2. HEALTH EFFECTS\n\n• **Neurodevelopmental Endpoints.** Neurodevelopmental effects are a presumed effect in humans \nbased on a low level of evidence in humans and a high level of evidence in animals.  Available \nepidemiological data from general population studies are mixed.  A limited number of inhalation \nstudies and numerous oral studies in animals indicate that developmental cadmium exposure can \ncause alterations in sensorimotor function (including nerve conduction) and activity, \nsocioemotional behavior, and learning and memory in rodents; however, the timing and duration \nof exposure and assessment influence findings.  Available data indicate that neurodevelopmental \neffects are the most sensitive indicator of developmental toxicity of cadmium (occur at lower \nexposures than those associated with standard developmental outcomes or specialized evaluations \nof other systems, such as reproductive development).\n\n---\n\n**Figure 2-1.  Overview of the Number of Studies Examining Cadmium Health Effects***\n\n## Most studies examined the potential body weight, renal, and developmental effects of cadmium\n\nNumerous studies are available in both **humans** and **animals** (counts represent studies examining endpoint)\n\n| Category | Series 1 (unlabelled) (number of studies) | Series 2 (unlabelled) (number of studies) |\n| --- | --- | --- |\n| Death | 11 | 42 |\n| Body weight |  | 98 |\n| Respiratory | 15 | 29 |\n| Cardiovascular | 28 | 13 |\n| Gastrointestinal | 6 | 9 |\n| Hematological | 5 | 31 |\n| Musculoskeletal | 30 | 16 |\n| Hepatic | 21 | 23 |\n| Renal | 54 | 34 |\n| Dermal | 2 | 1 |\n| Ocular | 2 | 2 |\n| Endocrine | 19 | 15 |\n| Immunological | 14 | 26 |\n| Neurolgical | 12 | 12 |\n| Reproductive | 30 | 39 |\n| Developmental | 33 | 45 |\n| Other Noncancer | 4 | 4 |\n| Cancer | 34 | 10 |\n\n**Exposure Route**\n\n| Category | Share of studies (%) |\n| --- | --- |\n| Multi-route | 56 |\n| Oral | 30 |\n| Dermal | 1 |\n| Inhalation | 13 |\n\n**Exposure Duration**\n\n| Category | Share of studies (%) |\n| --- | --- |\n| Chronic | 60 |\n| Intermediate | 25 |\n| Acute | 15 |\n\n*Includes studies discussed in Chapter 2.  A total of 69 meta-analyses and 411 studies meeting inclusion criteria (including those finding no effect) have examined \ntoxicity; most studies examined multiple endpoints. Note: Meta-analyses are counted as a single data-point in the figure above because only the overall results of \nthe meta-analysis, not the individual studies included in the meta-analyses, were included in Chapter 2.\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| ACUTE EXPOSURE |  |  |  |  |  |  |  |  |  |\n| Beton et al. 1966 |  |  |  |  |  |  |  |  | Cadmium oxide fume |\n| 1 | Human 5 M | 5 hours (occup) | 8.63 | LE, CS | Death Resp |  |  | 8.63 | 1/5 exposed workers died Severe dyspnea, wheezing, chest pain and precordial constriction, persistent cough (lasting up to 7 days post-exposure); severe pulmonary edema and alveolar cell metaplasia in the worker that died |\n| Barrett et al. 1947 |  |  |  |  |  |  |  |  | Cadmium oxide fume |\n| 2 | Rat (NS) 10–25 NS | 10–15 minutes (WB) | 8.8, 13, 18, 19, 22, 25, 31, 41, 79.2, 110 | LE | Death |  |  | 30 | LC50 at 7 days |\n| Buckley and Bassett 1987 |  |  |  |  |  |  |  |  | Cadmium oxide dust |\n| 3 | Rat (Wistar) 20 M | 3 hours (WB) | 0, 0.4, 4.6 | BW | Bd wt | 0.4 | 4.6 |  | 15% decrease in body weight 7 days post-exposure |\n| Bus et al. 1978 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 4 | Rat (Sprague-Dawley) 18 M | 1 hour (WB) | 0, 6.5 | LE, BW, BI, OW, OF | Bd wt |  | 6.5 |  | 11% decrease in body weight 11 days post-exposure |\n|  |  |  |  |  | Resp |  | 6.5 |  | Decreased tidal volume and increased respiratory frequency 1 and 5 days post-exposure |\n| Rats were examined at 1, 5, and 11 days post-exposure (6/group/timepoint) |  |  |  |  |  |  |  |  |  |\n| Grose et al. 1987 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 5 | Rat (Sprague-Dawley) 40 M | 2 hours (H) | 0, 0.25, 0.48, 4.50 | LE, CS, BW | Bd wt | 0.25 |  | 4.5 | 20% decrease in body weight 72 hours post-exposure |\n\nRats were examined immediately and 72 hours post-exposure (20/group/timepoint)\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects | Cadmium oxide dust |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Grose et al. 1987 |  |  |  |  |  |  |  |  |  |  |\n| 6 | Rat (Sprague-Dawley) 40 M | 2 hours (H) | 0, 0.25, 0.44, 4.45 | LE, CS, BW | Bd wt | 4.45 |  |  |  |  |\n| Rats were examined immediately and 72 hours post-exposure (20/group/timepoint) |  |  |  |  |  |  |  |  |  |  |\n| Hart 1986 |  |  |  |  |  |  |  |  |  |  |\n| 7 | Rat (Lewis) 3 M | 1 or 2 weeks 5 days/week 3 hours/day (N) | 0, 1.6 | BI, OW, HP | Resp |  | 1.6 |  |  | Cadmium acetate Increase in BALF cellularity (macrophages, PMNs, lymphocytes) and markers of cytotoxicity (LDH, ALP, AP, total protein) |\n| Jacobo-Estrada et al. 2016 |  |  |  |  |  |  |  |  |  |  |\n| 8 | Rat (Wistar) 6 F | 13 days GDs 8–20 2 hours/day (WB) | 0, 17.43 | BW, OW, DX | Bd wt Repro Develop | 17.43 | 17.43 | 17.43 |  | Cadmium chloride Decreased absolute placental weight Fetal kidney injury (decreased fetal plasma creatinine levels, increased total histopathological lesion score in fetal kidney); decreased fetal body weight (8%) |\n| NTP 1995 |  |  |  |  |  |  |  |  |  |  |\n| 9 | Rat (Fischer-344) 5 M, 5 F | 2 weeks 5 days/week 6.2 hours/day (WB) | 0, 0.081, 0.249, 0.844, 2.49, 8.60 | LE, CS, BW, OW, HP | Death Bd wt Resp | 2.49 | 0.081 | 8.6 |  | Cadmium oxide aerosol 100% mortality by day 6 |\n|  |  |  |  |  | Cardio | 2.49 |  |  |  | SLOAEL: Marked necrosis of alveolar ducts LOAEL: Minimal-to-mild alveolar histiocytic infiltrate and focal inflammation in alveolar septa |\n|  |  |  |  |  | Hepatic | 2.49 |  |  |  |  |\n|  |  |  |  |  | Renal | 2.49 |  |  |  |  |\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects | Cadmium chloride |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Palmer et al. 1986 |  |  |  |  |  |  |  |  |  |  |\n| 10 | Rat (Sprague-Dawley) 20–30 M | 2 hours (WB) | 0, 6.0 | BW, BC, BI, OW | Bd wt | 6 |  |  |  |  |\n| 10 | Rat (Sprague-Dawley) 20–30 M | 2 hours (WB) | 0, 6.0 | BW, BC, BI, OW | Resp |  | 6 |  |  | Increased BALF cellularity (primarily macrophages) 3 days post-exposure |\n| 10 | Rat (Sprague-Dawley) 20–30 M | 2 hours (WB) | 0, 6.0 | BW, BC, BI, OW | Endocr | 6 |  |  |  |  |\n| Rats were sacrificed |  | 1, 3, 7, or 10 days post-exposure (≥4/group/timepoint) |  |  |  |  |  |  |  |  |\n| Rusch et al. 1986 |  |  |  |  |  |  |  |  |  | Cadmium carbonate |\n| 11 | Rat (Sprague-Dawley) 26 M, 26 F | 2 hours (WB) | 0, 94 | LE, CS, GN | Resp |  |  | 94 |  | Rales persisting up to 4 hours post-exposure |\n| Rats were sacrificed immediately or 1, 3, 7, or 30 days post-exposure (10/group/timepoint); extra two rats were replacement animals |  |  |  |  |  |  |  |  |  |  |\n| Rusch et al. 1986 |  |  |  |  |  |  |  |  |  | Cadmium sulfide |\n| 12 | Rat (Sprague-Dawley) 26 M, 26 F | 2 hours (WB) | 0, 140 | LE, CS, BW | Bd wt | 140 |  |  |  |  |\n| Rats were sacrificed immediately or 1, 3, 7, or 30 days post-exposure (10/group/timepoint); extra two rats were replacement animals |  |  |  |  |  |  |  |  |  |  |\n| Rusch et al. 1986 |  |  |  |  |  |  |  |  |  | Cadmium selenide |\n| 13 | Rat (Sprague-Dawley) 26 M, 26 F | 2 hours (WB) | 0, 105 | LE, CS, BW | Bd wt | 105 |  |  |  |  |\n| Rats were sacrificed immediately or 1, 3, 7, or 30 days post-exposure (10/group/timepoint); extra two rats were replacement animals |  |  |  |  |  |  |  |  |  |  |\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Rusch et al. 1986 |  |  |  |  |  |  |  |  | Cadmium acetate |\n| 14 | Rat (Sprague-Dawley) 26 M, 26 F | 2 hours (WB) | 0, 83 | LE, CS | Death |  |  | 83 | 25/32 died between 1 and 7 days post-exposure |\n| 14 | Rat (Sprague-Dawley) 26 M, 26 F | 2 hours (WB) | 0, 83 | LE, CS | Resp |  |  | 83 | Labored breathing and rales persisting up to 4 hours post-exposure |\n| 14 | Rat (Sprague-Dawley) 26 M, 26 F | 2 hours (WB) | 0, 83 | LE, CS | Neuro |  | 83 |  | Reduced activity during exposure |\n| Rats were sacrificed immediately or 1, 3, 7, or 30 days post-exposure (10/group/timepoint); extra two rats were replacement animals |  |  |  |  |  |  |  |  |  |\n| Snider et al. 1973 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 15 | Rat (Sprague-Dawley) 18 M | 3 days 1 hour/day (WB) | 61 | LE, GN | Death |  |  | 61 | 17/18 died within 3 days |\n| 15 | Rat (Sprague-Dawley) 18 M | 3 days 1 hour/day (WB) | 61 | LE, GN | Resp |  |  | 61 | Pulmonary hemorrhage |\n| Barrett et al. 1947 |  |  |  |  |  |  |  |  | Cadmium oxide fume |\n| 16 | Mouse (NS) 10 NS | 15 minutes (WB) | 39, 61.3, 65.9 | LE | Death |  |  | 39 | 9/10 died within 7 days |\n| Graham et al. 1978 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 17 | Mouse (CD-1) 16–20 F | 2 hours (WB) | 0, 0.110, 0.190 | IX | Immuno | 0.11 | 0.19 |  | Decreased humoral immune response |\n| Krzystyniak et al. 1987 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 18 | Mouse (C57BL/6) 4–5 F | 60 minutes (N) | 0, 0.88 | IX | Immuno |  | 0.88 |  | Reduced humoral and cell-mediated immune responses |\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| NTP 1995 |  |  |  |  |  |  |  |  | Cadmium oxide aerosol |\n| 19 | Mouse (B6C3F1) 5 M, 5 F | 2 weeks 5 days/week 6.2 hours/day (WB) | 0, 0.081, 0.249, 0.844, 2.49, 8.60 | LE, CS, BW, OW, HP | Death Bd wt Resp | 2.49 | 0.081 | 8.6 | 100% mortality by day 7 |\n| 19 | Mouse (B6C3F1) 5 M, 5 F | 2 weeks 5 days/week 6.2 hours/day (WB) | 0, 0.081, 0.249, 0.844, 2.49, 8.60 | LE, CS, BW, OW, HP | Cardio Hepatic Renal | 2.49 2.49 2.49 | 0.081 | 0.844 | LOAEL: Minimal-to-mild alveolar histiocytic infiltrates SLOAEL: Fibrosis, inflammation, and mild necrosis of the alveolar ducts; degeneration of the nasal olfactory epithelium |\n| NTP 1995 |  |  |  |  |  |  |  |  | Cadmium oxide aerosol |\n| 20 | Mouse (Swiss) 33 F | 14 days GDs 4–17 6.27 hours/day (WB) | 0, 0.04, 0.4, 1.7 | LE, CS, BW, OW, DX | Bd wt Develop | 0.4 | 0.04 | 1.7 | 22% decrease in maternal body weight on GD 18 Increased total litter resorption; decreased fetal body weight (29–30%); reduced ossification of sternebrae Decreased male (9%) and female (8%) fetal body weight |\n| Friberg 1950 |  |  |  |  |  |  |  |  | Cadmium metal dust |\n| 21 | Rabbit (NS) 8 NS | 4 hours (H) | 11.5 - 48.4 | LE | Death |  |  | 28.4 | LC50 at 14 days |\n| Henderson et al. 1979 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 22 | Hamster (Golden Syrian) 30 B | 30 minutes (N) | 0, 1.1, 10.1 | LE, BI, HP | Resp |  | 1.1 | 10.1 | LOAEL: Increased BALF PMN and AP levels SLOAEL: Necrosis of bronchiolar epithelium 1 day post-exposure; severe pneumonitis 7 days post-exposure |\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| INTERMEDIATE EXPOSURE |  |  |  |  |  |  |  |  |  |\n| Baranski 1984 |  |  |  |  |  |  |  |  | Cadmium oxide aerosol |\n| 23 | Rat (Wistar) 7–15 F | 6-7 months (5 months premating, up to 3 weeks mating, GDs 1–20) 5 hours/day 5 days/week (WB) | 0, 0.02, 0.16 | RX, DX | Repro Develop | 0.16 | 0.02 | 0.16 | LOAEL: Age- and sex-dependent changes in offspring motor activity; impaired avoidance acquisition in 3- and 7-month-old females SLOAEL: 25% mortality by PND 4 (decreased viability index); 15% decrease in weanling body weight |\n| Baranski 1985 |  |  |  |  |  |  |  |  | Cadmium oxide dust |\n| 24 | Rat (Wistar) 5–16 F | 5–7 months (4–5 months premating, mating, GDs 1–20) 5 days/week 5 hours/day (WB) | 0, 0.02, 0.16, 1.0 | LE, BW, RX, DX | Death Bd wt Repro Develop | 1 1 | 0.02 | 1 | 55.1% mortality |\n| Baranski and Sitarek 1987 |  |  |  |  |  |  |  |  | LOAEL: Decreased motor activity in 3-month-old males and decreased conditioned reflexes in 5-month-old females SLOAEL: 23% decrease in pup viability index; unspecified decrease in pup weight during first 2 months |\n| 25 | Rat (Wistar) 13–14 F | 20 weeks 5 days/week 5 hours/day (WB) | 0, 0.02, 0.16, 1.0 | LE, CS, BW, RX | Death Bd wt Repro | 0.16 | 0.02 | 1 | Cadmium oxide dust 38% mortality by week 13; 100% mortality by week 20 30–50% decrease in body weight gain starting at week 4 Increased duration of estrous cycle |\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Glaser et al. 1986 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 26 | Rat (Wistar) 12 M | 30 days 7 days/week 22 hours/day (WB) | 0, 0.105 | LE, CS, BW, HE, BC, BI, UR | Bd wt Resp | 0.105 | 0.105 |  | Increase in BALF cellularity (PMNs, macrophages, leukocytes) and markers of cytotoxicity (LDH, total protein levels); macrophages, total protein and LDH remained elevated at 2-months post-exposure |\n| 26 | Rat (Wistar) 12 M | 30 days 7 days/week 22 hours/day (WB) | 0, 0.105 | LE, CS, BW, HE, BC, BI, UR | Hemato | 0.105 | 0.105 |  | Increased WBC counts at terminal sacrifice |\n| 26 | Rat (Wistar) 12 M | 30 days 7 days/week 22 hours/day (WB) | 0, 0.105 | LE, CS, BW, HE, BC, BI, UR | Renal | 0.105 |  |  |  |\n| Rats were sacrificed immediately following exposure (terminal sacrifice) or 2 months post-exposure (6/group/timepoint) |  |  |  |  |  |  |  |  |  |\n| Glaser et al. 1986 |  |  |  |  |  |  |  |  | Cadmium sulfide |\n| 27 | Rat (Wistar) 12 M | 30 days 7 days/week 22 hours/day (WB) | 0, 1.034 | LE, CS, BW, HE, BC, BI, OW | Bd wt Resp | 1.034 | 1.034 |  | Increase in BALF cellularity (PMNs, macrophages, leukocytes) and markers of cytotoxicity (LDH, total protein levels); macrophages, total protein and LDH remained elevated at 2-months post-exposure |\n| 27 | Rat (Wistar) 12 M | 30 days 7 days/week 22 hours/day (WB) | 0, 1.034 | LE, CS, BW, HE, BC, BI, OW | Hemato | 1.034 |  |  |  |\n| 27 | Rat (Wistar) 12 M | 30 days 7 days/week 22 hours/day (WB) | 0, 1.034 | LE, CS, BW, HE, BC, BI, OW | Renal | 1.034 |  |  |  |\n| Rats were sacrificed immediately following exposure (terminal sacrifice) or 2 months post-exposure (6/group/timepoint) |  |  |  |  |  |  |  |  |  |\n| Glaser et al. 1986 |  |  |  |  |  |  |  |  | Cadmium oxide dust |\n| 28 | Rat (Wistar) 12 M | 30 days 7 days/week 22 hours/day (WB) | 0, 0.098 | LE, CS, BW, HE, BC, BI, OW | Bd wt Resp | 0.098 | 0.098 |  | Increase in BALF cellularity (PMNs, macrophages, leukocytes) and markers of cytotoxicity (LDH, total protein levels); total protein remained elevated at 2-months post-exposure |\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n|  |  |  |  |  | Hemato |  | 0.098 |  | Increased WBC count at terminal sacrifice |\n|  |  |  |  |  | Renal | 0.098 |  |  |  |\n\n| Rats were sacrificed immediately following exposure (terminal sacrifice) or 2 months post-exposure (6/group/timepoint) |  |  |  |  |  |  |  |  |  |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Hart 1986 |  |  |  |  |  |  |  | Cadmium acetate |  |\n| 29 | Rat (Lewis) 3 M | 3–6 weeks 5 days/week 3 hours/day (N) | 0, 1.6 | BI, OW, HP | Resp |  | 1.6 |  | Transient increase in BALF cellularity (macrophages, PMNs, lymphocytes) and markers of cytotoxicity (LDH, ALP, AP, total protein); resolving weeks 4–6 |\n| Kutzman et al. 1986 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 30 | Rat (Fischer 344) 20 M | 62 days 5 days/week 6 hours/day (WB) | 0, 0.33, 1.06, 2.13 | LE, CS, BW, BI, OW, HP | Death |  |  | 2.13 | 100% mortality by day 45 |\n| 30 | Rat (Fischer 344) 20 M | 62 days 5 days/week 6 hours/day (WB) | 0, 0.33, 1.06, 2.13 | LE, CS, BW, BI, OW, HP | Bd wt | 0.33 |  | 1.06 | 27% decrease in body weight |\n| Kutzman et al. 1986 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 31 | Rat (Fischer 344) 8 M, 8 F | 62 days 5 days/week 6 hours/day (WB) | 0, 0.33, 1.06, 2.13 | LE, BW, RX | Death |  |  | 2.13 | 100% mortality by day 45 |\n| 31 | Rat (Fischer 344) 8 M, 8 F | 62 days 5 days/week 6 hours/day (WB) | 0, 0.33, 1.06, 2.13 | LE, BW, RX | Bd wt | 0.33 | 1.03 | 2.13 | LOAEL: 14% decreased in body weight SLOAEL: Body weight loss (decreased 40% compared to starting body weight) |\n| Repro |  |  |  |  |  | 1.06 M |  |  |  |\n| Exposed rats were mated with both exposed and unexposed rats 6 days post-exposure |  |  |  |  |  |  |  |  |  |\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| NTP 1995 |  |  |  |  |  |  |  |  | Cadmium oxide aerosol |\n| 32 | Rat (Fischer-344) 10 M, 10 F | 13 weeks 5 days/week 6.33 hours/day (WB) | 0, 0.021, 0.046, 0.088, 0.212, 0.902 | LE, CS, BW, HE, BC, UR, OW, HP, OF, RX | Bd wt Resp | 0.902 | 0.021 F | 0.902 M | Minimal epithelial degeneration in the larynx LOAEL: Minimal alveolar histiocytic infiltrate and epithelial hyperplasia; minimal epithelial degeneration in the larynx SLOAEL: Marked inflammation and moderate fibrosis in interstitium around alveolar ducts and terminal bronchioles |\n| 32 | Rat (Fischer-344) 10 M, 10 F | 13 weeks 5 days/week 6.33 hours/day (WB) | 0, 0.021, 0.046, 0.088, 0.212, 0.902 | LE, CS, BW, HE, BC, UR, OW, HP, OF, RX | Cardio Gastro Hemato Musc/skel Hepatic Renal Endocr Immuno Neuro Repro | 0.902 0.902 0.902 0.902 0.902 0.902 0.902 | 0.021 M | 0.046 M | Minimal epithelial degeneration in the larynx LOAEL: Minimal alveolar histiocytic infiltrate and epithelial hyperplasia; minimal epithelial degeneration in the larynx SLOAEL: Marked inflammation and moderate fibrosis in interstitium around alveolar ducts and terminal bronchioles |\n| NTP 1995 |  |  |  |  |  |  |  |  | Decreased spermatid counts in males, increased estrous cycle length in females |\n| 33 | Rat (Sprague-Dawley) 32 F | 16 days GDs 4–19 6.27 hours/day (WB) | 0, 0.04, 0.4, 1.7 | LE, CS, BW,OW, DX | Bd wt | 0.4 | 1.7 | Cadmium oxide aerosol | 14% decrease in maternal body weight on GD 20 Decreased male (16%) and female (17%) fetal body weight; reduced ossification of pelvis and sternebrae |\n| 33 | Rat (Sprague-Dawley) 32 F | 16 days GDs 4–19 6.27 hours/day (WB) | 0, 0.04, 0.4, 1.7 | LE, CS, BW,OW, DX | Develop | 0.4 |  | 1.7 | 14% decrease in maternal body weight on GD 20 Decreased male (16%) and female (17%) fetal body weight; reduced ossification of pelvis and sternebrae |\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects | Cadmium chloride |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Oberdörster et al. 1994 |  |  |  |  |  |  |  |  |  |  |\n| 34 | Rat (Fischer 344) 48 M | 4 weeks 5 days/week 6 hours/day (WB) | 0, 0.100 | BI | Resp |  | 0.1 |  | Increase in BALF PMNs (1 day post-exposure) |  |\n\n| Rats were sacrificed at 1, 7, or 28 days post-exposure (≥4/group/timepoint per endpoint) |  |  |  |  |  |  |  |\n| --- | --- | --- | --- | --- | --- | --- | --- |\n| Oldiges and Glaser 1986 |  |  |  |  |  |  | Cadmium oxide dust |\n| 35 | Rat (Wistar) 20 M, 20 F | 218–343 days 7 days/week 22 hours/day (WB) | M: 0, 0.030, 0.090 F: 0, 0.026, 0.081 | LE, GN, BW, Death FI, WI, HE, OW |  | 0.081 F 0.09 M | 6/20 died 6/20 died |\n| Oldiges and Glaser 1986 |  |  |  |  |  |  | Cadmium sulfide |\n| 36 | Rat (Wistar) 20–24 M, 20–24 F | 105–298 days 7 days/week 22 hours/day (WB) | M: 0, 0.843, 2.270 F: 0, 0.841, 2.247 | LE, GN, BW, Death FI, WI, HE, OW |  | 0.841 F 0.843 M | 7/20 died by day 298 6/20 died by day 208 |\n| Oldiges et al. 1989 |  |  |  |  |  |  | Cadmium chloride |\n| 37 | Rat (Wistar) 20 M, 18–20 F | 6 months 7 days/week 22 hours/day (WB) | 0, 0.090 | LE, GN, HP Death Cancer |  | 0.09 0.09 M | 25% mortality at 6 months CEL: Lung tumors (bronchioalveolar adenoma, adenocarcinoma, or squamous cell carcinoma) |\n| Scheduled sacrifice at 31 months; surviving Cd-exposed rats sacrificed at 29–30 months due to mortality ≥75% |  |  |  |  |  |  |  |\n| Oldiges et al. 1989 |  |  |  |  |  |  | Cadmium sulfide |\n| 38 | Rat (Wistar) 20 M, 20 F | 6 months 40 hours/week (WB) | 0, 0.270 | LE, GN, HP Death |  | 0.27 | 75% mortality at 27–29 months |\n| Scheduled sacrifice at 31 months; surviving Cd-exposed rats sacrificed at 27–29 months due to mortality ≥75% |  |  |  |  |  |  |  |\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Oldiges et al. 1989 |  |  |  |  |  |  |  |  | Cadmium sulfide |\n| 39 | Rat (Wistar) 16–20 M, 19–20 F | 3–10 months 7 days/week 22 hours/day (WB) | 0, 0.810, 2.430 | LE, GN, HP | Death Cancer |  |  | 0.81 | 25% mortality at 7–10 months CEL: Lung tumors (bronchioalveolar adenoma, adenocarcinoma, squamous cell carcinoma, or mixed tumor type) |\n\nScheduled sacrifice at 31 months; most surviving Cd-exposed rats sacrificed at 29-30 months due to mortality ≥75%\n\n| Oldiges et al. 1989 |  |  |  |  |  |  |  | Cadmium oxide dust |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| 40 | Rat (Wistar) 17–20 M, 16–20 F | 7–11 months 7 days/week 22 hours/day (WB) | 0, 0.090 | LE, GN, HP | Death Cancer | 0.09 | 0.09 | 25% mortality at 7–11 months CEL: Lung tumors (bronchioalveolar adenoma, adenocarcinoma, squamous cell carcinoma, or mixed tumor type) |\n\n| Scheduled sacrifice at 31 months |  |  |  |  |  |  |  |  |  |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Prigge 1978a |  |  |  |  |  |  |  | Cadmium oxide dust |  |\n| 41 | Rat (Wistar) 12 F | 90 days 24 hours/day (WB) | 0, 0.025, 0.052 | LE, BW, HE, BC, UR, OW, HP | Bd wt Resp | 0.025 | 0.025 | 0.052 | 23% decrease in body weight gain Proliferative lung lesions, histiocytic cell granulomas Increased hemoglobin and hematocrit |\n| 41 | Rat (Wistar) 12 F | 90 days 24 hours/day (WB) | 0, 0.025, 0.052 | LE, BW, HE, BC, UR, OW, HP | Hematoc | 0.025 | 0.052 | 0.052 | 23% decrease in body weight gain Proliferative lung lesions, histiocytic cell granulomas Increased hemoglobin and hematocrit |\n| 41 | Rat (Wistar) 12 F | 90 days 24 hours/day (WB) | 0, 0.025, 0.052 | LE, BW, HE, BC, UR, OW, HP | Hepatic Renal | 0.052 | 0.052 | 0.052 | 23% decrease in body weight gain Proliferative lung lesions, histiocytic cell granulomas Increased hemoglobin and hematocrit |\n\n| Prigge 1978a |  |  |  |  |  |  |  | Cadmium oxide dust |  |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| 42 | Rat (Wistar) 12 F | 63 days 24 hours/day (WB) | 0, 0.105 | LE, BW, HE, BC, UR | Death |  |  | 0.105 | 5/12 died |\n| 42 | Rat (Wistar) 12 F | 63 days 24 hours/day (WB) | 0, 0.105 | LE, BW, HE, BC, UR | Bd wt Hematoc |  |  | 0.105 | 51% decrease in body weight gain Increased hemoglobin and hematocrit |\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Prigge 1978b |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 43 | Rat (Wistar) 12–13 F | 21 days 24 hours/day (WB) | 0, 0.204, 0.394, 0.581 | BW, HE, BC, UR, OW, HP | Bd wt Hemato | 0.581 | 0.204 |  | Increase in hemoglobin and hematocrit |\n|  |  |  |  |  | Renal | 0.581 |  |  |  |\n| Prigge 1978b |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 44 | Rat (Wistar) 12–13 F | 21 days GDs 1–21 24 hours/day (WB) | 0, 0.204, 0.394, 0.581 | BW, HE, BC, UR, OW, HP, DX | Bd wt |  | 0.204 | 0.394 | LOAEL: 12% decrease in maternal body weight gain SLOAEL: 35% decrease in maternal body weight gain Increased hemoglobin and hematocrit; elevated total (but not direct) bilirubin |\n|  |  |  |  |  | Hemato | 0.394 | 0.581 |  |  |\n|  |  |  |  |  | Renal | 0.581 |  |  |  |\n|  |  |  |  |  | Develop | 0.394 |  | 0.581 | 19% decrease in fetal body weight; decreased fetal hemoglobin |\n| NTP 1995 |  |  |  |  |  |  |  |  | Cadmium oxide aerosol |\n| 45 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week 6.33 hours/day (WB) | 0, 0.021, 0.046, 0.088, 0.211, 0.910 | LE, CS, BW, OW, HP, RX | Bd wt Resp | 0.91 | 0.021 |  | Minimal alveolar histiocytic infiltrates and squamous metaplasia of the larynx |\n|  |  |  |  |  | Cardio | 0.91 |  |  |  |\n|  |  |  |  |  | Gastro | 0.91 |  |  |  |\n|  |  |  |  |  | Musc/skel | 0.91 |  |  |  |\n|  |  |  |  |  | Hepatic | 0.91 |  |  |  |\n|  |  |  |  |  | Renal | 0.91 |  |  |  |\n|  |  |  |  |  | Endocr | 0.91 |  |  |  |\n|  |  |  |  |  | Immuno | 0.91 |  |  |  |\n|  |  |  |  |  | Neuro | 0.91 |  |  |  |\n|  |  |  |  |  | Repro | 0.91 |  |  |  |\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Oberdörster et al. 1994 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 46 | Mouse (BALB/c) 72 M | 4 weeks 5 days/week 6 hours/day (WB) | 0, 0.100 | BI | Resp |  | 0.1 |  | Increase in BALF PMNs and LDH levels (1, 7, and 28 days post-exposure); increase cell proliferation in alveolar epithelium and macrophage infiltration (1 and 7 days post-exposure) |\n| Mice were sacrificed at 1, 7, or 28 days post-exposure (≥4/group/timepoint per endpoint) |  |  |  |  |  |  |  |  |  |\n| Johansson et al. 1984 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 47 | Rabbit (NS) 8 M | 4–6 weeks 5 days/week 6 hours/day (WB) | 0, 0.4 | BI, OW, HP | Resp |  | 0.4 |  | Lung interstitial inflammation, type 2 cell hyperplasia |\n| CHRONIC EXPOSURE |  |  |  |  |  |  |  |  |  |\n| Buchet et al. 1990; Hoo et al. 2004; Järup and Elinder 1994; Järup et al. 2000; Kobayashi et al. 2008; Lei et al. 2007; Shao et al. 2007; Suwazono et al. 2006; Uno et al. 2005; Wu et al. 2001; Zhang et al. 2016a |  |  |  |  |  |  |  |  | Cadmium |\n| 48 | Human 85–3,454 per dataset | 17 datasets (3 occupational and 8 general population cohorts) | UR | Renal |  |  |  | LMW proteinuria; 95% LCL weighted median of 17 UC10 values = 0.00106 mg Cd/m3 c |  |\n| Oldiges and Glaser 1986 |  |  |  |  |  |  |  |  | Cadmium sulfate |\n| 49 | Rat (Wistar) 20–40 M, 20 F | 413–455 days 7 days/week 22 hours/day (WB) | M: 0, 0.095 F: 0, 0.092 | LE, BW, FI, WI, HE, OW, GN | Death |  |  | 0.095 M | 6/20 died |\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Oldiges et al. 1989 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 50 | Rat (Wistar) 20 M, 18–20 F | 18 months 7 days/week 22 hours/day (WB) | 0, 0.030 | LE, GN, HP | Death Cancer |  |  | 0.03 M 0.03 | 75% mortality at 30 months CEL: Lung tumors (bronchioalveolar adenoma, adenocarcinoma, squamous cell carcinoma, or mixed tumor type) |\n| Scheduled sacrifice at 31 months; surviving Cd-exposed males sacrificed at 30 months due to mortality ≥75% |  |  |  |  |  |  |  |  |  |\n| Oldiges et al. 1989 |  |  |  |  |  |  |  |  | Cadmium sulfide |\n| 51 | Rat (Wistar) 19–20 M, 19–20 F | 16–18 months 7 days/week 22 hours/day (WB) | 0, 0.090, 0.270 | LE, GN, HP | Death Cancer |  |  | 0.09 0.270 | 75% mortality at 30 months in males 25% mortality at 16 months in females CEL: Lung tumors (bronchioalveolar adenoma, adenocarcinoma, squamous cell carcinoma, or mixed tumor type) |\n| Scheduled sacrifice at 31 months; surviving Cd-exposed rats sacrificed at 30 months due to mortality ≥75% |  |  |  |  |  |  |  |  |  |\n| Oldiges et al. 1989 |  |  |  |  |  |  |  |  | Cadmium oxide dust |\n| 52 | Rat (Wistar) 20 M, 20 F | 18 months 7 days/week 22 hours/day (WB) | 0, 0.030 | LE, GN, HP | Cancer |  |  | 0.03 | CEL: Lung tumors (bronchioalveolar adenoma, adenocarcinoma, squamous cell carcinoma, or mixed tumor type) |\n| Scheduled sacrifice at 31 months |  |  |  |  |  |  |  |  |  |\n| Oldiges et al. 1989 |  |  |  |  |  |  |  |  | Cadmium sulfate |\n| 53 | Rat (Wistar) 20 M, 20 F | 14–18 months 7 days/week 22 hours/day (WB) | 0, 0.09 | LE, GN, HP | Death Cancer |  |  | 0.09 | 25% mortality in males by 14 months; 75% mortality in females by 29 months CEL: Lung tumors (bronchioalveolar adenoma, adenocarcinoma, squamous cell carcinoma, or mixed tumor type) |\n\nScheduled sacrifice at 31 months; surviving Cd-exposed females sacrificed at 29 months due to mortality ≥75%\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Oldiges et al. 1989 |  |  |  |  |  |  |  |  | Cadmium oxide fume |\n| 54 | Rat (Wistar) 17–20 M | 18 months 7 days/week 22 hours/day (WB) | 0, 0.01, 0.03 | LE, GN, HP | Cancer |  |  | 0.03 | CEL: Lung tumors (bronchioalveolar adenoma, adenocarcinoma) |\n| Takenaka et al. 1983 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 55 | Rat (Wistar) 40–41 M | 18 months 7 days/week 23 hours/day (WB) | 0, 0.0134, 0.0257, 0.0508 | LE, BW, HP | Bd wt Cancer | 0.0508 |  | 0.0134 | CEL: Lung tumors (lung epidermoid carcinomas, or adenocarcinomas) |\n| Scheduled sacrifice at 31 months |  |  |  |  |  |  |  |  |  |\n\n<sup>a</sup>The number corresponds to entries in Figure 2-2; differences in levels of health effects between male and females are not indicated in Figure 2-2.  Where such \ndifferences exist, only the levels of effect for the most sensitive sex are presented.\n\n<sup>b</sup>Concentrations are expressed as mg Cd/m<sup>3</sup>. If concentrations were reported by the study authors in terms of the administered compound (e.g., cadmium chloride \n[CdCl2]), they were converted to the equivalent concentration in terms of the metal (i.e., cadmium [Cd])) for easy comparison across studies.  Conversion was based on \nthe ratio of the molecular weights using the following equation: Concentration in terms of administered compound x (molecular weight Cd/molecular weight administered \ncompound).\n\n<sup>c</sup>Used to derive a chronic-duration inhalation MRL of 0.0001 mg Cd/m<sup>3</sup> (0.1 μg Cd/m<sup>3</sup>).  The point of departure (POD) is based on the 95% lower confidence limit (LCL) \non the weighted median of the UC10 values from 17 datasets from 11 human studies; the weighted median and 95% LCL were 2.04 and 1.57 μg Cd/g Cr, respectively.  \nThese values were converted into inhalation concentration equivalents of 0.00141 and 0.00106 mg Cd/m<sup>3</sup>, respectively, using PBPK modeling.  The POD of 0.00106 mg \nCd/m<sup>3</sup> was divided by an uncertainty factor of 3 for human variability and a modifying factor of 3 for database deficiencies.  See Appendix A for more detailed information \nregarding the MRL.\n\n## Principal studies for the MRL\n\nALP = alkaline phosphatase; AP = acid phosphatase; BALF = bronchoalveolar lavage fluid; BC = serum (blood) chemistry; Bd wt or BW = body weight; BI = biochemical \nchanges; Cardio = cardiovascular; Cd = cadmium; CEL = cancer effect level; Cr = creatinine; CS = clinical signs; Develop = developmental; DX = developmental toxicity; \nEndocr = endocrine; F = female(s); FI = food intake; Gastro = gastrointestinal; GD = gestation day; GN = gross necropsy; (H) = head only; HE = hematology; \nHemato = hematological; HP = histopathology; Immuno = immunological; IX = immune function; LC50 = lethal concentration, 50% kill; LDH = lactate dehydrogenase; \nLE = lethality; LMW = low molecular weight; LOAEL = lowest-observed-adverse-effect level; M = male(s); MRL = Minimal Risk Level; Musc/skel = musculoskeletal; \n(N) = nose-only; Neuro = neurological; NOAEL = no-observed-adverse-effect level; NS = not specified; (occup) = occupational; OF = organ function; OW = organ weight; \nPMN = polymorphonuclear leukocyte; PND = postnatal day; Repro = reproductive; Resp = respiratory; RX = reproductive function; SLOAEL = serious lowest-observedadverse-effect level; UC10 = urinary cadmium level associated with 10% extra risk; UR = urinalysis; (WB) = whole body; WBC = white blood cell; WI = water intake\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Cadmium – Inhalation**\nAcute (≤14 days)\n\n**Figure 2-2. Levels of Significant Exposure to Cadmium – Inhalation, Acute (≤14 days) - Death**\n\n| Category | mg Cd/m3 |\n| --- | --- |\n| 1 | 9 |\n| 2R | 30 |\n| 9R | 9 |\n| 14R | 85 |\n| 15R | 65 |\n| 16M | 40 |\n| 19M | 9 |\n| 21H | 30 |\n\n**Figure 2-2. Levels of Significant Exposure to Cadmium – Inhalation, Acute (≤14 days) - Body Weight**\n\n| Category | Animal - NOAEL (mg Cd/m3) | Animal - LOAEL (mg Cd/m3) | Animal - SLOAEL (mg Cd/m3) |\n| --- | --- | --- | --- |\n| 3R | 0.4 | 4.5 |  |\n| 4R |  | 6.5 |  |\n| 5R | 0.23 | 4.5 |  |\n| 6R | 4.0 |  |  |\n| 8R | 17 |  |  |\n| 9R | 2.5 |  |  |\n| 10R | 6.0 |  |  |\n| 12R | 140 |  |  |\n| 13R | 110 |  |  |\n| 19M | 2.5 |  |  |\n| 20M | 0.4 | 1.7 |  |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Cadmium – Inhalation**\nAcute (≤14 days)\n\n| Category | Human - SLOAEL (mg Cd/m3) | Animal - NOAEL (mg Cd/m3) | Animal - LOAEL (mg Cd/m3) | Animal - SLOAEL (mg Cd/m3) |\n| --- | --- | --- | --- | --- |\n| 1 | 9 |  |  |  |\n| 4R |  | 6 |  |  |\n| 7R |  | 1.6 |  |  |\n| 9R |  | 0.08 |  | 9 |\n| 10R |  | 6 |  |  |\n| 11R |  |  |  | 100 |\n| 14R |  |  |  | 85 |\n| 15R |  |  |  | 65 |\n| 19M |  | 0.008 |  | 0.8 |\n| 22S |  | 1.1 |  | 10 |\n| 9R |  | 2.5 |  |  |\n| 19M |  | 2.7 |  |  |\n| 9R |  | 2.7 |  |  |\n| 19M |  | 2.7 |  |  |\n| 9R |  | 2.7 |  |  |\n| 19M |  | 2.7 |  |  |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Cadmium – Inhalation**\nAcute (≤14 days)\n\n**Figure 2-2. Levels of Significant Exposure to Cadmium – Inhalation (Acute ≤14 days)**\n\n| Category | Human - SLOAEL (mg Cd/m3) | Animal - NOAEL (mg Cd/m3) | Animal - SLOAEL (mg Cd/m3) | Animal - LOAEL (mg Cd/m3) | Animal - LD50/LC50 (mg Cd/m3) |\n| --- | --- | --- | --- | --- | --- |\n| Endocrine |  | 6 |  |  |  |\n| Immunological |  | 0.12 |  | 0.2 | 1.0 |\n| Neurolgical |  |  |  | 90 |  |\n| Reproductive |  |  |  | 17 |  |\n| Developmental |  | 0.045 | 1.7 | 0.35 |  |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Cadmium – Inhalation**\nIntermediate (15–364 days)\n\n**Figure 2-2. Levels of Significant Exposure to Cadmium – Inhalation Intermediate (15–364 days)**\n\n| Category | Death NOAEL (mg Cd/m3) | Death LOAEL (mg Cd/m3) | Body Weight NOAEL (mg Cd/m3) | Body Weight LOAEL (mg Cd/m3) |\n| --- | --- | --- | --- | --- |\n| 24R |  | 1.0 | 1.0 |  |\n| 25R |  | 1.0 | 0.17 | 1.0 |\n| 30R |  | 2.6 | 0.40 | 1.1 |\n| 31R |  | 2.6 | 0.40 | 1.1 |\n| 35R |  | 0.080 |  |  |\n| 36R |  | 0.80 |  |  |\n| 37R |  | 0.090 |  |  |\n| 38R |  | 0.33 |  |  |\n| 39R |  | 0.80 |  |  |\n| 40R |  | 0.090 |  |  |\n| 42R |  | 0.11 |  | 0.11 |\n| 26R |  |  | 0.11 |  |\n| 27R |  |  | 1.0 |  |\n| 28R |  |  | 0.10 |  |\n| 31R |  |  |  | 2.6 |\n| 32R |  |  | 0.90 |  |\n| 33R |  |  | 0.47 | 1.9 |\n| 41R |  |  | 0.028 | 0.055 |\n| 43R |  |  | 0.60 |  |\n| 44R |  |  |  | 0.44 |\n| 44R |  |  |  | 0.22 |\n| 45M |  |  | 0.90 |  |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Cadmium – Inhalation**\nIntermediate (15–364 days)\n\n**Figure 2-2. Levels of Significant Exposure to Cadmium – Inhalation Intermediate (15–364 days)**\n\n| Category | Respiratory Animal - NOAEL (mg Cd/m3) | Respiratory Animal - LOAEL (mg Cd/m3) | Respiratory Animal - SLOAEL (mg Cd/m3) | Respiratory Animal - Cancer Effect Level (mg Cd/m3) | Cardiovascular Animal - NOAEL (mg Cd/m3) | Cardiovascular Animal - LOAEL (mg Cd/m3) | Cardiovascular Animal - SLOAEL (mg Cd/m3) | Cardiovascular Animal - Cancer Effect Level (mg Cd/m3) | Gastrointestinal Animal - NOAEL (mg Cd/m3) | Gastrointestinal Animal - LOAEL (mg Cd/m3) | Gastrointestinal Animal - SLOAEL (mg Cd/m3) | Gastrointestinal Animal - Cancer Effect Level (mg Cd/m3) | Hematological Animal - NOAEL (mg Cd/m3) | Hematological Animal - LOAEL (mg Cd/m3) | Hematological Animal - SLOAEL (mg Cd/m3) | Hematological Animal - Cancer Effect Level (mg Cd/m3) |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| 26R | 0.11 |  |  |  |  |  |  |  |  |  |  |  | 0.11 |  |  |  |\n| 27R |  | 1.1 |  |  |  |  |  |  |  |  |  |  | 1.1 |  |  |  |\n| 28R |  | 0.10 |  |  |  |  |  |  |  |  |  |  |  | 0.10 |  |  |\n| 29R |  | 1.7 |  |  |  |  |  |  |  |  |  |  |  |  |  |  |\n| 32R |  | 0.023 | 0.90 |  | 0.90 |  |  |  | 0.90 |  |  |  | 0.90 |  |  |  |\n| 34R |  | 0.10 |  |  |  |  |  |  |  |  |  |  |  |  |  |  |\n| 41R |  | 0.026 |  |  |  |  |  |  |  |  |  |  | 0.026 | 0.050 |  |  |\n| 45M |  | 0.022 |  |  | 0.90 |  |  |  | 0.90 |  |  |  |  |  |  |  |\n| 46M |  | 0.10 |  |  |  |  |  |  |  |  |  |  |  |  |  |  |\n| 47H |  | 0.45 |  |  |  |  |  |  |  |  |  |  |  |  |  |  |\n| 42R |  |  |  |  |  |  |  |  |  |  |  |  |  | 0.11 |  |  |\n| 43R |  |  |  |  |  |  |  |  |  |  |  |  |  | 0.21 |  |  |\n| 44R |  |  |  |  |  |  |  |  |  |  |  |  | 0.45 |  | 0.60 |  |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Cadmium – Inhalation**\nIntermediate (15–364 days)\n\n**Figure 2-2. Levels of Significant Exposure to Cadmium – Inhalation Intermediate (15–364 days)**\n\n| Category | 32R (mg Cd/m3) | 45M (mg Cd/m3) | 41R (mg Cd/m3) | 26R (mg Cd/m3) | 27R (mg Cd/m3) | 28R (mg Cd/m3) | 32R (mg Cd/m3) | 43R (mg Cd/m3) | 44R (mg Cd/m3) | 45M (mg Cd/m3) | 32R (mg Cd/m3) | 45M (mg Cd/m3) | 32R (mg Cd/m3) | 45M (mg Cd/m3) |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Musculoskeletal | 0.9 | 0.9 |  |  |  |  |  |  |  |  |  |  |  |  |\n| Hepatic | 0.85 | 0.9 | 0.05 |  |  |  |  |  |  |  |  |  |  |  |\n| Renal |  |  |  | 0.11 | 1.1 | 0.1 | 0.9 | 0.55 | 0.55 | 0.85 |  |  |  |  |\n| Endocrine | 0.85 | 0.9 |  |  |  |  |  |  |  |  |  |  |  |  |\n| Immunological | 0.9 | 0.9 |  |  |  |  |  |  |  |  |  |  |  |  |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Cadmium – Inhalation**\nIntermediate (15–364 days)\n\n**Figure 2-2. Levels of Significant Exposure to Cadmium – Inhalation Intermediate (15–364 days)**\n\n| Category | Neurolgical mg Cd/m3 | Reproductive mg Cd/m3 | Developmental mg Cd/m3 | Cancer mg Cd/m3 |\n| --- | --- | --- | --- | --- |\n| 32R | 0.9 | 0.9 |  |  |\n| 45M | 0.9 | 0.9 |  |  |\n| 23R |  | 0.17 | 0.17 |  |\n| 24R |  | 1.0 | 0.17 |  |\n| 25R |  | 1.0 |  |  |\n| 25R |  | 0.18 |  |  |\n| 31R |  | 1.1 |  |  |\n| 32R |  | 0.24 |  |  |\n| 23R |  |  | 0.022 |  |\n| 24R |  |  | 0.022 |  |\n| 33R |  |  | 2.0 |  |\n| 33R |  |  | 0.53 |  |\n| 44R |  |  | 0.6 |  |\n| 44R |  |  | 0.5 |  |\n| 37R |  |  |  | 0.09 |\n| 39R |  |  |  | 0.75 |\n| 40R |  |  |  | 0.09 |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Cadmium – Inhalation**\nChronic (≥365 days)\n\n**Figure 2-2. Levels of Significant Exposure to Cadmium – Inhalation Chronic (≥365 days)**\n\n| Category | Death mg Cd/m3 | Body Weight mg Cd/m3 |\n| --- | --- | --- |\n| 49R | 0.095 |  |\n| 50R | 0.035 |  |\n| 51R | 0.090 |  |\n| 53R | 0.090 |  |\n| 55R |  | 0.050 |\n\n**Figure 2-2. Levels of Significant Exposure to Cadmium – Inhalation Chronic (≥365 days) - Renal**\n\n| Category | Human - Weighted median (mg Cd/m3) | Human - 95% lower confidence limit of weighted median (mg Cd/m3) |\n| --- | --- | --- |\n| 48 | 0.0014 | 0.00011 |\n\n**Figure 2-2. Levels of Significant Exposure to Cadmium – Inhalation Chronic (≥365 days) - Cancer**\n\n| Category | Animal - Cancer Effect Level (mg Cd/m3) |\n| --- | --- |\n| 50R | 0.033 |\n| 51R | 0.095 |\n| 52R | 0.033 |\n| 53R | 0.095 |\n| 54R | 0.033 |\n| 55R | 0.013 |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| ACUTE EXPOSURE |  |  |  |  |  |  |  |  |  |\n| Andjelkovic et al. 2019 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 1 | Rat (Wistar) 6–8 M | Once (GW) | 0, 15, 30 | HE, BC, HP | Hemato |  | 15 |  | Decreased RBC count, hemoglobin, hematocrit, lymphocyte, and serum iron levels; increased MCHC |\n| Baranski 1985 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 2 | Rat (Wistar) 6–18 F | 10 days GDs 7–16 (GW) | 0, 2, 12, 40 | BW, OW, DX | Bd wt |  | 2 | 12 | LOAEL: 14% decrease in maternal body weight gain SLOAEL: 34% decrease in maternal body weight gain |\n| 2 | Rat (Wistar) 6–18 F | 10 days GDs 7–16 (GW) | 0, 2, 12, 40 | BW, OW, DX | Develop | 2 | 12 | 40 | LOAEL: 9% decrease in fetal weight SLOAEL: 23% decrease in fetal weight, decreased live fetuses/litter, increased resorptions/litter, fetal malformations (fused lower limbs, absent limbs) |\n| Bomhard et al. 1987 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 3 | Rat (Wistar) 25–35 M | Once (GW) | 0, 50, 100, 200 | LE, BW, CS, FI, WI, HP | Death Repro | 50 |  | 100 | 28/35 died within 3 days Testicular necrosis, focal proliferation of Leydig cells (6 months post-exposure); hyperemia and slight hemorrhages in testes and epididymides in rats that died |\n| Surviving rats sacrificed 6–30 months post-exposure |  |  |  |  |  |  |  |  |  |\n| Borzelleca et al. 1989 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 4 | Rat (Sprague-Dawley) 10 M, 10 F | Once (GW) | 0, 15, 31, 65.6, 138 | LE, CS, BW, HE, BC, GN, OW | Death |  |  | 138 F 65.6 M | 2/10 died within 24 hours 3/10 died within 24 hours |\n| 4 | Rat (Sprague-Dawley) 10 M, 10 F | Once (GW) | 0, 15, 31, 65.6, 138 | LE, CS, BW, HE, BC, GN, OW | Bd wt Hemato Hepatic Renal | 138 138 138 |  |  |  |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Borzelleca et al. 1989 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 5 | Rat (Sprague-Dawley) 10 M, 10 F | 10 days (W) | M: 0, 1.1, 7.85, 11.2 F: 0, 1.1, 8.16, 13.9 | LE, CS, BW, HE, BC, UR, GN, OW, HP | Bd wt | 13.9 F 1.1 M | 7.85 M | 11.2 M | LOAEL: 14% decrease in body weight SLOAEL: 25% decrease in body weight |\n| 5 | Rat (Sprague-Dawley) 10 M, 10 F | 10 days (W) | M: 0, 1.1, 7.85, 11.2 F: 0, 1.1, 8.16, 13.9 | LE, CS, BW, HE, BC, UR, GN, OW, HP | Hematocrit | 13.9 F 11.2 M 13.9 F 11.2 M 13.9 F 11.2 M |  |  |  |\n| 5 | Rat (Sprague-Dawley) 10 M, 10 F | 10 days (W) | M: 0, 1.1, 7.85, 11.2 F: 0, 1.1, 8.16, 13.9 | LE, CS, BW, HE, BC, UR, GN, OW, HP | Renal | 13.9 F 11.2 M 13.9 F 11.2 M |  |  |  |\n| 5 | Rat (Sprague-Dawley) 10 M, 10 F | 10 days (W) | M: 0, 1.1, 7.85, 11.2 F: 0, 1.1, 8.16, 13.9 | LE, CS, BW, HE, BC, UR, GN, OW, HP | Repro | 13.9 F 11.2 M |  |  |  |\n| Borzelleca et al. 1989 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 6 | Rat (Sprague-Dawley) 10 M, 10 F | 10 days (GW) | 0, 15, 31, 65.6, 138 | LE, CS, BW, HE, BC, UR, GN, OW, HP | Death | 31 F | 65.6 F 15 M | 31 M | 3/10 males and 4/10 females died within 7 days 18% decrease in terminal body weight LOAEL: 18% decrease in terminal body weight SLOAEL: 23% decrease in terminal body weight Increased WBC and platelet counts Increased RBC count Elevated serum ALT, decreased serum cholesterol Mild focal necrosis of hepatocytes or congestion Mild focal necrosis of tubular epithelium |\n| 6 | Rat (Sprague-Dawley) 10 M, 10 F | 10 days (GW) | 0, 15, 31, 65.6, 138 | LE, CS, BW, HE, BC, UR, GN, OW, HP | Bd wt | 31 F | 65.6 F 15 M 31 F |  |  |\n| 6 | Rat (Sprague-Dawley) 10 M, 10 F | 10 days (GW) | 0, 15, 31, 65.6, 138 | LE, CS, BW, HE, BC, UR, GN, OW, HP | Hematocrit | 15 F | 65.6 F 15 M 31 F |  |  |\n| 6 | Rat (Sprague-Dawley) 10 M, 10 F | 10 days (GW) | 0, 15, 31, 65.6, 138 | LE, CS, BW, HE, BC, UR, GN, OW, HP | 65.6 M | 138 M 138 M |  |  |  |\n| 6 | Rat (Sprague-Dawley) 10 M, 10 F | 10 days (GW) | 0, 15, 31, 65.6, 138 | LE, CS, BW, HE, BC, UR, GN, OW, HP | Renal | 31 F | 65.6 F |  |  |\n\n***DRAFT FOR PUBLIC COMMENT***\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n|  |  |  |  |  | Repro | 65.6 M 138 F 31 M | 138 M |  | Mild focal necrosis of tubular epithelium |\n|  |  |  |  |  | Repro | 65.6 M 138 F 31 M | 138 M | 65.6 M | Necrotic changes in testes with atrophy and loss of spermatogenic elements |\n| Dixon et al. 1976 |  |  |  |  |  |  |  |  |  |\n| 7 | Rat (Sprague-Dawley) 10 M | Once (GW) | 0, 6.25, 12.5, 25 | RX | Repro | 25 |  |  | Cadmium chloride |\n| Males serially mated to untreated females for 70 days post-treatment |  |  |  |  |  |  |  |  |  |\n| Kostial et al. 1978 |  |  |  |  |  |  |  |  |  |\n| 8 | Rat (NS) 6 B | Once (G) | NS | LE | Death |  |  | 29 | Cadmium chloride LD50 calculated 8 days post-exposure |\n| Age at exposure: 2 weeks |  |  |  |  |  |  |  |  |  |\n| Kostial et al. 1978 |  |  |  |  |  |  |  |  |  |\n| 9 | Rat (NS) 6 B | Once (G) | NS | LE | Death |  |  | 147 | Cadmium chloride LD50 calculated 8 days post-exposure |\n| Age at exposure: 3 weeks |  |  |  |  |  |  |  |  |  |\n| Kostial et al. 1978 |  |  |  |  |  |  |  |  |  |\n| 10 | Rat (NS) 6 B | Once (G) | NS | LE | Death |  |  | 129 | Cadmium chloride LD50 calculated 8 days post-exposure |\n| Age at exposure: 6 weeks |  |  |  |  |  |  |  |  |  |\n| Kostial et al. 1978 |  |  |  |  |  |  |  |  |  |\n| 11 | Rat (NS) 6 B | Once (G) | NS | LE | Death |  |  | 104 | Cadmium chloride LD50 calculated 8 days post-exposure |\n| Age at exposure: 18 weeks |  |  |  |  |  |  |  |  |  |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Kostial et al. 1978 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 12 | Rat (NS) 6 B | Once (G) | NS | LE | Death |  |  | 66.8 | LD50 calculated 8 days post-exposure |\n| Age at exposure: 54 weeks |  |  |  |  |  |  |  |  |  |\n| Kotsonis and Klaassen 1977 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 13 | Rat (Sprague-Dawley) 6 M | Once (premating) (GW) | 0, 25, 50, 100, 150 | HP, RX, NX | Neuro Repro | 25 50 | 50 | 100 | Decreased motor activity Testicular necrosis; decreased spermatogenesis; decreased fertility (fewer females producing pups) |\n| Males mated to unexposed females |  |  |  |  |  |  |  |  |  |\n| Kotsonis and Klaassen 1977 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 14 | Rat (Sprague-Dawley) 6–12 M | Once (GW) | 0, 25, 50, 100, 150 | CS, BW, HE, BC, BI, UR, HP, OF | Bd wt Resp Cardio Gastro Hematoc Hepatic Renal Endocr | 100 150 150 150 150 150 |  | 150 | Initial body weight loss resulting in approximate 10% decrease in terminal body weight (2 weeks post-exposure) |\n| Kotsonis and Klaassen 1977 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 15 | Rat (Sprague-Dawley) 15–20 M | Once (GW) | NS | LE | Death |  |  | 225 | LD50 at 14 days |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Kotsonis and Klaassen 1978 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 16 | Rat (Sprague-Dawley) 9 M | 2 weeks (W) | 0, 42 | LE | Death |  |  | 42 | 7/9 died within 2 weeks |\n| Machemer and Lorke 1981 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 17 | Rat (Long-Evans) 22–28 F | 10 days GDs 6–15 (GW) | 0, 1.84, 6.13, 18.39, 61.32 | LE, CS, BW, DX | Death Bd wt | 1.84 |  | 61.32 6.13 | 15/25 dams died 27% decrease in maternal body weight gain during treatment period |\n| 17 | Rat (Long-Evans) 22–28 F | 10 days GDs 6–15 (GW) | 0, 1.84, 6.13, 18.39, 61.32 | LE, CS, BW, DX | Gastro | 18.39 |  | 61.32 | Intestinal necrosis, hemorrhage, ulcers, constipation/absence of defecation |\n| 17 | Rat (Long-Evans) 22–28 F | 10 days GDs 6–15 (GW) | 0, 1.84, 6.13, 18.39, 61.32 | LE, CS, BW, DX | Dermal Develop | 1.84 6.13 | 6.13 | 18.39 | Coarse fur Increased number of fetuses with malformations, increased number of runts (<3 g), 7% decrease in fetal body weight |\n| Machemer and Lorke 1981 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 18 | Rat (Long-Evans) 21–24 F | 10 days GDs 6–15 (F) | 0, 1.2, 3.5, 12.5 | LE, CS, BW, FI, DX | Bd wt | 3.5 | 12.5 |  | 19% decrease in maternal body weight gain during treatment period |\n| 18 | Rat (Long-Evans) 21–24 F | 10 days GDs 6–15 (F) | 0, 1.2, 3.5, 12.5 | LE, CS, BW, FI, DX | Develop | 12.5 |  |  |  |\n| Saedi et al. 2020a, 2020b |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 19 | Rat (Sprague-Dawley) 4 F | 13 days PNDs 21–33 (GW) | 0, 15, 31, 46 | BW, BC, HE, OW, HP, DX | Bd wt Hemato | Endocr Develop | 46 15 | 15 | 21% decrease in terminal body weight Decreased RBC and increased WBC levels |\n| 19 | Rat (Sprague-Dawley) 4 F | 13 days PNDs 21–33 (GW) | 0, 15, 31, 46 | BW, BC, HE, OW, HP, DX | Hemat | 15 | 46 15 | 15 | 21% decrease in terminal body weight Decreased RBC and increased WBC levels |\n| 19 | Rat (Sprague-Dawley) 4 F | 13 days PNDs 21–33 (GW) | 0, 15, 31, 46 | BW, BC, HE, OW, HP, DX | Develop | 46 15 | 31 | 15 | Increased atretic follicles and decreased secondary follicles in ovaries; decreased serum estradiol levels |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Samuel et al. 2011 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 20 | Rat (Wistar) 18 F | 13 days GDs 9–21 (W) | 0, 6, 18 | BW, FI, WI, DX | Bd wt | 6 | 18 |  | 11% decrease in maternal body weight on GD 21 |\n| 20 | Rat (Wistar) 18 F | 13 days GDs 9–21 (W) | 0, 6, 18 | BW, FI, WI, DX | Develop |  |  | 6 | Fetal effects: Increased resorption Postnatal effects (female offspring): Decreased postnatal weight on PND 10 (22%) and PND 21 (14%), ovarian follicular degeneration, decreased estradiol and testosterone, delayed vaginal opening, and altered estrous cycling |\n| 20 | Rat (Wistar) 18 F | 13 days GDs 9–21 (W) | 0, 6, 18 | BW, FI, WI, DX | Other noncancer | 6 | 18 |  | Decreased maternal food intake |\n| Three dams/group were sacrificed on GD 21; remaining offspring were sacrificed on PND 10, PND 21, or evaluated during puberty |  |  |  |  |  |  |  |  |  |\n| Shimizu and Morita 1990 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 21 | Rat (Sprague-Dawley) 10 M | Once (GW) | NS | LE | Death |  |  | 106.9 | LD50 at 24 hours (fasted rats) |\n| Shimizu and Morita 1990 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 22 | Rat (Sprague-Dawley) 10 M | Once (GW) | NS | LE | Death |  |  | 327.3 | LD50 at 24 hours (fed rats) |\n| Stacey et al. 1988 |  |  |  |  |  |  |  |  | Cadmium acetate |\n| 23 | Rat (Sprague-Dawley) 4 M | 6 weeks 5 days/week (G) | 0, 0.0025, 0.025, 0.250 | BW, OW, IX | Bd wt | 0.25 |  |  | Enhanced spleen cell proliferative responses |\n| 23 | Rat (Sprague-Dawley) 4 M | 6 weeks 5 days/week (G) | 0, 0.0025, 0.025, 0.250 | BW, OW, IX | Immuno | 0.025 | 0.25 |  | Enhanced spleen cell proliferative responses |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Stacey et al. 1988 |  |  |  |  |  |  |  |  | Cadmium acetate |\n| 24 | Rat (Sprague-Dawley) 4 M | 2 weeks 5 days/week (G) | 0, 0.0025, 0.025, 0.250 | BW, OW, IX | Bd wt Immuno | 0.25 0.25 |  |  |  |\n| Wan et al. 2022 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 25 | Rat (Sprague-Dawley) 3 M, 3 F | 2 weeks (G) | 0, 2, 4 | BW, WI, BC, UR, OW, HP | Bd wt Renal | 4 | 2c |  | Increased 24-hour urinary protein excretion, elevated urinary β 2M levels, increased serum BUN |\n| Andersen et al. 1988 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 26 | Mouse (CBA/Bom) 7–42 M | Once (GW) | 0, 0.6, 3.9, 7.9, 15.7, 30.3, 59.6, 88.8 | LE, HP | Death Gastro | 15.7 | 30.3 | 88.8 | 36/42 mice died within 10 days LOAEL: Gastritis and enteritis SLOAEL: Severe gastric necrosis Fatty infiltration of liver cells, occasional hepatocellular necrosis Proximal tubular necrosis with poor cell differentiation and irregular granulation of cells Testicular necrosis in most tubules and interstitial tissue |\n| 26 | Mouse (CBA/Bom) 7–42 M | Once (GW) | 0, 0.6, 3.9, 7.9, 15.7, 30.3, 59.6, 88.8 | LE, HP | Hepatic | 15.7 | 30.3 | 88.8 | 36/42 mice died within 10 days LOAEL: Gastritis and enteritis SLOAEL: Severe gastric necrosis Fatty infiltration of liver cells, occasional hepatocellular necrosis Proximal tubular necrosis with poor cell differentiation and irregular granulation of cells Testicular necrosis in most tubules and interstitial tissue |\n| 26 | Mouse (CBA/Bom) 7–42 M | Once (GW) | 0, 0.6, 3.9, 7.9, 15.7, 30.3, 59.6, 88.8 | LE, HP | Renal | 59.6 |  | 88.8 | 36/42 mice died within 10 days LOAEL: Gastritis and enteritis SLOAEL: Severe gastric necrosis Fatty infiltration of liver cells, occasional hepatocellular necrosis Proximal tubular necrosis with poor cell differentiation and irregular granulation of cells Testicular necrosis in most tubules and interstitial tissue |\n| 26 | Mouse (CBA/Bom) 7–42 M | Once (GW) | 0, 0.6, 3.9, 7.9, 15.7, 30.3, 59.6, 88.8 | LE, HP | Repro | 30.3 |  | 59.6 | 36/42 mice died within 10 days LOAEL: Gastritis and enteritis SLOAEL: Severe gastric necrosis Fatty infiltration of liver cells, occasional hepatocellular necrosis Proximal tubular necrosis with poor cell differentiation and irregular granulation of cells Testicular necrosis in most tubules and interstitial tissue |\n| Ara et al. 2016 |  |  |  |  |  |  |  |  | Form not specified |\n| 27 | Mouse (Swiss-Webster) 5 F | 7 days GDs 6–12 (GW) | 0, 3.13, 6.25, 12.5, 25.0 | RX, DX | Develop |  |  | 3.13 | 49% decrease in fetal body weight; decreased crown-rump length, head and eye circumference, and forelimb, hindlimb and tail length; anomalies in the brain, eyes, forelimbs, hindlimbs, and tail |\n| Baer and Benson 1987 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 28 | Mouse (Swiss-Webster) 10 M | Once (GW) | 100, 150 | LE | Death |  |  | 95.5 | LD50 at 96 hours |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Yi et al. 2021a |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 29 | Mouse (ICR) 13 F | 10 days GDs 8–17 (W) | 0, 8.1, 24 | DX | Develop |  | 8.1 |  | Impaired glucose tolerance in adult male offspring |\n| INTERMEDIATE EXPOSURE |  |  |  |  |  |  |  |  |  |\n| Chopra et al. 1984 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 30 | Monkey (Rhesus) 3–4 M | 6 months (F) | 0, 5 | CS, BW, IX | Bd wt Immuno | 5 5 |  |  |  |\n| Afolabi et al. 2012 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 31 | Rat (Wistar) 8 M | 7 weeks (W) | 0, 4.6, 9.1 | BW, BC, BI | Hepatic Immuno |  | 4.6 4.6 |  | Increased plasma lipid levels Increased plasma pro-inflammatory cytokines |\n| Ali et al. 1986 |  |  |  |  |  |  |  |  | Cadmium acetate |\n| 32 | Rat (Wistar) 10 F | 21 days GDs 1–21 (W) | 0, 0.706, 1.2 | BW, FI, WI, RX, DX | Bd wt Repro Develop | 1.2 1.2 | 0.706 | 1.2 | Decreased offspring body weight, persisting through PND 45 (~20%) Delayed development of sensory motor coordination reflexes; altered motor activity (increased PNDs 7–21; decreased PND 60) |\n| Aprioku et al. 2014 |  |  |  |  |  |  |  |  | Cadmium sulfate |\n| 33 | Rat (Wistar) 8 F | 21 days GDs 0–20 (W) | 0, 4, 8 | BW, OW, HP, RX, DX | Bd wt Repro Develop |  | 4 | 4 | 40% decrease in maternal body weight on GD 20 Increased abortions |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Baranski 1987 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 34 | Rat (Wistar) 12–16 F | 20 days GDs 1–20 (W) | 0, 4.6, 11.1 | LE, BW, FI, WI, HE, BC, DX | Bd wt Repro Develop | 11.1 |  | 4.6 | 37% decrease in maternal body weight gain |\n| 34 | Rat (Wistar) 12–16 F | 20 days GDs 1–20 (W) | 0, 4.6, 11.1 | LE, BW, FI, WI, HE, BC, DX | Bd wt Repro Develop | 11.1 |  | 4.6 | 12% decrease in fetal body weight and 7% decrease in fetal body length |\n| 34 | Rat (Wistar) 12–16 F | 20 days GDs 1–20 (W) | 0, 4.6, 11.1 | LE, BW, FI, WI, HE, BC, DX | Other noncancer |  | 4.6 |  | Decreased maternal food intake |\n| Baranski and Sitarek 1987 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 35 | Rat (Wistar) 11–13 F | 14 weeks 5 days/week (GW) | 0, 0.04, 0.4, 4, 40 | LE, CS, BW, RX | Death |  |  | 40 | 4/13 died by week 8; 7/13 by week 14 |\n| 35 | Rat (Wistar) 11–13 F | 14 weeks 5 days/week (GW) | 0, 0.04, 0.4, 4, 40 | LE, CS, BW, RX | Bd wt Repro | 0.4 |  | 4 | 40% decrease in body weight gain |\n| 35 | Rat (Wistar) 11–13 F | 14 weeks 5 days/week (GW) | 0, 0.04, 0.4, 4, 40 | LE, CS, BW, RX | Bd wt Repro | 4 |  | 40 | Increased duration of estrus cycle |\n| Baranski et al. 1983 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 36 | Rat (Wistar) NS F | 11 weeks (5 weeks premating, 3 weeks mating, 3 weeks gestation) 5 days/week (GW) | 0, 0.04, 0.4, 4 | RX, DX | Repro Develop | 4 |  |  | Decreased pup locomotor activity and impaired motor coordination at 2 months |\n| 36 | Rat (Wistar) NS F | 11 weeks (5 weeks premating, 3 weeks mating, 3 weeks gestation) 5 days/week (GW) | 0, 0.04, 0.4, 4 | RX, DX | Repro Develop | 4 | 0.04 |  | Decreased pup locomotor activity and impaired motor coordination at 2 months |\n| Half of dams were sacrificed on GD 21; half were allowed to deliver naturally and pups (8/sex/group) were assessed for 2 months after parturition |  |  |  |  |  |  |  |  |  |\n| Brzóska and Moniuszko-Jakoniuk 2005a, 2005b; 2010 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 37 | Rat (Wistar) 10 M | 12 months (W) | 0, 0.2, 0.5, 4 | BW, FI, WI, BC, BI, HP | Bd wt Musc/skel | 4 |  |  | Increased lumbar spine deformities, decreased in lumbar spine and femur mineralization, altered bone turnover parameters |\n| 37 | Rat (Wistar) 10 M | 12 months (W) | 0, 0.2, 0.5, 4 | BW, FI, WI, BC, BI, HP | Bd wt Musc/skel | 0.2 | 0.5 |  | Increased lumbar spine deformities, decreased in lumbar spine and femur mineralization, altered bone turnover parameters |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Brzóska and Moniuszko-Jakoniuk 2005c; Brzóska et al. 2005a, 2005c |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 38 | Rat (Wistar) 40 F | 12 months (W) | 0, 0.2, 0.5, 4 | BW, FI, WI, BC, BI, HP, OF | Bd wt Musc/skel | 4 | 0.2 |  | Decreased bone mineralization, mechanical properties of tibia and femur, and altered bone turnover parameters |\n| Brzóska et al. 2004, 2005b |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 39 | Rat (Wistar) 8–10 F | 12 months (W) | 0, 0.3, 0.7, 4, 8 | BW, FI, WI, BI, OF | Musc/skel |  | 0.3 |  | Alterations in bone mineral content and density and mechanical properties of lumbar vertebral and femoral bones |\n| Buha et al. 2013, 2019 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 40 | Rat (Wistar) 7 M | 28 days (G) | 0, 0.3, 0.6, 1.25, 2.5, 5, 10 | BW, BC, BI | Bd wt Musc/skel | 0.6 | 0.3 | 1.25 | 36% decrease in body weight gain Decreased bone mineral content in femur Increased serum creatinine and urea Decreased serum T3 levels |\n|  |  |  |  |  | Renal Endocr | 2.5 | 5 0.3 |  |  |\n| Caride et al. 2010 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 41 | Rat (Sprague-Dawley) 60 M | 30 days (W) | 0, 0.92, 1.8 | BC | Endocr |  | 0.92 |  | Altered daily secretory pattern of ACTH and growth hormone; increased median levels of ACTH and TSH |\n| Carmignani and Boscolo 1984 |  |  |  |  |  |  |  |  | Cadmium acetate |\n| 42 | Rat (Sprague-Dawley) 10 M | 190 days (W) | 0, 1.4, 2.8 | CS, BW, OF | Bd wt Cardio | 2.8 | 1.4 |  | Increased systolic and diastolic blood pressure |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Chen et al. 2013 |  |  |  |  |  |  |  |  | Form not specified |\n| 43 | Rat (Sprague-Dawley) 6 M | 12 weeks (W) | 0, 0.2, 1.1, 5.0 | BW, BC, BI, UR, HP | Bd wt Musc/skel | 5 | 0.2 |  | Trabecular bone damage in tibia (decreased number, thickness; increased separation, increased dissociated ends); altered bone turnover parameters |\n| Cifone et al. 1989 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 44 | Rat (Wistar) 4 F | 170 days (W) | 0, 29, 58 | CS, BW, FI, WI, OW, IX | Bd wt Immuno | 58 | 29 |  | Biphasic decrease (first 30–50 days) then increase in NK cell activity, splenic cellularity, and the number of large granular lymphocytes in the peripheral blood; increased total peripheral lymphocytes |\n| Desi et al. 1998 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 45 | Rat (Wistar) NS F | 94 days F0: GDs 5–15 + PNDs 2–28 F1: PNWs 5–12 5 days/week (GW) | 0, 3.5, 7.0, 14.0 | DX | Develop | 3.5 | 7 |  | Decreased peripheral nerve conduction velocity with increased refractory periods |\n| Locomotor and sensory function assessed in F1 males at 12 weeks of age |  |  |  |  |  |  |  |  |  |\n| Desi et al. 1998 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 46 | Rat (Wistar) NS F | 11 days GDs 5–15 (GW) | 0, 3.5, 7.0, 14.0 | DX | Develop | 14 |  |  |  |\n| Locomotor and sensory function assessed in F1 males at 12 weeks of age |  |  |  |  |  |  |  |  |  |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Desi et al. 1998 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 47 | Rat (Wistar) NS F | 38 days GDs 5–15 plus PNDs 2–28 (GW) | 0, 3.5, 7.0, 14.0 | DX | Develop | 3.5 | 7 |  | Decreased horizontal ambulation and rearing activity |\n| Locomotor and sensory function assessed in F1 males at 12 weeks of age |  |  |  |  |  |  |  |  |  |\n| Dixon et al. 1976 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 48 | Rat (Sprague-Dawley) 10 M | 30–90 days (W) | 0, 0.00014, 0.0014, 0.014 | BC, OW, RX | Repro | 0.014 |  |  |  |\n| Males mated to untreated females |  |  |  |  |  |  |  |  |  |\n| Feng et al. 2019 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 49 | Rat (Sprague-Dawley) NS F | 6 weeks GD 0 to PND 21 (W) | 0, 0.6, 3 | DX | Develop |  | 0.6 |  | Impaired learning and memory in F1 males at PNDs 35 and 56 |\n| Huang et al. 2020 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 50 | Rat (Sprague-Dawley) <10 F | 3 weeks GD 1 to birth (GW) | 0, 0.3, 1.2, 4.9 | DX | Develop |  | 0.3 |  | F1 males: Decreased serum testosterone and increased seminiferous tubule diameter at PND 21; decreased Johnsen score (decreased testicular maturity) on PND 56 |\n| Iqbal et al. 2021 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 51 | Rat (Sprague-Dawley) 6 M | 17 days (GW) | 0, 5, 10, 15 | BW, OW, HP | Bd wt | 10 |  | 15 | 12% body weight loss during exposure (compared to 12% body weight gain in control) |\n|  |  |  |  |  | Repro | 5 | 10 |  | Structural changes in the testis and epididymis |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\nstimulated plasma insulin levels\n\nAltered glucose tolerance at PND 21\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects | Cadmium chloride |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Jacquet et al. 2018 |  |  |  |  |  |  |  |  |  |  |\n| 52 | Rat (Wistar) 9 M, 9 F | 12 weeks (W) | M: 0, 0.0053, 0.0558, 0.515; F: 0, 0.0055, 0.053, 0.4959 | LE, BW, BC, UR, OW, OF | Bd wt | 0.4959 F 0.515 M 0.4959 F 0.515 M Endocr | 0.053 F |  |  |  |\n| Jacquet et al. 2019 |  |  |  |  |  |  |  |  |  |  |\n| 53 | Rat (Wistar) 15–17 F | 11 weeks 3 weeks prior to mating GD 0–PND 35 (W) | 0, 0, 0.05, 0.5 | UR, RX, DX | Renal Repro Develop | 0.5 0.5 | 0.05 |  |  | Cadmium chloride |\n| Dams were sacrificed on PND 35; pups were sacrificed on PND 21, 26, and 60 |  |  |  |  |  |  |  |  |  |  |\n| Kelman et al. 1978 |  |  |  |  |  |  |  |  |  |  |\n| 54 | Rat (Sprague-Dawley) 15 F | 22 days GDs 0–21 (W) | 0, 1.5, 3.8 | HE, BI, DX | Hemato Musc/skel Develop | 3.8 | 1.5 | 1.5 | Decreased hematocrit | Form not specified |\n| Kotsonis and Klaassen 1978 |  |  |  |  |  |  |  |  |  |  |\n| 55 | Rat (Sprague-Dawley) 6 M | 24 weeks (W) | 0, 1.1, 2.92, 8.49 | CS, BW, FI, WI, HE, BC, BI, OW, HP, OF, RX, NX | Bd wt Resp Cardio Gastro Hemato Musc/skel Hepatic Renal Endocr | 8.49 8.49 8.49 8.49 8.49 1.1 | 8.49 8.49 8.49 1.1 | 8.49 8.49 8.49 1.1 | 8.49 8.49 8.49 1.1 | Cadmium chloride |\n\nProteinuria (starting at week 6)\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n|  |  |  |  |  | Immuno Neuro Repro | 8.49 1.1 8.49 | 2.92 |  | Decreased motor activity (starting at week 3) |\n| Males mated to unexposed females |  |  |  |  |  |  |  |  |  |\n| Kulas et al. 2019 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 56 | Rat (Dark Agouti) 8 M | 30 days (W) | 0, 0.35, 3.51 | OW, HP | Resp |  | 0.35 |  | Minimal to mild perivascular edema and respiratory epithelial desquamation in lungs |\n| Larregle et al. 2008 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 57 | Rat (Wistar) 8 M | 8 weeks daily (W) | 0, 18 | BC | Hepatic |  | 18 |  | Increased serum and liver triglyceride levels; increased serum cholesterol levels |\n| Li et al. 2018 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 58 | Rat (Sprague-Dawley) 10 F | 42 days GD 0-PND 21 (GW) | 0, 0.6, 3 | DX | Develop |  | 0.6 |  | F1 females: Decreased primordial follicles (PND 21) and increased serum estradiol (PND 21, PND 35) F2: females: Increased serum progesterone (PND 21) |\n| Liu et al. 2019 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 59 | Rat (Sprague-Dawley) 10 M | 60 days (G) | 0, 0.6, 1.5, 3 | CS, FI, WI, BW, BC, UR, OW, HP | Bd wt |  |  | 1.5 | 20% decrease in terminal body weights Decreased serum iron Increased BUN and serum creatinine |\n| Liu et al. 2020 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 60 | Rat (Sprague-Dawley) 5 F | 20 days GDs 1-21 (GW) | 0, 0.3, 1.2, 4.9 | DX | Develop |  | 0.3 |  | Decreased ovarian granulosa cell progesterone in F1 female offspring on PND 56 |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects | Cadmium chloride |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Loeser and Lorke 1977 |  |  |  |  |  |  |  |  |  |  |\n| 61 | Rat (Wistar) 20 M, 20 F | 3 months (F) | 0, 0.1, 0.3, 1, 3 | HP, BC, CS, UR, OW, OF, BW, FI | Bd wt Cardio Hematoc Hepatic Renal Endocr Immuno Repro | 3 3 3 3 3 3 | 0.439 | Decreased offspring body weights (by up to ~19% on PNW 9) | Cadmium chloride |  |\n| Luo et al. 2015 |  |  |  |  |  |  |  |  |  |  |\n| 62 | Rat (Sprague-Dawley) 10 F | 42 days GD 0-PND 21 (W) | 0, 0.089, 0.439, 0.955 | BW, RX, DX | Bd wt Repro Develop | 0.955 0.955 0.089 |  | 0.439 | Decreased offspring body weights (by up to ~19% on PNW 9) | Cadmium chloride |\n| McCalla et al. 2024 |  |  |  |  |  |  |  |  |  |  |\n| 63 | Rat (Sprague-Dawley) 10 M | 8 weeks 3 times/week (GW) | 0, 2.5, 5 | BW, HE, OF | Cardio Hematoc | 2.5 | 2.5 5 |  | Increased blood pressure Decreased mean cell volume and mean cell hemoglobin; increased red cell distribution width | Cadmium chloride |\n| Muller et al. 1988 |  |  |  |  |  |  |  |  |  |  |\n| 64 | Rat (Sprague-Dawley) 4 M | 6 weeks 5 days/week (GW) | 0, 0.0025, 0.025, 0.25 | BW, BC, BI, OW | Bd wt Hepatic | 0.25 0.25 |  |  |  | Cadmium acetate |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Nagymajtenyi et al. 1997 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 65 | Rat (Wistar) 5 M, 10 F | 3 generations ~16–18 weeks per generation (GW) | 0, 3.5, 7.0, 14.0 | CS, BW, RX, DX | Bd wt Repro Develop | 14 14 3.5 M | 7 M |  | Decreased tail nerve conduction velocity (all generations); prolonged latency and duration of somatosensory evoked potentials (F2, F3); increased frequency in auditory and visual evoked potentials (F3); 5% decrease in F3 body weight at PNW 12 |\n| Nasiadek et al. 2018 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 66 | Rat (Wistar) 20 F | 30 days (GW) | 0, 0.09, 1.8, 4.5 | CS, BW, BC, OW, HP | Bd wt Repro | 4.5 0.09 | 1.8 |  | Decreased plasma estradiol |\n| Nasiadek et al. 2019 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 67 | Rat (Wistar) 24 F | 90 days (GW) | 0, 0.09, 0.9, 1.8, 4.5 | LE, CS, BW, FI, WI, BC, OW, HP | Bd wt Repro | 4.5 0.09 | 0.9 |  | Decreased plasma estradiol |\n| Nation et al. 1984 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 68 | Rat (Sprague-Dawley) 9 M | 55 days (F) | 0, 1, 5 | CS, NX | Neuro | 1 | 5 |  | Increased anxiety-like behavior (passive avoidance) |\n| Ninkov et al. 2016 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 69 | Rat (Albino Oxford) 8–16 M | 30 days (W) | 0, 0.4, 4.1 | OW, HP, IX | Gastro Immuno | 4.1 | 0.4 |  | Increased intestinal lymphocyte counts, and mesenteric lymph node relative weight and cellularity; decreased spleen cell proliferative response |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Ogoshi et al. 1989 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 70 | Rat (NS) 19–22 F | 4 weeks (W) | 0, 1, 2.5 | BW, HE, BC, BI, OF | Bd wt Hemato | 2.5 | 1 |  | Decreased hematocrit, hemoglobin, MCHC, and MCV |\n|  |  |  |  |  | Musc/skel |  | 1 |  | Decreased bone strength |\n| Weanling rats (21-day-old) |  |  |  |  |  |  |  |  |  |\n| Ogoshi et al. 1989 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 71 | Rat (NS) 18–25 NS | 4 weeks (W) | 0, 1.6, 3.3, 6.6, 13, 26.2 | BW, HE, BC, BI, OF | Bd wt Hemato | 26.2 | 13 |  | Decreased hematocrit and MCV |\n|  |  |  |  |  | Musc/skel | 6.6 |  |  |  |\n| Adult rats (24-week-old) |  |  |  |  |  |  |  |  |  |\n| Ogoshi et al. 1989 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 72 | Rat (NS) 25–27 NS | 4 weeks (W) | 0, 11, 21.5 | BW, HE, BC, BI, OF | Bd wt Hemato | 11 | 21.5 |  | 10% decrease in body weight gain |\n|  |  |  |  |  | Musc/skel | 21.5 |  |  | Decreased hemoglobin and MCHC |\n| Aged rats (1.5-year-old) |  |  |  |  |  |  |  |  |  |\n| Oluranti et al. 2021 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 73 | Rat (Wistar) 5 M | 21 days (G) | 0, 3, 18 | BC, BI, OW | Endocr |  | 3 |  | Decreased plasma insulin and glucose levels |\n| Petering et al. 1979 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 74 | Rat (Sprague-Dawley) 5 F | 111 days (90 days prior mating through GD 21) (W) | 0, 0.56, 1.3, 2.61, 5.23 | HE, RX, DX | Repro Develop | 5.23 | 1.3 | 2.61 | 10% decrease in birth weight |\n| Prigge 1978a |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 75 | Rat (Wistar) 12 F | 90 days (W) | 0, 3.8, 7.6, 15.2 | LE, BW, HE, BC, BI, UR, OW | Bd wt Hemato | 3.8 | 3.8 | 7.6 | 28% decrease in body weight gain |\n|  |  |  |  |  | Renal | 3.8 | 7.6 |  | Decreased serum iron |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Sarmiento-Ortega et al. 2017 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 76 | Rat (Wistar) 10 M | 3, 4, or 5 months (W) | 0, 2.94 | BC, OF | Hepatic |  | 2.94 |  | Increased serum and hepatic lipid concentrations |\n| 76 | Rat (Wistar) 10 M | 3, 4, or 5 months (W) | 0, 2.94 | BC, OF | Endocr |  | 2.94 |  | Increased serum glucose and insulin levels following administration of an oral glucose load |\n| 76 | Rat (Wistar) 10 M | 3, 4, or 5 months (W) | 0, 2.94 | BC, OF | Other noncancer |  | 2.94 |  | Increased abdominal circumference, body mass index, and percentage of body fat |\n| Sorell and Graziano 1990 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 77 | Rat (Sprague-Dawley) 42–66 F | 15 days GDs 6–20 (W) | 0, 0.629, 4.714, 8.171 | BW, WI, HE, DX | Bd wt | 0.629 | 4.714 | 8.171 | LOAEL: 13% decrease in maternal weight gain SLOAEL: 30% decrease in maternal body weight gain |\n| 77 | Rat (Sprague-Dawley) 42–66 F | 15 days GDs 6–20 (W) | 0, 0.629, 4.714, 8.171 | BW, WI, HE, DX | Hemato | 4.714 | 8.171 |  | Reduced maternal hemoglobin levels |\n| 77 | Rat (Sprague-Dawley) 42–66 F | 15 days GDs 6–20 (W) | 0, 0.629, 4.714, 8.171 | BW, WI, HE, DX | Develop | 0.629 | 4.714 |  | 8% decrease in fetal body weight |\n| Sun et al. 2023 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 78 | Rat (Sprague-Dawley) 10 M | 29 days (GW) | 0, 0.3, 1, 5 | DX | Develop | 0.3 | 1 |  | Decreased serum estradiol and progesterone in adult F1 females |\n| F0 males were mated to unexposed females; reproductive development was assessed in F1 and F2 female offspring |  |  |  |  |  |  |  |  |  |\n| Sutou et al. 1980 |  |  |  |  |  |  |  |  | Form not specified |\n| 79 | Rat (Sprague-Dawley) 14 M, 14 F | 9 weeks (premating through GD 20) (GW) | 0, 0.1, 1.0, 10 | RX, DX | Repro | 1 |  | 10 | Decreased number of copulating and pregnant females; 49% reduction in number of live fetuses/litter; decreased total implants/litter, increased resorptions/litter |\n| 79 | Rat (Sprague-Dawley) 14 M, 14 F | 9 weeks (premating through GD 20) (GW) | 0, 0.1, 1.0, 10 | RX, DX | Develop | 1 |  | 10 | Decreased fetal body weight in males (34%) and females (33%); decreased body and tail length; delayed ossification |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Tang et al. 2016 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 80 | Rat (Sprague-Dawley) 6 M | 3 months (W) | 0, 0.28, 1.41, 7.07 | HP | Musc/skel | 1.41 | 7.07 |  | Decreased bone density and trabecular bone loss and damage in tibia (decreased trabecular volume and number, increased trabecular separation) |\n| Tian et al. 2017 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 81 | Rat (Sprague-Dawley) NS F | 6 weeks GD 0 to PND 21 (GW) | 0, 0.6, 3 | DX | Develop |  | 0.6 |  | Decreased serum progesterone and testosterone and in male offspring on PND 35 and 56, respectively; decreased relative testis weight on PND 21 |\n| Tucovic et al. 2018 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 82 | Rat (Dark Agouti) 4–6 M | 30 days (W) | 0, 0.7, 6.6 | BW, FI, WI, HE BC, UR, HP | Bd wt Hemato | 6.6 |  |  | Increased percent neutrophil leukocytes and eosinophil leukocytes |\n| 82 | Rat (Dark Agouti) 4–6 M | 30 days (W) | 0, 0.7, 6.6 | BW, FI, WI, HE BC, UR, HP | Hepatic Immuno | 6.6 0.7 | 6.6 |  | Increased IL-6 and TNF in skin |\n| Wan et al. 2022 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 83 | Rat (Sprague-Dawley) 3 M, 3 F | 4 weeks (G) | 0, 2, 4 | BW, WI, BC, UR, OW, HP | Bd wt Renal | 4 |  |  | Increased 24-hour urinary protein excretion, elevated urinary β 2M levels, increased serum BUN |\n| Wan et al. 2022 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 84 | Rat (Sprague-Dawley) 3 M, 3 F | 8 weeks (G) | 0, 2, 4 | BW, WI, BC, UR, OW, HP | Bd wt Renal | 4 |  |  | Increased 24-hour urinary protein excretion, elevated urinary β 2M levels, increased serum BUN |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Wang et al. 2014 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 85 | Rat (Sprague-Dawley) 8 M, 8 F | 28 days (GW) | 0, 1, 2.5, 5, 10, 20 | LE, CS, BW, FI, HE, BC, UR, GN, OW, HP | Bd wt | 5 | 10 |  | Decrease in terminal body weight in males (12%) and females (11%) |\n| 85 | Rat (Sprague-Dawley) 8 M, 8 F | 28 days (GW) | 0, 1, 2.5, 5, 10, 20 | LE, CS, BW, FI, HE, BC, UR, GN, OW, HP | Cardio | 20 |  |  | Decrease in terminal body weight in males (12%) and females (11%) |\n| 85 | Rat (Sprague-Dawley) 8 M, 8 F | 28 days (GW) | 0, 1, 2.5, 5, 10, 20 | LE, CS, BW, FI, HE, BC, UR, GN, OW, HP | Hemat | 10 F | 20 F |  | Increased platelets |\n| 85 | Rat (Sprague-Dawley) 8 M, 8 F | 28 days (GW) | 0, 1, 2.5, 5, 10, 20 | LE, CS, BW, FI, HE, BC, UR, GN, OW, HP | Hepatic | 2.5 M | 5 M |  | Increased platelets |\n| 85 | Rat (Sprague-Dawley) 8 M, 8 F | 28 days (GW) | 0, 1, 2.5, 5, 10, 20 | LE, CS, BW, FI, HE, BC, UR, GN, OW, HP | Renal | 10 F | 20 F |  | Increased serum ALT |\n| 85 | Rat (Sprague-Dawley) 8 M, 8 F | 28 days (GW) | 0, 1, 2.5, 5, 10, 20 | LE, CS, BW, FI, HE, BC, UR, GN, OW, HP | Endocr | 20 |  |  |  |\n| 85 | Rat (Sprague-Dawley) 8 M, 8 F | 28 days (GW) | 0, 1, 2.5, 5, 10, 20 | LE, CS, BW, FI, HE, BC, UR, GN, OW, HP | Immuno | 20 |  |  |  |\n| 85 | Rat (Sprague-Dawley) 8 M, 8 F | 28 days (GW) | 0, 1, 2.5, 5, 10, 20 | LE, CS, BW, FI, HE, BC, UR, GN, OW, HP | Neuro | 20 |  |  |  |\n| 85 | Rat (Sprague-Dawley) 8 M, 8 F | 28 days (GW) | 0, 1, 2.5, 5, 10, 20 | LE, CS, BW, FI, HE, BC, UR, GN, OW, HP | Repro | 5 | 10 |  | Decreased serum LH and testosterone in males; increased absolute and relative uterine weight |\n| 85 | Rat (Sprague-Dawley) 8 M, 8 F | 28 days (GW) | 0, 1, 2.5, 5, 10, 20 | LE, CS, BW, FI, HE, BC, UR, GN, OW, HP | Other | 1 F | 2.5 F |  | Decreased food intake |\n| 85 | Rat (Sprague-Dawley) 8 M, 8 F | 28 days (GW) | 0, 1, 2.5, 5, 10, 20 | LE, CS, BW, FI, HE, BC, UR, GN, OW, HP | noncancer |  |  |  |  |\n| Weng et al. 2014 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 86 | Rat (Wistar) 12 F | 8 weeks (G) | 0, 0.3, 1.2, 4.9 | BW, OW, HP | Bd wt | 4.9 |  |  |  |\n| 86 | Rat (Wistar) 12 F | 8 weeks (G) | 0, 0.3, 1.2, 4.9 | BW, OW, HP | Repro | 0.3 | 1.2 |  | Decreased absolute and relative ovary weight, increased atretic follicles, follicular cell apoptosis |\n| Xu et al. 2015 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 87 | Rat (Sprague-Dawley) 6 M | 90 days (GW) | 0, 0.7, 2.0, 6.0 | LE, CS, BW, HP | Bd wt | 6 |  |  |  |\n| 87 | Rat (Sprague-Dawley) 6 M | 90 days (GW) | 0, 0.7, 2.0, 6.0 | LE, CS, BW, HP | Neuro | 0.7 | 2 |  | Neuronal degeneration in cortex |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Yang et al. 2021a |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 88 | Rat (Sprague-Dawley) 9 NR | 8 weeks 5 days/week (GW) | 0, 0.15, 0.61, 2.5 | BC | Hepatic | 0.15 | 0.61 |  | Increased serum triglycerides, total cholesterol, and LDL cholesterol; decreased serum HDL cholesterol |\n|  |  |  |  |  | Renal | 0.61 | 2.5 |  | Increased serum urea nitrogen |\n| Yi et al. 2021b |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 89 | Rat (Sprague-Dawley) 6 M | 28 days (GO) | 0, 1, 3 | BW, BC, OW, HP, RX | Bd wt Repro | 3 | 1 |  | Decreased serum testosterone levels |\n| Zenick et al. 1982 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 90 | Rat (Long-Evans) 5 M | 70–80 days (W) | 0, 1.16, 2.32, 4.64 | BW, FI, WI, HP, RX, DX | Bd wt Repro Develop for fetal effects | 4.64 4.64 4.64 | 25 | 12 | LOAEL: 13% decrease in terminal body weight SLOAEL: 25% decrease in terminal body weight |\n| Males were mated with three untreated females; one litter evaluated for fetal effects and two litters evaluated for neurobehavior on PND 21 or 90 |  |  |  |  |  |  |  |  |  |\n| Zhang et al. 2022a |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 91 | Rat (Sprague-Dawley) 8 M | 12 weeks (G) | 0, 1.5, 3, 6.1, 12, 25 | LE, CS, BW, BC, OW, HP | Bd wt | 6.1 | 12 | 25 | LOAEL: 13% decrease in terminal body weight SLOAEL: 25% decrease in terminal body weight |\n|  |  |  |  |  | Hepatic | 1.5 | 3 | 12 | LOAEL: Hepatic fibrosis SLOAEL: Hepatic fibrous tissue proliferation |\n| Zhang et al. 2023a |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 92 | Rat (Sprague-Dawley) 6 M | 4 weeks (GW) | 0, 2.5, 5 | BC, HP, RX | Repro | 2.5 |  | 5 | Decreased serum testosterone, LH, and GnRH; decreased sperm count and motility; decreased seminiferous tubule diameter and seminiferous epithelial thickness |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Zhang et al. 2024a |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 93 | Rat (Sprague-Dawley) 10–30 M | 4 weeks (GW) | 0, 5 | BW, RX, DX | Bd wt Repro |  | 5 | 5 | 13% decrease in body weight Decreased fertility and percent live births, sperm quality, and levels of serum testosterone and gonad releasing hormone; decreased seminiferous tubule diameter and area, seminiferous epithelium thickness, and Johnsen score; decreased number of cells in interstitial region of testes and disordered cellular arrangement |\n| Males were mated with unexposed females. |  |  |  |  | Develop |  |  | 5 | 21% decrease in male fetal weight |\n| Blakley 1985 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 94 | Mouse (BDF1) 22 F | 3 weeks (W) | 0, 1.4, 2.8, 14 | CS, BW, GN, IX | Bd wt Immuno | 14 1.4 | 2.8 |  | Decreased humoral immune response |\n| Blakley 1988 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 95 | Mouse (BDF1) 14–16 F | 26 days (W) | 0, 2.5, 12.5 | BW, WI, IX | Immuno | 12.5 |  |  |  |\n| Aged mice (12-month-old) |  |  |  |  |  |  |  |  |  |\n| Chatterjee and Saxena 2015 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 96 | Mouse (C57BL/6) 10–15 M | 6 weeks (W) | 0, 7.6, 150 | HE, BC | Hemato Immuno | 150 | 7.6 |  | Decreased RBC count and hemoglobin |\n| Chou et al. 2023 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 97 | Mouse (C57BL/6) 11–18 M | 12 weeks (W) | 0, 11, 21 | BW, OF, HP | Bd wt Cardio | 21 |  | 11 | Cardiomyocyte apoptosis |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects | Cadmium chloride |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Exon et al. 1986 |  |  |  |  |  |  |  |  |  |  |\n| 98 | Mouse (Swiss-Webster) 20 M | 10 weeks (W) | 0, 0.57, 5.7, 57 | LE, BW, GN, HP, IX | Bd wt Immuno | 57 57 |  |  |  |  |\n| Exon et al. 1986 |  |  |  |  |  |  |  |  |  |  |\n| 99 | Mouse (Swiss-Webster) 20 M | 10 weeks (W) | 0, 0.57, 5.7, 57 | LE, BW, GN, HP, IX | Bd wt Immuno | 0.57 57 | 5.7 |  | Cadmium acetate | 14% decrease in body weight |\n| Exon et al. 1986 |  |  |  |  |  |  |  |  |  |  |\n| 100 | Mouse (Swiss-Webster) 20 M | 10 weeks (W) | 0, 0.57, 5.7, 57 | LE, BW, GN, HP, IX | Bd wt Immuno | 57 57 |  |  |  | Cadmium sulfate |\n| Gathwan and Albir 2020 |  |  |  |  |  |  |  |  |  |  |\n| 101 | Mouse (Swiss) 6 M | 30 days (G) | 0, 6.1, 12.3, 19.5 | BW, FI, WI, OW, HP | Bd wt | 6.1 | 12.3 | 19.5 | LOAEL: 13% decrease in terminal body weight SLOAEL: 23% decrease in terminal body weight | Cadmium oxide |\n| He et al. 2019a |  |  |  |  |  |  |  |  |  |  |\n| 102 | Mouse (C57BL/6) 10 M | 20 weeks (W) | 0, 1.475, 6.566 | LE, CS, WI, BC, BI, OW, HP | Bd wt Hepatic | Endocr | 6.566 | 1.475 | 6.566 | Cadmium chloride 22% decrease in body weight gain NAFLD; increased hepatic triglyceride levels |\n| He et al. 2019b |  |  |  |  |  |  |  |  |  |  |\n| 103 | Mouse (BALB/c) 12 F | 16 weeks (W) | 0, 2, 6.5 | BW, FI, BC, BI, HP | Bd wt Musc/skel | 6.5 | 2 |  |  | Cadmium chloride |\n\nTrabecular bone damage\n(decreased number, thickness;\nincreased separation, fat cells);\naltered bone turnover parameters\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| He et al. 2020 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 104 | Mouse (C57BL/6) 10 M | 20 weeks (W) | 0, 1.5, 7.6 | LE, CS, BW, HP | Bd wt Gastro | 7.6 1.5 | 7.6 |  | Decreased length of intestinal villus and thickness of intestinal wall |\n| Hudson et al. 2019 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 105 | Mouse (C57BL/6J) NS F | 8 weeks 5 weeks prior to mating until birth (W) | 0, 0.3, 13 | RX, DX | Repro Develop | 13 | 0.3 | 13 | LOAEL: Increased absolute and relative heart weight in female pups at birth; increased tail blood volume and tail blood flow in female offspring at 5.5 months of age SLOAEL: 12% decrease in birth weight in both sexes; increased absolute and relative heart weight in male pups at birth; increased systolic, diastolic, and mean arterial blood pressure in female offspring at 5.5 months of age |\n| C57BL/6J dams mated to unexposed CAST/EiJ males, to generate F1 hybrid mice |  |  |  |  |  |  |  |  |  |\n| Hudson et al. 2019 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 106 | Mouse (CAST/EiJ) NS F | 8 weeks 5 weeks prior to mating until birth (W) | 0, 0.3, 13 | RX, DX | Repro Develop | 13 | 0.3 | 13 | LOAEL: Decreased body weight at birth in males; increased absolute heart weight in females SLOAEL: 22% decrease in birth weight |\n| CAST/EiJ dams mated to unexposed C57BL/6J males, to generate F1 hybrid mice |  |  |  |  |  |  |  |  |  |\n| Krzystyniak et al. 1987 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 107 | Mouse (C57BL/6) 10 F | 12–16 weeks (W) | 0, 0.6, 17, 52 | IX | Immuno | 17 | 52 |  | Reduced humoral immune response |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Kurita et al. 2018 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 108 | Mouse (C57BL/6J) 3–10 F | 18 days GDs 1–18 (G) | 0, 5, 10 | DX | Develop | 5 |  | 10 | 34% decrease in fetal weight, decreased fetal length |\n| Li et al. 2022 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 109 | Mouse (ICR) 10 F | 70 days 4 weeks premating to PND 21 (W) | 0, 2.6, 19.7 | WI, DX | Develop |  | 2.6 | 19.7 | LOAEL: Decreased serum estradiol and increased primordial follicles and decreased secondary follicles at PND 21 in female offspring; increased prevalence of irregular estrous cycles SLOAEL: 40% decreased in PND 21 body weight in female offspring; delayed vaginal opening |\n| Liu et al. 2023 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 110 | Mouse F0: 9–12 F F1: 5-7 M, 5–7 F | ~220 days F0: 1 week premating through PND 21 F1: PND 21 to 6 months of age (W) | F0: 0, 0.1, 1.5 F1: 0, 0.2, 1.6 | BC, OW, HP, NX | Immuno Neuro | 1.6 | 0.2 |  | Increased locomotor activity, impaired spatial memory (Y-maze test) in adult F1 mice |\n| Mei et al. 2017 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 111 | Mouse (C57BL/6) 5 M | 8 weeks (W) | 0, 1.5, 4.5, 7.6 | IX | Immuno |  | 1.5 |  | Delayed wound healing |\n| Ohsawa et al. 1988 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 112 | Mouse (BALB/c) 9–10 M | 10 weeks (W) | 0, 0.75, 7.5, 75 | IX | Immuno | 7.5 | 75 |  | Induction of anti-nuclear autoantibodies |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Ohsawa et al. 1988 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 113 | Mouse (ICR) 5–12 M | 10 weeks (W) | 0, 0.75, 7.5, 75 | IX | Immuno |  | 0.75 |  | Induction of anti-nuclear autoantibodies; biphasic immune response (stimulation at low dose, suppression at high dose) |\n| Tan et al. 2023 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 114 | Mouse (C57BL/6) 20 M | 10 weeks (W) | 0, 1.5, 15 | DX | Develop | 1.5 | 15 |  | Impaired growth in both sexes (10% at terminal sacrifice on PND 125); impaired glucose metabolism in adult female offspring |\n| Males mated to untreated females after 10-week exposure |  |  |  |  |  |  |  |  |  |\n| Valois and Webster 1989 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 115 | Mouse (QS) 25 F | 22 weeks (W) | 0, 0.20, 1.4, 11 | CS, BW, WI, HP | Bd wt | 0.2 | 1.4 | 11 | LOAEL: 19% decrease in body weight SLOAEL: 28% decrease in body weight |\n|  |  |  |  |  | Neuro | 0.2 |  | 1.4 | Degenerative and necrotic cellular changes in choroid plexus |\n| Marked decreases in water consumption at 1.4 and 11 mg Cd/kg/day |  |  |  |  |  |  |  |  |  |\n| Wang et al. 2016a |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 116 | Mouse (CD-1) 10 F | 19 days GDs 0–18 (W) | 0, 1.3, 9.3, 26.9 | BW, WI, RX, DX | Bd wt Repro Develop | 26.9 26.9 9.3 |  | 26.9 | 17% decrease in fetal weight; decreased crown-rump length |\n| Xiong et al. 2022a |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 117 | Mouse (C57BL/6) F0: 6–7 M, 17 F F1: 4 M | 32 weeks F0: 2 weeks premating–PNW 3 F1: PNWs 3–27 (W) | 0, 0.1, 1.3 | BW, WI, OW, HP | Bd wt Repro | 1.3 M 0.1 M | 1.3 M |  | Decreased absolute testis weight, germ cell loss |\n| Endpoints reported for F1 males (evaluated at PNW 27) |  |  |  |  |  |  |  |  |  |\n\nEndpoints reported for F1 males (evaluated at PNW 27)\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects | Cadmium chloride |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Zhang et al. 2019a |  |  |  |  |  |  |  |  |  |  |\n| 118 | Mouse (C57BL/6J) F0: 10 M, 10 F F1: 6 M, 6 F | 17-18 weeks F0: 1 month premating to PNW 3 F1: PNWs 3–10 (W) | 0, 0.001089, 0.01003, 0.10012 | DX | Develop | 0.10012 |  |  |  |  |\n| F1 pups examined for developmental landmarks, neurobehavior (PNWs 8-9), endocrine, and reproductive endpoints at PNW 10 |  |  |  |  |  |  |  |  |  |  |\n| Zhang et al. 2019a |  |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 119 | Mouse (C57BL/6J) F0: 10 M, 10 F F1: 6 M, 6 F | 25-26 weeks F0: 3 months premating to PNW 3 F1: PNWs 3–10 (W) | 0, 0.001089, 0.01003, 0.10012 | DX | Develop | 0.10012 |  |  |  |  |\n| F1 pups examined for developmental landmarks, neurobehavior (PNWs 8-9), endocrine, and reproductive endpoints at PNW 10 |  |  |  |  |  |  |  |  |  | Cadmium chloride |\n| Zhang et al. 2019a |  |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 120 | Mouse (C57BL/6J) F0: 10 M, 10 F F1: 6 M, 6 F | 33–34 weeks F0: 5 months premating to PNW 3 F1: PNWs 3–10 (W) | 0, 0.001089, 0.01003, 0.10012 | DX | Develop | 0.01003 | 0.10012 |  | Increased anxiety-like behavior in open field; elevated corticosterone levels |  |\n| F1 pups examined for developmental landmarks, neurobehavior (PNWs 8-9), endocrine, and reproductive endpoints at PNW 10 |  |  |  |  |  |  |  |  |  | Cadmium chloride |\n| Zhang et al. 2024b |  |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 121 | Mouse (ICR) 9–11 M | 21 days PNDs 22–42 (W) | 0, 0.9, 1.5 | DX | Develop | 0.9 | 1.5 |  | Altered socioemotional behaviors during adolescence (immobility in forced swim and tail suspension, decreased social interaction/preference for novelty) |  |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Boscolo and Carmignani 1986 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 122 | Rabbit (New Zealand) 8 M | 9 months (W) | 0, 1.6 | CS, BW, HP, OF | Bd wt Cardio Renal | 1.6 | 1.6 |  | Increased aortic resistance, reduced contractility |\n| Stowe et al. 1972 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 123 | Rabbit (New Zealand) 5 M | 200 days (W) | 0, 14.9 | CS, BW, WI, HE | Bd wt Hemato |  | 14.9 | 14.9 | 20% decrease in body weight Decreased hematocrit and hemoglobin; elevated neutrophils and decreased lymphocytes |\n| Stowe et al. 1972 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 124 | Rabbit (Belgian Giant) 5 M | 200 days (W) | 0, 14.9 | CS, BW, WI, HE | Bd wt Hemato |  | 14.9 | 14.9 | 15% decrease in body weight Decreased hematocrit and hemoglobin; elevated neutrophils and decreased lymphocytes |\n| CHRONIC EXPOSURE |  |  |  |  |  |  |  |  |  |\n| Buchet et al. 1990; Shao et al. 2007; Suwazono et al. 2006; Uno et al. 2005; Wu et al. 2001; Zhang et al. 2016a |  |  |  |  |  |  |  |  | Cadmium |\n| 125 | Human 85–3,454 per dataset | 17 datasets (3 occupational and 8 general population cohorts) | UR | Renal |  |  |  | LMW proteinuria; 95% LCL weighted median of 17 UC10 values = 0.000760 mg Cd/kg/dayd |  |\n| Bernard et al. 1992 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 126 | Rat (Sprague-Dawley) 50 F | up to 18 months (W) | 0, 13 | BI, BC, UR, HP, OF | Renal |  |  | 13 | Loss of glomerular polyanion charge barrier, proteinuria |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Bomhard et al. 1984 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 127 | Rat (Wistar) 12 M, 12 F | 72 weeks (F) | M: 0, 0.7, 3.5, 17.5 F: 0, 0.8, 4.0, 20.0 | BC, UR | Renal | 4 F | 20 F |  | Increase in urinary LDH and GST levels Increase in urinary LDH and GST levels |\n| 127 | Rat (Wistar) 12 M, 12 F | 72 weeks (F) | M: 0, 0.7, 3.5, 17.5 F: 0, 0.8, 4.0, 20.0 | BC, UR | Renal | 3.5 M | 17.5 M |  | Increase in urinary LDH and GST levels Increase in urinary LDH and GST levels |\n| Brzóska 2012; Brzóska and Moniuszko-Jakoniuk 2004a, 2004b |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 128 | Rat (Wistar) 10 F | 24 months (W) | 0, 0.08 | BW, FI, WI, BC, BI, UR, HP, OF | Bd wt Musc/skel | 0.08 |  | 0.08 | Decreases in bone mineral content and density of lumbar spine, altered bone turnover parameters, increases in deformed and fractured vertebral bodies |\n| Decker et al. 1958 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 129 | Rat (Sprague-Dawley) 8–10 M, 8–10 F | 12 months (W) | M: 0, 0.008, 0.036, 0.197, 0.386, 0.696 F: 0, 0.012, 0.062, 0.315, 0.578, 1.052 | LE, BW, FI, WI, HE, HP | Bd wt Gastro | 1.052 F 0.696 M 1.052 F 0.696 M 1.052 F 0.696 M 1.052 F 0.696 M 1.052 F 0.696 M 1.052 F 0.696 M 0.696 M 0.696 M 0.696 M 0.696 M |  |  |  |\n| 129 | Rat (Sprague-Dawley) 8–10 M, 8–10 F | 12 months (W) | M: 0, 0.008, 0.036, 0.197, 0.386, 0.696 F: 0, 0.012, 0.062, 0.315, 0.578, 1.052 | LE, BW, FI, WI, HE, HP | Renal | 1.052 F 0.696 M 0.696 M |  |  |  |\n| 129 | Rat (Sprague-Dawley) 8–10 M, 8–10 F | 12 months (W) | M: 0, 0.008, 0.036, 0.197, 0.386, 0.696 F: 0, 0.012, 0.062, 0.315, 0.578, 1.052 | LE, BW, FI, WI, HE, HP | Endocrinoma | 1.052 F 0.696 M 0.696 M 0.696 M |  |  |  |\n| 129 | Rat (Sprague-Dawley) 8–10 M, 8–10 F | 12 months (W) | M: 0, 0.008, 0.036, 0.197, 0.386, 0.696 F: 0, 0.012, 0.062, 0.315, 0.578, 1.052 | LE, BW, FI, WI, HE, HP | Neuro | 1.052 F 0.696 M 0.696 M |  |  |  |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects | Cadmium chloride |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Fingerle et al. 1982 |  |  |  |  |  |  |  |  |  |  |\n| 130 | Rat (Sprague-Dawley) 10 M, 10 F | M: 92 weeks F: 84 weeks (W) | M: 0, 0.6, 1.51, 3.78 F: 0, 0.8, 1.64, 4.01 | HP, BW, OW, OF, FI, WI, CS, LE | Bd wt Cardio | 4.01 4.01 |  |  |  |  |\n| Mangler et al. 1988 |  |  |  |  |  |  |  |  |  |  |\n| 131 | Rat (Sprague-Dawley) 12 F | 18 months (W) | 0, 2.301 | LE, BW, HP | Bd wt Renal | 2.301 | 2.301 |  | Cloudy swelling of renal tubular cells | Cadmium chloride |\n| Mangler et al. 1988 |  |  |  |  |  |  |  |  |  |  |\n| 132 | Rat (Sprague-Dawley) 12 F | 12 months (W) | 0, 2.337 | LE, BW, HP | Bd wt Renal | 2.337 | 2.337 |  | Cloudy swelling of renal tubular cells | Cadmium chloride |\n| Sato et al. 1978 |  |  |  |  |  |  |  |  |  |  |\n| 133 | Rat (Wistar) 11 NS | 31 months (W) | 0, 2.7 | CS, BW, WI, HP | Bd wt Musc/skel Neuro | 2.7 |  | 2.7 2.7 | Muscle weakness and atrophy Peripheral neuropathy | Cadmium chloride |\n| Waalkes and Rehm 1992 |  |  |  |  |  |  |  |  |  |  |\n| 134 | Rat (Wistar) 24–28 M | 77 weeks (F) | 0, 1.1, 2.3, 5.28, 10.9 | LE, CS, BW, FI, GN, HP | Bd wt Cancer | 2.3 | 5.28 | 2.3 | 10% decrease in body weight CEL: Large granular lymphocyte leukemia | Cadmium chloride |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Hays and Margaretten 1985 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 135 | Mouse (CBA/H) 5–13 M; 5 F | 12 months (W) | 0, 40 | BW, FI, WI, HE, BC, HP | Bd wt Hematocrit | 40 |  | 40 | 21% decreased terminal body weight Decreased hematocrit and neutrophils; bone marrow hypoplasia |\n|  |  |  |  |  | Renal | 40 |  |  |  |\n\n<sup>a</sup>The number corresponds to entries in Figure 2-3; differences in levels of health effects between male and females are not indicated in Figure 2-3.  Where such \ndifferences exist, only the levels of effect for the most sensitive sex are presented.\n\n<sup>b</sup>Doses are expressed as mg Cd/kg/day.  If doses were reported by study authors in terms of the administered compound (e.g., cadmium chloride [CdCl2]), they were \nconverted to the equivalent dose in terms of the metal (i.e., cadmium [Cd])) for easy comparison across studies. Conversion was based on the ratio of the molecular \nweights using the following equation: Dose in terms of administered compound × (molecular weight Cd/molecular weight administered compound).\n\n<sup>c</sup>Used to derive an acute-duration oral MRL of 0.002 mg Cd/kg/day (2 μg Cd/kg/day).  The LOAEL of 2 mg Cd/kg/day divided by an uncertainty factor of 1,000 (10 for use \nof a LOAEL, 10 for animal to human, and 10 for human variability).\n\n<sup>d</sup>Used to derive a chronic-duration oral MRL of 0.0003 mg Cd/kg/day (0.3 μg Cd/kg/day).  The point of departure (POD) is based on the 95% lower confidence limit (LCL) \non the weighted median of the UC10 values from 17 datasets from 11 human studies; the weighted median and 95% LCL were 2.04 and 1.57 μg Cd/g Cr, respectively.  \nThese values were converted into oral dose equivalents of 9.88x10<sup>-4</sup> and 7.60x10<sup>-4</sup> mg Cd/kg/day, respectively, using PBPK modeling. The POD of 7.60x10<sup>-4</sup> mg \nCd/kg/day was divided by an uncertainty factor of 3 for human variability and a modifying factor of 3 for database deficiencies. See Appendix A for more detailed \ninformation regarding the MRL.\n\n## Principal studies for the MRLs\n\nACTH = adrenocorticotrophic hormone; ALT = alanine aminotransferase; β2M = β2-microglobulin; BC = serum (blood) chemistry; Bd wt or BW = body weight; \nBI = biochemical changes; BUN = blood urea nitrogen; Cardio = cardiovascular; Cd = cadmium; CEL = cancer effect level; Cr = creatinine; CS = clinical signs; Develop \n= developmental; DX = developmental toxicity; Endocr = endocrine; (F) = feed (dietary); F = female(s); FI = food intake; (G) = gavage; (GO) = gavage in oil; \n(GW) = gavage in water; Gastro = gastrointestinal; GD = gestation day; GN = gross necropsy; GnRH = gonadotropin releasing hormone; GST = glutathione \nS-transferase; HDL = high-density lipoprotein; HE = hematology; Hemato = hematological; HP = histopathology; IL-6 = interleukin-6; Immuno = immunological; \nIX = immune function; LD50 = lethal dose, 50% kill; LDH = lactate dehydrogenase; LDL = low-density lipoprotein; LE = lethality; LH = luteinizing hormone; LMW = low \nmolecular weight; LOAEL = lowest-observed-adverse-effect level; M = male(s); MCHC = mean corpuscular hemoglobin concentration; MCV = mean corpuscular volume; \nMRL = Minimal Risk Level; Musc/skel = musculoskeletal; NAFLD = non-alcoholic fatty liver disease; Neuro = neurological; NK = natural killer; NOAEL = no-observedadverse-effect level; NS = not specified; NX = neurological function; OF = organ function; OW = organ weight; PBPK = physiologically based pharmacokinetic; \nPND = postnatal day; PNW = postnatal week; RBC = red blood cell; Repro = reproductive; Resp = respiratory; RX = reproductive function; SLOAEL = serious lowestobserved-adverse-effect level; T3 = triiodothyronine; TNF = tumor necrosis factor; TSH = thyroid-stimulating hormone; UC10 = urinary cadmium level associated with \n10% extra risk; UR = urinalysis; (W) = drinking water; WBC = white blood cell; WI = water intake\n\n---\n\n**Figure 2-3.  Levels of Significant Exposure to Cadmium – Oral**\nAcute (≤14 days)\n\n**Figure 2-3. Levels of Significant Exposure to Cadmium – Oral Acute (≤14 days) - Death**\n\n| Category | Animal - LD50/LC50 (mg Cd/kg/day) | Animal - NOAEL (mg Cd/kg/day) | Animal - LOAEL (mg Cd/kg/day) | Animal - SLOAEL (mg Cd/kg/day) |\n| --- | --- | --- | --- | --- |\n| 3R |  |  |  | 100 |\n| 4R |  |  |  | 70 |\n| 6R |  |  |  | 30 |\n| 8R | 28 |  |  |  |\n| 9R | 140 |  |  |  |\n| 10R | 130 |  |  |  |\n| 11R | 100 |  |  |  |\n| 12R | 70 |  |  |  |\n| 15R | 230 |  |  |  |\n| 16R |  |  |  | 45 |\n| 17R |  |  |  | 65 |\n| 21R | 110 |  |  |  |\n| 22R | 340 |  |  |  |\n| 26M |  |  |  | 85 |\n| 28M | 95 |  |  |  |\n\n---\n\n**Figure 2-3.  Levels of Significant Exposure to Cadmium – Oral**\nAcute (≤14 days)\n\n**Figure 2-3. Levels of Significant Exposure to Cadmium – Oral Acute (≤14 days) - Body Weight**\n\n| Category | Animal - LD50/LC50 (mg Cd/kg/day) | Animal - LOAEL (mg Cd/kg/day) | Animal - NOAEL (mg Cd/kg/day) | Animal - SLOAEL (mg Cd/kg/day) |\n| --- | --- | --- | --- | --- |\n| 2R |  |  |  | 12 |\n| 2R |  |  | 2.0 |  |\n| 4R |  |  | 150 |  |\n| 5R |  | 8.0 |  |  |\n| 5R |  |  | 1.2 |  |\n| 5R |  |  |  | 11 |\n| 6R |  |  |  | 30 |\n| 6R |  |  |  | 15 |\n| 14R |  |  |  | 150 |\n| 14R |  |  | 100 |  |\n| 17R |  |  |  | 6.0 |\n| 17R |  |  | 1.8 |  |\n| 18R |  |  |  | 13 |\n| 18R |  |  | 3.3 |  |\n| 19R |  |  |  | 14 |\n| 20R |  |  |  | 18 |\n| 20R |  |  | 6.0 |  |\n| 23R |  |  | 0.20 |  |\n| 24R |  |  | 0.25 |  |\n| 25R |  |  | 4.0 |  |\n\n---\n\n**Figure 2-3.  Levels of Significant Exposure to Cadmium – Oral**\nAcute (≤14 days)\n\n| Category | Animal - NOAEL (mg Cd/kg/day) | Animal - LOAEL (mg Cd/kg/day) | Animal - SLOAEL (mg Cd/kg/day) |\n| --- | --- | --- | --- |\n| Respiratory | 14R: 160 |  |  |\n| Cardiovascular | 14R: 160 |  |  |\n| Gastrointestinal | 14R: 160 |  |  |\n|  |  | 17R: 65 |  |\n|  |  | 17R: 19 |  |\n|  |  | 26M: 30 |  |\n|  |  | 26M: 16 |  |\n|  |  | 26M: 85 |  |\n| Hematological | 1R: 15 |  |  |\n|  |  | 4R: 150 |  |\n|  |  | 5R: 14 |  |\n|  |  | 6R: 16 |  |\n|  |  | 14R: 160 |  |\n|  |  | 19R: 16 |  |\n| Hepatic | 4R: 150 |  |  |\n|  |  | 5R: 13 |  |\n|  |  | 6R: 16 |  |\n|  |  | 6R: 33 |  |\n|  |  | 14R: 160 |  |\n|  |  | 26M: 33 |  |\n|  |  | 26M: 16 |  |\n\n---\n\n**Figure 2-3.  Levels of Significant Exposure to Cadmium – Oral**\nAcute (≤14 days)\n\n**Figure 2-3. Levels of Significant Exposure to Cadmium – Oral Acute (≤14 days)**\n\n| Category | Animal - LD50/LC50 (mg Cd/kg/day) | Animal - LOAEL (mg Cd/kg/day) | Animal - NOAEL (mg Cd/kg/day) | Animal - SLOAEL (mg Cd/kg/day) | MRL for effect other than cancer (mg Cd/kg/day) |\n| --- | --- | --- | --- | --- | --- |\n| Renal |  |  | 4R: 150 |  |  |\n| Renal |  |  | 5R: 13 |  |  |\n| Renal |  |  | 6R: 70 | 6R: 70 |  |\n| Renal |  |  | 6R: 30 |  |  |\n| Renal |  |  | 14R: 160 |  |  |\n| Renal |  |  | 25R: 2.0 | 25R: 2.0 | 0.0022 |\n| Renal |  |  | 26M: 65 | 26M: 90 |  |\n| Dermal |  |  | 17R: 2.3 | 17R: 7.0 |  |\n| Endocrine |  |  | 14R: 150 |  |  |\n| Endocrine |  |  | 19R: 50 |  |  |\n| Immunological |  |  | 23R: 0.26 | 23R: 0.26 |  |\n| Immunological |  |  | 23R: 0.028 |  |  |\n| Immunological |  |  | 24R: 0.28 |  |  |\n| Neurolgical |  |  | 13R: 26 | 13R: 50 |  |\n| Neurolgical |  |  | 13R: 2.3 |  |  |\n\n---\n\n**Figure 2-3.  Levels of Significant Exposure to Cadmium – Oral**\nAcute (≤14 days)\n\n**Figure 2-3. Levels of Significant Exposure to Cadmium – Oral Acute (≤14 days)**\n\n| Category | Reproductive Animal - LD50/LC50 (mg Cd/kg/day) | Reproductive Animal - LOAEL (mg Cd/kg/day) | Reproductive Animal - NOAEL (mg Cd/kg/day) | Reproductive Animal - SLOAEL (mg Cd/kg/day) | Developmental Animal - LD50/LC50 (mg Cd/kg/day) | Developmental Animal - LOAEL (mg Cd/kg/day) | Developmental Animal - NOAEL (mg Cd/kg/day) | Developmental Animal - SLOAEL (mg Cd/kg/day) |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| 3R |  |  |  | 1', 'pages': None, 'truncated': True, 'extraction': 'firecrawl-public-document-markdown', 'request_id': '293c7827-ff96-4db1-b5ad-c97da5c1aeef', 'source_url': 'https://downloads.regulations.gov/ATSDR-2026-0133-0002/attachment_1.pdf', 'observed_at': '2026-10-04T00:38:44.750111+00:00', 'content_hash': '19390979349ee9f90ebdd60e3716b58502ea8d916d0b4add252a923c7eb753e3'}, 'title': 'Draft Toxicological Profile for Cadmium', 'check_failed': False}, {'url': 'https://downloads.regulations.gov/ATSDR-2026-0133-0002/content.pdf', 'body': {'text': '## Toxicological Profile for Cadmium\nDraft for Public Comment\nOctober 2026\n\nATSDR\nU.S. Department of Health and Human Services\nAgency for Toxic Substances and Disease Registry\n\nCS274127-A\n\n---\n\n## DISCLAIMER\n\nUse of trade names is for identification only and does not imply endorsement by the Agency for Toxic \nSubstances and Disease Registry, the Public Health Service, or the U.S. Department of Health and Human \nServices.\n\nThis information is distributed solely for the purpose of pre-dissemination for public comment under \napplicable information quality guidelines.  It has not been formally disseminated by the Agency for Toxic \nSubstances and Disease Registry.  It does not represent and should not be construed to represent any \nagency determination or policy.\n\n---\n\n## FOREWORD\n\nThis toxicological profile is prepared in accordance with guidelines developed by the Agency for Toxic \nSubstances and Disease Registry (ATSDR) and the Environmental Protection Agency (EPA).  The \noriginal guidelines were published in the *Federal Register* on April 17, 1987.  Each profile will be revised \nand republished as necessary.\n\nThe ATSDR toxicological profile succinctly characterizes the toxicologic and adverse health effects \ninformation for these toxic substances described therein.  Each peer-reviewed profile identifies and \nreviews the key literature that describes a substance\'s toxicologic properties.  Other pertinent literature is \nalso presented but is described in less detail than the key studies.  The profile is not intended to be an \nexhaustive document; however, more comprehensive sources of specialty information are referenced.\n\nThe focus of the profiles is on health and toxicologic information; therefore, each toxicological profile \nbegins with a relevance to public health discussion which would allow a public health professional to \nmake a real-time determination of whether the presence of a particular substance in the environment \nposes a potential threat to human health.  The adequacy of information to determine a substance\'s health \neffects is described in a health effects summary.  Data needs that are of significance to the protection of \npublic health are identified by ATSDR.\n\nEach profile includes the following:\n\n(A) The examination, summary, and interpretation of available toxicologic information and \nepidemiologic evaluations on a toxic substance to ascertain the levels of significant \nhuman exposure for the substance due to associated acute-, intermediate-, and chronicduration exposures;\n\n(B) A determination of whether adequate information on the health effects of each substance \nis available or in the process of development to determine the levels of exposure that \npresent a significant risk to human health due to acute-, intermediate-, and chronicduration exposures; and\n\n(C) Where appropriate, identification of toxicologic testing needed to identify the types or \nlevels of exposure that may present significant risk of adverse health effects in humans.\n\nThe principal audiences for the toxicological profiles are health professionals at the Federal, State, and \nlocal levels; interested private sector organizations and groups; and members of the public.  ATSDR plans \nto revise these documents in response to public comments and as additional data become available.  \nTherefore, we encourage comments that will make the toxicological profile series of the greatest use.\n\nElectronic comments may be submitted via: www.regulations.gov. Follow the on-line instructions for \nsubmitting comments.\n\nWritten comments may also be sent to:\n\nWritten comments may also be sent to:  Agency for Toxic Substances and Disease Registry\n\nOffice of Innovation and Analytics\n\nToxicology Section\n\n1600 Clifton Road, N.E.\n\nMail Stop S106-5\n\nAtlanta, Georgia 30329-4027\n\n---\n\nThe toxicological profiles are developed under the Comprehensive Environmental Response, \nCompensation, and Liability Act of 1980, as amended (CERCLA or Superfund).  CERCLA \nSection 104(i)(1) directs the Administrator of ATSDR to “…effectuate and implement the health-related \nauthorities” of the statute.  This includes the preparation of toxicological profiles for hazardous \nsubstances most commonly found at facilities on the CERCLA National Priorities List (NPL) and that \npose the most significant potential threat to human health, as determined by ATSDR and the EPA.  \nSection 104(i)(3) of CERCLA, as amended, directs the Administrator of ATSDR to prepare a \ntoxicological profile for each substance on the list.  In addition, ATSDR has the authority to prepare \ntoxicological profiles for substances not found at sites on the NPL, in an effort to “…establish and \nmaintain inventory of literature, research, and studies on the health effects of toxic substances” under \nCERCLA Section 104(i)(1)(B), to respond to requests for consultation under Section 104(i)(4), and as \notherwise necessary to support the site-specific response actions conducted by ATSDR.\n\nThis profile reflects ATSDR’s assessment of all relevant toxicologic testing and information that has been \npeer-reviewed.  Staffs of the Centers for Disease Control and Prevention and other Federal scientists have \nalso reviewed the profile.  In addition, this profile has been peer-reviewed by a nongovernmental panel \nand is being made available for public review.  Final responsibility for the contents and views expressed \nin this toxicological profile resides with ATSDR.\n\nChristopher M. Reh, Ph.D. \nAssociate Director,\nAgency for Toxic Substances and Disease Registry \nCenters for Disease Control and Prevention\n\n---\n\n**VERSION HISTORY**\n\n| Date | Description |\n| --- | --- |\n| October 2026 | Draft for public comment toxicological profile released |\n| September 2012 | Final toxicological profile released |\n| July 1999 | Final toxicological profile released |\n| April 1993 | Final toxicological profile released |\n| March 1989 | Final toxicological profile released |\n\n---\n\n# CONTRIBUTORS & REVIEWERS\n\n# CHEMICAL MANAGER TEAM\n\nBrittany Szafran, D.V.M, Ph.D., D.A.B.T. (lead)\nCustodio Muianga, M.P.H., Ph.D., C.H.M.M.\nMohammad Shoeb, Ph.D.\nBreanna Alman, M.P.H.\nFranco Scinicariello, M.D., M.P.H.\n\nKimberly Zaccaria, Ph.D., D.A.B.T.\nFrances Belmonte, Ph.D., D.A.B.T.\nHeather Carlson-Lynch, M.S., D.A.B.T.\nMario Citra, Ph.D.\nGary L. Diamond, Ph.D.\nZach Guerrette, Ph.D., D.A.B.T\nDeborah M. Herber, Ph.D.\nClaire Heit, Ph.D.\nLisa Ingerman, Ph.D., D.A.B.T.\nConnor McGuire, Ph.D.\nJennifer Rhoades, B.S.\n\nATSDR, Office of Innovation and Analytics, \nToxicology Section, Atlanta, GA\n\nSRC, Inc., North Syracuse, NY\n\n## REVIEWERS\n\n## Interagency Minimal Risk Level Workgroup:\n\nIncludes ATSDR; National Center for Environmental Health (NCEH); U.S. Environmental Protection \nAgency (EPA); National Toxicology Program (NTP).\n\n## Additional reviews for science and/or policy:\n\nATSDR, Office of Community Health Hazard Assessment; ATSDR, Office of Capacity Development \nand Applied Prevention Science; ATSDR, Office of Science; NCEH, Division of Laboratory Sciences; \nNCEH, Division of Environmental Health Science and Practice; National Institute for Occupational \nSafety and Health (NIOSH); EPA, Office of Research and Development; EPA, Office of Water.\n\n## PEER REVIEWERS\n\n1. Kristen Upson, Ph.D., M.P.H.; Associate Professor of Epidemiology and Biostatistics; Michigan \nState University; Department of Epidemiology and Biostatistics; 909 Wilson Road Room B601; \nEast Lansing, MI\n\n2. Zahir Shaikh, Ph.D.; Professor Emeritus and Former Founding Director of RI-INBRE; The \nUniversity of Rhode Island, College of Pharmacy; Kingston, RI\n\n3. Curtis D. Klaassen, M.S., Ph.D., FATS, FAASLD, FASPET; Director of the Mid-America \nToxicology Course; Previously University Distinguished Professor and Chair at The University \nof Kansas School of Medicine; Kansas City, KS (retired)\n\nThese experts collectively have knowledge of toxicology, chemistry, and/or health effects.  All reviewers \nwere selected in conformity with Section 104(I)(13) of the Comprehensive Environmental Response, \nCompensation, and Liability Act, as amended.\n\n---\n\nATSDR scientists review peer reviewers’ comments and determine whether changes will be made to the \nprofile based on comments.  The peer reviewers’ comments and responses to these comments are part of \nthe administrative record for this compound.\n\nThe listing of peer reviewers should not be understood to imply their approval of the profile\'s final \ncontent.  The responsibility for the content of this profile lies with ATSDR.\n\n---\n\n## CONTENTS\n\nDISCLAIMER .............................................................................................................................................. ii\nFOREWORD ............................................................................................................................................... iii\nVERSION HISTORY ................................................................................................................................... v\nCONTRIBUTORS & REVIEWERS ........................................................................................................... vi\nCONTENTS ............................................................................................................................................... viii\nLIST OF FIGURES ...................................................................................................................................... x\nLIST OF TABLES ....................................................................................................................................... xi\nCHAPTER 1. RELEVANCE TO PUBLIC HEALTH ................................................................................. 1\n1.1 OVERVIEW AND U.S. EXPOSURES ......................................................................................... 1\n1.2 SUMMARY OF HEALTH EFFECTS........................................................................................... 2\n1.3 MINIMAL RISK LEVELS (MRLs) .............................................................................................. 8\nCHAPTER 2. HEALTH EFFECTS ............................................................................................................ 12\n2.1 INTRODUCTION ........................................................................................................................ 12\n2.2 DEATH ........................................................................................................................................ 92\n2.3 BODY WEIGHT .......................................................................................................................... 99\n2.4 RESPIRATORY ........................................................................................................................ 104\n2.5 CARDIOVASCULAR ............................................................................................................... 113\n2.6 GASTROINTESTINAL ............................................................................................................. 124\n2.7 HEMATOLOGICAL ................................................................................................................. 125\n2.8 MUSCULOSKELETAL ............................................................................................................ 131\n2.9 HEPATIC ................................................................................................................................... 143\n2.10 RENAL ...................................................................................................................................... 151\n2.11 DERMAL ................................................................................................................................... 171\n2.12 OCULAR ................................................................................................................................... 172\n2.13 ENDOCRINE ............................................................................................................................. 172\n2.14 IMMUNOLOGICAL ................................................................................................................. 182\n2.15 NEUROLOGICAL..................................................................................................................... 189\n2.16 REPRODUCTIVE ..................................................................................................................... 196\n2.17 DEVELOPMENTAL ................................................................................................................. 213\n2.18 OTHER NONCANCER ............................................................................................................. 239\n2.19 CANCER .................................................................................................................................... 241\n2.20 GENOTOXICITY ...................................................................................................................... 256\n2.21 MECHANISMS OF ACTION ................................................................................................... 266\nCHAPTER 3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, \nCHEMICAL INTERACTIONS ......................................................................................... 269\n3.1 TOXICOKINETICS................................................................................................................... 269\n3.1.1 Absorption ........................................................................................................................... 269\n3.1.2 Distribution ......................................................................................................................... 274\n3.1.3 Metabolism .......................................................................................................................... 277\n3.1.4 Excretion ............................................................................................................................. 278\n3.1.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models ........... 278\n3.1.6 Animal-to-Human Extrapolations ....................................................................................... 285\n3.2 CHILDREN AND OTHER POPULATIONS THAT ARE UNUSUALLY \nSUSCEPTIBLE .......................................................................................................................... 286\n\n---\n\n3.3 BIOMARKERS OF EXPOSURE AND EFFECT ..................................................................... 290\n3.3.1 Biomarkers of Exposure ...................................................................................................... 291\n3.3.2 Biomarkers of Effect ........................................................................................................... 294\n3.4 INTERACTIONS WITH OTHER CHEMICALS ..................................................................... 297\nCHAPTER 4. CHEMICAL AND PHYSICAL INFORMATION ........................................................... 303\n4.1 CHEMICAL IDENTITY ........................................................................................................... 303\n4.2 PHYSICAL AND CHEMICAL PROPERTIES ........................................................................ 304\nCHAPTER 5. POTENTIAL FOR HUMAN EXPOSURE ....................................................................... 307\n5.1 OVERVIEW .............................................................................................................................. 307\n5.2 PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL ................................................ 310\n5.2.1 Production ........................................................................................................................... 310\n5.2.2 Import/Export ...................................................................................................................... 313\n5.2.3 Use ...................................................................................................................................... 314\n5.2.4 Disposal ............................................................................................................................... 314\n5.3 RELEASES TO THE ENVIRONMENT ................................................................................... 315\n5.3.1 Air ....................................................................................................................................... 315\n5.3.2 Water ................................................................................................................................... 319\n5.3.3 Soil ...................................................................................................................................... 320\n5.4 ENVIRONMENTAL FATE ...................................................................................................... 321\n5.4.1 Transport and Partitioning ................................................................................................... 321\n5.4.2 Transformation and Degradation ........................................................................................ 325\n5.5 LEVELS IN THE ENVIRONMENT ......................................................................................... 326\n5.5.1 Air ....................................................................................................................................... 327\n5.5.2 Water ................................................................................................................................... 328\n5.5.3 Sediment and Soil ............................................................................................................... 330\n5.5.4 Other Media ........................................................................................................................ 332\n5.6 GENERAL POPULATION EXPOSURE.................................................................................. 335\n5.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES .............................................. 362\nCHAPTER 6. ADEQUACY OF THE DATABASE ................................................................................ 363\n6.1 EXISTING INFORMATION ON HEALTH EFFECTS ........................................................... 363\n6.2 IDENTIFICATION OF DATA NEEDS .................................................................................... 365\n6.3 ONGOING STUDIES ................................................................................................................ 372\nCHAPTER 7. REGULATIONS AND GUIDELINES ............................................................................. 376\nCHAPTER 8. REFERENCES .................................................................................................................. 380\nAPPENDICES\nAPPENDIX A.  ATSDR MINIMAL RISK LEVEL WORKSHEETS .................................................... A-1 \nAPPENDIX B.  LITERATURE SEARCH FRAMEWORK FOR CADMIUM ...................................... B-1 \nAPPENDIX C.  FRAMEWORK FOR ATSDR’S SYSTEMATIC REVIEW OF HEALTH EFFECTS \nDATA FOR CADMIUM ................................................................................................ C-1 \nAPPENDIX D.  USER’S GUIDE ............................................................................................................. D-1 \nAPPENDIX E.  QUICK REFERENCE FOR HEALTH CARE PROVIDERS ....................................... E-1 \nAPPENDIX F.  GLOSSARY .................................................................................................................... F-1 \nAPPENDIX G.  ACRONYMS, ABBREVIATIONS, AND SYMBOLS................................................. G-1\n\n---\n\n## LIST OF FIGURES\n\n1-1.  Health Effects Found in Animals Following Inhalation Exposure to Cadmium .................................. 4\n1-2.  Health Effects Found in Animals Following Oral Exposure to Cadmium ........................................... 5\n1-3.  Summary of Sensitive Targets of Cadmium – Inhalation ..................................................................... 9\n1-4.  Summary of Sensitive Targets of Cadmium – Oral ............................................................................ 10\n2-1.  Overview of the Number of Studies Examining Cadmium Health Effects ........................................ 17\n2-2.  Levels of Significant Exposure to Cadmium – Inhalation .................................................................. 33\n2-3.  Levels of Significant Exposure to Cadmium – Oral ........................................................................... 72\n3-1.  Structure of Kjellström-Nordberg Cadmium Biokinetic Model ....................................................... 280\n3-2.  Structure of Diamond and Klotzbach Cadmium Biokinetics Model ................................................ 283\n5-1.  Number of NPL Sites with Cadmium Contamination ...................................................................... 307\n6-1.  Summary of Existing Health Effects Studies on Cadmium by Route and Endpoint ........................ 364\n\n---\n\n## LIST OF TABLES\n\n1-1.  Minimal Risk Levels (MRLs) for Cadmium ...................................................................................... 11\n2-1.  Levels of Significant Exposure to Cadmium – Inhalation .................................................................. 18\n2-2.  Levels of Significant Exposure to Cadmium – Oral ........................................................................... 41\n2-3.  Levels of Significant Exposure to Cadmium – Dermal ...................................................................... 90\n2-4.  Results of Meta-Analyses Evaluating Exposure to Cadmium and Mortality Endpoints .................... 93\n2-5.  Studies Included in Meta-Analyses Evaluating Exposure to Cadmium and Mortality \nEndpoints ............................................................................................................................................ 94\n2-6.  Results of General Population Studies Evaluating Urinary Cadmium Levels and All-Cause \nMortality ............................................................................................................................................. 94\n2-7.  Results of Meta-Analysis Evaluating Exposure to Cadmium and Respiratory Endpoints ............... 106\n2-8.  Results of Epidemiological Studies Evaluating Urinary Cadmium Levels and Respiratory \nEffects ............................................................................................................................................... 108\n2-9.  Results of Meta-Analyses Evaluating Exposure to Cadmium and Cardiovascular Endpoints ......... 113\n2-10.  Studies Included in Meta-Analyses Evaluating Exposure to Cadmium and Cardiovascular \nEndpoints ........................................................................................................................................ 116\n2-11.  Results of General Population Studies Evaluating Urinary Cadmium Levels and Blood \nPressure or Hypertension ................................................................................................................ 118\n2-12.  Results of General Population Studies Evaluating Urinary Cadmium Levels and \nCardiovascular Disease-Related Effects ......................................................................................... 122\n2-13.  Results of General Population Epidemiological Studies Evaluating Urinary Cadmium \nLevels and Hematological Effects .................................................................................................. 126\n2-14.  Results of Meta-Analyses Evaluating Exposure to Cadmium and Skeletal Endpoints .................. 132\n2-15.  Studies Included in Meta Analyses Evaluating Exposure to Cadmium and Skeletal \nEndpoints ........................................................................................................................................ 133\n2-16.  Results of General Population Epidemiological Studies Evaluating Urinary Cadmium \nLevels and Musculoskeletal Effects ............................................................................................... 136\n2-17.  Results of Meta-Analyses Evaluating Exposure to Cadmium and Serum Lipids .......................... 143\n2-18.  Studies Included in Meta-Analyses Evaluating Exposure to Cadmium and Serum Lipids ............ 144\n2-19.  Results of General Population Studies Evaluating Urinary Cadmium Levels and Blood \nLipid Levels .................................................................................................................................... 145\n\n---\n\n2-20.  Results of General Population Studies Evaluating Exposure to Urinary Cadmium Levels \nand Hepatic Disease and Clinical Chemistry ................................................................................. 147\n2-21.  Results of Occupational Studies Evaluating Urine Cadmium Levels and Renal Outcomes .......... 154\n2-22.  Results of Meta-Analyses Evaluating Exposure to Cadmium and Renal Endpoints ...................... 157\n2-23.  Studies Included in Meta-Analyses Evaluating Exposure to Cadmium and Renal Endpoints ....... 158\n2-24.  Results of Epidemiological Studies of General Populations Evaluating Urine Cadmium \nLevels and Renal Effects ................................................................................................................ 161\n2-25.  Results of Meta-Analysis Evaluating Exposure to Cadmium and Thyroid Endpoints ................... 173\n2-26.  Results of General Population Studies Evaluating Urinary Cadmium Levels and Thyroid \nEffects ............................................................................................................................................. 174\n2-27.  Results of Meta-Analyses Evaluating Exposure to Cadmium and Diabetes Endpoints ................. 175\n2-28.  Studies Included in Meta Analyses Evaluating Exposure to Cadmium and Diabetes \nEndpoints ........................................................................................................................................ 177\n2-29.  Results of Epidemiological Studies Evaluating Exposure to Cadmium and Diabetes-\nRelated Effects ................................................................................................................................ 179\n2-30.  Results of Epidemiological Studies Evaluating Urinary Cadmium Levels and \nImmunological Effects ................................................................................................................... 182\n2-31.  Results of Meta-Analyses Evaluating Exposure to Cadmium and Neurological Endpoints .......... 190\n2-32.  Studies Included in Meta-Analyses Evaluating Exposure to Cadmium and Neurological \nEndpoints ........................................................................................................................................ 191\n2-33.  Results of General Population Studies Evaluating Exposure to Urinary Cadmium and \nNeurological Effects ....................................................................................................................... 192\n2-34.  Results of Meta-Analyses Evaluating Exposure to Cadmium and Male Reproductive \nEndpoints ........................................................................................................................................ 196\n2-35.  Studies Included in Meta-Analyses Evaluating Exposure to Cadmium and Male \nReproductive Endpoints ................................................................................................................. 197\n2-36.  Results of General Population Studies Evaluating Urinary Cadmium Levels and \nReproductive Effects in Men .......................................................................................................... 199\n2-37.  Results of Meta-Analyses Evaluating Exposure to Cadmium and Female Reproductive \nEndpoints ........................................................................................................................................ 202\n2-38.  Studies Included in Meta-Analyses Evaluating Exposure to Cadmium and Female \nReproductive Endpoints ................................................................................................................. 203\n2-39.  Results of General Population Studies Evaluating Urinary Cadmium Levels and \nReproductive Effects in Women..................................................................................................... 204\n\n---\n\n2-40.  Results of Meta-Analyses Evaluating Exposure to Cadmium and Neurodevelopmental \nEndpoints ........................................................................................................................................ 213\n2-41.  Studies Included in Meta-Analyses Evaluating Exposure to Cadmium and \nNeurodevelopmental Endpoints ..................................................................................................... 214\n2-42.  Results of General Population Studies Evaluating Exposure to Cadmium and \nNeurodevelopmental Effects .......................................................................................................... 217\n2-43.  Results of General Population Studies Evaluating Urinary Cadmium Levels and Growth \nand Metabolism During Infancy, Childhood, and Adolescence ..................................................... 228\n2-44.  Results of General Population Studies Evaluating Urinary Cadmium Levels and \nReproductive Developmental Effects ............................................................................................. 233\n2-45.  Results of Meta-Analyses Evaluating Exposure to Cadmium and Metabolic Syndrome \nEndpoints ........................................................................................................................................ 240\n2-46.  Studies Included in Meta Analyses Evaluating Exposure to Cadmium and Metabolic \nSyndrome Endpoints ...................................................................................................................... 240\n2-47.  Results of Meta-Analyses Evaluating Exposure to Cadmium and Cancer ..................................... 242\n2-48.  Studies Included in Meta-Analyses Evaluating Exposure to Cadmium and Cancer ...................... 245\n2-49.  Results of Epidemiological Studies Evaluating Exposure to Cadmium and Cancer ...................... 250\n2-50.  Genotoxicity of Cadmium *In Vivo* .................................................................................................. 257\n2-51.  Genotoxicity of Cadmium *In Vitro* ................................................................................................. 259\n4-1.  Chemical Identity of Cadmium and Compounds ............................................................................. 303\n4-2.  Physical and Chemical Properties of Cadmium and Compounds .................................................... 304\n5-1.  Facilities that Produce, Process, or Use Cadmium ........................................................................... 310\n5-2.  Facilities that Produce, Process, or Use Cadmium Compounds ....................................................... 311\n5-3.  Releases to the Environment from Facilities that Produce, Process, or Use Cadmium .................... 316\n5-4.  Releases to the Environment from Facilities that Produce, Process, or Use Cadmium \nCompounds ....................................................................................................................................... 317\n5-5.  Lowest Limit of Detection Based on Standards ............................................................................... 326\n5-6.  Summary of Environmental Levels of Cadmium ............................................................................. 327\n5-7.  Range of Arithmetic Means for Cadmium from the AQS ................................................................ 327\n5-8.  Total Cadmium Levels in Groundwater and Surface Water in U.S. Samples Collected in \n2022–2024 ........................................................................................................................................ 329\n5-9.  Total Cadmium Levels in Ambient Sediment Collected in 2022–2024 ........................................... 331\n\n---\n\n5-10.  Mean Concentrations of Cadmium for FDA’s Total Diet Study Market Baskets 2006-1\nthrough 2008-4 ............................................................................................................................... 333\n5-11.  Geometric Mean and Selected Percentile Blood Concentrations (μg/L) of Cadmium in the\nU.S. Population, 1999–2018 ........................................................................................................... 336\n5-12.  Geometric Mean and Selected Percentile Urine Concentrations (Creatinine Corrected)\n(μg/g Creatinine) of Cadmium in the U.S. Population, 1999––2018 ............................................. 343\n5-13.  Geometric Mean and Selected Percentile Urine Concentrations (μg/L) of Cadmium in the\nU.S. Population, 1999–2018 ........................................................................................................... 350\n5-14.  Blood Cadmium Concentrations, Geometric Means, Adjusted Proportional Change in\nMeans, and 95<sup>th</sup> Percentiles in New York City Adults in Population \nSubgroups....................................................................................................................................... 357\n5-15.  Occupations with Potential Exposure to Cadmium and Cadmium Compounds ............................ 361\n6-1.  Ongoing Studies on Cadmium .......................................................................................................... 372\n7-1.  Regulations and Guidelines Applicable to Cadmium ....................................................................... 376\n\n---\n\n## CHAPTER 1. RELEVANCE TO PUBLIC HEALTH\n\n### 1.1 OVERVIEW AND U.S. EXPOSURES\n\nCadmium (Cd) occurs in the earth’s crust at a concentration of roughly 0.1–0.5 ppm and is commonly \nassociated with zinc, lead, and copper ores.  It is also a natural constituent of ocean water with average \nlevels between <5 and 110 ng/L, with higher levels reported near coastal areas and in marine phosphates \nand phosphorites (Morrow 2010).  The cadmium concentration of natural surface water and groundwater \nis usually <1 μg/L (Elinder 1985a, 1992).  Surface soil concentrations will depend on several factors such \nas its mobility, natural geochemistry, and magnitude of contamination from sources such as fertilizers and \natmospheric deposition.  Natural emissions of cadmium to the environment can result from volcanic \neruptions, forest fires, generation of sea salt aerosols, or other natural phenomena (EPA 1985; Morrow \n2010; Shevchenko et al. 2003).\n\n$$\n<1\\;\\mu g/L\n$$\n\nIn the environment, cadmium exists in only one oxidation state (Cd<sup>+2</sup>) and does not undergo oxidationreduction reactions.  In surface water and groundwater, cadmium can exist as the hydrated ion or as ionic \ncomplexes with other inorganic or organic substances.  Soluble forms of cadmium can migrate in water.  \nInsoluble forms of cadmium will settle and adsorb to sediments.  Cadmium’s fate in soil depends on \nseveral factors such as pH of the soil and availability of organic matter.  Generally, cadmium will bind \nstrongly to organic matter and this will, for the most part, immobilize it (Autier and White 2004).  \nHowever, cadmium’s behavior in soil will vary depending on the environmental conditions.  It is not \nlikely that cadmium will undergo significant transformation in the atmosphere (EPA 1980).  It will exist \nin particulate form and sometimes vapor form (emitted from high-temperature processes) where it will \nundergo atmospheric transport and eventually deposit onto soils and surface waters.\n\n$$\n\\left(\\mathrm{Cd^{+2}}\\right)\n$$\n\nNon-ferrous metal mining and refining, manufacture and application of phosphate fertilizers, fossil fuel \ncombustion, and waste incineration and disposal are the main anthropogenic sources of cadmium in the \nenvironment.  Except for those who live near cadmium-emitting industries, inhalation of cadmium in the \nambient air may occur but is not a major source of exposure.  Similarly, cadmium exposure through the \ndrinking water supply is of minor concern for the majority of the U.S. population.  However, water \nsources near cadmium-emitting industries, both with historic and current operations, have shown a \nmarked elevation of cadmium in water sediments and aquatic organisms (Angelo et al. 2007; Arnason and \nFletcher 2003; Brumbaugh et al. 2005; Mason et al. 2000; Paulson 1997).  Concentrations of cadmium in these polluted waters have ranged from <1.0 to 77 μg/L.  Cadmium from polluted soil and water can \naccumulate in plants and organisms, thus entering the food supply (Morrow 2010).\n\n$$\n7 7 \\mu \\mathrm {g} / \\mathrm {L}\n$$\n\nIn the United States, the largest source of cadmium exposure for nonsmoking adults and children is \nthrough dietary intake (NTP 2005).  The average daily intake of cadmium for children and adults \n(≥2 years of age) in the United States was estimated as 4.63 µg/day (Kim et al. 2019).  In general, leafy \nvegetables such as lettuce and spinach and staples such as potatoes and grains contain relatively high \nvalues of cadmium.  Peanuts, soybeans, and sunflower seeds have naturally high levels of cadmium \n(Morrow 2010).  Shellfish and organ meats (liver and kidney) also have relatively high concentrations of \ncadmium (Elinder 1985a).\n\nMean values of cadmium in the blood and urine of the U.S. population were reported in the National \nHealth and Nutrition Examination Survey (NHANES) 1999–2018 (CDC 2024).  Blood cadmium tends to \nreflect recent exposures, and urinary cadmium reflects cumulative cadmium exposure and body burden \n(particularly, kidney cadmium levels).  The geometric mean blood cadmium levels for the total population \n(≥1 year of age) have decreased nearly 50% from survey years 1999–2000 (0.412 µg/L) to survey years \n2017–2018 (0.241 µg/L).\n\n$$\n1999-2000\\left(0.412\\ \\mu g/L\\right)\n$$\n\n$$\n2017-2018\\left(0.241\\ \\mu g/L\\right)\n$$\n\nSmoking greatly increases exposure to cadmium, as tobacco leaves naturally accumulate high amounts of \ncadmium (Morrow 2010).  It has been estimated that tobacco smokers are exposed to 0.5–2.0 μg \ncadmium per cigarette, and about 10% is inhaled when smoked (Morrow 2010; Nordberg et al. 2015; \nNTP 2005).  A geometric mean blood cadmium level for a heavy smoker has been reported as high as \n1.58 μg/L (McKelvey et al. 2007), compared to the estimated national mean of 0.295 μg/L for all adults\n≥20 years of age, based on survey years 2017–2018 (CDC 2024).  Nonsmokers may also be exposed to \ncadmium in cigarettes via second-hand smoke.\n\n$$\n1. 5 8 \\mu \\mathrm {g} / \\mathrm {L}\n$$\n\n### 1.2 SUMMARY OF HEALTH EFFECTS\n\nSince the early 1950s, when the hazards of occupational cadmium exposure were recognized (Friberg \n1950), a large amount of information has been generated concerning the toxic effects of cadmium \nexposure in humans and laboratory animals.  Toxicological properties of cadmium are similar for the \nseveral different salts and oxides of cadmium that have been investigated, although differences in \nabsorption and distribution lead to different effect levels.  For inhalation exposure, particle size and \nsolubility in biological fluids (in contrast to solubility in water) appear to be the more important determinants of the toxicokinetics (Hirano et al. 1989a, 1989b; Oldiges and Glaser 1986; Rusch et al. \n1986).  For oral exposure, most experimental studies have used soluble cadmium, which exists as the Cd<sup>+2</sup>\nion regardless of the initial salt.  Absorption appears to be similar for cadmium ion and cadmium \ncomplexed with proteins in food, except for a few specific types of foods such as Bluff oysters and seal \nmeat.  Also, poorly soluble cadmium pigments may be absorbed to a lesser extent than soluble cadmium \nion (ILZRO 1977; Oldiges and Glaser 1986).\n\nThe database on the toxicity of cadmium in humans and animals following inhalation or oral exposure is \nextensive.  Target organs are similar among species and, in general, toxicokinetics following systemic \nabsorption from the gastrointestinal and respiratory tracts are similar.  Most of the human data involve \nevaluation of health effects associated with chronic-duration exposure in occupational studies, \ncommunity-based studies of populations living in cadmium-polluted areas, or epidemiological studies in \nthe general population.  When adequate exposure characterization is available, human studies generally \nreport exposure levels in terms of an internal biomarker of exposure (e.g., urinary cadmium).  Numerous \nstudies have conducted dose-response analyses between urinary cadmium levels and biomarkers of renal \ndysfunction (see Section 2.10); similar rigorous dose-response analyses are not available for other targets \nof toxicity in humans.  In animals, evaluation of available dose-response data by route and duration \nindicates that sensitive noncancer targets of cadmium toxicity are respiratory and neurodevelopmental \neffects following inhalation exposure (Figure 1-1) and renal, skeletal, and neurodevelopmental effects \nfollowing oral exposure (Figure 1-2).\n\nA systematic review of these sensitive noncancer endpoints resulted in the following hazard identification \nconclusions:\n\n• Respiratory effects are a known effect for humans following inhalation exposure.\n\n• Skeletal effects are a known effect for humans.\n\n• Renal effects are a known effect for humans.\n\n• Neurodevelopmental effects are a presumed effect for humans.\n\n---\n\n**Figure 1-1.  Health Effects Found in Animals Following Inhalation Exposure to** \n**Cadmium**\n\nConcentration (mg Cd/m<sup>3</sup>) Effects in Animals\n>8 Acute:  Mortality; clinical signs of neurotoxicity, female reproductive effects\n0.9-1.7 Acute:  Decreased body weight\nIntermediate:  Male and female reproductive effects\n0.19-0.4 Acute:  Developmental and immune effects\n0.05-0.1 Acute:  Respiratory effects\nIntermediate:  Death\n0.02-0.03 Intermediate:  Respiratory and neurodevelopmental effects\nChronic:  Cancer, mortality\n1x10<sup>-4</sup> mg Cd/m<sup>3</sup> Provisional Chronic MRL (based on human data and exposure levels predicted from biomarkers)\n\nCd = cadmium; MRL = minimal risk level\n\n---\n\n**Figure 1-2.  Health Effects Found in Animals Following Oral Exposure to** \n**Cadmium**\n\n## Dose (mg Cd/kg/day)\n\n## Effects in Animals\n\n**Acute:**  Death; hepatic, gastrointestinal, neurological, and male \nreproductive effects\n\n**5.28-15**\n\n**Intermediate:**  Death\n\n**Chronic:**  Hematological effects\n\n**Acute:**  Hematological effects; altered reproductive development\n\n**0.6-3.13**\n\n**Intermediate:**  Gastrointestinal effects\n\n**Chronic:**  Decreased body weight\n\n**Acute:**  Renal and developmental effects, decreased body weight\n\n**0.2-0.4**\n\n**Intermediate:**  Renal, hepatic, hematological, and male and female \nreproductive effects; increased blood pressure; decreased body weight\n\n**Chronic:**  Renal and neurological effects; cancer\n\n**0.04-0.08**\n\n**Intermediate:**  Skeletal, neurological, respiratory, and immunological \neffects; decreased birth weight and altered reproductive development\n\n## 0.002 mg Cd/kg/day 3x10<sup>-4</sup> mg Cd/kg/day\n\n3x10 -4 mg Cd/kg/day\n\n**Intermediate:**  Neurodevelopmental and endocrine effects\n\n**Chronic:**  Skeletal effects\n\n**Provisional Acute MRL**\n\n**Provisional Chronic MRL (based on human data and exposure levels predicted from biomarkers)**\n\nCd = cadmium; MRL = minimal risk level\n\n---\n\n**_Respiratory Effects._** A meta-analysis of 12 studies reported an association between chronic-duration \ninhalation exposure to cadmium and reduced forced expiratory volume in the first second to forced vital \ncapacity (FEV1/FVC), which is indicative of an increased risk of chronic obstructive pulmonary disease \n(Wang et al. 2024a).  A limited number of occupational studies not included in the meta-analysis also \nreported associations between impaired lung function and urinary cadmium levels in workers (Moitra et \nal. 2013, 2015; Zhou et al. 2022).  These findings are supported by occupational case reports of clinical \nsigns of respiratory distress and pulmonary damage after acute-duration exposure to fatal concentrations \n(Beton et al. 1966; Townshend 1982).  In animal acute- and intermediate-duration inhalation studies, the \nrespiratory tract is the most sensitive target of toxicity in animals (NTP 1995).  Available studies \nconsistently report histopathological and inflammatory reactions in the respiratory tract of multiple \nspecies; in studies that provide quantitative data, findings are clearly concentration-related \n(see Section 2.4).\n\n**_Skeletal Effects._** Cadmium-associated bone effects were first described in 1955 in the Jinzu River Basin, \na cadmium-contaminated area in Japan, following the development of a bone disease called Itai-Itai\n("ouch-ouch") disease, characterized by multiple fractures of the long bones, osteomalacia, and \nosteoporosis in combination with proteinuria (Järup et al. 1998; Nordberg et al. 1997; Shigematsu 1984).  \nFour meta-analyses evaluating 41 unique references confirm the association between cadmium exposure \nand adverse bone effects, including fractures, osteoporosis, and decreased bone mineral density (Cheng et \nal. 2016; Kunioka et al. 2022; Li et al. 2021; Qing et al. 2021), as do several studies published since the \nmeta-analyses (Lv et al. 2021; Wang et al. 2021a; Xie et al. 2023a, 2023b).  Occupational case studies \nindicate that calcium deficiency, osteoporosis, or osteomalacia can develop in some workers after longterm occupational exposure to high levels of cadmium (Adams et al. 1969; Blainey et al. 1980; Bonnell \n1955; Kazantzis 1979; Scott et al. 1980).  In rodents, decreases in bone mineralization, bone mineral \ndensity, and mechanical properties have been consistently observed following oral exposure to cadmium \nchloride (see Section 2.8).  While bone effects may be secondary to cadmium-associated renal damage \n(Bhattacharyya et al. 2023; Shevchenko et al. 2021; Zhang et al. 2020a), there is also evidence for a direct \neffect of cadmium on bone, and acceleration of bone resorption can occur in the absence of renal \ndysfunction (Reyes-Hinojosa et al. 2019; Shevchenko et al. 2021; Zhang et al. 2020a).\n\n**_Renal Effects._** The kidney is a well-established target of cadmium toxicity in humans following \noccupational or dietary exposure.  Available meta-analyses consistently reported associations between \none or more biomarkers of cadmium exposure and risk of proteinuria, urolithiasis, chronic kidney disease, \nhyperuricemia, renal cytotoxicity, and low glomerular filtration rate (GFR) (Chen et al. 2024; Doccioli et al. 2024; Gu et al. 2022; Jalili et al. 2021; Liu et al. 2016a; Woo et al. 2015; Zhu et al. 2024a).  These \nfindings are supported by several studies conducted since the meta-analyses were published (see \nSection 2.10).  In animals, there is no evidence for renal effects in acute- and intermediate-duration \ninhalation studies; however, exposure duration and concentration may not have been enough to reach the \ncritical kidney concentration to induce renal effects and chronic-duration inhalation studies evaluating \nrenal toxicity were not identified.  In oral studies, some studies reported adverse changes in sensitive \nbiomarkers of kidney damage, such as a β2-microglobulin (β2M) or N-acetyl-β-d-glucosaminidase \n(NAG) (Bernard et al. 1992; Liu et al. 2019; Wan et al. 2022).  However, other studies did not find this \neffect at similar or higher doses (Wang et al. 2014).  Similar inconsistencies were observed for serum \nclinical chemistry values and histopathological findings (see Section 2.10).\n\n**_Neurodevelopmental Effects._** While several general population studies are available, findings are mixed.  \nAvailable meta-analysis reported mixed conclusions regarding the potential association between cadmium \nexposure and autism spectrum disorder (ASD) (Ding et al. 2023; Dou et al. 2023; Ramazani et al. 2024; \nSaghazadeh and Rezaei 2017; Sulaiman et al. 2020) and did not find an association with attention deficit \nhyperactivity disorder (ADHD) (Dimitrov et al. 2023).  Some studies reported associations between \ncadmium exposure and decreased measures of cognitive development in children and adolescents (Gustin \net al. 2018; Kippler et al. 2016; Rodríguez-Barranco et al. 2014; Zhou et al. 2020); however, other studies \ndid not support this finding (Forns et al. 2014; Lucchini et al. 2019; Pan et al. 2018; Yang et al. 2020).  \nNo consistent findings were observed regarding potential associations between cadmium exposure and \nneurobehavioral or neurosensory evaluations during childhood or adolescence (see Section 2.17).  In \ncontrast, available animal studies collectively indicate that developmental cadmium exposure can cause \nalterations in sensorimotor function (including nerve conduction) and activity, socioemotional behavior, \nand learning and memory in rodents; however, the timing and duration of exposure and assessment \ninfluence findings (see Section 2.17).\n\n**_Cancer Effects._** The carcinogenicity of cadmium has been studied extensively in humans in studies \ninvolving workers and general populations and in animals after inhalation or oral exposures.  The \nInternational Agency for Research on Cancer (IARC) classified cadmium and cadmium compounds as \ncarcinogenic to humans (Group 1) based on sufficient evidence in humans for the carcinogenicity of \ncadmium and cadmium compounds, sufficient evidence in animals for the carcinogenicity of cadmium \ncompounds, and limited evidence in animals for the carcinogenicity of cadmium metal (IARC \n2012).  Similarly, the Department of Health and Human Services (HHS) classified cadmium and \ncadmium compounds as substances known to be human carcinogens based on sufficient evidence of carcinogenicity in humans, including epidemiological and mechanistic studies (NTP 2021).  In 1989, the \nU.S. Environmental Protection Agency (EPA) classified cadmium as a probable human carcinogen by \ninhalation (Group B1) based on limited evidence in humans and sufficient evidence in animals (IRIS \n1989).\n\n### 1.3 MINIMAL RISK LEVELS (MRLs)\n\nMRLs for inhalation and oral exposures to cadmium were derived.  As presented in Figure 1-3, the most \nsensitive effects following inhalation exposure to cadmium are respiratory and developmental \n(specifically neurodevelopmental effects) following acute- and intermediate-duration exposure and renal \nfollowing chronic-duration exposure.  A provisional chronic-duration inhalation MRL was derived based \non renal effects in humans; the inhalation database was considered inadequate for the derivation of acuteor intermediate-duration MRLs.  The lack of renal toxicity at shorter durations in animal inhalation\nstudies is attributed to inadequate exposure duration to meet the critical renal burden required to elicit \nadverse renal effects.  The relationship between renal and urinary cadmium appears to be nearly linear at \nchronic-duration intakes and kidney burdens that do not produce nephrotoxicity (i.e., elimination halftime is independent of dose).  However, at high kidney cadmium burdens, associated with renal damage \n(>50 μg Cd/g cortex), the elimination half-time increases with increasing severity of renal damage.  \nLinearity in the dose-urinary excretion relationship also does not appear to apply following an acuteduration, high exposure to cadmium.  Multicompartment, physiologically based pharmacokinetic (PBPK) \nmodels (described in detail in Section 3.1.5) can be used to estimate cadmium intakes (inhalation and oral \nexposure) associated with a given urinary cadmium level and/or kidney cadmium burden.  These models \nhave been extensively evaluated for predicting dose-kidney-urinary cadmium relationships within the \nlinear range of the dose-urinary cadmium relationship, and PBPK modeling was used in the derivation of \nthe provisional inhalation chronic-duration MRL.\n\nAs presented in Figure 1-4, the most sensitive effects following oral exposure are renal, developmental \n(specifically neurodevelopmental), and skeletal effects.  Provisional acute- and chronic-duration oral \nMRLs were derived based on renal effects in animals and humans, respectively; the oral database was \nconsidered inadequate for the derivation an intermediate-duration oral MRL.  As discussed for the provisional chronic-duration inhalation MRL, PBPK modeling was used in the derivation of the \nprovisional oral chronic-duration MRL.\n\nMRLs derived for both the inhalation and oral exposure routes for cadmium are summarized in Table 1-1\nand are discussed in greater detail in Appendix A.\n\n**Figure 1-3.  Summary of Sensitive Targets of Cadmium – Inhalation**\n\n**Available data indicate that the respiratory system and developing nervous system are the most \nsensitive targets following acute- and intermediate-duration exposure and the renal system is the \nmost sensitive target following chronic-duration exposure to cadmium via inhalation.**\n\nNumbers in circles are the lowest lowest-observed-adverse-effect levels (LOAELs) for all health effects in \nanimals and the number in the triangle is the point of departure (POD) for the chronic-duration inhalation \nMRL based on human data.*\n\n**Acute (mg Cd/m³ )**\n\n| Category | Acute (mg Cd/m³) | Intermediate (mg Cd/m³) | Chronic (mg Cd/m³) |\n| --- | --- | --- | --- |\n| Respiratory | 0.081 | 0.021 |  |\n| Immunological | 0.19 |  |  |\n| Developmental | 0.4 | 0.02 |  |\n| Hematological |  | 0.052 |  |\n| Body weight |  | 0.052 | 0.03 |\n| Renal |  |  | 0.00106 |\n| Death |  |  | 0.03 |\n\n*See Table 2-1 for animal studies identifying the LOAELs in circles.  The value of 0.00106 mg Cd/m<sup>3</sup> represented by \nthe triangle (human data) is the renal POD used for the provisional chronic-duration MRL; the value represents the \nlower 95% confidence limit on the weighted median of the urinary cadmium level associated with a 10% extra risk \nassociated with low-molecular weight proteinuria in 17 datasets from 11 human studies (see Appendix A for details).\n\n---\n\n## Figure 1-4. Summary of Sensitive Targets of Cadmium – Oral\n\n**Available data indicate that the renal, skeletal, and developing nervous system are the most \nsensitive targets of cadmium oral exposure.**\n\nNumbers in circles are the lowest lowest-observed-adverse-effect levels (LOAELs) for all health effects in \nanimals and the number in the triangle is the point of departure (POD) for the chronic-duration oral MRL \nbased on human data.*\n\n**Acute (mg Cd/kg/day)**\n\n| Category | LOAEL (mg Cd/kg/day) |\n| --- | --- |\n| Acute - Renal | 2 |\n| Acute - Body weight | 2 |\n| Acute - Developmental | 3.13 |\n| Intermediate - Developmental | 0.04 |\n| Intermediate - Endocrine | 0.053 |\n| Intermediate - Musculoskeletal | 0.2 |\n| Chronic - Renal (POD) | 0.00076 |\n| Chronic - Musculoskeletal | 0.08 |\n| Chronic - Renal | 2.301 |\n| Chronic - Cancer | 2.3 |\n\n*See Table 2-2 for animal studies identifying the LOAELs in circles.  The value of 7.60x10<sup>-4</sup> mg Cd/kg/day \nrepresented by a triangle (human data) is the renal POD used for the provisional chronic-duration MRL; the value \nrepresents the lower 95% confidence limit on the weighted median of the urinary cadmium level associated with a \n10% extra risk associated with low-molecular weight proteinuria in 17 datasets from 11 human studies \n(see Appendix A for details).\n\n$$\n7.60\\times10^{-4}\n$$\n\n---\n\n**Table 1-1.**\n\n**Minimal Risk Levels (MRLs) for Cadmium**\n\n| Exposure route | Exposure duration | Provisional MRL | Critical effect (species) | POD type | POD value | Uncertainty/modifying factor | Reference |\n| --- | --- | --- | --- | --- | --- | --- | --- |\n| Inhalation | Acute | None | - | - | - | - | - |\n| Inhalation | Intermediate | None | - | - | - | - | - |\n| Inhalation | Chronic | 1 × 10-4 mg CD/m3 | LMW proteinuria (humans) | 95% LCL of weighted median of UC10 from 17 datasets | 0.00106 mg Cd/m3 | UF: 3 MF: 3 | Weighted median from 17 datasetsb |\n| Oral | Acute | 0.002 mg Cd/kg/day | Total and LMW proteinuria; increased serum BUN (rats) | LOAEL | 2 mg Cd/kg/day | UF: 1,000 | Wan et al. 2022 |\n| Oral | Intermediate | None | - | - | - | - | - |\n| Oral | Chronic | 3 × 10-4 mg CD/kg/day | LMW proteinuria (humans) | 95% LCL of weighted median of UC10 from 17 datasets | 7.60 × 10-4 mg Cd/kg/day | UF: 3 | Weighted median from 17 datasetsb |\n\n<sup>a</sup>See Appendix A for additional information.\n\n<sup>b</sup>17 datasets from 3 occupational cohorts (Järup and Elinder 1994; Lei et al. 2007; Shao et al. 2007) and 8 general population cohorts (Buchet et al. 1990; Hong et \nal. 2004; Järup et al. 2000; Kobayashi et al. 2008; Suwazono et al. 2006; Uno et al. 2005; Wu et al. 2001; Zhang et al. 2016a).\n\nBUN = blood urea nitrogen; LCL = lower confidence limit; LMW = low molecular weight; LOAEL = lowest-observed-adverse-effect level; MF = modifying factor; \nPOD = point of departure; UC10 = urinary concentration associated with 10% extra risk; UF = uncertainty factor\n\n---\n\n## CHAPTER 2. HEALTH EFFECTS\n\n### 2.1 INTRODUCTION\n\nThe primary purpose of this chapter is to provide public health officials, physicians, toxicologists, and \nother interested individuals and groups with an overall perspective on the toxicology of cadmium.  It \ncontains descriptions and evaluations of toxicological studies and epidemiological investigations and \nprovides conclusions, where possible, on the relevance of toxicity and toxicokinetic data to public health.  \nWhen available, mechanisms of action specific to target organs are discussed along with the health effects \ndata, while general mechanisms of action are discussed in Section 2.21; toxicokinetic mechanistic data are \ndiscussed in Section 3.1.\n\nA glossary and list of acronyms, abbreviations, and symbols can be found at the end of this profile.\n\nTo help public health professionals and others address the needs of persons living or working near hazardous \nwaste sites, the information in this section is organized by health effect.  These data are discussed in terms of \nroute of exposure (inhalation, oral, and dermal) and three exposure periods:  acute (≤14 days), intermediate \n(15–364 days), and chronic (≥365 days).\n\nAs discussed in Appendix B, a literature search was conducted to identify relevant studies examining health \neffect endpoints.  Figure 2-1 provides an overview of the database of studies in humans or experimental \nanimals included in this chapter of the profile.  These studies evaluate the potential health effects associated \nwith inhalation, oral, or dermal exposure to cadmium, but may not be inclusive of the entire body of \nliterature.  As discussed in *Prioritization of Human Data* in Appendix B, the epidemiological database for \ncadmium is extensive, including thousands of primary studies and dozens of meta-analyses of available \nstudies.  To focus the profile review and discussion on the weight-of-evidence, recent evidence, and most \nrelevant data for hazard identification, ATSDR focused the discussion in Chapter 2 on meta-analyses \nconducted within the past 15 years.  To supplement discussion, any epidemiological study published since \nthe most recent meta-analysis for an endpoint was included if it provided: (1) reliable and reported estimates \nof cadmium exposure (measured levels in air or via urinary cadmium levels, as this is the most reliable \nbiomarker [see Section 3.3.1]); (2) analysis of potential confounders of the measures of association; and \n(3) appropriate statistical analysis.  For endpoints without a published meta-analysis, any study meeting these \ninclusion criteria were included, regardless of publication date.  Studies were excluded if they did not \nprovide quantitative evidence for associations, relied on semi-quantitative measures of exposure (e.g., food frequency questionnaires), or evaluated cadmium exposure from medical implants.  Exceptions to the above \ncriteria included studies reporting rare effects, inclusion of select older studies to provide historical context \n(e.g., Itai-Itai disease in the Jinzu River Basin region of Japan, early case reports and investigations of \nworkers exposed to cadmium that established targets of toxicity, etc.), and studies that fill data gaps (e.g., \nlower quality occupational studies in less-studied organ systems/tissues). The animal database for cadmium \nis also extensive.  As discussed in *Prioritization of Animal Data* in Appendix B, animal studies evaluating \nadverse effects were prioritized for efficient review.  Since cadmium is a well-established model of renal \ntoxicity, there are hundreds of studies describing administration of cadmium via oral or other routes (e.g., \nintraperitoneal) at known toxic doses to evaluate potential interventions to rescue (or prevent) renal toxicity \nor other cadmium-associated adverse effects at higher exposure levels.  Studies of this nature were excluded \nfrom the profile, as they do not inform dose-response effects at low, environmentally-relevant \ndoses. Similarly, acute- and intermediate-duration oral studies in rats or mice utilizing only one cadmium \ndose group were excluded due to lack of dose-response data; exceptions were made for acute-lethality \nstudies or studies addressing data-poor endpoints (e.g., lipid homeostasis studies).  All chronic-duration oral \nstudies and all inhalation and dermal studies of adequate quality were included in the profile.  A systematic \nreview of the scientific evidence of the most sensitive health effects associated with exposure to cadmium\nwas also conducted; the results of this review are presented in Appendix C.\n\nHuman and animal inhalation studies are presented together in Table 2-1 and Figure 2-2 and human and \nanimal oral studies are presented in Table 2-2 and Figure 2-3; limited dermal data were identified for \ncadmium and are presented in Table 2-3.\n\nLevels of significant exposure (LSEs) for each route and duration are presented in tables and illustrated in \nfigures.  The points in the figures showing no-observed-adverse-effect levels (NOAELs) or lowestobserved-adverse-effect levels (LOAELs) reflect the actual doses (levels of exposure) used in the studies.  \nEffects have been classified into “less serious LOAELs” or “serious LOAELs (SLOAELs).”  “Serious” \neffects are those that evoke failure in a biological system and can lead to morbidity or mortality (e.g., \nacute respiratory distress or death).  “Less serious” effects are those that are not expected to cause \nsignificant dysfunction or death, or those whose significance to the organism is not entirely clear.  \nATSDR acknowledges that a considerable amount of judgment may be required in establishing whether \nan endpoint should be classified as a NOAEL, “less serious” LOAEL, or “serious” LOAEL, and that in \nsome cases, there will be insufficient data to decide whether the effect is indicative of significant \ndysfunction.  However, the Agency has established guidelines and policies that are used to classify these \nendpoints.  ATSDR believes that there is sufficient merit in this approach to warrant an attempt at distinguishing between “less serious” and “serious” effects.  The distinction between “less serious” effects \nand “serious” effects is considered to be important because it helps the users of the profiles to identify \nlevels of exposure at which major health effects start to appear.  LOAELs or NOAELs should also help in \ndetermining whether or not the effects vary with dose and/or duration, and place into perspective the \npossible significance of these effects to human health.  Levels of exposure associated with cancer (Cancer \nEffect Levels, CELs) of cadmium are indicated in Tables 2-1 and 2-2 and Figures 2-2 and 2-3.\n\nA User\'s Guide has been provided at the end of this profile (see Appendix D).  This guide should aid in \nthe interpretation of the tables and figures for LSEs and MRLs.\n\nThis section provides information regarding potential adverse health effects of cadmium and cadmium \ncompounds.  To appropriately compare doses following exposures to various cadmium compounds, \ninhalation exposures are expressed throughout the profile as mg Cd/m<sup>3</sup> and oral exposures are expressed as \nmg Cd/kg/day, when possible.  This allows for evaluation of relative toxicities and determination of whether \ncertain chemical properties (e.g., solubility) impact toxicity.  When available, information pertaining to \nrelative toxicity of different cadmium compounds is discussed throughout Chapter 2.\n\nThe health effects of cadmium and cadmium compounds have been extensively evaluated in human and \nanimal studies.  As discussed above, due to the vast amount of available data, studies were prioritized for \ninclusion in Chapter 2 based on criteria defined in Appendix B.  A total of 69 meta-analyses of human \ndata were included.  An additional 219 human studies and 192 animal studies meeting inclusion criteria \nwere identified.  Most of the human data involve evaluation of health effects associated with chronicduration exposure in occupational studies, community-based studies of populations living in cadmiumpolluted areas, or epidemiological studies in the general population.  For workers, the predominant \nexposure route is inhalation; however, some gastrointestinal tract exposure may also occur when dust is \nremoved from the lungs by mucociliary clearance and subsequently swallowed, or by ingestion of dust on \nhands, cigarettes, or food (Adamsson et al. 1979).  For the nonsmoking general population, dietary \nexposure to cadmium is the most likely route of exposure (Kim et al. 2018; Nordberg et al. 2018; Zhu et \nal. 2024a).  However, since cadmium is present in tobacco leaves, tobacco smoking can contribute \nsignificantly to cadmium exposure in general populations (Diamond and Klotzbach 2025; Ellis et al. \n1979; Friis et al. 1998).  Therefore, both occupational and general population studies are classified as \nmulti-route exposure in Figure 2-1.  In animal studies, most of the health effects data in animals come \nfrom oral exposure studies (Figure 2-1).\n\n---\n\nHuman studies are available for nearly every organ system, with the predominant focus on renal, cancer, \ndevelopmental, musculoskeletal, and cardiovascular endpoints.  Animal studies predominantly focused on \nrespiratory endpoints following inhalation exposure and examined a comprehensive set of endpoints \nfollowing oral exposure.  For oral studies, the most well-studied effects include body weight, developmental, \nand reproductive endpoints.  Data from dermal exposure are very limited.\n\nAs outlined in Chapter 1, the most sensitive effects following exposure to cadmium appear to be respiratory, \nrenal, and neurodevelopmental following inhalation exposure and renal, skeletal, and neurodevelopmental \nfollowing oral exposure.  A systematic review was conducted on the available human and animal studies for \nthese endpoints.  The information in these studies indicates the following on the potential targets of cadmium\ntoxicity:\n\n• **Respiratory Endpoints.**  Respiratory effects are a known effect of cadmium toxicity following \ninhalation exposure based on a low level of evidence in human occupational studies, a high level \nof evidence in laboratory animal inhalation studies, and other relevant data including a metaanalysis, occupational case reports, and a plausible mechanism of action.  In humans, \noccupational exposure has been associated with respiratory irritation and impaired respiratory \nfunction.  In animals, inhalation exposure is consistently associated with inflammatory changes in \nthe lung and upper and lower respiratory tract lesions with increasing concentration and duration \nin multiple species.\n\n• **Skeletal Endpoints.**  Adverse effects on the skeletal system (e.g., decreased bone density, \nstrength, and mineralization) are a known effect of cadmium toxicity based on a moderate level of \nevidence from human epidemiological studies, a high level of evidence from laboratory animals, \nand other relevant data including several meta-analyses, older studies and case reports of high \ndietary or occupational exposure, and plausible mechanisms of action.  In humans, cadmium \nexposure is associated with adverse bone effects, including fractures, osteoporosis, and decreased \nbone mineral density.  Bone effects associated with cadmium exposure were first described in \ncadmium-contaminated communities in Japan with high dietary intake; the disease called Itai-Itai \n(“ouch-ouch”) disease was characterized by multiple fractures of the long bones, osteomalacia, \nand osteoporosis.  Bone effects have been confirmed in animal studies following oral exposure; \nthese endpoints have not been assessed following inhalation exposure in animals.\n\n• **Renal Endpoints.** Renal effects are a known effect of cadmium toxicity based on a high level of \nevidence from human epidemiological studies, a moderate level of evidence in laboratory animal \ninhalation studies, and other relevant data including several meta-analyses and a well-defined \nmechanism of action. The kidney has been a well-established target of cadmium toxicity in \nhumans following occupational and dietary exposure for decades.  Several studies have \ndeveloped dose-response analyses of sensitive biomarkers of cadmium exposure and renal \ntoxicity (e.g., urinary cadmium levels and low molecular weight [LMW] proteinuria).  Data in \nanimals following inhalation exposure are inadequate.  While findings in multi-dose oral studies \nin animals meeting inclusion criteria are mixed, several studies reported alterations in biomarkers \nof renal functions (e.g., LMW proteinuria, serum blood urea nitrogen [BUN]) and \nhistopathological changes.\n\n---\n\n## 2. HEALTH EFFECTS\n\n• **Neurodevelopmental Endpoints.** Neurodevelopmental effects are a presumed effect in humans \nbased on a low level of evidence in humans and a high level of evidence in animals.  Available \nepidemiological data from general population studies are mixed.  A limited number of inhalation \nstudies and numerous oral studies in animals indicate that developmental cadmium exposure can \ncause alterations in sensorimotor function (including nerve conduction) and activity, \nsocioemotional behavior, and learning and memory in rodents; however, the timing and duration \nof exposure and assessment influence findings.  Available data indicate that neurodevelopmental \neffects are the most sensitive indicator of developmental toxicity of cadmium (occur at lower \nexposures than those associated with standard developmental outcomes or specialized evaluations \nof other systems, such as reproductive development).\n\n---\n\n**Figure 2-1.  Overview of the Number of Studies Examining Cadmium Health Effects***\n\n## Most studies examined the potential body weight, renal, and developmental effects of cadmium\n\nNumerous studies are available in both **humans** and **animals** (counts represent studies examining endpoint)\n\n| Category | humans (count) | animals (count) |\n| --- | --- | --- |\n| Death | 11 | 42 |\n| Body weight |  | 98 |\n| Respiratory | 15 | 29 |\n| Cardiovascular | 28 | 13 |\n| Gastrointestinal | 6 | 9 |\n| Hematological | 5 | 31 |\n| Musculoskeletal | 30 | 16 |\n| Hepatic | 21 | 23 |\n| Renal | 54 | 34 |\n| Dermal | 2 | 1 |\n| Ocular | 2 | 2 |\n| Endocrine | 19 | 15 |\n| Immunological | 14 | 26 |\n| Neurolgical | 12 | 12 |\n| Reproductive | 30 | 39 |\n| Developmental | 33 | 45 |\n| Other Noncancer | 4 | 4 |\n| Cancer | 34 | 10 |\n\n**Exposure Route**\n\n| Category | Share of studies (%) |\n| --- | --- |\n| Multi-route | 56 |\n| Oral | 30 |\n| Dermal | 1 |\n| Inhalation | 13 |\n\n**Exposure Duration**\n\n| Category | Share of studies (%) |\n| --- | --- |\n| Chronic | 60 |\n| Intermediate | 25 |\n| Acute | 15 |\n\n*Includes studies discussed in Chapter 2.  A total of 69 meta-analyses and 411 studies meeting inclusion criteria (including those finding no effect) have examined \ntoxicity; most studies examined multiple endpoints. Note: Meta-analyses are counted as a single data-point in the figure above because only the overall results of \nthe meta-analysis, not the individual studies included in the meta-analyses, were included in Chapter 2.\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| ACUTE EXPOSURE |  |  |  |  |  |  |  |  |  |\n| Beton et al. 1966 |  |  |  |  |  |  |  |  | Cadmium oxide fume |\n| 1 | Human 5 M | 5 hours (occup) | 8.63 | LE, CS | Death Resp |  |  | 8.63 | 1/5 exposed workers died Severe dyspnea, wheezing, chest pain and precordial constriction, persistent cough (lasting up to 7 days post-exposure); severe pulmonary edema and alveolar cell metaplasia in the worker that died |\n| Barrett et al. 1947 |  |  |  |  |  |  |  |  | Cadmium oxide fume |\n| 2 | Rat (NS) 10–25 NS | 10–15 minutes (WB) | 8.8, 13, 18, 19, 22, 25, 31, 41, 79.2, 110 | LE | Death |  |  | 30 | LC50 at 7 days |\n| Buckley and Bassett 1987 |  |  |  |  |  |  |  |  | Cadmium oxide dust |\n| 3 | Rat (Wistar) 20 M | 3 hours (WB) | 0, 0.4, 4.6 | BW | Bd wt | 0.4 | 4.6 |  | 15% decrease in body weight 7 days post-exposure |\n| Bus et al. 1978 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 4 | Rat (Sprague-Dawley) 18 M | 1 hour (WB) | 0, 6.5 | LE, BW, BI, OW, OF | Bd wt |  | 6.5 |  | 11% decrease in body weight 11 days post-exposure |\n|  |  |  |  |  | Resp |  | 6.5 |  | Decreased tidal volume and increased respiratory frequency 1 and 5 days post-exposure |\n| Rats were examined at 1, 5, and 11 days post-exposure (6/group/timepoint) |  |  |  |  |  |  |  |  |  |\n| Grose et al. 1987 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 5 | Rat (Sprague-Dawley) 40 M | 2 hours (H) | 0, 0.25, 0.48, 4.50 | LE, CS, BW | Bd wt | 0.25 |  | 4.5 | 20% decrease in body weight 72 hours post-exposure |\n\nRats were examined immediately and 72 hours post-exposure (20/group/timepoint)\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects | Cadmium oxide dust |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Grose et al. 1987 |  |  |  |  |  |  |  |  |  |  |\n| 6 | Rat (Sprague-Dawley) 40 M | 2 hours (H) | 0, 0.25, 0.44, 4.45 | LE, CS, BW | Bd wt | 4.45 |  |  |  |  |\n| Rats were examined immediately and 72 hours post-exposure (20/group/timepoint) |  |  |  |  |  |  |  |  |  |  |\n| Hart 1986 |  |  |  |  |  |  |  |  |  |  |\n| 7 | Rat (Lewis) 3 M | 1 or 2 weeks 5 days/week 3 hours/day (N) | 0, 1.6 | BI, OW, HP | Resp |  | 1.6 |  |  | Cadmium acetate Increase in BALF cellularity (macrophages, PMNs, lymphocytes) and markers of cytotoxicity (LDH, ALP, AP, total protein) |\n| Jacobo-Estrada et al. 2016 |  |  |  |  |  |  |  |  |  |  |\n| 8 | Rat (Wistar) 6 F | 13 days GDs 8–20 2 hours/day (WB) | 0, 17.43 | BW, OW, DX | Bd wt Repro Develop | 17.43 | 17.43 | 17.43 |  | Cadmium chloride Decreased absolute placental weight Fetal kidney injury (decreased fetal plasma creatinine levels, increased total histopathological lesion score in fetal kidney); decreased fetal body weight (8%) |\n| NTP 1995 |  |  |  |  |  |  |  |  |  |  |\n| 9 | Rat (Fischer-344) 5 M, 5 F | 2 weeks 5 days/week 6.2 hours/day (WB) | 0, 0.081, 0.249, 0.844, 2.49, 8.60 | LE, CS, BW, OW, HP | Death Bd wt Resp | 2.49 | 0.081 | 8.6 |  | Cadmium oxide aerosol 100% mortality by day 6 |\n|  |  |  |  |  | Cardio | 2.49 |  |  |  | SLOAEL: Marked necrosis of alveolar ducts LOAEL: Minimal-to-mild alveolar histiocytic infiltrate and focal inflammation in alveolar septa |\n|  |  |  |  |  | Hepatic | 2.49 |  |  |  |  |\n|  |  |  |  |  | Renal | 2.49 |  |  |  |  |\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects | Cadmium chloride |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Palmer et al. 1986 |  |  |  |  |  |  |  |  |  |  |\n| 10 | Rat (Sprague-Dawley) 20–30 M | 2 hours (WB) | 0, 6.0 | BW, BC, BI, OW | Bd wt | 6 |  |  |  |  |\n| 10 | Rat (Sprague-Dawley) 20–30 M | 2 hours (WB) | 0, 6.0 | BW, BC, BI, OW | Resp |  | 6 |  |  | Increased BALF cellularity (primarily macrophages) 3 days post-exposure |\n| 10 | Rat (Sprague-Dawley) 20–30 M | 2 hours (WB) | 0, 6.0 | BW, BC, BI, OW | Endocr | 6 |  |  |  |  |\n| Rats were sacrificed |  | 1, 3, 7, or 10 days post-exposure (≥4/group/timepoint) |  |  |  |  |  |  |  |  |\n| Rusch et al. 1986 |  |  |  |  |  |  |  |  |  | Cadmium carbonate |\n| 11 | Rat (Sprague-Dawley) 26 M, 26 F | 2 hours (WB) | 0, 94 | LE, CS, GN | Resp |  |  | 94 |  | Rales persisting up to 4 hours post-exposure |\n| Rats were sacrificed immediately or 1, 3, 7, or 30 days post-exposure (10/group/timepoint); extra two rats were replacement animals |  |  |  |  |  |  |  |  |  |  |\n| Rusch et al. 1986 |  |  |  |  |  |  |  |  |  | Cadmium sulfide |\n| 12 | Rat (Sprague-Dawley) 26 M, 26 F | 2 hours (WB) | 0, 140 | LE, CS, BW | Bd wt | 140 |  |  |  |  |\n| Rats were sacrificed immediately or 1, 3, 7, or 30 days post-exposure (10/group/timepoint); extra two rats were replacement animals |  |  |  |  |  |  |  |  |  |  |\n| Rusch et al. 1986 |  |  |  |  |  |  |  |  |  | Cadmium selenide |\n| 13 | Rat (Sprague-Dawley) 26 M, 26 F | 2 hours (WB) | 0, 105 | LE, CS, BW | Bd wt | 105 |  |  |  |  |\n| Rats were sacrificed immediately or 1, 3, 7, or 30 days post-exposure (10/group/timepoint); extra two rats were replacement animals |  |  |  |  |  |  |  |  |  |  |\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Rusch et al. 1986 |  |  |  |  |  |  |  |  | Cadmium acetate |\n| 14 | Rat (Sprague-Dawley) 26 M, 26 F | 2 hours (WB) | 0, 83 | LE, CS | Death |  |  | 83 | 25/32 died between 1 and 7 days post-exposure |\n| 14 | Rat (Sprague-Dawley) 26 M, 26 F | 2 hours (WB) | 0, 83 | LE, CS | Resp |  |  | 83 | Labored breathing and rales persisting up to 4 hours post-exposure |\n| 14 | Rat (Sprague-Dawley) 26 M, 26 F | 2 hours (WB) | 0, 83 | LE, CS | Neuro |  | 83 |  | Reduced activity during exposure |\n| Rats were sacrificed immediately or 1, 3, 7, or 30 days post-exposure (10/group/timepoint); extra two rats were replacement animals |  |  |  |  |  |  |  |  |  |\n| Snider et al. 1973 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 15 | Rat (Sprague-Dawley) 18 M | 3 days 1 hour/day (WB) | 61 | LE, GN | Death |  |  | 61 | 17/18 died within 3 days |\n| 15 | Rat (Sprague-Dawley) 18 M | 3 days 1 hour/day (WB) | 61 | LE, GN | Resp |  |  | 61 | Pulmonary hemorrhage |\n| Barrett et al. 1947 |  |  |  |  |  |  |  |  | Cadmium oxide fume |\n| 16 | Mouse (NS) 10 NS | 15 minutes (WB) | 39, 61.3, 65.9 | LE | Death |  |  | 39 | 9/10 died within 7 days |\n| Graham et al. 1978 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 17 | Mouse (CD-1) 16–20 F | 2 hours (WB) | 0, 0.110, 0.190 | IX | Immuno | 0.11 | 0.19 |  | Decreased humoral immune response |\n| Krzystyniak et al. 1987 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 18 | Mouse (C57BL/6) 4–5 F | 60 minutes (N) | 0, 0.88 | IX | Immuno |  | 0.88 |  | Reduced humoral and cell-mediated immune responses |\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| NTP 1995 |  |  |  |  |  |  |  |  | Cadmium oxide aerosol |\n| 19 | Mouse (B6C3F1) 5 M, 5 F | 2 weeks 5 days/week 6.2 hours/day (WB) | 0, 0.081, 0.249, 0.844, 2.49, 8.60 | LE, CS, BW, OW, HP | Death Bd wt Resp | 2.49 | 0.081 | 8.6 | 100% mortality by day 7 |\n| 19 | Mouse (B6C3F1) 5 M, 5 F | 2 weeks 5 days/week 6.2 hours/day (WB) | 0, 0.081, 0.249, 0.844, 2.49, 8.60 | LE, CS, BW, OW, HP | Cardio Hepatic Renal | 2.49 2.49 2.49 | 0.081 | 0.844 | LOAEL: Minimal-to-mild alveolar histiocytic infiltrates SLOAEL: Fibrosis, inflammation, and mild necrosis of the alveolar ducts; degeneration of the nasal olfactory epithelium |\n| NTP 1995 |  |  |  |  |  |  |  |  | Cadmium oxide aerosol |\n| 20 | Mouse (Swiss) 33 F | 14 days GDs 4–17 6.27 hours/day (WB) | 0, 0.04, 0.4, 1.7 | LE, CS, BW, OW, DX | Bd wt Develop | 0.4 | 0.04 | 1.7 | 22% decrease in maternal body weight on GD 18 Increased total litter resorption; decreased fetal body weight (29–30%); reduced ossification of sternebrae Decreased male (9%) and female (8%) fetal body weight |\n| Friberg 1950 |  |  |  |  |  |  |  |  | Cadmium metal dust |\n| 21 | Rabbit (NS) 8 NS | 4 hours (H) | 11.5 - 48.4 | LE | Death |  |  | 28.4 | LC50 at 14 days |\n| Henderson et al. 1979 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 22 | Hamster (Golden Syrian) 30 B | 30 minutes (N) | 0, 1.1, 10.1 | LE, BI, HP | Resp |  | 1.1 | 10.1 | LOAEL: Increased BALF PMN and AP levels SLOAEL: Necrosis of bronchiolar epithelium 1 day post-exposure; severe pneumonitis 7 days post-exposure |\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| INTERMEDIATE EXPOSURE |  |  |  |  |  |  |  |  |  |\n| Baranski 1984 |  |  |  |  |  |  |  |  | Cadmium oxide aerosol |\n| 23 | Rat (Wistar) 7–15 F | 6-7 months (5 months premating, up to 3 weeks mating, GDs 1–20) 5 hours/day 5 days/week (WB) | 0, 0.02, 0.16 | RX, DX | Repro Develop | 0.16 | 0.02 | 0.16 | LOAEL: Age- and sex-dependent changes in offspring motor activity; impaired avoidance acquisition in 3- and 7-month-old females SLOAEL: 25% mortality by PND 4 (decreased viability index); 15% decrease in weanling body weight |\n| Baranski 1985 |  |  |  |  |  |  |  |  | Cadmium oxide dust |\n| 24 | Rat (Wistar) 5–16 F | 5–7 months (4–5 months premating, mating, GDs 1–20) 5 days/week 5 hours/day (WB) | 0, 0.02, 0.16, 1.0 | LE, BW, RX, DX | Death Bd wt Repro Develop | 1 1 | 0.02 | 1 | 55.1% mortality |\n| Baranski and Sitarek 1987 |  |  |  |  |  |  |  |  | LOAEL: Decreased motor activity in 3-month-old males and decreased conditioned reflexes in 5-month-old females SLOAEL: 23% decrease in pup viability index; unspecified decrease in pup weight during first 2 months |\n| 25 | Rat (Wistar) 13–14 F | 20 weeks 5 days/week 5 hours/day (WB) | 0, 0.02, 0.16, 1.0 | LE, CS, BW, RX | Death Bd wt Repro | 0.16 | 0.02 | 1 | Cadmium oxide dust 38% mortality by week 13; 100% mortality by week 20 30–50% decrease in body weight gain starting at week 4 Increased duration of estrous cycle |\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Glaser et al. 1986 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 26 | Rat (Wistar) 12 M | 30 days 7 days/week 22 hours/day (WB) | 0, 0.105 | LE, CS, BW, HE, BC, BI, UR | Bd wt Resp | 0.105 | 0.105 |  | Increase in BALF cellularity (PMNs, macrophages, leukocytes) and markers of cytotoxicity (LDH, total protein levels); macrophages, total protein and LDH remained elevated at 2-months post-exposure |\n| 26 | Rat (Wistar) 12 M | 30 days 7 days/week 22 hours/day (WB) | 0, 0.105 | LE, CS, BW, HE, BC, BI, UR | Hemato | 0.105 | 0.105 |  | Increased WBC counts at terminal sacrifice |\n| 26 | Rat (Wistar) 12 M | 30 days 7 days/week 22 hours/day (WB) | 0, 0.105 | LE, CS, BW, HE, BC, BI, UR | Renal | 0.105 |  |  |  |\n| Rats were sacrificed immediately following exposure (terminal sacrifice) or 2 months post-exposure (6/group/timepoint) |  |  |  |  |  |  |  |  |  |\n| Glaser et al. 1986 |  |  |  |  |  |  |  |  | Cadmium sulfide |\n| 27 | Rat (Wistar) 12 M | 30 days 7 days/week 22 hours/day (WB) | 0, 1.034 | LE, CS, BW, HE, BC, BI, OW | Bd wt Resp | 1.034 | 1.034 |  | Increase in BALF cellularity (PMNs, macrophages, leukocytes) and markers of cytotoxicity (LDH, total protein levels); macrophages, total protein and LDH remained elevated at 2-months post-exposure |\n| 27 | Rat (Wistar) 12 M | 30 days 7 days/week 22 hours/day (WB) | 0, 1.034 | LE, CS, BW, HE, BC, BI, OW | Hemato | 1.034 |  |  |  |\n| 27 | Rat (Wistar) 12 M | 30 days 7 days/week 22 hours/day (WB) | 0, 1.034 | LE, CS, BW, HE, BC, BI, OW | Renal | 1.034 |  |  |  |\n| Rats were sacrificed immediately following exposure (terminal sacrifice) or 2 months post-exposure (6/group/timepoint) |  |  |  |  |  |  |  |  |  |\n| Glaser et al. 1986 |  |  |  |  |  |  |  |  | Cadmium oxide dust |\n| 28 | Rat (Wistar) 12 M | 30 days 7 days/week 22 hours/day (WB) | 0, 0.098 | LE, CS, BW, HE, BC, BI, OW | Bd wt Resp | 0.098 | 0.098 |  | Increase in BALF cellularity (PMNs, macrophages, leukocytes) and markers of cytotoxicity (LDH, total protein levels); total protein remained elevated at 2-months post-exposure |\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n|  |  |  |  |  | Hemato |  | 0.098 |  | Increased WBC count at terminal sacrifice |\n|  |  |  |  |  | Renal | 0.098 |  |  |  |\n\n| Rats were sacrificed immediately following exposure (terminal sacrifice) or 2 months post-exposure (6/group/timepoint) |  |  |  |  |  |  |  |  |  |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Hart 1986 |  |  |  |  |  |  |  | Cadmium acetate |  |\n| 29 | Rat (Lewis) 3 M | 3–6 weeks 5 days/week 3 hours/day (N) | 0, 1.6 | BI, OW, HP | Resp |  | 1.6 |  | Transient increase in BALF cellularity (macrophages, PMNs, lymphocytes) and markers of cytotoxicity (LDH, ALP, AP, total protein); resolving weeks 4–6 |\n| Kutzman et al. 1986 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 30 | Rat (Fischer 344) 20 M | 62 days 5 days/week 6 hours/day (WB) | 0, 0.33, 1.06, 2.13 | LE, CS, BW, BI, OW, HP | Death |  |  | 2.13 | 100% mortality by day 45 |\n| 30 | Rat (Fischer 344) 20 M | 62 days 5 days/week 6 hours/day (WB) | 0, 0.33, 1.06, 2.13 | LE, CS, BW, BI, OW, HP | Bd wt | 0.33 |  | 1.06 | 27% decrease in body weight |\n| Kutzman et al. 1986 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 31 | Rat (Fischer 344) 8 M, 8 F | 62 days 5 days/week 6 hours/day (WB) | 0, 0.33, 1.06, 2.13 | LE, BW, RX | Death |  |  | 2.13 | 100% mortality by day 45 |\n| 31 | Rat (Fischer 344) 8 M, 8 F | 62 days 5 days/week 6 hours/day (WB) | 0, 0.33, 1.06, 2.13 | LE, BW, RX | Bd wt | 0.33 | 1.03 | 2.13 | LOAEL: 14% decreased in body weight SLOAEL: Body weight loss (decreased 40% compared to starting body weight) |\n| Repro |  |  |  |  |  | 1.06 M |  |  |  |\n| Exposed rats were mated with both exposed and unexposed rats 6 days post-exposure |  |  |  |  |  |  |  |  |  |\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| NTP 1995 |  |  |  |  |  |  |  |  | Cadmium oxide aerosol |\n| 32 | Rat (Fischer-344) 10 M, 10 F | 13 weeks 5 days/week 6.33 hours/day (WB) | 0, 0.021, 0.046, 0.088, 0.212, 0.902 | LE, CS, BW, HE, BC, UR, OW, HP, OF, RX | Bd wt Resp | 0.902 | 0.021 F | 0.902 M | Minimal epithelial degeneration in the larynx LOAEL: Minimal alveolar histiocytic infiltrate and epithelial hyperplasia; minimal epithelial degeneration in the larynx SLOAEL: Marked inflammation and moderate fibrosis in interstitium around alveolar ducts and terminal bronchioles |\n| 32 | Rat (Fischer-344) 10 M, 10 F | 13 weeks 5 days/week 6.33 hours/day (WB) | 0, 0.021, 0.046, 0.088, 0.212, 0.902 | LE, CS, BW, HE, BC, UR, OW, HP, OF, RX | Cardio Gastro Hemato Musc/skel Hepatic Renal Endocr Immuno Neuro Repro | 0.902 0.902 0.902 0.902 0.902 0.902 0.902 | 0.021 M | 0.046 M | Minimal epithelial degeneration in the larynx LOAEL: Minimal alveolar histiocytic infiltrate and epithelial hyperplasia; minimal epithelial degeneration in the larynx SLOAEL: Marked inflammation and moderate fibrosis in interstitium around alveolar ducts and terminal bronchioles |\n| NTP 1995 |  |  |  |  |  |  |  |  | Decreased spermatid counts in males, increased estrous cycle length in females |\n| 33 | Rat (Sprague-Dawley) 32 F | 16 days GDs 4–19 6.27 hours/day (WB) | 0, 0.04, 0.4, 1.7 | LE, CS, BW,OW, DX | Bd wt | 0.4 | 1.7 | Cadmium oxide aerosol | 14% decrease in maternal body weight on GD 20 Decreased male (16%) and female (17%) fetal body weight; reduced ossification of pelvis and sternebrae |\n| 33 | Rat (Sprague-Dawley) 32 F | 16 days GDs 4–19 6.27 hours/day (WB) | 0, 0.04, 0.4, 1.7 | LE, CS, BW,OW, DX | Develop | 0.4 |  | 1.7 | 14% decrease in maternal body weight on GD 20 Decreased male (16%) and female (17%) fetal body weight; reduced ossification of pelvis and sternebrae |\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects | Cadmium chloride |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Oberdörster et al. 1994 |  |  |  |  |  |  |  |  |  |  |\n| 34 | Rat (Fischer 344) 48 M | 4 weeks 5 days/week 6 hours/day (WB) | 0, 0.100 | BI | Resp |  | 0.1 |  | Increase in BALF PMNs (1 day post-exposure) |  |\n\n| Rats were sacrificed at 1, 7, or 28 days post-exposure (≥4/group/timepoint per endpoint) |  |  |  |  |  |  |  |\n| --- | --- | --- | --- | --- | --- | --- | --- |\n| Oldiges and Glaser 1986 |  |  |  |  |  |  | Cadmium oxide dust |\n| 35 | Rat (Wistar) 20 M, 20 F | 218–343 days 7 days/week 22 hours/day (WB) | M: 0, 0.030, 0.090 F: 0, 0.026, 0.081 | LE, GN, BW, Death FI, WI, HE, OW |  | 0.081 F 0.09 M | 6/20 died 6/20 died |\n| Oldiges and Glaser 1986 |  |  |  |  |  |  | Cadmium sulfide |\n| 36 | Rat (Wistar) 20–24 M, 20–24 F | 105–298 days 7 days/week 22 hours/day (WB) | M: 0, 0.843, 2.270 F: 0, 0.841, 2.247 | LE, GN, BW, Death FI, WI, HE, OW |  | 0.841 F 0.843 M | 7/20 died by day 298 6/20 died by day 208 |\n| Oldiges et al. 1989 |  |  |  |  |  |  | Cadmium chloride |\n| 37 | Rat (Wistar) 20 M, 18–20 F | 6 months 7 days/week 22 hours/day (WB) | 0, 0.090 | LE, GN, HP Death Cancer |  | 0.09 0.09 M | 25% mortality at 6 months CEL: Lung tumors (bronchioalveolar adenoma, adenocarcinoma, or squamous cell carcinoma) |\n| Scheduled sacrifice at 31 months; surviving Cd-exposed rats sacrificed at 29–30 months due to mortality ≥75% |  |  |  |  |  |  |  |\n| Oldiges et al. 1989 |  |  |  |  |  |  | Cadmium sulfide |\n| 38 | Rat (Wistar) 20 M, 20 F | 6 months 40 hours/week (WB) | 0, 0.270 | LE, GN, HP Death |  | 0.27 | 75% mortality at 27–29 months |\n| Scheduled sacrifice at 31 months; surviving Cd-exposed rats sacrificed at 27–29 months due to mortality ≥75% |  |  |  |  |  |  |  |\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Oldiges et al. 1989 |  |  |  |  |  |  |  |  | Cadmium sulfide |\n| 39 | Rat (Wistar) 16–20 M, 19–20 F | 3–10 months 7 days/week 22 hours/day (WB) | 0, 0.810, 2.430 | LE, GN, HP | Death Cancer |  |  | 0.81 | 25% mortality at 7–10 months CEL: Lung tumors (bronchioalveolar adenoma, adenocarcinoma, squamous cell carcinoma, or mixed tumor type) |\n\nScheduled sacrifice at 31 months; most surviving Cd-exposed rats sacrificed at 29-30 months due to mortality ≥75%\n\n| Oldiges et al. 1989 |  |  |  |  |  |  |  | Cadmium oxide dust |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| 40 | Rat (Wistar) 17–20 M, 16–20 F | 7–11 months 7 days/week 22 hours/day (WB) | 0, 0.090 | LE, GN, HP | Death Cancer | 0.09 | 0.09 | 25% mortality at 7–11 months CEL: Lung tumors (bronchioalveolar adenoma, adenocarcinoma, squamous cell carcinoma, or mixed tumor type) |\n\n| Scheduled sacrifice at 31 months |  |  |  |  |  |  |  |  |  |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Prigge 1978a |  |  |  |  |  |  |  | Cadmium oxide dust |  |\n| 41 | Rat (Wistar) 12 F | 90 days 24 hours/day (WB) | 0, 0.025, 0.052 | LE, BW, HE, BC, UR, OW, HP | Bd wt Resp | 0.025 | 0.025 | 0.052 | 23% decrease in body weight gain Proliferative lung lesions, histiocytic cell granulomas Increased hemoglobin and hematocrit |\n| 41 | Rat (Wistar) 12 F | 90 days 24 hours/day (WB) | 0, 0.025, 0.052 | LE, BW, HE, BC, UR, OW, HP | Hematoc | 0.025 | 0.052 | 0.052 | 23% decrease in body weight gain Proliferative lung lesions, histiocytic cell granulomas Increased hemoglobin and hematocrit |\n| 41 | Rat (Wistar) 12 F | 90 days 24 hours/day (WB) | 0, 0.025, 0.052 | LE, BW, HE, BC, UR, OW, HP | Hepatic Renal | 0.052 | 0.052 | 0.052 | 23% decrease in body weight gain Proliferative lung lesions, histiocytic cell granulomas Increased hemoglobin and hematocrit |\n\n| Prigge 1978a |  |  |  |  |  |  |  | Cadmium oxide dust |  |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| 42 | Rat (Wistar) 12 F | 63 days 24 hours/day (WB) | 0, 0.105 | LE, BW, HE, BC, UR | Death |  |  | 0.105 | 5/12 died |\n| 42 | Rat (Wistar) 12 F | 63 days 24 hours/day (WB) | 0, 0.105 | LE, BW, HE, BC, UR | Bd wt |  |  | 0.105 | 51% decrease in body weight gain |\n| 42 | Rat (Wistar) 12 F | 63 days 24 hours/day (WB) | 0, 0.105 | LE, BW, HE, BC, UR | Hematoc |  | 0.105 |  | Increased hemoglobin and hematocrit |\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Prigge 1978b |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 43 | Rat (Wistar) 12–13 F | 21 days 24 hours/day (WB) | 0, 0.204, 0.394, 0.581 | BW, HE, BC, UR, OW, HP | Bd wt Hemato | 0.581 | 0.204 |  | Increase in hemoglobin and hematocrit |\n|  |  |  |  |  | Renal | 0.581 |  |  |  |\n| Prigge 1978b |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 44 | Rat (Wistar) 12–13 F | 21 days GDs 1–21 24 hours/day (WB) | 0, 0.204, 0.394, 0.581 | BW, HE, BC, UR, OW, HP, DX | Bd wt |  | 0.204 | 0.394 | LOAEL: 12% decrease in maternal body weight gain SLOAEL: 35% decrease in maternal body weight gain Increased hemoglobin and hematocrit; elevated total (but not direct) bilirubin |\n|  |  |  |  |  | Hemato | 0.394 | 0.581 |  |  |\n|  |  |  |  |  | Renal | 0.581 |  |  |  |\n|  |  |  |  |  | Develop | 0.394 |  | 0.581 | 19% decrease in fetal body weight; decreased fetal hemoglobin |\n| NTP 1995 |  |  |  |  |  |  |  |  | Cadmium oxide aerosol |\n| 45 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week 6.33 hours/day (WB) | 0, 0.021, 0.046, 0.088, 0.211, 0.910 | LE, CS, BW, OW, HP, RX | Bd wt Resp | 0.91 | 0.021 |  | Minimal alveolar histiocytic infiltrates and squamous metaplasia of the larynx |\n|  |  |  |  |  | Cardio | 0.91 |  |  |  |\n|  |  |  |  |  | Gastro | 0.91 |  |  |  |\n|  |  |  |  |  | Musc/skel | 0.91 |  |  |  |\n|  |  |  |  |  | Hepatic | 0.91 |  |  |  |\n|  |  |  |  |  | Renal | 0.91 |  |  |  |\n|  |  |  |  |  | Endocr | 0.91 |  |  |  |\n|  |  |  |  |  | Immuno | 0.91 |  |  |  |\n|  |  |  |  |  | Neuro | 0.91 |  |  |  |\n|  |  |  |  |  | Repro | 0.91 |  |  |  |\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Oberdörster et al. 1994 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 46 | Mouse (BALB/c) 72 M | 4 weeks 5 days/week 6 hours/day (WB) | 0, 0.100 | BI | Resp |  | 0.1 |  | Increase in BALF PMNs and LDH levels (1, 7, and 28 days post-exposure); increase cell proliferation in alveolar epithelium and macrophage infiltration (1 and 7 days post-exposure) |\n| Mice were sacrificed at 1, 7, or 28 days post-exposure (≥4/group/timepoint per endpoint) |  |  |  |  |  |  |  |  |  |\n| Johansson et al. 1984 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 47 | Rabbit (NS) 8 M | 4–6 weeks 5 days/week 6 hours/day (WB) | 0, 0.4 | BI, OW, HP | Resp |  | 0.4 |  | Lung interstitial inflammation, type 2 cell hyperplasia |\n| CHRONIC EXPOSURE |  |  |  |  |  |  |  |  |  |\n| Buchet et al. 1990; Hoo et al. 2004; Järup and Elinder 1994; Järup et al. 2000; Kobayashi et al. 2008; Lei et al. 2007; Shao et al. 2007; Suwazono et al. 2006; Uno et al. 2005; Wu et al. 2001; Zhang et al. 2016a |  |  |  |  |  |  |  |  | Cadmium |\n| 48 | Human 85–3,454 per dataset | 17 datasets (3 occupational and 8 general population cohorts) | UR | Renal |  |  |  | LMW proteinuria; 95% LCL weighted median of 17 UC10 values = 0.00106 mg Cd/m3 c |  |\n| Oldiges and Glaser 1986 |  |  |  |  |  |  |  |  | Cadmium sulfate |\n| 49 | Rat (Wistar) 20–40 M, 20 F | 413–455 days 7 days/week 22 hours/day (WB) | M: 0, 0.095 F: 0, 0.092 | LE, BW, FI, WI, HE, OW, GN | Death |  |  | 0.095 M | 6/20 died |\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Oldiges et al. 1989 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 50 | Rat (Wistar) 20 M, 18–20 F | 18 months 7 days/week 22 hours/day (WB) | 0, 0.030 | LE, GN, HP | Death Cancer |  |  | 0.03 M 0.03 | 75% mortality at 30 months CEL: Lung tumors (bronchioalveolar adenoma, adenocarcinoma, squamous cell carcinoma, or mixed tumor type) |\n| Scheduled sacrifice at 31 months; surviving Cd-exposed males sacrificed at 30 months due to mortality ≥75% |  |  |  |  |  |  |  |  |  |\n| Oldiges et al. 1989 |  |  |  |  |  |  |  |  | Cadmium sulfide |\n| 51 | Rat (Wistar) 19–20 M, 19–20 F | 16–18 months 7 days/week 22 hours/day (WB) | 0, 0.090, 0.270 | LE, GN, HP | Death Cancer |  |  | 0.09 0.270 | 75% mortality at 30 months in males 25% mortality at 16 months in females CEL: Lung tumors (bronchioalveolar adenoma, adenocarcinoma, squamous cell carcinoma, or mixed tumor type) |\n| Scheduled sacrifice at 31 months; surviving Cd-exposed rats sacrificed at 30 months due to mortality ≥75% |  |  |  |  |  |  |  |  |  |\n| Oldiges et al. 1989 |  |  |  |  |  |  |  |  | Cadmium oxide dust |\n| 52 | Rat (Wistar) 20 M, 20 F | 18 months 7 days/week 22 hours/day (WB) | 0, 0.030 | LE, GN, HP | Cancer |  |  | 0.03 | CEL: Lung tumors (bronchioalveolar adenoma, adenocarcinoma, squamous cell carcinoma, or mixed tumor type) |\n| Scheduled sacrifice at 31 months |  |  |  |  |  |  |  |  |  |\n| Oldiges et al. 1989 |  |  |  |  |  |  |  |  | Cadmium sulfate |\n| 53 | Rat (Wistar) 20 M, 20 F | 14–18 months 7 days/week 22 hours/day (WB) | 0, 0.09 | LE, GN, HP | Death Cancer |  |  | 0.09 | 25% mortality in males by 14 months; 75% mortality in females by 29 months CEL: Lung tumors (bronchioalveolar adenoma, adenocarcinoma, squamous cell carcinoma, or mixed tumor type) |\n\nScheduled sacrifice at 31 months; surviving Cd-exposed females sacrificed at 29 months due to mortality ≥75%\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Oldiges et al. 1989 |  |  |  |  |  |  |  |  | Cadmium oxide fume |\n| 54 | Rat (Wistar) 17–20 M | 18 months 7 days/week 22 hours/day (WB) | 0, 0.01, 0.03 | LE, GN, HP | Cancer |  |  | 0.03 | CEL: Lung tumors (bronchioalveolar adenoma, adenocarcinoma) |\n| Takenaka et al. 1983 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 55 | Rat (Wistar) 40–41 M | 18 months 7 days/week 23 hours/day (WB) | 0, 0.0134, 0.0257, 0.0508 | LE, BW, HP | Bd wt Cancer | 0.0508 |  | 0.0134 | CEL: Lung tumors (lung epidermoid carcinomas, or adenocarcinomas) |\n| Scheduled sacrifice at 31 months |  |  |  |  |  |  |  |  |  |\n\n<sup>a</sup>The number corresponds to entries in Figure 2-2; differences in levels of health effects between male and females are not indicated in Figure 2-2.  Where such \ndifferences exist, only the levels of effect for the most sensitive sex are presented.\n\n<sup>b</sup>Concentrations are expressed as mg Cd/m<sup>3</sup>. If concentrations were reported by the study authors in terms of the administered compound (e.g., cadmium chloride \n[CdCl2]), they were converted to the equivalent concentration in terms of the metal (i.e., cadmium [Cd])) for easy comparison across studies.  Conversion was based on \nthe ratio of the molecular weights using the following equation: Concentration in terms of administered compound x (molecular weight Cd/molecular weight administered \ncompound).\n\n<sup>c</sup>Used to derive a chronic-duration inhalation MRL of 0.0001 mg Cd/m<sup>3</sup> (0.1 μg Cd/m<sup>3</sup>).  The point of departure (POD) is based on the 95% lower confidence limit (LCL) \non the weighted median of the UC10 values from 17 datasets from 11 human studies; the weighted median and 95% LCL were 2.04 and 1.57 μg Cd/g Cr, respectively.  \nThese values were converted into inhalation concentration equivalents of 0.00141 and 0.00106 mg Cd/m<sup>3</sup>, respectively, using PBPK modeling.  The POD of 0.00106 mg \nCd/m<sup>3</sup> was divided by an uncertainty factor of 3 for human variability and a modifying factor of 3 for database deficiencies.  See Appendix A for more detailed information \nregarding the MRL.\n\n## Principal studies for the MRL\n\nALP = alkaline phosphatase; AP = acid phosphatase; BALF = bronchoalveolar lavage fluid; BC = serum (blood) chemistry; Bd wt or BW = body weight; BI = biochemical \nchanges; Cardio = cardiovascular; Cd = cadmium; CEL = cancer effect level; Cr = creatinine; CS = clinical signs; Develop = developmental; DX = developmental toxicity; \nEndocr = endocrine; F = female(s); FI = food intake; Gastro = gastrointestinal; GD = gestation day; GN = gross necropsy; (H) = head only; HE = hematology; \nHemato = hematological; HP = histopathology; Immuno = immunological; IX = immune function; LC50 = lethal concentration, 50% kill; LDH = lactate dehydrogenase; \nLE = lethality; LMW = low molecular weight; LOAEL = lowest-observed-adverse-effect level; M = male(s); MRL = Minimal Risk Level; Musc/skel = musculoskeletal; \n(N) = nose-only; Neuro = neurological; NOAEL = no-observed-adverse-effect level; NS = not specified; (occup) = occupational; OF = organ function; OW = organ weight; \nPMN = polymorphonuclear leukocyte; PND = postnatal day; Repro = reproductive; Resp = respiratory; RX = reproductive function; SLOAEL = serious lowest-observedadverse-effect level; UC10 = urinary cadmium level associated with 10% extra risk; UR = urinalysis; (WB) = whole body; WBC = white blood cell; WI = water intake\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Cadmium – Inhalation**\nAcute (≤14 days)\n\n**Figure 2-2. Levels of Significant Exposure to Cadmium – Inhalation, Acute (≤14 days) - Death**\n\n| Category | mg Cd/m3 |\n| --- | --- |\n| 1 | 9 |\n| 2R | 30 |\n| 9R | 9 |\n| 14R | 85 |\n| 15R | 65 |\n| 16M | 40 |\n| 19M | 9 |\n| 21H | 30 |\n\n**Figure 2-2. Levels of Significant Exposure to Cadmium – Inhalation, Acute (≤14 days) - Body Weight**\n\n| Category | Animal - NOAEL (mg Cd/m3) | Animal - LOAEL (mg Cd/m3) | Animal - SLOAEL (mg Cd/m3) |\n| --- | --- | --- | --- |\n| 3R | 0.4 | 4.5 |  |\n| 4R |  | 6.5 |  |\n| 5R | 0.23 | 4.5 |  |\n| 6R | 4.0 |  |  |\n| 8R | 17 |  |  |\n| 9R | 2.6 |  |  |\n| 10R | 6.0 |  |  |\n| 12R | 140 |  |  |\n| 13R | 110 |  |  |\n| 19M | 2.6 |  |  |\n| 20M | 0.4 |  | 1.7 |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Cadmium – Inhalation**\nAcute (≤14 days)\n\n| Category | Human - SLOAEL (mg Cd/m3) | Animal - NOAEL (mg Cd/m3) | Animal - LOAEL (mg Cd/m3) | Animal - SLOAEL (mg Cd/m3) |\n| --- | --- | --- | --- | --- |\n| 1 | 9 |  |  |  |\n| 4R |  | 6 |  |  |\n| 7R |  | 1.6 |  |  |\n| 9R |  | 0.08 |  | 9 |\n| 10R |  | 6 |  |  |\n| 11R |  |  |  | 100 |\n| 14R |  |  |  | 85 |\n| 15R |  |  |  | 65 |\n| 19M |  | 0.008 | 0.8 |  |\n| 22S |  | 1.1 |  | 10 |\n| 9R |  | 2.5 |  |  |\n| 19M |  | 2.7 |  |  |\n| 9R |  | 2.7 |  |  |\n| 19M |  | 2.7 |  |  |\n| 9R |  | 2.7 |  |  |\n| 19M |  | 2.7 |  |  |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Cadmium – Inhalation**\nAcute (≤14 days)\n\n**Figure 2-2. Levels of Significant Exposure to Cadmium – Inhalation (Acute ≤14 days)**\n\n| Category | Animal - NOAEL (mg Cd/m3) | Animal - LOAEL (mg Cd/m3) | Animal - SLOAEL (mg Cd/m3) |\n| --- | --- | --- | --- |\n| Endocrine | 6 |  |  |\n| Immunological | 0.11 | 0.19 |  |\n| Neuropsychological |  | 85 |  |\n| Reproductive |  | 16 |  |\n| Developmental | 0.043 | 0.35 | 1.7 |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Cadmium – Inhalation**\nIntermediate (15–364 days)\n\n**Figure 2-2. Levels of Significant Exposure to Cadmium – Inhalation Intermediate (15–364 days) - Death**\n\n| Category | mg Cd/m3 |\n| --- | --- |\n| 24R | 1.0 |\n| 25R | 1.0 |\n| 30R | 2.6 |\n| 31R | 2.6 |\n| 35R | 0.080 |\n| 36R | 0.80 |\n| 37R | 0.090 |\n| 38R | 0.33 |\n| 39R | 0.80 |\n| 40R | 0.090 |\n| 42R | 0.11 |\n\n**Figure 2-2. Levels of Significant Exposure to Cadmium – Inhalation Intermediate (15–364 days) - Body Weight**\n\n| Category | Animal - NOAEL (mg Cd/m3) | Animal - LOAEL (mg Cd/m3) | Animal - SLOAEL (mg Cd/m3) |\n| --- | --- | --- | --- |\n| 24R | 1.0 |  |  |\n| 25R | 0.17 | 1.0 |  |\n| 26R | 0.11 |  |  |\n| 27R | 1.1 |  |  |\n| 28R | 0.10 |  |  |\n| 30R | 0.40 | 1.1 |  |\n| 31R | 0.40 | 1.1 |  |\n| 31R |  |  | 2.6 |\n| 32R | 0.90 |  |  |\n| 33R | 0.50 | 1.8 |  |\n| 33R |  |  | 1.8 |\n| 41R | 0.030 | 0.055 |  |\n| 42R |  |  | 0.11 |\n| 43R | 0.60 |  |  |\n| 44R |  | 0.23 | 0.44 |\n| 45M | 0.90 |  |  |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Cadmium – Inhalation**\nIntermediate (15–364 days)\n\n**Figure 2-2. Levels of Significant Exposure to Cadmium – Inhalation Intermediate (15–364 days)**\n\n| Category | Respiratory Animal - NOAEL (mg Cd/m3) | Respiratory Animal - LOAEL (mg Cd/m3) | Respiratory Animal - SLOAEL (mg Cd/m3) | Respiratory Animal - Cancer Effect Level (mg Cd/m3) | Cardiovascular Animal - NOAEL (mg Cd/m3) | Cardiovascular Animal - LOAEL (mg Cd/m3) | Cardiovascular Animal - SLOAEL (mg Cd/m3) | Cardiovascular Animal - Cancer Effect Level (mg Cd/m3) | Gastrointestinal Animal - NOAEL (mg Cd/m3) | Gastrointestinal Animal - LOAEL (mg Cd/m3) | Gastrointestinal Animal - SLOAEL (mg Cd/m3) | Gastrointestinal Animal - Cancer Effect Level (mg Cd/m3) | Hematological Animal - NOAEL (mg Cd/m3) | Hematological Animal - LOAEL (mg Cd/m3) | Hematological Animal - SLOAEL (mg Cd/m3) | Hematological Animal - Cancer Effect Level (mg Cd/m3) |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| 26R | 0.11 |  |  |  |  |  |  |  |  |  |  |  | 0.11 |  |  |  |\n| 27R |  | 1.1 |  |  |  |  |  |  |  |  |  |  | 1.1 |  |  |  |\n| 28R |  | 0.10 |  |  |  |  |  |  |  |  |  |  |  | 0.10 |  |  |\n| 29R |  | 1.7 |  |  |  |  |  |  |  |  |  |  |  |  |  |  |\n| 32R |  | 0.023 | 0.90 |  | 0.90 |  |  |  | 0.90 |  |  |  | 0.90 |  |  |  |\n| 34R |  | 0.10 |  |  |  |  |  |  |  |  |  |  |  |  |  |  |\n| 41R |  | 0.026 |  |  |  |  |  |  |  |  |  |  | 0.026 | 0.053 |  |  |\n| 45M |  | 0.022 |  |  | 0.90 |  |  |  | 0.90 |  |  |  |  |  |  |  |\n| 46M |  | 0.10 |  |  |  |  |  |  |  |  |  |  |  |  |  |  |\n| 47H |  | 0.45 |  |  |  |  |  |  |  |  |  |  |  |  |  |  |\n| 42R |  |  |  |  |  |  |  |  |  |  |  |  |  | 0.11 |  |  |\n| 43R |  |  |  |  |  |  |  |  |  |  |  |  |  | 0.21 |  |  |\n| 44R |  |  |  |  |  |  |  |  |  |  |  |  | 0.45 |  | 0.60 |  |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Cadmium – Inhalation**\nIntermediate (15–364 days)\n\n**Figure 2-2. Levels of Significant Exposure to Cadmium – Inhalation Intermediate (15–364 days)**\n\n| Category | 32R (mg Cd/m3) | 45M (mg Cd/m3) | 41R (mg Cd/m3) | 26R (mg Cd/m3) | 27R (mg Cd/m3) | 28R (mg Cd/m3) | 32R (mg Cd/m3) | 43R (mg Cd/m3) | 44R (mg Cd/m3) | 45M (mg Cd/m3) | 32R (mg Cd/m3) | 45M (mg Cd/m3) | 32R (mg Cd/m3) | 45M (mg Cd/m3) |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Musculoskeletal | 0.9 | 0.9 |  |  |  |  |  |  |  |  |  |  |  |  |\n| Hepatic | 0.85 | 0.9 | 0.05 |  |  |  |  |  |  |  |  |  |  |  |\n| Renal |  |  |  | 0.11 | 1.1 | 0.1 | 0.9 | 0.55 | 0.55 | 0.85 |  |  |  |  |\n| Endocrine | 0.85 | 0.9 |  |  |  |  |  |  |  |  |  |  |  |  |\n| Immunological | 0.9 | 0.9 |  |  |  |  |  |  |  |  |  |  |  |  |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Cadmium – Inhalation**\nIntermediate (15–364 days)\n\n**Figure 2-2. Levels of Significant Exposure to Cadmium – Inhalation Intermediate (15–364 days)**\n\n| Category | Neurolgical mg Cd/m3 | Reproductive mg Cd/m3 | Developmental mg Cd/m3 | Cancer mg Cd/m3 |\n| --- | --- | --- | --- | --- |\n| 32R | 0.9 | 0.9 |  |  |\n| 45M | 0.9 | 0.9 |  |  |\n| 23R |  | 0.17 | 0.17 |  |\n| 24R |  | 1.0 | 0.17 |  |\n| 25R |  | 1.0 |  |  |\n| 25R |  | 0.18 |  |  |\n| 31R |  | 1.1 |  |  |\n| 32R |  | 0.24 |  |  |\n| 23R |  |  | 0.022 |  |\n| 24R |  |  | 0.022 |  |\n| 33R |  |  | 2.0 |  |\n| 33R |  |  | 0.53 |  |\n| 44R |  |  | 0.6 |  |\n| 44R |  |  | 0.5 |  |\n| 37R |  |  |  | 0.09 |\n| 39R |  |  |  | 0.75 |\n| 40R |  |  |  | 0.09 |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Cadmium – Inhalation**\nChronic (≥365 days)\n\n**Figure 2-2. Levels of Significant Exposure to Cadmium – Inhalation (Chronic ≥365 days)**\n\n| Category | Death mg Cd/m3 | Body Weight mg Cd/m3 |\n| --- | --- | --- |\n| 49R | 0.095 |  |\n| 50R | 0.033 |  |\n| 51R | 0.088 |  |\n| 53R | 0.088 |  |\n| 55R |  | 0.050 |\n\n**Figure 2-2. Levels of Significant Exposure to Cadmium – Inhalation (Chronic ≥365 days) - Renal**\n\n| Category | Human - Weighted median (mg Cd/m3) | Human - 95% lower confidence limit of weighted median (mg Cd/m3) |\n| --- | --- | --- |\n| 48 | 0.0014 | 0.00011 |\n\n**Figure 2-2. Levels of Significant Exposure to Cadmium – Inhalation (Chronic ≥365 days) - Cancer**\n\n| Category | Animal - Cancer Effect Level (mg Cd/m3) |\n| --- | --- |\n| 50R | 0.033 |\n| 51R | 0.092 |\n| 52R | 0.033 |\n| 53R | 0.092 |\n| 54R | 0.033 |\n| 55R | 0.013 |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| ACUTE EXPOSURE |  |  |  |  |  |  |  |  |  |\n| Andjelkovic et al. 2019 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 1 | Rat (Wistar) 6–8 M | Once (GW) | 0, 15, 30 | HE, BC, HP | Hemato |  | 15 |  | Decreased RBC count, hemoglobin, hematocrit, lymphocyte, and serum iron levels; increased MCHC |\n| Baranski 1985 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 2 | Rat (Wistar) 6–18 F | 10 days GDs 7–16 (GW) | 0, 2, 12, 40 | BW, OW, DX | Bd wt |  | 2 | 12 | LOAEL: 14% decrease in maternal body weight gain SLOAEL: 34% decrease in maternal body weight gain |\n| 2 | Rat (Wistar) 6–18 F | 10 days GDs 7–16 (GW) | 0, 2, 12, 40 | BW, OW, DX | Develop | 2 | 12 | 40 | LOAEL: 9% decrease in fetal weight SLOAEL: 23% decrease in fetal weight, decreased live fetuses/litter, increased resorptions/litter, fetal malformations (fused lower limbs, absent limbs) |\n| Bomhard et al. 1987 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 3 | Rat (Wistar) 25–35 M | Once (GW) | 0, 50, 100, 200 | LE, BW, CS, FI, WI, HP | Death Repro | 50 |  | 100 | 28/35 died within 3 days Testicular necrosis, focal proliferation of Leydig cells (6 months post-exposure); hyperemia and slight hemorrhages in testes and epididymides in rats that died |\n| Surviving rats sacrificed 6–30 months post-exposure |  |  |  |  |  |  |  |  |  |\n| Borzelleca et al. 1989 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 4 | Rat (Sprague-Dawley) 10 M, 10 F | Once (GW) | 0, 15, 31, 65.6, 138 | LE, CS, BW, HE, BC, GN, OW | Death |  |  | 138 F 65.6 M | 2/10 died within 24 hours 3/10 died within 24 hours |\n| 4 | Rat (Sprague-Dawley) 10 M, 10 F | Once (GW) | 0, 15, 31, 65.6, 138 | LE, CS, BW, HE, BC, GN, OW | Bd wt Hemato Hepatic Renal | 138 138 138 |  |  |  |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Borzelleca et al. 1989 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 5 | Rat (Sprague-Dawley) 10 M, 10 F | 10 days (W) | M: 0, 1.1, 7.85, 11.2 F: 0, 1.1, 8.16, 13.9 | LE, CS, BW, HE, BC, UR, GN, OW, HP | Bd wt | 13.9 F 1.1 M | 7.85 M | 11.2 M | LOAEL: 14% decrease in body weight SLOAEL: 25% decrease in body weight |\n| 5 | Rat (Sprague-Dawley) 10 M, 10 F | 10 days (W) | M: 0, 1.1, 7.85, 11.2 F: 0, 1.1, 8.16, 13.9 | LE, CS, BW, HE, BC, UR, GN, OW, HP | Hematocrit | 13.9 F 11.2 M 13.9 F 11.2 M 13.9 F 11.2 M |  |  |  |\n| 5 | Rat (Sprague-Dawley) 10 M, 10 F | 10 days (W) | M: 0, 1.1, 7.85, 11.2 F: 0, 1.1, 8.16, 13.9 | LE, CS, BW, HE, BC, UR, GN, OW, HP | Renal | 13.9 F 11.2 M 13.9 F 11.2 M |  |  |  |\n| 5 | Rat (Sprague-Dawley) 10 M, 10 F | 10 days (W) | M: 0, 1.1, 7.85, 11.2 F: 0, 1.1, 8.16, 13.9 | LE, CS, BW, HE, BC, UR, GN, OW, HP | Repro | 13.9 F 11.2 M |  |  |  |\n| Borzelleca et al. 1989 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 6 | Rat (Sprague-Dawley) 10 M, 10 F | 10 days (GW) | 0, 15, 31, 65.6, 138 | LE, CS, BW, HE, BC, UR, GN, OW, HP | Death | 31 F | 65.6 F 15 M | 31 M | 3/10 males and 4/10 females died within 7 days 18% decrease in terminal body weight LOAEL: 18% decrease in terminal body weight SLOAEL: 23% decrease in terminal body weight Increased WBC and platelet counts Increased RBC count Elevated serum ALT, decreased serum cholesterol Mild focal necrosis of hepatocytes or congestion Mild focal necrosis of tubular epithelium |\n| 6 | Rat (Sprague-Dawley) 10 M, 10 F | 10 days (GW) | 0, 15, 31, 65.6, 138 | LE, CS, BW, HE, BC, UR, GN, OW, HP | Bd wt | 31 F | 65.6 F 15 M 31 F |  |  |\n| 6 | Rat (Sprague-Dawley) 10 M, 10 F | 10 days (GW) | 0, 15, 31, 65.6, 138 | LE, CS, BW, HE, BC, UR, GN, OW, HP | Hematocrit | 15 F | 65.6 F 15 M 31 F |  |  |\n| 6 | Rat (Sprague-Dawley) 10 M, 10 F | 10 days (GW) | 0, 15, 31, 65.6, 138 | LE, CS, BW, HE, BC, UR, GN, OW, HP | Renal | 65.6 M | 138 M 65.6 F |  |  |\n\n***DRAFT FOR PUBLIC COMMENT***\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n|  |  |  |  |  | Repro | 65.6 M 138 F 31 M | 138 M |  | Mild focal necrosis of tubular epithelium |\n|  |  |  |  |  | Repro | 65.6 M 138 F 31 M | 138 M | 65.6 M | Necrotic changes in testes with atrophy and loss of spermatogenic elements |\n| Dixon et al. 1976 |  |  |  |  |  |  |  |  |  |\n| 7 | Rat (Sprague-Dawley) 10 M | Once (GW) | 0, 6.25, 12.5, 25 | RX | Repro | 25 |  |  | Cadmium chloride |\n| Males serially mated to untreated females for 70 days post-treatment |  |  |  |  |  |  |  |  |  |\n| Kostial et al. 1978 |  |  |  |  |  |  |  |  |  |\n| 8 | Rat (NS) 6 B | Once (G) | NS | LE | Death |  |  | 29 | Cadmium chloride LD50 calculated 8 days post-exposure |\n| Age at exposure: 2 weeks |  |  |  |  |  |  |  |  |  |\n| Kostial et al. 1978 |  |  |  |  |  |  |  |  |  |\n| 9 | Rat (NS) 6 B | Once (G) | NS | LE | Death |  |  | 147 | Cadmium chloride LD50 calculated 8 days post-exposure |\n| Age at exposure: 3 weeks |  |  |  |  |  |  |  |  |  |\n| Kostial et al. 1978 |  |  |  |  |  |  |  |  |  |\n| 10 | Rat (NS) 6 B | Once (G) | NS | LE | Death |  |  | 129 | Cadmium chloride LD50 calculated 8 days post-exposure |\n| Age at exposure: 6 weeks |  |  |  |  |  |  |  |  |  |\n| Kostial et al. 1978 |  |  |  |  |  |  |  |  |  |\n| 11 | Rat (NS) 6 B | Once (G) | NS | LE | Death |  |  | 104 | Cadmium chloride LD50 calculated 8 days post-exposure |\n| Age at exposure: 18 weeks |  |  |  |  |  |  |  |  |  |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Kostial et al. 1978 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 12 | Rat (NS) 6 B | Once (G) | NS | LE | Death |  |  | 66.8 | LD50 calculated 8 days post-exposure |\n| Age at exposure: 54 weeks |  |  |  |  |  |  |  |  |  |\n| Kotsonis and Klaassen 1977 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 13 | Rat (Sprague-Dawley) 6 M | Once (premating) (GW) | 0, 25, 50, 100, 150 | HP, RX, NX | Neuro Repro | 25 50 | 50 | 100 | Decreased motor activity Testicular necrosis; decreased spermatogenesis; decreased fertility (fewer females producing pups) |\n| Males mated to unexposed females |  |  |  |  |  |  |  |  |  |\n| Kotsonis and Klaassen 1977 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 14 | Rat (Sprague-Dawley) 6–12 M | Once (GW) | 0, 25, 50, 100, 150 | CS, BW, HE, BC, BI, UR, HP, OF | Bd wt Resp Cardio Gastro Hematoc Hepatic Renal Endocr | 100 150 150 150 150 150 |  | 150 | Initial body weight loss resulting in approximate 10% decrease in terminal body weight (2 weeks post-exposure) |\n| Kotsonis and Klaassen 1977 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 15 | Rat (Sprague-Dawley) 15–20 M | Once (GW) | NS | LE | Death |  |  | 225 | LD50 at 14 days |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Kotsonis and Klaassen 1978 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 16 | Rat (Sprague-Dawley) 9 M | 2 weeks (W) | 0, 42 | LE | Death |  |  | 42 | 7/9 died within 2 weeks |\n| Machemer and Lorke 1981 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 17 | Rat (Long-Evans) 22–28 F | 10 days GDs 6–15 (GW) | 0, 1.84, 6.13, 18.39, 61.32 | LE, CS, BW, DX | Death Bd wt | 1.84 |  | 61.32 6.13 | 15/25 dams died 27% decrease in maternal body weight gain during treatment period |\n| 17 | Rat (Long-Evans) 22–28 F | 10 days GDs 6–15 (GW) | 0, 1.84, 6.13, 18.39, 61.32 | LE, CS, BW, DX | Gastro | 18.39 |  | 61.32 | Intestinal necrosis, hemorrhage, ulcers, constipation/absence of defecation |\n| 17 | Rat (Long-Evans) 22–28 F | 10 days GDs 6–15 (GW) | 0, 1.84, 6.13, 18.39, 61.32 | LE, CS, BW, DX | Dermal Develop | 1.84 6.13 | 6.13 | 18.39 | Coarse fur Increased number of fetuses with malformations, increased number of runts (<3 g), 7% decrease in fetal body weight |\n| Machemer and Lorke 1981 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 18 | Rat (Long-Evans) 21–24 F | 10 days GDs 6–15 (F) | 0, 1.2, 3.5, 12.5 | LE, CS, BW, FI, DX | Bd wt | 3.5 | 12.5 |  | 19% decrease in maternal body weight gain during treatment period |\n| 18 | Rat (Long-Evans) 21–24 F | 10 days GDs 6–15 (F) | 0, 1.2, 3.5, 12.5 | LE, CS, BW, FI, DX | Develop | 12.5 |  |  |  |\n| Saedi et al. 2020a, 2020b |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 19 | Rat (Sprague-Dawley) 4 F | 13 days PNDs 21–33 (GW) | 0, 15, 31, 46 | BW, BC, HE, OW, HP, DX | Bd wt Hemato | Endocr Develop | 46 15 | 15 | 21% decrease in terminal body weight Decreased RBC and increased WBC levels |\n| 19 | Rat (Sprague-Dawley) 4 F | 13 days PNDs 21–33 (GW) | 0, 15, 31, 46 | BW, BC, HE, OW, HP, DX | Hemat | 15 | 46 15 | 15 | 21% decrease in terminal body weight Decreased RBC and increased WBC levels |\n| 19 | Rat (Sprague-Dawley) 4 F | 13 days PNDs 21–33 (GW) | 0, 15, 31, 46 | BW, BC, HE, OW, HP, DX | Develop | 46 15 | 31 | 15 | Increased atretic follicles and decreased secondary follicles in ovaries; decreased serum estradiol levels |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Samuel et al. 2011 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 20 | Rat (Wistar) 18 F | 13 days GDs 9–21 (W) | 0, 6, 18 | BW, FI, WI, DX | Bd wt | 6 | 18 |  | 11% decrease in maternal body weight on GD 21 |\n| 20 | Rat (Wistar) 18 F | 13 days GDs 9–21 (W) | 0, 6, 18 | BW, FI, WI, DX | Develop |  |  | 6 | Fetal effects: Increased resorption Postnatal effects (female offspring): Decreased postnatal weight on PND 10 (22%) and PND 21 (14%), ovarian follicular degeneration, decreased estradiol and testosterone, delayed vaginal opening, and altered estrous cycling |\n| 20 | Rat (Wistar) 18 F | 13 days GDs 9–21 (W) | 0, 6, 18 | BW, FI, WI, DX | Other noncancer | 6 | 18 |  | Decreased maternal food intake |\n| Three dams/group were sacrificed on GD 21; remaining offspring were sacrificed on PND 10, PND 21, or evaluated during puberty |  |  |  |  |  |  |  |  |  |\n| Shimizu and Morita 1990 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 21 | Rat (Sprague-Dawley) 10 M | Once (GW) | NS | LE | Death |  |  | 106.9 | LD50 at 24 hours (fasted rats) |\n| Shimizu and Morita 1990 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 22 | Rat (Sprague-Dawley) 10 M | Once (GW) | NS | LE | Death |  |  | 327.3 | LD50 at 24 hours (fed rats) |\n| Stacey et al. 1988 |  |  |  |  |  |  |  |  | Cadmium acetate |\n| 23 | Rat (Sprague-Dawley) 4 M | 6 weeks 5 days/week (G) | 0, 0.0025, 0.025, 0.250 | BW, OW, IX | Bd wt | 0.25 |  |  | Enhanced spleen cell proliferative responses |\n| 23 | Rat (Sprague-Dawley) 4 M | 6 weeks 5 days/week (G) | 0, 0.0025, 0.025, 0.250 | BW, OW, IX | Immuno | 0.025 | 0.25 |  | Enhanced spleen cell proliferative responses |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Stacey et al. 1988 |  |  |  |  |  |  |  |  | Cadmium acetate |\n| 24 | Rat (Sprague-Dawley) 4 M | 2 weeks 5 days/week (G) | 0, 0.0025, 0.025, 0.250 | BW, OW, IX | Bd wt Immuno | 0.25 0.25 |  |  |  |\n| Wan et al. 2022 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 25 | Rat (Sprague-Dawley) 3 M, 3 F | 2 weeks (G) | 0, 2, 4 | BW, WI, BC, UR, OW, HP | Bd wt Renal | 4 | 2c |  | Increased 24-hour urinary protein excretion, elevated urinary β 2M levels, increased serum BUN |\n| Andersen et al. 1988 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 26 | Mouse (CBA/Bom) 7–42 M | Once (GW) | 0, 0.6, 3.9, 7.9, 15.7, 30.3, 59.6, 88.8 | LE, HP | Death Gastro | 15.7 | 30.3 | 88.8 | 36/42 mice died within 10 days LOAEL: Gastritis and enteritis SLOAEL: Severe gastric necrosis Fatty infiltration of liver cells, occasional hepatocellular necrosis Proximal tubular necrosis with poor cell differentiation and irregular granulation of cells Testicular necrosis in most tubules and interstitial tissue |\n| 26 | Mouse (CBA/Bom) 7–42 M | Once (GW) | 0, 0.6, 3.9, 7.9, 15.7, 30.3, 59.6, 88.8 | LE, HP | Hepatic | 15.7 | 30.3 | 88.8 | 36/42 mice died within 10 days LOAEL: Gastritis and enteritis SLOAEL: Severe gastric necrosis Fatty infiltration of liver cells, occasional hepatocellular necrosis Proximal tubular necrosis with poor cell differentiation and irregular granulation of cells Testicular necrosis in most tubules and interstitial tissue |\n| 26 | Mouse (CBA/Bom) 7–42 M | Once (GW) | 0, 0.6, 3.9, 7.9, 15.7, 30.3, 59.6, 88.8 | LE, HP | Renal | 59.6 |  | 88.8 | 36/42 mice died within 10 days LOAEL: Gastritis and enteritis SLOAEL: Severe gastric necrosis Fatty infiltration of liver cells, occasional hepatocellular necrosis Proximal tubular necrosis with poor cell differentiation and irregular granulation of cells Testicular necrosis in most tubules and interstitial tissue |\n| 26 | Mouse (CBA/Bom) 7–42 M | Once (GW) | 0, 0.6, 3.9, 7.9, 15.7, 30.3, 59.6, 88.8 | LE, HP | Repro | 30.3 |  | 59.6 | 36/42 mice died within 10 days LOAEL: Gastritis and enteritis SLOAEL: Severe gastric necrosis Fatty infiltration of liver cells, occasional hepatocellular necrosis Proximal tubular necrosis with poor cell differentiation and irregular granulation of cells Testicular necrosis in most tubules and interstitial tissue |\n| Ara et al. 2016 |  |  |  |  |  |  |  |  | Form not specified |\n| 27 | Mouse (Swiss-Webster) 5 F | 7 days GDs 6–12 (GW) | 0, 3.13, 6.25, 12.5, 25.0 | RX, DX | Develop |  |  | 3.13 | 49% decrease in fetal body weight; decreased crown-rump length, head and eye circumference, and forelimb, hindlimb and tail length; anomalies in the brain, eyes, forelimbs, hindlimbs, and tail |\n| Baer and Benson 1987 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 28 | Mouse (Swiss-Webster) 10 M | Once (GW) | 100, 150 | LE | Death |  |  | 95.5 | LD50 at 96 hours |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Yi et al. 2021a |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 29 | Mouse (ICR) 13 F | 10 days GDs 8–17 (W) | 0, 8.1, 24 | DX | Develop |  | 8.1 |  | Impaired glucose tolerance in adult male offspring |\n| INTERMEDIATE EXPOSURE |  |  |  |  |  |  |  |  |  |\n| Chopra et al. 1984 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 30 | Monkey (Rhesus) 3–4 M | 6 months (F) | 0, 5 | CS, BW, IX | Bd wt Immuno | 5 5 |  |  |  |\n| Afolabi et al. 2012 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 31 | Rat (Wistar) 8 M | 7 weeks (W) | 0, 4.6, 9.1 | BW, BC, BI | Hepatic Immuno |  | 4.6 4.6 |  | Increased plasma lipid levels Increased plasma pro-inflammatory cytokines |\n| Ali et al. 1986 |  |  |  |  |  |  |  |  | Cadmium acetate |\n| 32 | Rat (Wistar) 10 F | 21 days GDs 1–21 (W) | 0, 0.706, 1.2 | BW, FI, WI, RX, DX | Bd wt Repro Develop | 1.2 1.2 | 0.706 | 1.2 | Decreased offspring body weight, persisting through PND 45 (~20%) Delayed development of sensory motor coordination reflexes; altered motor activity (increased PNDs 7–21; decreased PND 60) |\n| Aprioku et al. 2014 |  |  |  |  |  |  |  |  | Cadmium sulfate |\n| 33 | Rat (Wistar) 8 F | 21 days GDs 0–20 (W) | 0, 4, 8 | BW, OW, HP, RX, DX | Bd wt Repro Develop |  | 4 | 4 | 40% decrease in maternal body weight on GD 20 Increased abortions |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Baranski 1987 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 34 | Rat (Wistar) 12–16 F | 20 days GDs 1–20 (W) | 0, 4.6, 11.1 | LE, BW, FI, WI, HE, BC, DX | Bd wt Repro Develop | 11.1 |  | 4.6 | 37% decrease in maternal body weight gain |\n| 34 | Rat (Wistar) 12–16 F | 20 days GDs 1–20 (W) | 0, 4.6, 11.1 | LE, BW, FI, WI, HE, BC, DX | Bd wt Repro Develop | 11.1 |  | 4.6 | 12% decrease in fetal body weight and 7% decrease in fetal body length |\n| 34 | Rat (Wistar) 12–16 F | 20 days GDs 1–20 (W) | 0, 4.6, 11.1 | LE, BW, FI, WI, HE, BC, DX | Other noncancer |  | 4.6 |  | Decreased maternal food intake |\n| Baranski and Sitarek 1987 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 35 | Rat (Wistar) 11–13 F | 14 weeks 5 days/week (GW) | 0, 0.04, 0.4, 4, 40 | LE, CS, BW, RX | Death |  |  | 40 | 4/13 died by week 8; 7/13 by week 14 |\n| 35 | Rat (Wistar) 11–13 F | 14 weeks 5 days/week (GW) | 0, 0.04, 0.4, 4, 40 | LE, CS, BW, RX | Bd wt Repro | 0.4 |  | 4 | 40% decrease in body weight gain |\n| 35 | Rat (Wistar) 11–13 F | 14 weeks 5 days/week (GW) | 0, 0.04, 0.4, 4, 40 | LE, CS, BW, RX | Bd wt Repro | 4 |  | 40 | Increased duration of estrus cycle |\n| Baranski et al. 1983 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 36 | Rat (Wistar) NS F | 11 weeks (5 weeks premating, 3 weeks mating, 3 weeks gestation) 5 days/week (GW) | 0, 0.04, 0.4, 4 | RX, DX | Repro Develop | 4 |  |  | Decreased pup locomotor activity and impaired motor coordination at 2 months |\n| 36 | Rat (Wistar) NS F | 11 weeks (5 weeks premating, 3 weeks mating, 3 weeks gestation) 5 days/week (GW) | 0, 0.04, 0.4, 4 | RX, DX | Repro Develop | 4 | 0.04 |  | Decreased pup locomotor activity and impaired motor coordination at 2 months |\n| Half of dams were sacrificed on GD 21; half were allowed to deliver naturally and pups (8/sex/group) were assessed for 2 months after parturition |  |  |  |  |  |  |  |  |  |\n| Brzóska and Moniuszko-Jakoniuk 2005a, 2005b; 2010 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 37 | Rat (Wistar) 10 M | 12 months (W) | 0, 0.2, 0.5, 4 | BW, FI, WI, BC, BI, HP | Bd wt Musc/skel | 4 |  |  | Increased lumbar spine deformities, decreased in lumbar spine and femur mineralization, altered bone turnover parameters |\n| 37 | Rat (Wistar) 10 M | 12 months (W) | 0, 0.2, 0.5, 4 | BW, FI, WI, BC, BI, HP | Bd wt Musc/skel | 0.2 | 0.5 |  | Increased lumbar spine deformities, decreased in lumbar spine and femur mineralization, altered bone turnover parameters |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Brzóska and Moniuszko-Jakoniuk 2005c; Brzóska et al. 2005a, 2005c |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 38 | Rat (Wistar) 40 F | 12 months (W) | 0, 0.2, 0.5, 4 | BW, FI, WI, BC, BI, HP, OF | Bd wt Musc/skel | 4 | 0.2 |  | Decreased bone mineralization, mechanical properties of tibia and femur, and altered bone turnover parameters |\n| Brzóska et al. 2004, 2005b |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 39 | Rat (Wistar) 8–10 F | 12 months (W) | 0, 0.3, 0.7, 4, 8 | BW, FI, WI, BI, OF | Musc/skel |  | 0.3 |  | Alterations in bone mineral content and density and mechanical properties of lumbar vertebral and femoral bones |\n| Buha et al. 2013, 2019 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 40 | Rat (Wistar) 7 M | 28 days (G) | 0, 0.3, 0.6, 1.25, 2.5, 5, 10 | BW, BC, BI | Bd wt Musc/skel | 0.6 | 0.3 | 1.25 | 36% decrease in body weight gain Decreased bone mineral content in femur Increased serum creatinine and urea Decreased serum T3 levels |\n|  |  |  |  |  | Renal Endocr | 2.5 | 5 0.3 |  |  |\n| Caride et al. 2010 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 41 | Rat (Sprague-Dawley) 60 M | 30 days (W) | 0, 0.92, 1.8 | BC | Endocr |  | 0.92 |  | Altered daily secretory pattern of ACTH and growth hormone; increased median levels of ACTH and TSH |\n| Carmignani and Boscolo 1984 |  |  |  |  |  |  |  |  | Cadmium acetate |\n| 42 | Rat (Sprague-Dawley) 10 M | 190 days (W) | 0, 1.4, 2.8 | CS, BW, OF | Bd wt Cardio | 2.8 | 1.4 |  | Increased systolic and diastolic blood pressure |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Chen et al. 2013 |  |  |  |  |  |  |  |  | Form not specified |\n| 43 | Rat (Sprague-Dawley) 6 M | 12 weeks (W) | 0, 0.2, 1.1, 5.0 | BW, BC, BI, UR, HP | Bd wt Musc/skel | 5 | 0.2 |  | Trabecular bone damage in tibia (decreased number, thickness; increased separation, increased dissociated ends); altered bone turnover parameters |\n| Cifone et al. 1989 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 44 | Rat (Wistar) 4 F | 170 days (W) | 0, 29, 58 | CS, BW, FI, WI, OW, IX | Bd wt Immuno | 58 | 29 |  | Biphasic decrease (first 30–50 days) then increase in NK cell activity, splenic cellularity, and the number of large granular lymphocytes in the peripheral blood; increased total peripheral lymphocytes |\n| Desi et al. 1998 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 45 | Rat (Wistar) NS F | 94 days F0: GDs 5–15 + PNDs 2–28 F1: PNWs 5–12 5 days/week (GW) | 0, 3.5, 7.0, 14.0 | DX | Develop | 3.5 | 7 |  | Decreased peripheral nerve conduction velocity with increased refractory periods |\n| Locomotor and sensory function assessed in F1 males at 12 weeks of age |  |  |  |  |  |  |  |  |  |\n| Desi et al. 1998 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 46 | Rat (Wistar) NS F | 11 days GDs 5–15 (GW) | 0, 3.5, 7.0, 14.0 | DX | Develop | 14 |  |  |  |\n| Locomotor and sensory function assessed in F1 males at 12 weeks of age |  |  |  |  |  |  |  |  |  |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Desi et al. 1998 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 47 | Rat (Wistar) NS F | 38 days GDs 5–15 plus PNDs 2–28 (GW) | 0, 3.5, 7.0, 14.0 | DX | Develop | 3.5 | 7 |  | Decreased horizontal ambulation and rearing activity |\n| Locomotor and sensory function assessed in F1 males at 12 weeks of age |  |  |  |  |  |  |  |  |  |\n| Dixon et al. 1976 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 48 | Rat (Sprague-Dawley) 10 M | 30–90 days (W) | 0, 0.00014, 0.0014, 0.014 | BC, OW, RX | Repro | 0.014 |  |  |  |\n| Males mated to untreated females |  |  |  |  |  |  |  |  |  |\n| Feng et al. 2019 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 49 | Rat (Sprague-Dawley) NS F | 6 weeks GD 0 to PND 21 (W) | 0, 0.6, 3 | DX | Develop |  | 0.6 |  | Impaired learning and memory in F1 males at PNDs 35 and 56 |\n| Huang et al. 2020 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 50 | Rat (Sprague-Dawley) <10 F | 3 weeks GD 1 to birth (GW) | 0, 0.3, 1.2, 4.9 | DX | Develop |  | 0.3 |  | F1 males: Decreased serum testosterone and increased seminiferous tubule diameter at PND 21; decreased Johnsen score (decreased testicular maturity) on PND 56 |\n| Iqbal et al. 2021 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 51 | Rat (Sprague-Dawley) 6 M | 17 days (GW) | 0, 5, 10, 15 | BW, OW, HP | Bd wt | 10 |  | 15 | 12% body weight loss during exposure (compared to 12% body weight gain in control) |\n|  |  |  |  |  | Repro | 5 | 10 |  | Structural changes in the testis and epididymis |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\nstimulated plasma insulin levels\n\nAltered glucose tolerance at PND 21\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects | Cadmium chloride |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Jacquet et al. 2018 |  |  |  |  |  |  |  |  |  |  |\n| 52 | Rat (Wistar) 9 M, 9 F | 12 weeks (W) | M: 0, 0.0053, 0.0558, 0.515; F: 0, 0.0055, 0.053, 0.4959 | LE, BW, BC, UR, OW, OF | Bd wt | 0.4959 F 0.515 M 0.4959 F 0.515 M Endocr | 0.053 F |  |  |  |\n| Jacquet et al. 2019 |  |  |  |  |  |  |  |  |  |  |\n| 53 | Rat (Wistar) 15–17 F | 11 weeks 3 weeks prior to mating GD 0–PND 35 (W) | 0, 0, 0.05, 0.5 | UR, RX, DX | Renal Repro Develop | 0.5 0.5 | 0.05 |  |  | Cadmium chloride |\n| Dams were sacrificed on PND 35; pups were sacrificed on PND 21, 26, and 60 |  |  |  |  |  |  |  |  |  |  |\n| Kelman et al. 1978 |  |  |  |  |  |  |  |  |  |  |\n| 54 | Rat (Sprague-Dawley) 15 F | 22 days GDs 0–21 (W) | 0, 1.5, 3.8 | HE, BI, DX | Hemato Musc/skel Develop | 3.8 | 1.5 | 1.5 | Decreased hematocrit | Form not specified |\n| Kotsonis and Klaassen 1978 |  |  |  |  |  |  |  |  |  |  |\n| 55 | Rat (Sprague-Dawley) 6 M | 24 weeks (W) | 0, 1.1, 2.92, 8.49 | CS, BW, FI, WI, HE, BC, BI, OW, HP, OF, RX, NX | Bd wt Resp Cardio Gastro Hematocell Musc/skel Hepatic Renal Endocr | 8.49 8.49 8.49 8.49 | 8.49 8.49 8.49 | 8.49 8.49 | 8.49 | Cadmium chloride |\n\nProteinuria (starting at week 6)\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n|  |  |  |  |  | Immuno Neuro Repro | 8.49 1.1 8.49 | 2.92 |  | Decreased motor activity (starting at week 3) |\n| Males mated to unexposed females |  |  |  |  |  |  |  |  |  |\n| Kulas et al. 2019 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 56 | Rat (Dark Agouti) 8 M | 30 days (W) | 0, 0.35, 3.51 | OW, HP | Resp |  | 0.35 |  | Minimal to mild perivascular edema and respiratory epithelial desquamation in lungs |\n| Larregle et al. 2008 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 57 | Rat (Wistar) 8 M | 8 weeks daily (W) | 0, 18 | BC | Hepatic |  | 18 |  | Increased serum and liver triglyceride levels; increased serum cholesterol levels |\n| Li et al. 2018 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 58 | Rat (Sprague-Dawley) 10 F | 42 days GD 0-PND 21 (GW) | 0, 0.6, 3 | DX | Develop |  | 0.6 |  | F1 females: Decreased primordial follicles (PND 21) and increased serum estradiol (PND 21, PND 35) F2: females: Increased serum progesterone (PND 21) |\n| Liu et al. 2019 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 59 | Rat (Sprague-Dawley) 10 M | 60 days (G) | 0, 0.6, 1.5, 3 | CS, FI, WI, BW, BC, UR, OW, HP | Bd wt |  |  | 1.5 | 20% decrease in terminal body weights Decreased serum iron Increased BUN and serum creatinine |\n| Liu et al. 2020 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 60 | Rat (Sprague-Dawley) 5 F | 20 days GDs 1-21 (GW) | 0, 0.3, 1.2, 4.9 | DX | Develop |  | 0.3 |  | Decreased ovarian granulosa cell progesterone in F1 female offspring on PND 56 |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects | Cadmium chloride |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Loeser and Lorke 1977 |  |  |  |  |  |  |  |  |  |  |\n| 61 | Rat (Wistar) 20 M, 20 F | 3 months (F) | 0, 0.1, 0.3, 1, 3 | HP, BC, CS, UR, OW, OF, BW, FI | Bd wt Cardio Hematoc Hepatic Renal Endocr Immuno Repro | 3 3 3 3 3 3 | 0.439 | Decreased offspring body weights (by up to ~19% on PNW 9) | Cadmium chloride |  |\n| Luo et al. 2015 |  |  |  |  |  |  |  |  |  |  |\n| 62 | Rat (Sprague-Dawley) 10 F | 42 days GD 0-PND 21 (W) | 0, 0.089, 0.439, 0.955 | BW, RX, DX | Bd wt Repro Develop | 0.955 0.955 0.089 |  | 0.439 | Decreased offspring body weights (by up to ~19% on PNW 9) | Cadmium chloride |\n| McCalla et al. 2024 |  |  |  |  |  |  |  |  |  |  |\n| 63 | Rat (Sprague-Dawley) 10 M | 8 weeks 3 times/week (GW) | 0, 2.5, 5 | BW, HE, OF | Cardio Hematoc | 2.5 | 2.5 5 |  | Increased blood pressure Decreased mean cell volume and mean cell hemoglobin; increased red cell distribution width | Cadmium chloride |\n| Muller et al. 1988 |  |  |  |  |  |  |  |  |  |  |\n| 64 | Rat (Sprague-Dawley) 4 M | 6 weeks 5 days/week (GW) | 0, 0.0025, 0.025, 0.25 | BW, BC, BI, OW | Bd wt Hepatic | 0.25 0.25 |  |  |  | Cadmium acetate |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Nagymajtenyi et al. 1997 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 65 | Rat (Wistar) 5 M, 10 F | 3 generations ~16–18 weeks per generation (GW) | 0, 3.5, 7.0, 14.0 | CS, BW, RX, DX | Bd wt Repro Develop | 14 14 3.5 M | 7 M |  | Decreased tail nerve conduction velocity (all generations); prolonged latency and duration of somatosensory evoked potentials (F2, F3); increased frequency in auditory and visual evoked potentials (F3); 5% decrease in F3 body weight at PNW 12 |\n| Nasiadek et al. 2018 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 66 | Rat (Wistar) 20 F | 30 days (GW) | 0, 0.09, 1.8, 4.5 | CS, BW, BC, OW, HP | Bd wt Repro | 4.5 0.09 | 1.8 |  | Decreased plasma estradiol |\n| Nasiadek et al. 2019 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 67 | Rat (Wistar) 24 F | 90 days (GW) | 0, 0.09, 0.9, 1.8, 4.5 | LE, CS, BW, FI, WI, BC, OW, HP | Bd wt Repro | 4.5 0.09 | 0.9 |  | Decreased plasma estradiol |\n| Nation et al. 1984 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 68 | Rat (Sprague-Dawley) 9 M | 55 days (F) | 0, 1, 5 | CS, NX | Neuro | 1 | 5 |  | Increased anxiety-like behavior (passive avoidance) |\n| Ninkov et al. 2016 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 69 | Rat (Albino Oxford) 8–16 M | 30 days (W) | 0, 0.4, 4.1 | OW, HP, IX | Gastro Immuno | 4.1 | 0.4 |  | Increased intestinal lymphocyte counts, and mesenteric lymph node relative weight and cellularity; decreased spleen cell proliferative response |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Ogoshi et al. 1989 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 70 | Rat (NS) 19–22 F | 4 weeks (W) | 0, 1, 2.5 | BW, HE, BC, BI, OF | Bd wt Hemato | 2.5 | 1 |  | Decreased hematocrit, hemoglobin, MCHC, and MCV |\n|  |  |  |  |  | Musc/skel |  | 1 |  | Decreased bone strength |\n| Weanling rats (21-day-old) |  |  |  |  |  |  |  |  |  |\n| Ogoshi et al. 1989 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 71 | Rat (NS) 18–25 NS | 4 weeks (W) | 0, 1.6, 3.3, 6.6, 13, 26.2 | BW, HE, BC, BI, OF | Bd wt Hemato | 26.2 6.6 Musc/skel | 13 |  | Decreased hematocrit and MCV |\n| Adult rats (24-week-old) |  |  |  |  |  |  |  |  |  |\n| Ogoshi et al. 1989 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 72 | Rat (NS) 25–27 NS | 4 weeks (W) | 0, 11, 21.5 | BW, HE, BC, BI, OF | Bd wt Hemato | 11 21.5 | 11 21.5 |  | 10% decrease in body weight gain |\n|  |  |  |  |  | Musc/skel |  |  |  | Decreased hemoglobin and MCHC |\n| Aged rats (1.5-year-old) |  |  |  |  |  |  |  |  |  |\n| Oluranti et al. 2021 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 73 | Rat (Wistar) 5 M | 21 days (G) | 0, 3, 18 | BC, BI, OW | Endocr |  | 3 |  | Decreased plasma insulin and glucose levels |\n| Petering et al. 1979 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 74 | Rat (Sprague-Dawley) 5 F | 111 days (90 days prior mating through GD 21) (W) | 0, 0.56, 1.3, 2.61, 5.23 | HE, RX, DX | Repro Develop | 5.23 1.3 |  | 2.61 | 10% decrease in birth weight |\n| Prigge 1978a |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 75 | Rat (Wistar) 12 F | 90 days (W) | 0, 3.8, 7.6, 15.2 | LE, BW, HE, BC, BI, UR, OW | Bd wt Hemato | 3.8 3.8 Renal | 3.8 7.6 | 7.6 | 28% decrease in body weight gain |\n|  |  |  |  |  |  |  |  |  | Decreased serum iron |\n|  |  |  |  |  |  |  |  |  | Proteinuria |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Sarmiento-Ortega et al. 2017 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 76 | Rat (Wistar) 10 M | 3, 4, or 5 months (W) | 0, 2.94 | BC, OF | Hepatic |  | 2.94 |  | Increased serum and hepatic lipid concentrations |\n| 76 | Rat (Wistar) 10 M | 3, 4, or 5 months (W) | 0, 2.94 | BC, OF | Endocr |  | 2.94 |  | Increased serum glucose and insulin levels following administration of an oral glucose load |\n| 76 | Rat (Wistar) 10 M | 3, 4, or 5 months (W) | 0, 2.94 | BC, OF | Other noncancer |  | 2.94 |  | Increased abdominal circumference, body mass index, and percentage of body fat |\n| Sorell and Graziano 1990 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 77 | Rat (Sprague-Dawley) 42–66 F | 15 days GDs 6–20 (W) | 0, 0.629, 4.714, 8.171 | BW, WI, HE, DX | Bd wt | 0.629 | 4.714 | 8.171 | LOAEL: 13% decrease in maternal weight gain SLOAEL: 30% decrease in maternal body weight gain |\n| 77 | Rat (Sprague-Dawley) 42–66 F | 15 days GDs 6–20 (W) | 0, 0.629, 4.714, 8.171 | BW, WI, HE, DX | Hemato | 4.714 | 8.171 |  | Reduced maternal hemoglobin levels |\n| 77 | Rat (Sprague-Dawley) 42–66 F | 15 days GDs 6–20 (W) | 0, 0.629, 4.714, 8.171 | BW, WI, HE, DX | Develop | 0.629 | 4.714 |  | 8% decrease in fetal body weight |\n| Sun et al. 2023 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 78 | Rat (Sprague-Dawley) 10 M | 29 days (GW) | 0, 0.3, 1, 5 | DX | Develop | 0.3 | 1 |  | Decreased serum estradiol and progesterone in adult F1 females |\n| F0 males were mated to unexposed females; reproductive development was assessed in F1 and F2 female offspring |  |  |  |  |  |  |  |  |  |\n| Sutou et al. 1980 |  |  |  |  |  |  |  |  | Form not specified |\n| 79 | Rat (Sprague-Dawley) 14 M, 14 F | 9 weeks (premating through GD 20) (GW) | 0, 0.1, 1.0, 10 | RX, DX | Repro | 1 |  | 10 | Decreased number of copulating and pregnant females; 49% reduction in number of live fetuses/litter; decreased total implants/litter, increased resorptions/litter |\n| 79 | Rat (Sprague-Dawley) 14 M, 14 F | 9 weeks (premating through GD 20) (GW) | 0, 0.1, 1.0, 10 | RX, DX | Develop | 1 |  | 10 | Decreased fetal body weight in males (34%) and females (33%); decreased body and tail length; delayed ossification |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Tang et al. 2016 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 80 | Rat (Sprague-Dawley) 6 M | 3 months (W) | 0, 0.28, 1.41, 7.07 | HP | Musc/skel | 1.41 | 7.07 |  | Decreased bone density and trabecular bone loss and damage in tibia (decreased trabecular volume and number, increased trabecular separation) |\n| Tian et al. 2017 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 81 | Rat (Sprague-Dawley) NS F | 6 weeks GD 0 to PND 21 (GW) | 0, 0.6, 3 | DX | Develop |  | 0.6 |  | Decreased serum progesterone and testosterone and in male offspring on PND 35 and 56, respectively; decreased relative testis weight on PND 21 |\n| Tucovic et al. 2018 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 82 | Rat (Dark Agouti) 4–6 M | 30 days (W) | 0, 0.7, 6.6 | BW, FI, WI, HE BC, UR, HP | Bd wt Hemato | 6.6 |  |  | Increased percent neutrophil leukocytes and eosinophil leukocytes |\n| 82 | Rat (Dark Agouti) 4–6 M | 30 days (W) | 0, 0.7, 6.6 | BW, FI, WI, HE BC, UR, HP | Hepatic Immuno | 6.6 0.7 | 6.6 |  | Increased IL-6 and TNF in skin |\n| Wan et al. 2022 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 83 | Rat (Sprague-Dawley) 3 M, 3 F | 4 weeks (G) | 0, 2, 4 | BW, WI, BC, UR, OW, HP | Bd wt Renal | 4 | 2 |  | Increased 24-hour urinary protein excretion, elevated urinary β 2M levels, increased serum BUN |\n| Wan et al. 2022 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 84 | Rat (Sprague-Dawley) 3 M, 3 F | 8 weeks (G) | 0, 2, 4 | BW, WI, BC, UR, OW, HP | Bd wt Renal | 4 | 2 |  | Increased 24-hour urinary protein excretion, elevated urinary β 2M levels, increased serum BUN |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Wang et al. 2014 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 85 | Rat (Sprague-Dawley) 8 M, 8 F | 28 days (GW) | 0, 1, 2.5, 5, 10, 20 | LE, CS, BW, FI, HE, BC, UR, GN, OW, HP | Bd wt | 5 | 10 |  | Decrease in terminal body weight in males (12%) and females (11%) |\n| 85 | Rat (Sprague-Dawley) 8 M, 8 F | 28 days (GW) | 0, 1, 2.5, 5, 10, 20 | LE, CS, BW, FI, HE, BC, UR, GN, OW, HP | Cardio | 20 |  |  | Decrease in terminal body weight in males (12%) and females (11%) |\n| 85 | Rat (Sprague-Dawley) 8 M, 8 F | 28 days (GW) | 0, 1, 2.5, 5, 10, 20 | LE, CS, BW, FI, HE, BC, UR, GN, OW, HP | Hemat | 10 F | 20 F |  | Increased platelets |\n| 85 | Rat (Sprague-Dawley) 8 M, 8 F | 28 days (GW) | 0, 1, 2.5, 5, 10, 20 | LE, CS, BW, FI, HE, BC, UR, GN, OW, HP | Hepatic | 2.5 M | 5 M |  | Increased platelets |\n| 85 | Rat (Sprague-Dawley) 8 M, 8 F | 28 days (GW) | 0, 1, 2.5, 5, 10, 20 | LE, CS, BW, FI, HE, BC, UR, GN, OW, HP | Renal | 10 F | 20 F |  | Increased serum ALT |\n| 85 | Rat (Sprague-Dawley) 8 M, 8 F | 28 days (GW) | 0, 1, 2.5, 5, 10, 20 | LE, CS, BW, FI, HE, BC, UR, GN, OW, HP | Endocr | 20 |  |  |  |\n| 85 | Rat (Sprague-Dawley) 8 M, 8 F | 28 days (GW) | 0, 1, 2.5, 5, 10, 20 | LE, CS, BW, FI, HE, BC, UR, GN, OW, HP | Immuno | 20 |  |  |  |\n| 85 | Rat (Sprague-Dawley) 8 M, 8 F | 28 days (GW) | 0, 1, 2.5, 5, 10, 20 | LE, CS, BW, FI, HE, BC, UR, GN, OW, HP | Neuro | 20 |  |  |  |\n| 85 | Rat (Sprague-Dawley) 8 M, 8 F | 28 days (GW) | 0, 1, 2.5, 5, 10, 20 | LE, CS, BW, FI, HE, BC, UR, GN, OW, HP | Repro | 5 | 10 |  | Decreased serum LH and testosterone in males; increased absolute and relative uterine weight |\n| 85 | Rat (Sprague-Dawley) 8 M, 8 F | 28 days (GW) | 0, 1, 2.5, 5, 10, 20 | LE, CS, BW, FI, HE, BC, UR, GN, OW, HP | Other | 1 F | 2.5 F |  | Decreased food intake |\n| 85 | Rat (Sprague-Dawley) 8 M, 8 F | 28 days (GW) | 0, 1, 2.5, 5, 10, 20 | LE, CS, BW, FI, HE, BC, UR, GN, OW, HP | noncancer |  |  |  |  |\n| Weng et al. 2014 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 86 | Rat (Wistar) 12 F | 8 weeks (G) | 0, 0.3, 1.2, 4.9 | BW, OW, HP | Bd wt | 4.9 |  |  |  |\n| 86 | Rat (Wistar) 12 F | 8 weeks (G) | 0, 0.3, 1.2, 4.9 | BW, OW, HP | Repro | 0.3 | 1.2 |  | Decreased absolute and relative ovary weight, increased atretic follicles, follicular cell apoptosis |\n| Xu et al. 2015 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 87 | Rat (Sprague-Dawley) 6 M | 90 days (GW) | 0, 0.7, 2.0, 6.0 | LE, CS, BW, HP | Bd wt | 6 |  |  |  |\n| 87 | Rat (Sprague-Dawley) 6 M | 90 days (GW) | 0, 0.7, 2.0, 6.0 | LE, CS, BW, HP | Neuro | 0.7 | 2 |  | Neuronal degeneration in cortex |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Yang et al. 2021a |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 88 | Rat (Sprague-Dawley) 9 NR | 8 weeks 5 days/week (GW) | 0, 0.15, 0.61, 2.5 | BC | Hepatic | 0.15 | 0.61 |  | Increased serum triglycerides, total cholesterol, and LDL cholesterol; decreased serum HDL cholesterol |\n|  |  |  |  |  | Renal | 0.61 | 2.5 |  | Increased serum urea nitrogen |\n| Yi et al. 2021b |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 89 | Rat (Sprague-Dawley) 6 M | 28 days (GO) | 0, 1, 3 | BW, BC, OW, HP, RX | Bd wt Repro | 3 | 1 |  | Decreased serum testosterone levels |\n| Zenick et al. 1982 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 90 | Rat (Long-Evans) 5 M | 70–80 days (W) | 0, 1.16, 2.32, 4.64 | BW, FI, WI, HP, RX, DX | Bd wt Repro Develop for fetal effects | 4.64 4.64 4.64 | 25 | 12 | LOAEL: 13% decrease in terminal body weight SLOAEL: 25% decrease in terminal body weight |\n| Males were mated with three untreated females; one litter evaluated for fetal effects and two litters evaluated for neurobehavior on PND 21 or 90 |  |  |  |  |  |  |  |  |  |\n| Zhang et al. 2022a |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 91 | Rat (Sprague-Dawley) 8 M | 12 weeks (G) | 0, 1.5, 3, 6.1, 12, 25 | LE, CS, BW, BC, OW, HP | Bd wt | 6.1 | 12 | 25 | LOAEL: 13% decrease in terminal body weight SLOAEL: 25% decrease in terminal body weight |\n|  |  |  |  |  | Hepatic | 1.5 | 3 | 12 | LOAEL: Hepatic fibrosis SLOAEL: Hepatic fibrous tissue proliferation |\n| Zhang et al. 2023a |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 92 | Rat (Sprague-Dawley) 6 M | 4 weeks (GW) | 0, 2.5, 5 | BC, HP, RX | Repro | 2.5 |  | 5 | Decreased serum testosterone, LH, and GnRH; decreased sperm count and motility; decreased seminiferous tubule diameter and seminiferous epithelial thickness |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Zhang et al. 2024a |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 93 | Rat (Sprague-Dawley) 10–30 M | 4 weeks (GW) | 0, 5 | BW, RX, DX | Bd wt Repro |  | 5 | 5 | 13% decrease in body weight Decreased fertility and percent live births, sperm quality, and levels of serum testosterone and gonad releasing hormone; decreased seminiferous tubule diameter and area, seminiferous epithelium thickness, and Johnsen score; decreased number of cells in interstitial region of testes and disordered cellular arrangement |\n| Males were mated with unexposed females. |  |  |  |  | Develop |  |  | 5 | 21% decrease in male fetal weight |\n| Blakley 1985 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 94 | Mouse (BDF1) 22 F | 3 weeks (W) | 0, 1.4, 2.8, 14 | CS, BW, GN, IX | Bd wt Immuno | 14 1.4 | 2.8 |  | Decreased humoral immune response |\n| Blakley 1988 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 95 | Mouse (BDF1) 14–16 F | 26 days (W) | 0, 2.5, 12.5 | BW, WI, IX | Immuno | 12.5 |  |  |  |\n| Aged mice (12-month-old) |  |  |  |  |  |  |  |  |  |\n| Chatterjee and Saxena 2015 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 96 | Mouse (C57BL/6) 10–15 M | 6 weeks (W) | 0, 7.6, 150 | HE, BC | Hemato Immuno | 150 | 7.6 |  | Decreased RBC count and hemoglobin |\n| Chou et al. 2023 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 97 | Mouse (C57BL/6) 11–18 M | 12 weeks (W) | 0, 11, 21 | BW, OF, HP | Bd wt Cardio | 21 |  | 11 | Cardiomyocyte apoptosis |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects | Cadmium chloride |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Exon et al. 1986 |  |  |  |  |  |  |  |  |  |  |\n| 98 | Mouse (Swiss-Webster) 20 M | 10 weeks (W) | 0, 0.57, 5.7, 57 | LE, BW, GN, HP, IX | Bd wt Immuno | 57 57 |  |  |  |  |\n| Exon et al. 1986 |  |  |  |  |  |  |  |  |  |  |\n| 99 | Mouse (Swiss-Webster) 20 M | 10 weeks (W) | 0, 0.57, 5.7, 57 | LE, BW, GN, HP, IX | Bd wt Immuno | 0.57 57 | 5.7 |  | Cadmium acetate | 14% decrease in body weight |\n| Exon et al. 1986 |  |  |  |  |  |  |  |  |  |  |\n| 100 | Mouse (Swiss-Webster) 20 M | 10 weeks (W) | 0, 0.57, 5.7, 57 | LE, BW, GN, HP, IX | Bd wt Immuno | 57 57 |  |  |  | Cadmium sulfate |\n| Gathwan and Albir 2020 |  |  |  |  |  |  |  |  |  |  |\n| 101 | Mouse (Swiss) 6 M | 30 days (G) | 0, 6.1, 12.3, 19.5 | BW, FI, WI, OW, HP | Bd wt | 6.1 | 12.3 | 19.5 | LOAEL: 13% decrease in terminal body weight SLOAEL: 23% decrease in terminal body weight | Cadmium oxide |\n| He et al. 2019a |  |  |  |  |  |  |  |  |  |  |\n| 102 | Mouse (C57BL/6) 10 M | 20 weeks (W) | 0, 1.475, 6.566 | LE, CS, WI, BC, BI, OW, HP | Bd wt Hepatic | Endocr | 6.566 | 1.475 | 6.566 | Cadmium chloride 22% decrease in body weight gain NAFLD; increased hepatic triglyceride levels |\n| He et al. 2019b |  |  |  |  |  |  |  |  |  |  |\n| 103 | Mouse (BALB/c) 12 F | 16 weeks (W) | 0, 2, 6.5 | BW, FI, BC, BI, HP | Bd wt Musc/skel | 6.5 | 2 |  |  | Cadmium chloride |\n\nTrabecular bone damage\n(decreased number, thickness;\nincreased separation, fat cells);\naltered bone turnover parameters\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| He et al. 2020 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 104 | Mouse (C57BL/6) 10 M | 20 weeks (W) | 0, 1.5, 7.6 | LE, CS, BW, HP | Bd wt Gastro | 7.6 1.5 | 7.6 |  | Decreased length of intestinal villus and thickness of intestinal wall |\n| Hudson et al. 2019 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 105 | Mouse (C57BL/6J) NS F | 8 weeks 5 weeks prior to mating until birth (W) | 0, 0.3, 13 | RX, DX | Repro Develop | 13 | 0.3 | 13 | LOAEL: Increased absolute and relative heart weight in female pups at birth; increased tail blood volume and tail blood flow in female offspring at 5.5 months of age SLOAEL: 12% decrease in birth weight in both sexes; increased absolute and relative heart weight in male pups at birth; increased systolic, diastolic, and mean arterial blood pressure in female offspring at 5.5 months of age |\n| C57BL/6J dams mated to unexposed CAST/EiJ males, to generate F1 hybrid mice |  |  |  |  |  |  |  |  |  |\n| Hudson et al. 2019 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 106 | Mouse (CAST/EiJ) NS F | 8 weeks 5 weeks prior to mating until birth (W) | 0, 0.3, 13 | RX, DX | Repro Develop | 13 | 0.3 | 13 | LOAEL: Decreased body weight at birth in males; increased absolute heart weight in females SLOAEL: 22% decrease in birth weight |\n| CAST/EiJ dams mated to unexposed C57BL/6J males, to generate F1 hybrid mice |  |  |  |  |  |  |  |  |  |\n| Krzystyniak et al. 1987 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 107 | Mouse (C57BL/6) 10 F | 12–16 weeks (W) | 0, 0.6, 17, 52 | IX | Immuno | 17 | 52 |  | Reduced humoral immune response |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Kurita et al. 2018 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 108 | Mouse (C57BL/6J) 3–10 F | 18 days GDs 1–18 (G) | 0, 5, 10 | DX | Develop | 5 |  | 10 | 34% decrease in fetal weight, decreased fetal length |\n| Li et al. 2022 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 109 | Mouse (ICR) 10 F | 70 days 4 weeks premating to PND 21 (W) | 0, 2.6, 19.7 | WI, DX | Develop |  | 2.6 | 19.7 | LOAEL: Decreased serum estradiol and increased primordial follicles and decreased secondary follicles at PND 21 in female offspring; increased prevalence of irregular estrous cycles SLOAEL: 40% decreased in PND 21 body weight in female offspring; delayed vaginal opening |\n| Liu et al. 2023 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 110 | Mouse F0: 9–12 F F1: 5-7 M, 5–7 F | ~220 days F0: 1 week premating through PND 21 F1: PND 21 to 6 months of age (W) | F0: 0, 0.1, 1.5 F1: 0, 0.2, 1.6 | BC, OW, HP, NX | Immuno Neuro | 1.6 | 0.2 |  | Increased locomotor activity, impaired spatial memory (Y-maze test) in adult F1 mice |\n| Mei et al. 2017 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 111 | Mouse (C57BL/6) 5 M | 8 weeks (W) | 0, 1.5, 4.5, 7.6 | IX | Immuno |  | 1.5 |  | Delayed wound healing |\n| Ohsawa et al. 1988 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 112 | Mouse (BALB/c) 9–10 M | 10 weeks (W) | 0, 0.75, 7.5, 75 | IX | Immuno | 7.5 | 75 |  | Induction of anti-nuclear autoantibodies |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Ohsawa et al. 1988 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 113 | Mouse (ICR) 5–12 M | 10 weeks (W) | 0, 0.75, 7.5, 75 | IX | Immuno |  | 0.75 |  | Induction of anti-nuclear autoantibodies; biphasic immune response (stimulation at low dose, suppression at high dose) |\n| Tan et al. 2023 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 114 | Mouse (C57BL/6) 20 M | 10 weeks (W) | 0, 1.5, 15 | DX | Develop | 1.5 | 15 |  | Impaired growth in both sexes (10% at terminal sacrifice on PND 125); impaired glucose metabolism in adult female offspring |\n| Males mated to untreated females after 10-week exposure |  |  |  |  |  |  |  |  |  |\n| Valois and Webster 1989 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 115 | Mouse (QS) 25 F | 22 weeks (W) | 0, 0.20, 1.4, 11 | CS, BW, WI, HP | Bd wt | 0.2 | 1.4 | 11 | LOAEL: 19% decrease in body weight SLOAEL: 28% decrease in body weight |\n|  |  |  |  |  | Neuro | 0.2 |  | 1.4 | Degenerative and necrotic cellular changes in choroid plexus |\n| Marked decreases in water consumption at 1.4 and 11 mg Cd/kg/day |  |  |  |  |  |  |  |  |  |\n| Wang et al. 2016a |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 116 | Mouse (CD-1) 10 F | 19 days GDs 0–18 (W) | 0, 1.3, 9.3, 26.9 | BW, WI, RX, DX | Bd wt Repro Develop | 26.9 26.9 9.3 |  | 26.9 | 17% decrease in fetal weight; decreased crown-rump length |\n| Xiong et al. 2022a |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 117 | Mouse (C57BL/6) F0: 6–7 M, 17 F F1: 4 M | 32 weeks F0: 2 weeks premating–PNW 3 F1: PNWs 3–27 (W) | 0, 0.1, 1.3 | BW, WI, OW, HP | Bd wt Repro | 1.3 M 0.1 M | 1.3 M |  | Decreased absolute testis weight, germ cell loss |\n| Endpoints reported for F1 males (evaluated at PNW 27) |  |  |  |  |  |  |  |  |  |\n\nEndpoints reported for F1 males (evaluated at PNW 27)\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects | Cadmium chloride |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Zhang et al. 2019a |  |  |  |  |  |  |  |  |  |  |\n| 118 | Mouse (C57BL/6J) F0: 10 M, 10 F F1: 6 M, 6 F | 17-18 weeks F0: 1 month premating to PNW 3 F1: PNWs 3–10 (W) | 0, 0.001089, 0.01003, 0.10012 | DX | Develop | 0.10012 |  |  |  |  |\n| F1 pups examined for developmental landmarks, neurobehavior (PNWs 8-9), endocrine, and reproductive endpoints at PNW 10 |  |  |  |  |  |  |  |  |  |  |\n| Zhang et al. 2019a |  |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 119 | Mouse (C57BL/6J) F0: 10 M, 10 F F1: 6 M, 6 F | 25-26 weeks F0: 3 months premating to PNW 3 F1: PNWs 3–10 (W) | 0, 0.001089, 0.01003, 0.10012 | DX | Develop | 0.10012 |  |  |  |  |\n| F1 pups examined for developmental landmarks, neurobehavior (PNWs 8-9), endocrine, and reproductive endpoints at PNW 10 |  |  |  |  |  |  |  |  |  | Cadmium chloride |\n| Zhang et al. 2019a |  |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 120 | Mouse (C57BL/6J) F0: 10 M, 10 F F1: 6 M, 6 F | 33–34 weeks F0: 5 months premating to PNW 3 F1: PNWs 3–10 (W) | 0, 0.001089, 0.01003, 0.10012 | DX | Develop | 0.01003 | 0.10012 |  | Increased anxiety-like behavior in open field; elevated corticosterone levels |  |\n| F1 pups examined for developmental landmarks, neurobehavior (PNWs 8-9), endocrine, and reproductive endpoints at PNW 10 |  |  |  |  |  |  |  |  |  | Cadmium chloride |\n| Zhang et al. 2024b |  |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 121 | Mouse (ICR) 9–11 M | 21 days PNDs 22–42 (W) | 0, 0.9, 1.5 | DX | Develop | 0.9 | 1.5 |  | Altered socioemotional behaviors during adolescence (immobility in forced swim and tail suspension, decreased social interaction/preference for novelty) |  |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Boscolo and Carmignani 1986 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 122 | Rabbit (New Zealand) 8 M | 9 months (W) | 0, 1.6 | CS, BW, HP, OF | Bd wt Cardio Renal | 1.6 | 1.6 |  | Increased aortic resistance, reduced contractility |\n| Stowe et al. 1972 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 123 | Rabbit (New Zealand) 5 M | 200 days (W) | 0, 14.9 | CS, BW, WI, HE | Bd wt Hemato |  | 14.9 | 14.9 | 20% decrease in body weight Decreased hematocrit and hemoglobin; elevated neutrophils and decreased lymphocytes |\n| Stowe et al. 1972 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 124 | Rabbit (Belgian Giant) 5 M | 200 days (W) | 0, 14.9 | CS, BW, WI, HE | Bd wt Hemato |  | 14.9 | 14.9 | 15% decrease in body weight Decreased hematocrit and hemoglobin; elevated neutrophils and decreased lymphocytes |\n| CHRONIC EXPOSURE |  |  |  |  |  |  |  |  |  |\n| Buchet et al. 1990; Shao et al. 2007; Suwazono et al. 2006; Uno et al. 2005; Wu et al. 2001; Zhang et al. 2016a |  |  |  |  |  |  |  |  | Cadmium |\n| 125 | Human 85–3,454 per dataset | 17 datasets (3 occupational and 8 general population cohorts) | UR | Renal |  |  |  | LMW proteinuria; 95% LCL weighted median of 17 UC10 values = 0.000760 mg Cd/kg/dayd |  |\n| Bernard et al. 1992 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 126 | Rat (Sprague-Dawley) 50 F | up to 18 months (W) | 0, 13 | BI, BC, UR, HP, OF | Renal |  |  | 13 | Loss of glomerular polyanion charge barrier, proteinuria |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Bomhard et al. 1984 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 127 | Rat (Wistar) 12 M, 12 F | 72 weeks (F) | M: 0, 0.7, 3.5, 17.5 F: 0, 0.8, 4.0, 20.0 | BC, UR | Renal | 4 F | 20 F |  | Increase in urinary LDH and GST levels Increase in urinary LDH and GST levels |\n| 127 | Rat (Wistar) 12 M, 12 F | 72 weeks (F) | M: 0, 0.7, 3.5, 17.5 F: 0, 0.8, 4.0, 20.0 | BC, UR | Renal | 3.5 M | 17.5 M |  | Increase in urinary LDH and GST levels Increase in urinary LDH and GST levels |\n| Brzóska 2012; Brzóska and Moniuszko-Jakoniuk 2004a, 2004b |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 128 | Rat (Wistar) 10 F | 24 months (W) | 0, 0.08 | BW, FI, WI, BC, BI, UR, HP, OF | Bd wt Musc/skel | 0.08 |  | 0.08 | Decreases in bone mineral content and density of lumbar spine, altered bone turnover parameters, increases in deformed and fractured vertebral bodies |\n| Decker et al. 1958 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 129 | Rat (Sprague-Dawley) 8–10 M, 8–10 F | 12 months (W) | M: 0, 0.008, 0.036, 0.197, 0.386, 0.696 F: 0, 0.012, 0.062, 0.315, 0.578, 1.052 | LE, BW, FI, WI, HE, HP | Bd wt Gastro | 1.052 F 0.696 M 1.052 F 0.696 M 1.052 F 0.696 M 1.052 F 0.696 M 1.052 F 0.696 M 1.052 F 0.696 M 0.696 M 0.696 M 0.696 M 0.696 M |  |  |  |\n| 129 | Rat (Sprague-Dawley) 8–10 M, 8–10 F | 12 months (W) | M: 0, 0.008, 0.036, 0.197, 0.386, 0.696 F: 0, 0.012, 0.062, 0.315, 0.578, 1.052 | LE, BW, FI, WI, HE, HP | Renal | 1.052 F 0.696 M 0.696 M |  |  |  |\n| 129 | Rat (Sprague-Dawley) 8–10 M, 8–10 F | 12 months (W) | M: 0, 0.008, 0.036, 0.197, 0.386, 0.696 F: 0, 0.012, 0.062, 0.315, 0.578, 1.052 | LE, BW, FI, WI, HE, HP | Endocrinoma | 1.052 F 0.696 M 0.696 M 0.696 M |  |  |  |\n| 129 | Rat (Sprague-Dawley) 8–10 M, 8–10 F | 12 months (W) | M: 0, 0.008, 0.036, 0.197, 0.386, 0.696 F: 0, 0.012, 0.062, 0.315, 0.578, 1.052 | LE, BW, FI, WI, HE, HP | Neuro | 1.052 F 0.696 M 0.696 M |  |  |  |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects | Cadmium chloride |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Fingerle et al. 1982 |  |  |  |  |  |  |  |  |  |  |\n| 130 | Rat (Sprague-Dawley) 10 M, 10 F | M: 92 weeks F: 84 weeks (W) | M: 0, 0.6, 1.51, 3.78 F: 0, 0.8, 1.64, 4.01 | HP, BW, OW, OF, FI, WI, CS, LE | Bd wt Cardio | 4.01 4.01 |  |  |  |  |\n| Mangler et al. 1988 |  |  |  |  |  |  |  |  |  |  |\n| 131 | Rat (Sprague-Dawley) 12 F | 18 months (W) | 0, 2.301 | LE, BW, HP | Bd wt Renal | 2.301 | 2.301 |  | Cloudy swelling of renal tubular cells | Cadmium chloride |\n| Mangler et al. 1988 |  |  |  |  |  |  |  |  |  |  |\n| 132 | Rat (Sprague-Dawley) 12 F | 12 months (W) | 0, 2.337 | LE, BW, HP | Bd wt Renal | 2.337 | 2.337 |  | Cloudy swelling of renal tubular cells | Cadmium chloride |\n| Sato et al. 1978 |  |  |  |  |  |  |  |  |  |  |\n| 133 | Rat (Wistar) 11 NS | 31 months (W) | 0, 2.7 | CS, BW, WI, HP | Bd wt Musc/skel Neuro | 2.7 |  | 2.7 2.7 | Muscle weakness and atrophy Peripheral neuropathy | Cadmium chloride |\n| Waalkes and Rehm 1992 |  |  |  |  |  |  |  |  |  |  |\n| 134 | Rat (Wistar) 24–28 M | 77 weeks (F) | 0, 1.1, 2.3, 5.28, 10.9 | LE, CS, BW, FI, GN, HP | Bd wt Cancer | 2.3 | 5.28 | 2.3 | 10% decrease in body weight CEL: Large granular lymphocyte leukemia | Cadmium chloride |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Hays and Margaretten 1985 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 135 | Mouse (CBA/H) 5–13 M; 5 F | 12 months (W) | 0, 40 | BW, FI, WI, HE, BC, HP | Bd wt Hematoc | 40 | 40 | 21% decreased terminal body weight Decreased hematocrit and neutrophils; bone marrow hypoplasia |  |\n|  |  |  |  |  | Renal | 40 |  |  |  |\n\n<sup>a</sup>The number corresponds to entries in Figure 2-3; differences in levels of health effects between male and females are not indicated in Figure 2-3.  Where such \ndifferences exist, only the levels of effect for the most sensitive sex are presented.\n\n<sup>b</sup>Doses are expressed as mg Cd/kg/day.  If doses were reported by study authors in terms of the administered compound (e.g., cadmium chloride [CdCl2]), they were \nconverted to the equivalent dose in terms of the metal (i.e., cadmium [Cd])) for easy comparison across studies. Conversion was based on the ratio of the molecular \nweights using the following equation: Dose in terms of administered compound × (molecular weight Cd/molecular weight administered compound).\n\n<sup>c</sup>Used to derive an acute-duration oral MRL of 0.002 mg Cd/kg/day (2 μg Cd/kg/day).  The LOAEL of 2 mg Cd/kg/day divided by an uncertainty factor of 1,000 (10 for use \nof a LOAEL, 10 for animal to human, and 10 for human variability).\n\n<sup>d</sup>Used to derive a chronic-duration oral MRL of 0.0003 mg Cd/kg/day (0.3 μg Cd/kg/day).  The point of departure (POD) is based on the 95% lower confidence limit (LCL) \non the weighted median of the UC10 values from 17 datasets from 11 human studies; the weighted median and 95% LCL were 2.04 and 1.57 μg Cd/g Cr, respectively.  \nThese values were converted into oral dose equivalents of 9.88x10<sup>-4</sup> and 7.60x10<sup>-4</sup> mg Cd/kg/day, respectively, using PBPK modeling. The POD of 7.60x10<sup>-4</sup> mg \nCd/kg/day was divided by an uncertainty factor of 3 for human variability and a modifying factor of 3 for database deficiencies. See Appendix A for more detailed \ninformation regarding the MRL.\n\n## Principal studies for the MRLs\n\nACTH = adrenocorticotrophic hormone; ALT = alanine aminotransferase; β2M = β2-microglobulin; BC = serum (blood) chemistry; Bd wt or BW = body weight; \nBI = biochemical changes; BUN = blood urea nitrogen; Cardio = cardiovascular; Cd = cadmium; CEL = cancer effect level; Cr = creatinine; CS = clinical signs; Develop \n= developmental; DX = developmental toxicity; Endocr = endocrine; (F) = feed (dietary); F = female(s); FI = food intake; (G) = gavage; (GO) = gavage in oil; \n(GW) = gavage in water; Gastro = gastrointestinal; GD = gestation day; GN = gross necropsy; GnRH = gonadotropin releasing hormone; GST = glutathione \nS-transferase; HDL = high-density lipoprotein; HE = hematology; Hemato = hematological; HP = histopathology; IL-6 = interleukin-6; Immuno = immunological; \nIX = immune function; LD50 = lethal dose, 50% kill; LDH = lactate dehydrogenase; LDL = low-density lipoprotein; LE = lethality; LH = luteinizing hormone; LMW = low \nmolecular weight; LOAEL = lowest-observed-adverse-effect level; M = male(s); MCHC = mean corpuscular hemoglobin concentration; MCV = mean corpuscular volume; \nMRL = Minimal Risk Level; Musc/skel = musculoskeletal; NAFLD = non-alcoholic fatty liver disease; Neuro = neurological; NK = natural killer; NOAEL = no-observedadverse-effect level; NS = not specified; NX = neurological function; OF = organ function; OW = organ weight; PBPK = physiologically based pharmacokinetic; \nPND = postnatal day; PNW = postnatal week; RBC = red blood cell; Repro = reproductive; Resp = respiratory; RX = reproductive function; SLOAEL = serious lowestobserved-adverse-effect level; T3 = triiodothyronine; TNF = tumor necrosis factor; TSH = thyroid-stimulating hormone; UC10 = urinary cadmium level associated with \n10% extra risk; UR = urinalysis; (W) = drinking water; WBC = white blood cell; WI = water intake\n\n---\n\n**Figure 2-3.  Levels of Significant Exposure to Cadmium – Oral**\nAcute (≤14 days)\n\n**Figure 2-3. Levels of Significant Exposure to Cadmium – Oral Acute (≤14 days) - Death**\n\n| Category | Animal - LD50/LC50 (mg Cd/kg/day) | Animal - NOAEL (mg Cd/kg/day) | Animal - LOAEL (mg Cd/kg/day) | Animal - SLOAEL (mg Cd/kg/day) |\n| --- | --- | --- | --- | --- |\n| 3R |  |  |  | 100 |\n| 4R |  |  |  | 70 |\n| 6R |  |  |  | 30 |\n| 8R | 30 |  |  |  |\n| 9R | 140 |  |  |  |\n| 10R | 130 |  |  |  |\n| 11R | 100 |  |  |  |\n| 12R | 70 |  |  |  |\n| 15R | 230 |  |  |  |\n| 16R |  |  |  | 45 |\n| 17R |  |  |  | 65 |\n| 21R | 110 |  |  |  |\n| 22R | 340 |  |  |  |\n| 26M |  |  |  | 85 |\n| 28M | 95 |  |  |  |\n\n---\n\n**Figure 2-3.  Levels of Significant Exposure to Cadmium – Oral**\nAcute (≤14 days)\n\n**Figure 2-3. Levels of Significant Exposure to Cadmium – Oral Acute (≤14 days) - Body Weight**\n\n| Category | Animal - LD50/LC50 (mg Cd/kg/day) | Animal - LOAEL (mg Cd/kg/day) | Animal - NOAEL (mg Cd/kg/day) | Animal - SLOAEL (mg Cd/kg/day) |\n| --- | --- | --- | --- | --- |\n| 2R |  |  |  | 12 |\n| 2R |  |  | 2.0 |  |\n| 4R |  |  | 150 |  |\n| 5R |  | 8.0 |  |  |\n| 5R |  |  | 1.2 |  |\n| 5R |  |  |  | 11 |\n| 6R |  |  |  | 30 |\n| 6R |  |  |  | 15 |\n| 6R |  |  | 14 |  |\n| 14R |  |  |  | 150 |\n| 14R |  |  | 100 |  |\n| 17R |  |  |  | 6.0 |\n| 17R |  |  | 1.8 |  |\n| 18R |  |  |  | 12 |\n| 18R |  |  | 3.3 |  |\n| 19R |  |  |  | 13 |\n| 20R |  |  |  | 18 |\n| 20R |  |  | 6.0 |  |\n| 23R |  |  | 0.20 |  |\n| 24R |  |  | 0.25 |  |\n| 25R |  |  | 4.0 |  |\n\n---\n\n**Figure 2-3.  Levels of Significant Exposure to Cadmium – Oral**\nAcute (≤14 days)\n\n| Category | Animal - NOAEL (mg Cd/kg/day) | Animal - LOAEL (mg Cd/kg/day) | Animal - SLOAEL (mg Cd/kg/day) |\n| --- | --- | --- | --- |\n| Respiratory | 14R: 160 |  |  |\n| Cardiovascular | 14R: 160 |  |  |\n| Gastrointestinal | 14R: 160 |  |  |\n|  |  | 17R: 65 |  |\n|  |  | 17R: 19 |  |\n|  |  | 26M: 30 |  |\n|  |  | 26M: 16 |  |\n|  |  | 26M: 85 |  |\n| Hematological | 1R: 15 |  |  |\n|  |  | 4R: 150 |  |\n|  |  | 5R: 14 |  |\n|  |  | 6R: 16 |  |\n|  |  | 14R: 160 |  |\n|  |  | 19R: 16 |  |\n| Hepatic | 4R: 150 |  |  |\n|  |  | 5R: 13 |  |\n|  |  | 6R: 16 |  |\n|  |  | 6R: 33 |  |\n|  |  | 14R: 160 |  |\n|  |  | 26M: 33 |  |\n|  |  | 26M: 16 |  |\n\n---\n\n**Figure 2-3.  Levels of Significant Exposure to Cadmium – Oral**\nAcute (≤14 days)\n\n**Figure 2-3. Levels of Significant Exposure to Cadmium – Oral Acute (≤14 days)**\n\n| Category | Animal - LD50/LC50 (mg Cd/kg/day) | Animal - LOAEL (mg Cd/kg/day) | Animal - NOAEL (mg Cd/kg/day) | Animal - SLOAEL (mg Cd/kg/day) | MRL for effect other than cancer (mg Cd/kg/day) |\n| --- | --- | --- | --- | --- | --- |\n| Renal |  |  | 160 |  |  |\n|  |  |  | 13 |  |  |\n|  |  |  | 65 |  |  |\n|  |  |  | 30 |  |  |\n|  |  |  | 160 |  |  |\n|  |  |  | 2.0 |  |  |\n|  |  |  | 90 |  |  |\n|  |  |  | 60 |  |  |\n|  |  |  | 1.8 |  |  |\n| Dermal |  |  | 6.5 |  |  |\n|  |  |  | 2.0 |  |  |\n| Endocrine |  |  | 160 |  |  |\n|  |  |  | 55 |  |  |\n| Immunological |  |  | 0.26 |  |  |\n|  |  |  | 0.030 |  |  |\n| Neurolgical |  |  | 50 |  |  |\n|  |  |  | 24 |  |  |\n\n---\n\n**Figure 2-3.  Levels of Significant Exposure to Cadmium – Oral**\nAcute (≤14 days)\n\n**Figure 2-3. Levels of Significant Exposure to Cadmium – Oral Acute (≤14 days)**\n\n| Category | Reproductive Animal - LD50/LC50 (mg Cd/kg/day) | Reproductive Animal - LOAEL (mg Cd/kg/day) | Reproductive Animal - NOAEL (mg Cd/kg/day) | Reproductive Animal - SLOAEL (mg Cd/kg/day) | Developmental Animal - LD50/LC50 (mg Cd/kg/day) | Developmental Animal - LOAEL (mg Cd/kg/day) | Developmental Animal - NOAEL (mg Cd/kg/day) | Developmental Animal - SLOAEL (mg Cd/kg/day) |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| 3R |  |  | 55 | 100 |  |  |  |  |\n| 5R |  |  | 13 |  |  |  |  |  |\n| 6R |  | 30 |  | 70 |  |  |  |  |\n| 7R |  |  | 26 |  |  |  |  |  |\n| 13R |  |  | 55 | 100 |  |  |  |  |\n| 26M |  | 34 |  | 65 |  |  |  |  |\n| 2R |  |  |  |  |  | 1.7 |  | 40 |\n| 17R |  |  |  |  ', 'pages': None, 'truncated': True, 'extraction': 'firecrawl-public-document-markdown', 'request_id': '6dbf2162-3841-4eb2-a566-2e2a25ac24a4', 'source_url': 'https://downloads.regulations.gov/ATSDR-2026-0133-0002/content.pdf', 'observed_at': '2026-10-04T00:39:30.279437+00:00', 'content_hash': '48479c728d0b8f13ff13edfd55d511d6e1fa5337c3b6b487129b37d5698c38f2'}, 'title': 'pdf', 'check_failed': False}]}

{'attachments': [{'url': 'https://downloads.regulations.gov/ATSDR-2026-0133-0002/attachment_1.pdf', 'body': {'text': '## Toxicological Profile for Cadmium\nDraft for Public Comment\nOctober 2026\n\nATSDR\nU.S. Department of Health and Human Services\nAgency for Toxic Substances and Disease Registry\n\nCS274127-A\n\n---\n\n## DISCLAIMER\n\nUse of trade names is for identification only and does not imply endorsement by the Agency for Toxic \nSubstances and Disease Registry, the Public Health Service, or the U.S. Department of Health and Human \nServices.\n\nThis information is distributed solely for the purpose of pre-dissemination for public comment under \napplicable information quality guidelines.  It has not been formally disseminated by the Agency for Toxic \nSubstances and Disease Registry.  It does not represent and should not be construed to represent any \nagency determination or policy.\n\n---\n\n## FOREWORD\n\nThis toxicological profile is prepared in accordance with guidelines developed by the Agency for Toxic \nSubstances and Disease Registry (ATSDR) and the Environmental Protection Agency (EPA).  The \noriginal guidelines were published in the *Federal Register* on April 17, 1987.  Each profile will be revised \nand republished as necessary.\n\nThe ATSDR toxicological profile succinctly characterizes the toxicologic and adverse health effects \ninformation for these toxic substances described therein.  Each peer-reviewed profile identifies and \nreviews the key literature that describes a substance\'s toxicologic properties.  Other pertinent literature is \nalso presented but is described in less detail than the key studies.  The profile is not intended to be an \nexhaustive document; however, more comprehensive sources of specialty information are referenced.\n\nThe focus of the profiles is on health and toxicologic information; therefore, each toxicological profile \nbegins with a relevance to public health discussion which would allow a public health professional to \nmake a real-time determination of whether the presence of a particular substance in the environment \nposes a potential threat to human health.  The adequacy of information to determine a substance\'s health \neffects is described in a health effects summary.  Data needs that are of significance to the protection of \npublic health are identified by ATSDR.\n\nEach profile includes the following:\n\n(A) The examination, summary, and interpretation of available toxicologic information and \nepidemiologic evaluations on a toxic substance to ascertain the levels of significant \nhuman exposure for the substance due to associated acute-, intermediate-, and chronicduration exposures;\n\n(B) A determination of whether adequate information on the health effects of each substance \nis available or in the process of development to determine the levels of exposure that \npresent a significant risk to human health due to acute-, intermediate-, and chronicduration exposures; and\n\n(C) Where appropriate, identification of toxicologic testing needed to identify the types or \nlevels of exposure that may present significant risk of adverse health effects in humans.\n\nThe principal audiences for the toxicological profiles are health professionals at the Federal, State, and \nlocal levels; interested private sector organizations and groups; and members of the public.  ATSDR plans \nto revise these documents in response to public comments and as additional data become available.  \nTherefore, we encourage comments that will make the toxicological profile series of the greatest use.\n\nElectronic comments may be submitted via: www.regulations.gov. Follow the on-line instructions for \nsubmitting comments.\n\nWritten comments may also be sent to:\n\nWritten comments may also be sent to:  Agency for Toxic Substances and Disease Registry\n\nOffice of Innovation and Analytics\n\nToxicology Section\n\n1600 Clifton Road, N.E.\n\nMail Stop S106-5\n\nAtlanta, Georgia 30329-4027\n\n---\n\nThe toxicological profiles are developed under the Comprehensive Environmental Response, \nCompensation, and Liability Act of 1980, as amended (CERCLA or Superfund).  CERCLA \nSection 104(i)(1) directs the Administrator of ATSDR to “…effectuate and implement the health-related \nauthorities” of the statute.  This includes the preparation of toxicological profiles for hazardous \nsubstances most commonly found at facilities on the CERCLA National Priorities List (NPL) and that \npose the most significant potential threat to human health, as determined by ATSDR and the EPA.  \nSection 104(i)(3) of CERCLA, as amended, directs the Administrator of ATSDR to prepare a \ntoxicological profile for each substance on the list.  In addition, ATSDR has the authority to prepare \ntoxicological profiles for substances not found at sites on the NPL, in an effort to “…establish and \nmaintain inventory of literature, research, and studies on the health effects of toxic substances” under \nCERCLA Section 104(i)(1)(B), to respond to requests for consultation under Section 104(i)(4), and as \notherwise necessary to support the site-specific response actions conducted by ATSDR.\n\nThis profile reflects ATSDR’s assessment of all relevant toxicologic testing and information that has been \npeer-reviewed.  Staffs of the Centers for Disease Control and Prevention and other Federal scientists have \nalso reviewed the profile.  In addition, this profile has been peer-reviewed by a nongovernmental panel \nand is being made available for public review.  Final responsibility for the contents and views expressed \nin this toxicological profile resides with ATSDR.\n\nChristopher M. Reh, Ph.D. \nAssociate Director,\nAgency for Toxic Substances and Disease Registry \nCenters for Disease Control and Prevention\n\n---\n\n**VERSION HISTORY**\n\n| Date | Description |\n| --- | --- |\n| October 2026 | Draft for public comment toxicological profile released |\n| September 2012 | Final toxicological profile released |\n| July 1999 | Final toxicological profile released |\n| April 1993 | Final toxicological profile released |\n| March 1989 | Final toxicological profile released |\n\n---\n\n# CONTRIBUTORS & REVIEWERS\n\n# CHEMICAL MANAGER TEAM\n\nBrittany Szafran, D.V.M, Ph.D., D.A.B.T. (lead)\nCustodio Muianga, M.P.H., Ph.D., C.H.M.M.\nMohammad Shoeb, Ph.D.\nBreanna Alman, M.P.H.\nFranco Scinicariello, M.D., M.P.H.\n\nKimberly Zaccaria, Ph.D., D.A.B.T.\nFrances Belmonte, Ph.D., D.A.B.T.\nHeather Carlson-Lynch, M.S., D.A.B.T.\nMario Citra, Ph.D.\nGary L. Diamond, Ph.D.\nZach Guerrette, Ph.D., D.A.B.T\nDeborah M. Herber, Ph.D.\nClaire Heit, Ph.D.\nLisa Ingerman, Ph.D., D.A.B.T.\nConnor McGuire, Ph.D.\nJennifer Rhoades, B.S.\n\nATSDR, Office of Innovation and Analytics, \nToxicology Section, Atlanta, GA\n\nSRC, Inc., North Syracuse, NY\n\n## REVIEWERS\n\n## Interagency Minimal Risk Level Workgroup:\n\nIncludes ATSDR; National Center for Environmental Health (NCEH); U.S. Environmental Protection \nAgency (EPA); National Toxicology Program (NTP).\n\n## Additional reviews for science and/or policy:\n\nATSDR, Office of Community Health Hazard Assessment; ATSDR, Office of Capacity Development \nand Applied Prevention Science; ATSDR, Office of Science; NCEH, Division of Laboratory Sciences; \nNCEH, Division of Environmental Health Science and Practice; National Institute for Occupational \nSafety and Health (NIOSH); EPA, Office of Research and Development; EPA, Office of Water.\n\n## PEER REVIEWERS\n\n1. Kristen Upson, Ph.D., M.P.H.; Associate Professor of Epidemiology and Biostatistics; Michigan \nState University; Department of Epidemiology and Biostatistics; 909 Wilson Road Room B601; \nEast Lansing, MI\n\n2. Zahir Shaikh, Ph.D.; Professor Emeritus and Former Founding Director of RI-INBRE; The \nUniversity of Rhode Island, College of Pharmacy; Kingston, RI\n\n3. Curtis D. Klaassen, M.S., Ph.D., FATS, FAASLD, FASPET; Director of the Mid-America \nToxicology Course; Previously University Distinguished Professor and Chair at The University \nof Kansas School of Medicine; Kansas City, KS (retired)\n\nThese experts collectively have knowledge of toxicology, chemistry, and/or health effects.  All reviewers \nwere selected in conformity with Section 104(I)(13) of the Comprehensive Environmental Response, \nCompensation, and Liability Act, as amended.\n\n---\n\nATSDR scientists review peer reviewers’ comments and determine whether changes will be made to the \nprofile based on comments.  The peer reviewers’ comments and responses to these comments are part of \nthe administrative record for this compound.\n\nThe listing of peer reviewers should not be understood to imply their approval of the profile\'s final \ncontent.  The responsibility for the content of this profile lies with ATSDR.\n\n---\n\n## CONTENTS\n\nDISCLAIMER .............................................................................................................................................. ii\nFOREWORD ............................................................................................................................................... iii\nVERSION HISTORY ................................................................................................................................... v\nCONTRIBUTORS & REVIEWERS ........................................................................................................... vi\nCONTENTS ............................................................................................................................................... viii\nLIST OF FIGURES ...................................................................................................................................... x\nLIST OF TABLES ....................................................................................................................................... xi\nCHAPTER 1. RELEVANCE TO PUBLIC HEALTH ................................................................................. 1\n1.1 OVERVIEW AND U.S. EXPOSURES ......................................................................................... 1\n1.2 SUMMARY OF HEALTH EFFECTS........................................................................................... 2\n1.3 MINIMAL RISK LEVELS (MRLs) .............................................................................................. 8\nCHAPTER 2. HEALTH EFFECTS ............................................................................................................ 12\n2.1 INTRODUCTION ........................................................................................................................ 12\n2.2 DEATH ........................................................................................................................................ 92\n2.3 BODY WEIGHT .......................................................................................................................... 99\n2.4 RESPIRATORY ........................................................................................................................ 104\n2.5 CARDIOVASCULAR ............................................................................................................... 113\n2.6 GASTROINTESTINAL ............................................................................................................. 124\n2.7 HEMATOLOGICAL ................................................................................................................. 125\n2.8 MUSCULOSKELETAL ............................................................................................................ 131\n2.9 HEPATIC ................................................................................................................................... 143\n2.10 RENAL ...................................................................................................................................... 151\n2.11 DERMAL ................................................................................................................................... 171\n2.12 OCULAR ................................................................................................................................... 172\n2.13 ENDOCRINE ............................................................................................................................. 172\n2.14 IMMUNOLOGICAL ................................................................................................................. 182\n2.15 NEUROLOGICAL..................................................................................................................... 189\n2.16 REPRODUCTIVE ..................................................................................................................... 196\n2.17 DEVELOPMENTAL ................................................................................................................. 213\n2.18 OTHER NONCANCER ............................................................................................................. 239\n2.19 CANCER .................................................................................................................................... 241\n2.20 GENOTOXICITY ...................................................................................................................... 256\n2.21 MECHANISMS OF ACTION ................................................................................................... 266\nCHAPTER 3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, \nCHEMICAL INTERACTIONS ......................................................................................... 269\n3.1 TOXICOKINETICS................................................................................................................... 269\n3.1.1 Absorption ........................................................................................................................... 269\n3.1.2 Distribution ......................................................................................................................... 274\n3.1.3 Metabolism .......................................................................................................................... 277\n3.1.4 Excretion ............................................................................................................................. 278\n3.1.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models ........... 278\n3.1.6 Animal-to-Human Extrapolations ....................................................................................... 285\n3.2 CHILDREN AND OTHER POPULATIONS THAT ARE UNUSUALLY \nSUSCEPTIBLE .......................................................................................................................... 286\n\n---\n\n3.3 BIOMARKERS OF EXPOSURE AND EFFECT ..................................................................... 290\n3.3.1 Biomarkers of Exposure ...................................................................................................... 291\n3.3.2 Biomarkers of Effect ........................................................................................................... 294\n3.4 INTERACTIONS WITH OTHER CHEMICALS ..................................................................... 297\nCHAPTER 4. CHEMICAL AND PHYSICAL INFORMATION ........................................................... 303\n4.1 CHEMICAL IDENTITY ........................................................................................................... 303\n4.2 PHYSICAL AND CHEMICAL PROPERTIES ........................................................................ 304\nCHAPTER 5. POTENTIAL FOR HUMAN EXPOSURE ....................................................................... 307\n5.1 OVERVIEW .............................................................................................................................. 307\n5.2 PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL ................................................ 310\n5.2.1 Production ........................................................................................................................... 310\n5.2.2 Import/Export ...................................................................................................................... 313\n5.2.3 Use ...................................................................................................................................... 314\n5.2.4 Disposal ............................................................................................................................... 314\n5.3 RELEASES TO THE ENVIRONMENT ................................................................................... 315\n5.3.1 Air ....................................................................................................................................... 315\n5.3.2 Water ................................................................................................................................... 319\n5.3.3 Soil ...................................................................................................................................... 320\n5.4 ENVIRONMENTAL FATE ...................................................................................................... 321\n5.4.1 Transport and Partitioning ................................................................................................... 321\n5.4.2 Transformation and Degradation ........................................................................................ 325\n5.5 LEVELS IN THE ENVIRONMENT ......................................................................................... 326\n5.5.1 Air ....................................................................................................................................... 327\n5.5.2 Water ................................................................................................................................... 328\n5.5.3 Sediment and Soil ............................................................................................................... 330\n5.5.4 Other Media ........................................................................................................................ 332\n5.6 GENERAL POPULATION EXPOSURE.................................................................................. 335\n5.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES .............................................. 362\nCHAPTER 6. ADEQUACY OF THE DATABASE ................................................................................ 363\n6.1 EXISTING INFORMATION ON HEALTH EFFECTS ........................................................... 363\n6.2 IDENTIFICATION OF DATA NEEDS .................................................................................... 365\n6.3 ONGOING STUDIES ................................................................................................................ 372\nCHAPTER 7. REGULATIONS AND GUIDELINES ............................................................................. 376\nCHAPTER 8. REFERENCES .................................................................................................................. 380\nAPPENDICES\nAPPENDIX A.  ATSDR MINIMAL RISK LEVEL WORKSHEETS .................................................... A-1 \nAPPENDIX B.  LITERATURE SEARCH FRAMEWORK FOR CADMIUM ...................................... B-1 \nAPPENDIX C.  FRAMEWORK FOR ATSDR’S SYSTEMATIC REVIEW OF HEALTH EFFECTS \nDATA FOR CADMIUM ................................................................................................ C-1 \nAPPENDIX D.  USER’S GUIDE ............................................................................................................. D-1 \nAPPENDIX E.  QUICK REFERENCE FOR HEALTH CARE PROVIDERS ....................................... E-1 \nAPPENDIX F.  GLOSSARY .................................................................................................................... F-1 \nAPPENDIX G.  ACRONYMS, ABBREVIATIONS, AND SYMBOLS................................................. G-1\n\n---\n\n## LIST OF FIGURES\n\n1-1.  Health Effects Found in Animals Following Inhalation Exposure to Cadmium .................................. 4\n1-2.  Health Effects Found in Animals Following Oral Exposure to Cadmium ........................................... 5\n1-3.  Summary of Sensitive Targets of Cadmium – Inhalation ..................................................................... 9\n1-4.  Summary of Sensitive Targets of Cadmium – Oral ............................................................................ 10\n2-1.  Overview of the Number of Studies Examining Cadmium Health Effects ........................................ 17\n2-2.  Levels of Significant Exposure to Cadmium – Inhalation .................................................................. 33\n2-3.  Levels of Significant Exposure to Cadmium – Oral ........................................................................... 72\n3-1.  Structure of Kjellström-Nordberg Cadmium Biokinetic Model ....................................................... 280\n3-2.  Structure of Diamond and Klotzbach Cadmium Biokinetics Model ................................................ 283\n5-1.  Number of NPL Sites with Cadmium Contamination ...................................................................... 307\n6-1.  Summary of Existing Health Effects Studies on Cadmium by Route and Endpoint ........................ 364\n\n---\n\n## LIST OF TABLES\n\n1-1.  Minimal Risk Levels (MRLs) for Cadmium ...................................................................................... 11\n2-1.  Levels of Significant Exposure to Cadmium – Inhalation .................................................................. 18\n2-2.  Levels of Significant Exposure to Cadmium – Oral ........................................................................... 41\n2-3.  Levels of Significant Exposure to Cadmium – Dermal ...................................................................... 90\n2-4.  Results of Meta-Analyses Evaluating Exposure to Cadmium and Mortality Endpoints .................... 93\n2-5.  Studies Included in Meta-Analyses Evaluating Exposure to Cadmium and Mortality \nEndpoints ............................................................................................................................................ 94\n2-6.  Results of General Population Studies Evaluating Urinary Cadmium Levels and All-Cause \nMortality ............................................................................................................................................. 94\n2-7.  Results of Meta-Analysis Evaluating Exposure to Cadmium and Respiratory Endpoints ............... 106\n2-8.  Results of Epidemiological Studies Evaluating Urinary Cadmium Levels and Respiratory \nEffects ............................................................................................................................................... 108\n2-9.  Results of Meta-Analyses Evaluating Exposure to Cadmium and Cardiovascular Endpoints ......... 113\n2-10.  Studies Included in Meta-Analyses Evaluating Exposure to Cadmium and Cardiovascular \nEndpoints ........................................................................................................................................ 116\n2-11.  Results of General Population Studies Evaluating Urinary Cadmium Levels and Blood \nPressure or Hypertension ................................................................................................................ 118\n2-12.  Results of General Population Studies Evaluating Urinary Cadmium Levels and \nCardiovascular Disease-Related Effects ......................................................................................... 122\n2-13.  Results of General Population Epidemiological Studies Evaluating Urinary Cadmium \nLevels and Hematological Effects .................................................................................................. 126\n2-14.  Results of Meta-Analyses Evaluating Exposure to Cadmium and Skeletal Endpoints .................. 132\n2-15.  Studies Included in Meta Analyses Evaluating Exposure to Cadmium and Skeletal \nEndpoints ........................................................................................................................................ 133\n2-16.  Results of General Population Epidemiological Studies Evaluating Urinary Cadmium \nLevels and Musculoskeletal Effects ............................................................................................... 136\n2-17.  Results of Meta-Analyses Evaluating Exposure to Cadmium and Serum Lipids .......................... 143\n2-18.  Studies Included in Meta-Analyses Evaluating Exposure to Cadmium and Serum Lipids ............ 144\n2-19.  Results of General Population Studies Evaluating Urinary Cadmium Levels and Blood \nLipid Levels .................................................................................................................................... 145\n\n---\n\n2-20.  Results of General Population Studies Evaluating Exposure to Urinary Cadmium Levels \nand Hepatic Disease and Clinical Chemistry ................................................................................. 147\n2-21.  Results of Occupational Studies Evaluating Urine Cadmium Levels and Renal Outcomes .......... 154\n2-22.  Results of Meta-Analyses Evaluating Exposure to Cadmium and Renal Endpoints ...................... 157\n2-23.  Studies Included in Meta-Analyses Evaluating Exposure to Cadmium and Renal Endpoints ....... 158\n2-24.  Results of Epidemiological Studies of General Populations Evaluating Urine Cadmium \nLevels and Renal Effects ................................................................................................................ 161\n2-25.  Results of Meta-Analysis Evaluating Exposure to Cadmium and Thyroid Endpoints ................... 173\n2-26.  Results of General Population Studies Evaluating Urinary Cadmium Levels and Thyroid \nEffects ............................................................................................................................................. 174\n2-27.  Results of Meta-Analyses Evaluating Exposure to Cadmium and Diabetes Endpoints ................. 175\n2-28.  Studies Included in Meta Analyses Evaluating Exposure to Cadmium and Diabetes \nEndpoints ........................................................................................................................................ 177\n2-29.  Results of Epidemiological Studies Evaluating Exposure to Cadmium and Diabetes-\nRelated Effects ................................................................................................................................ 179\n2-30.  Results of Epidemiological Studies Evaluating Urinary Cadmium Levels and \nImmunological Effects ................................................................................................................... 182\n2-31.  Results of Meta-Analyses Evaluating Exposure to Cadmium and Neurological Endpoints .......... 190\n2-32.  Studies Included in Meta-Analyses Evaluating Exposure to Cadmium and Neurological \nEndpoints ........................................................................................................................................ 191\n2-33.  Results of General Population Studies Evaluating Exposure to Urinary Cadmium and \nNeurological Effects ....................................................................................................................... 192\n2-34.  Results of Meta-Analyses Evaluating Exposure to Cadmium and Male Reproductive \nEndpoints ........................................................................................................................................ 196\n2-35.  Studies Included in Meta-Analyses Evaluating Exposure to Cadmium and Male \nReproductive Endpoints ................................................................................................................. 197\n2-36.  Results of General Population Studies Evaluating Urinary Cadmium Levels and \nReproductive Effects in Men .......................................................................................................... 199\n2-37.  Results of Meta-Analyses Evaluating Exposure to Cadmium and Female Reproductive \nEndpoints ........................................................................................................................................ 202\n2-38.  Studies Included in Meta-Analyses Evaluating Exposure to Cadmium and Female \nReproductive Endpoints ................................................................................................................. 203\n2-39.  Results of General Population Studies Evaluating Urinary Cadmium Levels and \nReproductive Effects in Women..................................................................................................... 204\n\n---\n\n2-40.  Results of Meta-Analyses Evaluating Exposure to Cadmium and Neurodevelopmental \nEndpoints ........................................................................................................................................ 213\n2-41.  Studies Included in Meta-Analyses Evaluating Exposure to Cadmium and \nNeurodevelopmental Endpoints ..................................................................................................... 214\n2-42.  Results of General Population Studies Evaluating Exposure to Cadmium and \nNeurodevelopmental Effects .......................................................................................................... 217\n2-43.  Results of General Population Studies Evaluating Urinary Cadmium Levels and Growth \nand Metabolism During Infancy, Childhood, and Adolescence ..................................................... 228\n2-44.  Results of General Population Studies Evaluating Urinary Cadmium Levels and \nReproductive Developmental Effects ............................................................................................. 233\n2-45.  Results of Meta-Analyses Evaluating Exposure to Cadmium and Metabolic Syndrome \nEndpoints ........................................................................................................................................ 240\n2-46.  Studies Included in Meta Analyses Evaluating Exposure to Cadmium and Metabolic \nSyndrome Endpoints ...................................................................................................................... 240\n2-47.  Results of Meta-Analyses Evaluating Exposure to Cadmium and Cancer ..................................... 242\n2-48.  Studies Included in Meta-Analyses Evaluating Exposure to Cadmium and Cancer ...................... 245\n2-49.  Results of Epidemiological Studies Evaluating Exposure to Cadmium and Cancer ...................... 250\n2-50.  Genotoxicity of Cadmium *In Vivo* .................................................................................................. 257\n2-51.  Genotoxicity of Cadmium *In Vitro* ................................................................................................. 259\n4-1.  Chemical Identity of Cadmium and Compounds ............................................................................. 303\n4-2.  Physical and Chemical Properties of Cadmium and Compounds .................................................... 304\n5-1.  Facilities that Produce, Process, or Use Cadmium ........................................................................... 310\n5-2.  Facilities that Produce, Process, or Use Cadmium Compounds ....................................................... 311\n5-3.  Releases to the Environment from Facilities that Produce, Process, or Use Cadmium .................... 316\n5-4.  Releases to the Environment from Facilities that Produce, Process, or Use Cadmium \nCompounds ....................................................................................................................................... 317\n5-5.  Lowest Limit of Detection Based on Standards ............................................................................... 326\n5-6.  Summary of Environmental Levels of Cadmium ............................................................................. 327\n5-7.  Range of Arithmetic Means for Cadmium from the AQS ................................................................ 327\n5-8.  Total Cadmium Levels in Groundwater and Surface Water in U.S. Samples Collected in \n2022–2024 ........................................................................................................................................ 329\n5-9.  Total Cadmium Levels in Ambient Sediment Collected in 2022–2024 ........................................... 331\n\n---\n\n5-10.  Mean Concentrations of Cadmium for FDA’s Total Diet Study Market Baskets 2006-1\nthrough 2008-4 ............................................................................................................................... 333\n5-11.  Geometric Mean and Selected Percentile Blood Concentrations (μg/L) of Cadmium in the\nU.S. Population, 1999–2018 ........................................................................................................... 336\n5-12.  Geometric Mean and Selected Percentile Urine Concentrations (Creatinine Corrected)\n(μg/g Creatinine) of Cadmium in the U.S. Population, 1999––2018 ............................................. 343\n5-13.  Geometric Mean and Selected Percentile Urine Concentrations (μg/L) of Cadmium in the\nU.S. Population, 1999–2018 ........................................................................................................... 350\n5-14.  Blood Cadmium Concentrations, Geometric Means, Adjusted Proportional Change in\nMeans, and 95<sup>th</sup> Percentiles in New York City Adults in Population \nSubgroups....................................................................................................................................... 357\n5-15.  Occupations with Potential Exposure to Cadmium and Cadmium Compounds ............................ 361\n6-1.  Ongoing Studies on Cadmium .......................................................................................................... 372\n7-1.  Regulations and Guidelines Applicable to Cadmium ....................................................................... 376\n\n---\n\n## CHAPTER 1. RELEVANCE TO PUBLIC HEALTH\n\n### 1.1 OVERVIEW AND U.S. EXPOSURES\n\nCadmium (Cd) occurs in the earth’s crust at a concentration of roughly 0.1–0.5 ppm and is commonly \nassociated with zinc, lead, and copper ores.  It is also a natural constituent of ocean water with average \nlevels between <5 and 110 ng/L, with higher levels reported near coastal areas and in marine phosphates \nand phosphorites (Morrow 2010).  The cadmium concentration of natural surface water and groundwater \nis usually <1 μg/L (Elinder 1985a, 1992).  Surface soil concentrations will depend on several factors such \nas its mobility, natural geochemistry, and magnitude of contamination from sources such as fertilizers and \natmospheric deposition.  Natural emissions of cadmium to the environment can result from volcanic \neruptions, forest fires, generation of sea salt aerosols, or other natural phenomena (EPA 1985; Morrow \n2010; Shevchenko et al. 2003).\n\n$$\n<1\\;\\mu g/L\n$$\n\nIn the environment, cadmium exists in only one oxidation state (Cd<sup>+2</sup>) and does not undergo oxidationreduction reactions.  In surface water and groundwater, cadmium can exist as the hydrated ion or as ionic \ncomplexes with other inorganic or organic substances.  Soluble forms of cadmium can migrate in water.  \nInsoluble forms of cadmium will settle and adsorb to sediments.  Cadmium’s fate in soil depends on \nseveral factors such as pH of the soil and availability of organic matter.  Generally, cadmium will bind \nstrongly to organic matter and this will, for the most part, immobilize it (Autier and White 2004).  \nHowever, cadmium’s behavior in soil will vary depending on the environmental conditions.  It is not \nlikely that cadmium will undergo significant transformation in the atmosphere (EPA 1980).  It will exist \nin particulate form and sometimes vapor form (emitted from high-temperature processes) where it will \nundergo atmospheric transport and eventually deposit onto soils and surface waters.\n\n$$\n\\left(\\mathrm{Cd^{+2}}\\right)\n$$\n\nNon-ferrous metal mining and refining, manufacture and application of phosphate fertilizers, fossil fuel \ncombustion, and waste incineration and disposal are the main anthropogenic sources of cadmium in the \nenvironment.  Except for those who live near cadmium-emitting industries, inhalation of cadmium in the \nambient air may occur but is not a major source of exposure.  Similarly, cadmium exposure through the \ndrinking water supply is of minor concern for the majority of the U.S. population.  However, water \nsources near cadmium-emitting industries, both with historic and current operations, have shown a \nmarked elevation of cadmium in water sediments and aquatic organisms (Angelo et al. 2007; Arnason and \nFletcher 2003; Brumbaugh et al. 2005; Mason et al. 2000; Paulson 1997).  Concentrations of cadmium in these polluted waters have ranged from <1.0 to 77 μg/L.  Cadmium from polluted soil and water can \naccumulate in plants and organisms, thus entering the food supply (Morrow 2010).\n\n$$\n7 7 \\mu \\mathrm {g} / \\mathrm {L}\n$$\n\nIn the United States, the largest source of cadmium exposure for nonsmoking adults and children is \nthrough dietary intake (NTP 2005).  The average daily intake of cadmium for children and adults \n(≥2 years of age) in the United States was estimated as 4.63 µg/day (Kim et al. 2019).  In general, leafy \nvegetables such as lettuce and spinach and staples such as potatoes and grains contain relatively high \nvalues of cadmium.  Peanuts, soybeans, and sunflower seeds have naturally high levels of cadmium \n(Morrow 2010).  Shellfish and organ meats (liver and kidney) also have relatively high concentrations of \ncadmium (Elinder 1985a).\n\nMean values of cadmium in the blood and urine of the U.S. population were reported in the National \nHealth and Nutrition Examination Survey (NHANES) 1999–2018 (CDC 2024).  Blood cadmium tends to \nreflect recent exposures, and urinary cadmium reflects cumulative cadmium exposure and body burden \n(particularly, kidney cadmium levels).  The geometric mean blood cadmium levels for the total population \n(≥1 year of age) have decreased nearly 50% from survey years 1999–2000 (0.412 µg/L) to survey years \n2017–2018 (0.241 µg/L).\n\n$$\n1999-2000\\left(0.412\\ \\mu g/L\\right)\n$$\n\n$$\n2017-2018\\left(0.241\\ \\mu g/L\\right)\n$$\n\nSmoking greatly increases exposure to cadmium, as tobacco leaves naturally accumulate high amounts of \ncadmium (Morrow 2010).  It has been estimated that tobacco smokers are exposed to 0.5–2.0 μg \ncadmium per cigarette, and about 10% is inhaled when smoked (Morrow 2010; Nordberg et al. 2015; \nNTP 2005).  A geometric mean blood cadmium level for a heavy smoker has been reported as high as \n1.58 μg/L (McKelvey et al. 2007), compared to the estimated national mean of 0.295 μg/L for all adults\n≥20 years of age, based on survey years 2017–2018 (CDC 2024).  Nonsmokers may also be exposed to \ncadmium in cigarettes via second-hand smoke.\n\n$$\n1. 5 8 \\mu \\mathrm {g} / \\mathrm {L}\n$$\n\n### 1.2 SUMMARY OF HEALTH EFFECTS\n\nSince the early 1950s, when the hazards of occupational cadmium exposure were recognized (Friberg \n1950), a large amount of information has been generated concerning the toxic effects of cadmium \nexposure in humans and laboratory animals.  Toxicological properties of cadmium are similar for the \nseveral different salts and oxides of cadmium that have been investigated, although differences in \nabsorption and distribution lead to different effect levels.  For inhalation exposure, particle size and \nsolubility in biological fluids (in contrast to solubility in water) appear to be the more important determinants of the toxicokinetics (Hirano et al. 1989a, 1989b; Oldiges and Glaser 1986; Rusch et al. \n1986).  For oral exposure, most experimental studies have used soluble cadmium, which exists as the Cd<sup>+2</sup>\nion regardless of the initial salt.  Absorption appears to be similar for cadmium ion and cadmium \ncomplexed with proteins in food, except for a few specific types of foods such as Bluff oysters and seal \nmeat.  Also, poorly soluble cadmium pigments may be absorbed to a lesser extent than soluble cadmium \nion (ILZRO 1977; Oldiges and Glaser 1986).\n\nThe database on the toxicity of cadmium in humans and animals following inhalation or oral exposure is \nextensive.  Target organs are similar among species and, in general, toxicokinetics following systemic \nabsorption from the gastrointestinal and respiratory tracts are similar.  Most of the human data involve \nevaluation of health effects associated with chronic-duration exposure in occupational studies, \ncommunity-based studies of populations living in cadmium-polluted areas, or epidemiological studies in \nthe general population.  When adequate exposure characterization is available, human studies generally \nreport exposure levels in terms of an internal biomarker of exposure (e.g., urinary cadmium).  Numerous \nstudies have conducted dose-response analyses between urinary cadmium levels and biomarkers of renal \ndysfunction (see Section 2.10); similar rigorous dose-response analyses are not available for other targets \nof toxicity in humans.  In animals, evaluation of available dose-response data by route and duration \nindicates that sensitive noncancer targets of cadmium toxicity are respiratory and neurodevelopmental \neffects following inhalation exposure (Figure 1-1) and renal, skeletal, and neurodevelopmental effects \nfollowing oral exposure (Figure 1-2).\n\nA systematic review of these sensitive noncancer endpoints resulted in the following hazard identification \nconclusions:\n\n• Respiratory effects are a known effect for humans following inhalation exposure.\n\n• Skeletal effects are a known effect for humans.\n\n• Renal effects are a known effect for humans.\n\n• Neurodevelopmental effects are a presumed effect for humans.\n\n---\n\n**Figure 1-1.  Health Effects Found in Animals Following Inhalation Exposure to** \n**Cadmium**\n\nConcentration (mg Cd/m<sup>3</sup>) Effects in Animals\n>8 Acute:  Mortality; clinical signs of neurotoxicity, female reproductive effects\n0.9-1.7 Acute:  Decreased body weight\nIntermediate:  Male and female reproductive effects\n0.19-0.4 Acute:  Developmental and immune effects\n0.05-0.1 Acute:  Respiratory effects\nIntermediate:  Death\n0.02-0.03 Intermediate:  Respiratory and neurodevelopmental effects\nChronic:  Cancer, mortality\n1x10<sup>-4</sup> mg Cd/m<sup>3</sup> Provisional Chronic MRL (based on human data and exposure levels predicted from biomarkers)\n\nCd = cadmium; MRL = minimal risk level\n\n---\n\n**Figure 1-2.  Health Effects Found in Animals Following Oral Exposure to** \n**Cadmium**\n\n## Dose (mg Cd/kg/day)\n\n## Effects in Animals\n\n**Acute:**  Death; hepatic, gastrointestinal, neurological, and male \nreproductive effects\n\n**5.28-15**\n\n**Intermediate:**  Death\n\n**Chronic:**  Hematological effects\n\n**Acute:**  Hematological effects; altered reproductive development\n\n**0.6-3.13**\n\n**Intermediate:**  Gastrointestinal effects\n\n**Chronic:**  Decreased body weight\n\n**Acute:**  Renal and developmental effects, decreased body weight\n\n**0.2-0.4**\n\n**Intermediate:**  Renal, hepatic, hematological, and male and female \nreproductive effects; increased blood pressure; decreased body weight\n\n**Chronic:**  Renal and neurological effects; cancer\n\n**0.04-0.08**\n\n**Intermediate:**  Skeletal, neurological, respiratory, and immunological \neffects; decreased birth weight and altered reproductive development\n\n## 0.002 mg Cd/kg/day 3x10<sup>-4</sup> mg Cd/kg/day\n\n3x10 -4 mg Cd/kg/day\n\n**Intermediate:**  Neurodevelopmental and endocrine effects\n\n**Chronic:**  Skeletal effects\n\n**Provisional Acute MRL**\n\n**Provisional Chronic MRL (based on human data and exposure levels predicted from biomarkers)**\n\nCd = cadmium; MRL = minimal risk level\n\n---\n\n**_Respiratory Effects._** A meta-analysis of 12 studies reported an association between chronic-duration \ninhalation exposure to cadmium and reduced forced expiratory volume in the first second to forced vital \ncapacity (FEV1/FVC), which is indicative of an increased risk of chronic obstructive pulmonary disease \n(Wang et al. 2024a).  A limited number of occupational studies not included in the meta-analysis also \nreported associations between impaired lung function and urinary cadmium levels in workers (Moitra et \nal. 2013, 2015; Zhou et al. 2022).  These findings are supported by occupational case reports of clinical \nsigns of respiratory distress and pulmonary damage after acute-duration exposure to fatal concentrations \n(Beton et al. 1966; Townshend 1982).  In animal acute- and intermediate-duration inhalation studies, the \nrespiratory tract is the most sensitive target of toxicity in animals (NTP 1995).  Available studies \nconsistently report histopathological and inflammatory reactions in the respiratory tract of multiple \nspecies; in studies that provide quantitative data, findings are clearly concentration-related \n(see Section 2.4).\n\n**_Skeletal Effects._** Cadmium-associated bone effects were first described in 1955 in the Jinzu River Basin, \na cadmium-contaminated area in Japan, following the development of a bone disease called Itai-Itai\n("ouch-ouch") disease, characterized by multiple fractures of the long bones, osteomalacia, and \nosteoporosis in combination with proteinuria (Järup et al. 1998; Nordberg et al. 1997; Shigematsu 1984).  \nFour meta-analyses evaluating 41 unique references confirm the association between cadmium exposure \nand adverse bone effects, including fractures, osteoporosis, and decreased bone mineral density (Cheng et \nal. 2016; Kunioka et al. 2022; Li et al. 2021; Qing et al. 2021), as do several studies published since the \nmeta-analyses (Lv et al. 2021; Wang et al. 2021a; Xie et al. 2023a, 2023b).  Occupational case studies \nindicate that calcium deficiency, osteoporosis, or osteomalacia can develop in some workers after longterm occupational exposure to high levels of cadmium (Adams et al. 1969; Blainey et al. 1980; Bonnell \n1955; Kazantzis 1979; Scott et al. 1980).  In rodents, decreases in bone mineralization, bone mineral \ndensity, and mechanical properties have been consistently observed following oral exposure to cadmium \nchloride (see Section 2.8).  While bone effects may be secondary to cadmium-associated renal damage \n(Bhattacharyya et al. 2023; Shevchenko et al. 2021; Zhang et al. 2020a), there is also evidence for a direct \neffect of cadmium on bone, and acceleration of bone resorption can occur in the absence of renal \ndysfunction (Reyes-Hinojosa et al. 2019; Shevchenko et al. 2021; Zhang et al. 2020a).\n\n**_Renal Effects._** The kidney is a well-established target of cadmium toxicity in humans following \noccupational or dietary exposure.  Available meta-analyses consistently reported associations between \none or more biomarkers of cadmium exposure and risk of proteinuria, urolithiasis, chronic kidney disease, \nhyperuricemia, renal cytotoxicity, and low glomerular filtration rate (GFR) (Chen et al. 2024; Doccioli et al. 2024; Gu et al. 2022; Jalili et al. 2021; Liu et al. 2016a; Woo et al. 2015; Zhu et al. 2024a).  These \nfindings are supported by several studies conducted since the meta-analyses were published (see \nSection 2.10).  In animals, there is no evidence for renal effects in acute- and intermediate-duration \ninhalation studies; however, exposure duration and concentration may not have been enough to reach the \ncritical kidney concentration to induce renal effects and chronic-duration inhalation studies evaluating \nrenal toxicity were not identified.  In oral studies, some studies reported adverse changes in sensitive \nbiomarkers of kidney damage, such as a β2-microglobulin (β2M) or N-acetyl-β-d-glucosaminidase \n(NAG) (Bernard et al. 1992; Liu et al. 2019; Wan et al. 2022).  However, other studies did not find this \neffect at similar or higher doses (Wang et al. 2014).  Similar inconsistencies were observed for serum \nclinical chemistry values and histopathological findings (see Section 2.10).\n\n**_Neurodevelopmental Effects._** While several general population studies are available, findings are mixed.  \nAvailable meta-analysis reported mixed conclusions regarding the potential association between cadmium \nexposure and autism spectrum disorder (ASD) (Ding et al. 2023; Dou et al. 2023; Ramazani et al. 2024; \nSaghazadeh and Rezaei 2017; Sulaiman et al. 2020) and did not find an association with attention deficit \nhyperactivity disorder (ADHD) (Dimitrov et al. 2023).  Some studies reported associations between \ncadmium exposure and decreased measures of cognitive development in children and adolescents (Gustin \net al. 2018; Kippler et al. 2016; Rodríguez-Barranco et al. 2014; Zhou et al. 2020); however, other studies \ndid not support this finding (Forns et al. 2014; Lucchini et al. 2019; Pan et al. 2018; Yang et al. 2020).  \nNo consistent findings were observed regarding potential associations between cadmium exposure and \nneurobehavioral or neurosensory evaluations during childhood or adolescence (see Section 2.17).  In \ncontrast, available animal studies collectively indicate that developmental cadmium exposure can cause \nalterations in sensorimotor function (including nerve conduction) and activity, socioemotional behavior, \nand learning and memory in rodents; however, the timing and duration of exposure and assessment \ninfluence findings (see Section 2.17).\n\n**_Cancer Effects._** The carcinogenicity of cadmium has been studied extensively in humans in studies \ninvolving workers and general populations and in animals after inhalation or oral exposures.  The \nInternational Agency for Research on Cancer (IARC) classified cadmium and cadmium compounds as \ncarcinogenic to humans (Group 1) based on sufficient evidence in humans for the carcinogenicity of \ncadmium and cadmium compounds, sufficient evidence in animals for the carcinogenicity of cadmium \ncompounds, and limited evidence in animals for the carcinogenicity of cadmium metal (IARC \n2012).  Similarly, the Department of Health and Human Services (HHS) classified cadmium and \ncadmium compounds as substances known to be human carcinogens based on sufficient evidence of carcinogenicity in humans, including epidemiological and mechanistic studies (NTP 2021).  In 1989, the \nU.S. Environmental Protection Agency (EPA) classified cadmium as a probable human carcinogen by \ninhalation (Group B1) based on limited evidence in humans and sufficient evidence in animals (IRIS \n1989).\n\n### 1.3 MINIMAL RISK LEVELS (MRLs)\n\nMRLs for inhalation and oral exposures to cadmium were derived.  As presented in Figure 1-3, the most \nsensitive effects following inhalation exposure to cadmium are respiratory and developmental \n(specifically neurodevelopmental effects) following acute- and intermediate-duration exposure and renal \nfollowing chronic-duration exposure.  A provisional chronic-duration inhalation MRL was derived based \non renal effects in humans; the inhalation database was considered inadequate for the derivation of acuteor intermediate-duration MRLs.  The lack of renal toxicity at shorter durations in animal inhalation\nstudies is attributed to inadequate exposure duration to meet the critical renal burden required to elicit \nadverse renal effects.  The relationship between renal and urinary cadmium appears to be nearly linear at \nchronic-duration intakes and kidney burdens that do not produce nephrotoxicity (i.e., elimination halftime is independent of dose).  However, at high kidney cadmium burdens, associated with renal damage \n(>50 μg Cd/g cortex), the elimination half-time increases with increasing severity of renal damage.  \nLinearity in the dose-urinary excretion relationship also does not appear to apply following an acuteduration, high exposure to cadmium.  Multicompartment, physiologically based pharmacokinetic (PBPK) \nmodels (described in detail in Section 3.1.5) can be used to estimate cadmium intakes (inhalation and oral \nexposure) associated with a given urinary cadmium level and/or kidney cadmium burden.  These models \nhave been extensively evaluated for predicting dose-kidney-urinary cadmium relationships within the \nlinear range of the dose-urinary cadmium relationship, and PBPK modeling was used in the derivation of \nthe provisional inhalation chronic-duration MRL.\n\nAs presented in Figure 1-4, the most sensitive effects following oral exposure are renal, developmental \n(specifically neurodevelopmental), and skeletal effects.  Provisional acute- and chronic-duration oral \nMRLs were derived based on renal effects in animals and humans, respectively; the oral database was \nconsidered inadequate for the derivation an intermediate-duration oral MRL.  As discussed for the provisional chronic-duration inhalation MRL, PBPK modeling was used in the derivation of the \nprovisional oral chronic-duration MRL.\n\nMRLs derived for both the inhalation and oral exposure routes for cadmium are summarized in Table 1-1\nand are discussed in greater detail in Appendix A.\n\n**Figure 1-3.  Summary of Sensitive Targets of Cadmium – Inhalation**\n\n**Available data indicate that the respiratory system and developing nervous system are the most \nsensitive targets following acute- and intermediate-duration exposure and the renal system is the \nmost sensitive target following chronic-duration exposure to cadmium via inhalation.**\n\nNumbers in circles are the lowest lowest-observed-adverse-effect levels (LOAELs) for all health effects in \nanimals and the number in the triangle is the point of departure (POD) for the chronic-duration inhalation \nMRL based on human data.*\n\n**Acute (mg Cd/m³ )**\n\n| Category | Acute (mg Cd/m³) | Intermediate (mg Cd/m³) | Chronic (mg Cd/m³) |\n| --- | --- | --- | --- |\n| Respiratory | 0.081 | 0.021 |  |\n| Immunological | 0.19 |  |  |\n| Developmental | 0.4 | 0.02 |  |\n| Hematological |  | 0.052 |  |\n| Body weight |  | 0.052 | 0.03 |\n| Renal |  |  | 0.00106 |\n| Death |  |  | 0.03 |\n\n*See Table 2-1 for animal studies identifying the LOAELs in circles.  The value of 0.00106 mg Cd/m<sup>3</sup> represented by \nthe triangle (human data) is the renal POD used for the provisional chronic-duration MRL; the value represents the \nlower 95% confidence limit on the weighted median of the urinary cadmium level associated with a 10% extra risk \nassociated with low-molecular weight proteinuria in 17 datasets from 11 human studies (see Appendix A for details).\n\n---\n\n## Figure 1-4. Summary of Sensitive Targets of Cadmium – Oral\n\n**Available data indicate that the renal, skeletal, and developing nervous system are the most \nsensitive targets of cadmium oral exposure.**\n\nNumbers in circles are the lowest lowest-observed-adverse-effect levels (LOAELs) for all health effects in \nanimals and the number in the triangle is the point of departure (POD) for the chronic-duration oral MRL \nbased on human data.*\n\n**Acute (mg Cd/kg/day)**\n\n| Category | LOAEL (mg Cd/kg/day) |\n| --- | --- |\n| Acute - Renal | 2 |\n| Acute - Body weight | 2 |\n| Acute - Developmental | 3.13 |\n| Intermediate - Developmental | 0.04 |\n| Intermediate - Endocrine | 0.053 |\n| Intermediate - Musculoskeletal | 0.2 |\n| Chronic - Renal (POD) | 0.00076 |\n| Chronic - Musculoskeletal | 0.08 |\n| Chronic - Renal | 2.301 |\n| Chronic - Cancer | 2.3 |\n\n*See Table 2-2 for animal studies identifying the LOAELs in circles.  The value of 7.60x10<sup>-4</sup> mg Cd/kg/day \nrepresented by a triangle (human data) is the renal POD used for the provisional chronic-duration MRL; the value \nrepresents the lower 95% confidence limit on the weighted median of the urinary cadmium level associated with a \n10% extra risk associated with low-molecular weight proteinuria in 17 datasets from 11 human studies \n(see Appendix A for details).\n\n$$\n7.60\\times10^{-4}\n$$\n\n---\n\n**Table 1-1.**\n\n**Minimal Risk Levels (MRLs) for Cadmium**\n\n| Exposure route | Exposure duration | Provisional MRL | Critical effect (species) | POD type | POD value | Uncertainty/modifying factor | Reference |\n| --- | --- | --- | --- | --- | --- | --- | --- |\n| Inhalation | Acute | None | - | - | - | - | - |\n| Inhalation | Intermediate | None | - | - | - | - | - |\n| Inhalation | Chronic | 1 × 10-4 mg CD/m3 | LMW proteinuria (humans) | 95% LCL of weighted median of UC10 from 17 datasets | 0.00106 mg Cd/m3 | UF: 3 MF: 3 | Weighted median from 17 datasetsb |\n| Oral | Acute | 0.002 mg Cd/kg/day | Total and LMW proteinuria; increased serum BUN (rats) | LOAEL | 2 mg Cd/kg/day | UF: 1,000 | Wan et al. 2022 |\n| Oral | Intermediate | None | - | - | - | - | - |\n| Oral | Chronic | 3 × 10-4 mg CD/kg/day | LMW proteinuria (humans) | 95% LCL of weighted median of UC10 from 17 datasets | 7.60 × 10-4 mg Cd/kg/day | UF: 3 | Weighted median from 17 datasetsb |\n\n<sup>a</sup>See Appendix A for additional information.\n\n<sup>b</sup>17 datasets from 3 occupational cohorts (Järup and Elinder 1994; Lei et al. 2007; Shao et al. 2007) and 8 general population cohorts (Buchet et al. 1990; Hong et \nal. 2004; Järup et al. 2000; Kobayashi et al. 2008; Suwazono et al. 2006; Uno et al. 2005; Wu et al. 2001; Zhang et al. 2016a).\n\nBUN = blood urea nitrogen; LCL = lower confidence limit; LMW = low molecular weight; LOAEL = lowest-observed-adverse-effect level; MF = modifying factor; \nPOD = point of departure; UC10 = urinary concentration associated with 10% extra risk; UF = uncertainty factor\n\n---\n\n## CHAPTER 2. HEALTH EFFECTS\n\n### 2.1 INTRODUCTION\n\nThe primary purpose of this chapter is to provide public health officials, physicians, toxicologists, and \nother interested individuals and groups with an overall perspective on the toxicology of cadmium.  It \ncontains descriptions and evaluations of toxicological studies and epidemiological investigations and \nprovides conclusions, where possible, on the relevance of toxicity and toxicokinetic data to public health.  \nWhen available, mechanisms of action specific to target organs are discussed along with the health effects \ndata, while general mechanisms of action are discussed in Section 2.21; toxicokinetic mechanistic data are \ndiscussed in Section 3.1.\n\nA glossary and list of acronyms, abbreviations, and symbols can be found at the end of this profile.\n\nTo help public health professionals and others address the needs of persons living or working near hazardous \nwaste sites, the information in this section is organized by health effect.  These data are discussed in terms of \nroute of exposure (inhalation, oral, and dermal) and three exposure periods:  acute (≤14 days), intermediate \n(15–364 days), and chronic (≥365 days).\n\nAs discussed in Appendix B, a literature search was conducted to identify relevant studies examining health \neffect endpoints.  Figure 2-1 provides an overview of the database of studies in humans or experimental \nanimals included in this chapter of the profile.  These studies evaluate the potential health effects associated \nwith inhalation, oral, or dermal exposure to cadmium, but may not be inclusive of the entire body of \nliterature.  As discussed in *Prioritization of Human Data* in Appendix B, the epidemiological database for \ncadmium is extensive, including thousands of primary studies and dozens of meta-analyses of available \nstudies.  To focus the profile review and discussion on the weight-of-evidence, recent evidence, and most \nrelevant data for hazard identification, ATSDR focused the discussion in Chapter 2 on meta-analyses \nconducted within the past 15 years.  To supplement discussion, any epidemiological study published since \nthe most recent meta-analysis for an endpoint was included if it provided: (1) reliable and reported estimates \nof cadmium exposure (measured levels in air or via urinary cadmium levels, as this is the most reliable \nbiomarker [see Section 3.3.1]); (2) analysis of potential confounders of the measures of association; and \n(3) appropriate statistical analysis.  For endpoints without a published meta-analysis, any study meeting these \ninclusion criteria were included, regardless of publication date.  Studies were excluded if they did not \nprovide quantitative evidence for associations, relied on semi-quantitative measures of exposure (e.g., food frequency questionnaires), or evaluated cadmium exposure from medical implants.  Exceptions to the above \ncriteria included studies reporting rare effects, inclusion of select older studies to provide historical context \n(e.g., Itai-Itai disease in the Jinzu River Basin region of Japan, early case reports and investigations of \nworkers exposed to cadmium that established targets of toxicity, etc.), and studies that fill data gaps (e.g., \nlower quality occupational studies in less-studied organ systems/tissues). The animal database for cadmium \nis also extensive.  As discussed in *Prioritization of Animal Data* in Appendix B, animal studies evaluating \nadverse effects were prioritized for efficient review.  Since cadmium is a well-established model of renal \ntoxicity, there are hundreds of studies describing administration of cadmium via oral or other routes (e.g., \nintraperitoneal) at known toxic doses to evaluate potential interventions to rescue (or prevent) renal toxicity \nor other cadmium-associated adverse effects at higher exposure levels.  Studies of this nature were excluded \nfrom the profile, as they do not inform dose-response effects at low, environmentally-relevant \ndoses. Similarly, acute- and intermediate-duration oral studies in rats or mice utilizing only one cadmium \ndose group were excluded due to lack of dose-response data; exceptions were made for acute-lethality \nstudies or studies addressing data-poor endpoints (e.g., lipid homeostasis studies).  All chronic-duration oral \nstudies and all inhalation and dermal studies of adequate quality were included in the profile.  A systematic \nreview of the scientific evidence of the most sensitive health effects associated with exposure to cadmium\nwas also conducted; the results of this review are presented in Appendix C.\n\nHuman and animal inhalation studies are presented together in Table 2-1 and Figure 2-2 and human and \nanimal oral studies are presented in Table 2-2 and Figure 2-3; limited dermal data were identified for \ncadmium and are presented in Table 2-3.\n\nLevels of significant exposure (LSEs) for each route and duration are presented in tables and illustrated in \nfigures.  The points in the figures showing no-observed-adverse-effect levels (NOAELs) or lowestobserved-adverse-effect levels (LOAELs) reflect the actual doses (levels of exposure) used in the studies.  \nEffects have been classified into “less serious LOAELs” or “serious LOAELs (SLOAELs).”  “Serious” \neffects are those that evoke failure in a biological system and can lead to morbidity or mortality (e.g., \nacute respiratory distress or death).  “Less serious” effects are those that are not expected to cause \nsignificant dysfunction or death, or those whose significance to the organism is not entirely clear.  \nATSDR acknowledges that a considerable amount of judgment may be required in establishing whether \nan endpoint should be classified as a NOAEL, “less serious” LOAEL, or “serious” LOAEL, and that in \nsome cases, there will be insufficient data to decide whether the effect is indicative of significant \ndysfunction.  However, the Agency has established guidelines and policies that are used to classify these \nendpoints.  ATSDR believes that there is sufficient merit in this approach to warrant an attempt at distinguishing between “less serious” and “serious” effects.  The distinction between “less serious” effects \nand “serious” effects is considered to be important because it helps the users of the profiles to identify \nlevels of exposure at which major health effects start to appear.  LOAELs or NOAELs should also help in \ndetermining whether or not the effects vary with dose and/or duration, and place into perspective the \npossible significance of these effects to human health.  Levels of exposure associated with cancer (Cancer \nEffect Levels, CELs) of cadmium are indicated in Tables 2-1 and 2-2 and Figures 2-2 and 2-3.\n\nA User\'s Guide has been provided at the end of this profile (see Appendix D).  This guide should aid in \nthe interpretation of the tables and figures for LSEs and MRLs.\n\nThis section provides information regarding potential adverse health effects of cadmium and cadmium \ncompounds.  To appropriately compare doses following exposures to various cadmium compounds, \ninhalation exposures are expressed throughout the profile as mg Cd/m<sup>3</sup> and oral exposures are expressed as \nmg Cd/kg/day, when possible.  This allows for evaluation of relative toxicities and determination of whether \ncertain chemical properties (e.g., solubility) impact toxicity.  When available, information pertaining to \nrelative toxicity of different cadmium compounds is discussed throughout Chapter 2.\n\nThe health effects of cadmium and cadmium compounds have been extensively evaluated in human and \nanimal studies.  As discussed above, due to the vast amount of available data, studies were prioritized for \ninclusion in Chapter 2 based on criteria defined in Appendix B.  A total of 69 meta-analyses of human \ndata were included.  An additional 219 human studies and 192 animal studies meeting inclusion criteria \nwere identified.  Most of the human data involve evaluation of health effects associated with chronicduration exposure in occupational studies, community-based studies of populations living in cadmiumpolluted areas, or epidemiological studies in the general population.  For workers, the predominant \nexposure route is inhalation; however, some gastrointestinal tract exposure may also occur when dust is \nremoved from the lungs by mucociliary clearance and subsequently swallowed, or by ingestion of dust on \nhands, cigarettes, or food (Adamsson et al. 1979).  For the nonsmoking general population, dietary \nexposure to cadmium is the most likely route of exposure (Kim et al. 2018; Nordberg et al. 2018; Zhu et \nal. 2024a).  However, since cadmium is present in tobacco leaves, tobacco smoking can contribute \nsignificantly to cadmium exposure in general populations (Diamond and Klotzbach 2025; Ellis et al. \n1979; Friis et al. 1998).  Therefore, both occupational and general population studies are classified as \nmulti-route exposure in Figure 2-1.  In animal studies, most of the health effects data in animals come \nfrom oral exposure studies (Figure 2-1).\n\n---\n\nHuman studies are available for nearly every organ system, with the predominant focus on renal, cancer, \ndevelopmental, musculoskeletal, and cardiovascular endpoints.  Animal studies predominantly focused on \nrespiratory endpoints following inhalation exposure and examined a comprehensive set of endpoints \nfollowing oral exposure.  For oral studies, the most well-studied effects include body weight, developmental, \nand reproductive endpoints.  Data from dermal exposure are very limited.\n\nAs outlined in Chapter 1, the most sensitive effects following exposure to cadmium appear to be respiratory, \nrenal, and neurodevelopmental following inhalation exposure and renal, skeletal, and neurodevelopmental \nfollowing oral exposure.  A systematic review was conducted on the available human and animal studies for \nthese endpoints.  The information in these studies indicates the following on the potential targets of cadmium\ntoxicity:\n\n• **Respiratory Endpoints.**  Respiratory effects are a known effect of cadmium toxicity following \ninhalation exposure based on a low level of evidence in human occupational studies, a high level \nof evidence in laboratory animal inhalation studies, and other relevant data including a metaanalysis, occupational case reports, and a plausible mechanism of action.  In humans, \noccupational exposure has been associated with respiratory irritation and impaired respiratory \nfunction.  In animals, inhalation exposure is consistently associated with inflammatory changes in \nthe lung and upper and lower respiratory tract lesions with increasing concentration and duration \nin multiple species.\n\n• **Skeletal Endpoints.**  Adverse effects on the skeletal system (e.g., decreased bone density, \nstrength, and mineralization) are a known effect of cadmium toxicity based on a moderate level of \nevidence from human epidemiological studies, a high level of evidence from laboratory animals, \nand other relevant data including several meta-analyses, older studies and case reports of high \ndietary or occupational exposure, and plausible mechanisms of action.  In humans, cadmium \nexposure is associated with adverse bone effects, including fractures, osteoporosis, and decreased \nbone mineral density.  Bone effects associated with cadmium exposure were first described in \ncadmium-contaminated communities in Japan with high dietary intake; the disease called Itai-Itai \n(“ouch-ouch”) disease was characterized by multiple fractures of the long bones, osteomalacia, \nand osteoporosis.  Bone effects have been confirmed in animal studies following oral exposure; \nthese endpoints have not been assessed following inhalation exposure in animals.\n\n• **Renal Endpoints.** Renal effects are a known effect of cadmium toxicity based on a high level of \nevidence from human epidemiological studies, a moderate level of evidence in laboratory animal \ninhalation studies, and other relevant data including several meta-analyses and a well-defined \nmechanism of action. The kidney has been a well-established target of cadmium toxicity in \nhumans following occupational and dietary exposure for decades.  Several studies have \ndeveloped dose-response analyses of sensitive biomarkers of cadmium exposure and renal \ntoxicity (e.g., urinary cadmium levels and low molecular weight [LMW] proteinuria).  Data in \nanimals following inhalation exposure are inadequate.  While findings in multi-dose oral studies \nin animals meeting inclusion criteria are mixed, several studies reported alterations in biomarkers \nof renal functions (e.g., LMW proteinuria, serum blood urea nitrogen [BUN]) and \nhistopathological changes.\n\n---\n\n## 2. HEALTH EFFECTS\n\n• **Neurodevelopmental Endpoints.** Neurodevelopmental effects are a presumed effect in humans \nbased on a low level of evidence in humans and a high level of evidence in animals.  Available \nepidemiological data from general population studies are mixed.  A limited number of inhalation \nstudies and numerous oral studies in animals indicate that developmental cadmium exposure can \ncause alterations in sensorimotor function (including nerve conduction) and activity, \nsocioemotional behavior, and learning and memory in rodents; however, the timing and duration \nof exposure and assessment influence findings.  Available data indicate that neurodevelopmental \neffects are the most sensitive indicator of developmental toxicity of cadmium (occur at lower \nexposures than those associated with standard developmental outcomes or specialized evaluations \nof other systems, such as reproductive development).\n\n---\n\n**Figure 2-1.  Overview of the Number of Studies Examining Cadmium Health Effects***\n\n## Most studies examined the potential body weight, renal, and developmental effects of cadmium\n\nNumerous studies are available in both **humans** and **animals** (counts represent studies examining endpoint)\n\n| Category | Series 1 (unlabelled) (number of studies) | Series 2 (unlabelled) (number of studies) |\n| --- | --- | --- |\n| Death | 11 | 42 |\n| Body weight |  | 98 |\n| Respiratory | 15 | 29 |\n| Cardiovascular | 28 | 13 |\n| Gastrointestinal | 6 | 9 |\n| Hematological | 5 | 31 |\n| Musculoskeletal | 30 | 16 |\n| Hepatic | 21 | 23 |\n| Renal | 54 | 34 |\n| Dermal | 2 | 1 |\n| Ocular | 2 | 2 |\n| Endocrine | 19 | 15 |\n| Immunological | 14 | 26 |\n| Neurolgical | 12 | 12 |\n| Reproductive | 30 | 39 |\n| Developmental | 33 | 45 |\n| Other Noncancer | 4 | 4 |\n| Cancer | 34 | 10 |\n\n**Exposure Route**\n\n| Category | Share of studies (%) |\n| --- | --- |\n| Multi-route | 56 |\n| Oral | 30 |\n| Dermal | 1 |\n| Inhalation | 13 |\n\n**Exposure Duration**\n\n| Category | Share of studies (%) |\n| --- | --- |\n| Chronic | 60 |\n| Intermediate | 25 |\n| Acute | 15 |\n\n*Includes studies discussed in Chapter 2.  A total of 69 meta-analyses and 411 studies meeting inclusion criteria (including those finding no effect) have examined \ntoxicity; most studies examined multiple endpoints. Note: Meta-analyses are counted as a single data-point in the figure above because only the overall results of \nthe meta-analysis, not the individual studies included in the meta-analyses, were included in Chapter 2.\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| ACUTE EXPOSURE |  |  |  |  |  |  |  |  |  |\n| Beton et al. 1966 |  |  |  |  |  |  |  |  | Cadmium oxide fume |\n| 1 | Human 5 M | 5 hours (occup) | 8.63 | LE, CS | Death Resp |  |  | 8.63 | 1/5 exposed workers died Severe dyspnea, wheezing, chest pain and precordial constriction, persistent cough (lasting up to 7 days post-exposure); severe pulmonary edema and alveolar cell metaplasia in the worker that died |\n| Barrett et al. 1947 |  |  |  |  |  |  |  |  | Cadmium oxide fume |\n| 2 | Rat (NS) 10–25 NS | 10–15 minutes (WB) | 8.8, 13, 18, 19, 22, 25, 31, 41, 79.2, 110 | LE | Death |  |  | 30 | LC50 at 7 days |\n| Buckley and Bassett 1987 |  |  |  |  |  |  |  |  | Cadmium oxide dust |\n| 3 | Rat (Wistar) 20 M | 3 hours (WB) | 0, 0.4, 4.6 | BW | Bd wt | 0.4 | 4.6 |  | 15% decrease in body weight 7 days post-exposure |\n| Bus et al. 1978 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 4 | Rat (Sprague-Dawley) 18 M | 1 hour (WB) | 0, 6.5 | LE, BW, BI, OW, OF | Bd wt |  | 6.5 |  | 11% decrease in body weight 11 days post-exposure |\n|  |  |  |  |  | Resp |  | 6.5 |  | Decreased tidal volume and increased respiratory frequency 1 and 5 days post-exposure |\n| Rats were examined at 1, 5, and 11 days post-exposure (6/group/timepoint) |  |  |  |  |  |  |  |  |  |\n| Grose et al. 1987 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 5 | Rat (Sprague-Dawley) 40 M | 2 hours (H) | 0, 0.25, 0.48, 4.50 | LE, CS, BW | Bd wt | 0.25 |  | 4.5 | 20% decrease in body weight 72 hours post-exposure |\n\nRats were examined immediately and 72 hours post-exposure (20/group/timepoint)\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects | Cadmium oxide dust |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Grose et al. 1987 |  |  |  |  |  |  |  |  |  |  |\n| 6 | Rat (Sprague-Dawley) 40 M | 2 hours (H) | 0, 0.25, 0.44, 4.45 | LE, CS, BW | Bd wt | 4.45 |  |  |  |  |\n| Rats were examined immediately and 72 hours post-exposure (20/group/timepoint) |  |  |  |  |  |  |  |  |  |  |\n| Hart 1986 |  |  |  |  |  |  |  |  |  |  |\n| 7 | Rat (Lewis) 3 M | 1 or 2 weeks 5 days/week 3 hours/day (N) | 0, 1.6 | BI, OW, HP | Resp |  | 1.6 |  |  | Cadmium acetate Increase in BALF cellularity (macrophages, PMNs, lymphocytes) and markers of cytotoxicity (LDH, ALP, AP, total protein) |\n| Jacobo-Estrada et al. 2016 |  |  |  |  |  |  |  |  |  |  |\n| 8 | Rat (Wistar) 6 F | 13 days GDs 8–20 2 hours/day (WB) | 0, 17.43 | BW, OW, DX | Bd wt Repro Develop | 17.43 | 17.43 | 17.43 |  | Cadmium chloride Decreased absolute placental weight Fetal kidney injury (decreased fetal plasma creatinine levels, increased total histopathological lesion score in fetal kidney); decreased fetal body weight (8%) |\n| NTP 1995 |  |  |  |  |  |  |  |  |  |  |\n| 9 | Rat (Fischer-344) 5 M, 5 F | 2 weeks 5 days/week 6.2 hours/day (WB) | 0, 0.081, 0.249, 0.844, 2.49, 8.60 | LE, CS, BW, OW, HP | Death Bd wt Resp | 2.49 | 0.081 | 8.6 |  | Cadmium oxide aerosol 100% mortality by day 6 |\n|  |  |  |  |  | Cardio | 2.49 |  |  |  | SLOAEL: Marked necrosis of alveolar ducts LOAEL: Minimal-to-mild alveolar histiocytic infiltrate and focal inflammation in alveolar septa |\n|  |  |  |  |  | Hepatic | 2.49 |  |  |  |  |\n|  |  |  |  |  | Renal | 2.49 |  |  |  |  |\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects | Cadmium chloride |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Palmer et al. 1986 |  |  |  |  |  |  |  |  |  |  |\n| 10 | Rat (Sprague-Dawley) 20–30 M | 2 hours (WB) | 0, 6.0 | BW, BC, BI, OW | Bd wt | 6 |  |  |  |  |\n| 10 | Rat (Sprague-Dawley) 20–30 M | 2 hours (WB) | 0, 6.0 | BW, BC, BI, OW | Resp |  | 6 |  |  | Increased BALF cellularity (primarily macrophages) 3 days post-exposure |\n| 10 | Rat (Sprague-Dawley) 20–30 M | 2 hours (WB) | 0, 6.0 | BW, BC, BI, OW | Endocr | 6 |  |  |  |  |\n| Rats were sacrificed |  | 1, 3, 7, or 10 days post-exposure (≥4/group/timepoint) |  |  |  |  |  |  |  |  |\n| Rusch et al. 1986 |  |  |  |  |  |  |  |  |  | Cadmium carbonate |\n| 11 | Rat (Sprague-Dawley) 26 M, 26 F | 2 hours (WB) | 0, 94 | LE, CS, GN | Resp |  |  | 94 |  | Rales persisting up to 4 hours post-exposure |\n| Rats were sacrificed immediately or 1, 3, 7, or 30 days post-exposure (10/group/timepoint); extra two rats were replacement animals |  |  |  |  |  |  |  |  |  |  |\n| Rusch et al. 1986 |  |  |  |  |  |  |  |  |  | Cadmium sulfide |\n| 12 | Rat (Sprague-Dawley) 26 M, 26 F | 2 hours (WB) | 0, 140 | LE, CS, BW | Bd wt | 140 |  |  |  |  |\n| Rats were sacrificed immediately or 1, 3, 7, or 30 days post-exposure (10/group/timepoint); extra two rats were replacement animals |  |  |  |  |  |  |  |  |  |  |\n| Rusch et al. 1986 |  |  |  |  |  |  |  |  |  | Cadmium selenide |\n| 13 | Rat (Sprague-Dawley) 26 M, 26 F | 2 hours (WB) | 0, 105 | LE, CS, BW | Bd wt | 105 |  |  |  |  |\n| Rats were sacrificed immediately or 1, 3, 7, or 30 days post-exposure (10/group/timepoint); extra two rats were replacement animals |  |  |  |  |  |  |  |  |  |  |\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Rusch et al. 1986 |  |  |  |  |  |  |  |  | Cadmium acetate |\n| 14 | Rat (Sprague-Dawley) 26 M, 26 F | 2 hours (WB) | 0, 83 | LE, CS | Death |  |  | 83 | 25/32 died between 1 and 7 days post-exposure |\n| 14 | Rat (Sprague-Dawley) 26 M, 26 F | 2 hours (WB) | 0, 83 | LE, CS | Resp |  |  | 83 | Labored breathing and rales persisting up to 4 hours post-exposure |\n| 14 | Rat (Sprague-Dawley) 26 M, 26 F | 2 hours (WB) | 0, 83 | LE, CS | Neuro |  | 83 |  | Reduced activity during exposure |\n| Rats were sacrificed immediately or 1, 3, 7, or 30 days post-exposure (10/group/timepoint); extra two rats were replacement animals |  |  |  |  |  |  |  |  |  |\n| Snider et al. 1973 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 15 | Rat (Sprague-Dawley) 18 M | 3 days 1 hour/day (WB) | 61 | LE, GN | Death |  |  | 61 | 17/18 died within 3 days |\n| 15 | Rat (Sprague-Dawley) 18 M | 3 days 1 hour/day (WB) | 61 | LE, GN | Resp |  |  | 61 | Pulmonary hemorrhage |\n| Barrett et al. 1947 |  |  |  |  |  |  |  |  | Cadmium oxide fume |\n| 16 | Mouse (NS) 10 NS | 15 minutes (WB) | 39, 61.3, 65.9 | LE | Death |  |  | 39 | 9/10 died within 7 days |\n| Graham et al. 1978 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 17 | Mouse (CD-1) 16–20 F | 2 hours (WB) | 0, 0.110, 0.190 | IX | Immuno | 0.11 | 0.19 |  | Decreased humoral immune response |\n| Krzystyniak et al. 1987 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 18 | Mouse (C57BL/6) 4–5 F | 60 minutes (N) | 0, 0.88 | IX | Immuno |  | 0.88 |  | Reduced humoral and cell-mediated immune responses |\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| NTP 1995 |  |  |  |  |  |  |  |  | Cadmium oxide aerosol |\n| 19 | Mouse (B6C3F1) 5 M, 5 F | 2 weeks 5 days/week 6.2 hours/day (WB) | 0, 0.081, 0.249, 0.844, 2.49, 8.60 | LE, CS, BW, OW, HP | Death Bd wt Resp | 2.49 | 0.081 | 8.6 | 100% mortality by day 7 |\n| 19 | Mouse (B6C3F1) 5 M, 5 F | 2 weeks 5 days/week 6.2 hours/day (WB) | 0, 0.081, 0.249, 0.844, 2.49, 8.60 | LE, CS, BW, OW, HP | Cardio Hepatic Renal | 2.49 2.49 2.49 | 0.081 | 0.844 | LOAEL: Minimal-to-mild alveolar histiocytic infiltrates SLOAEL: Fibrosis, inflammation, and mild necrosis of the alveolar ducts; degeneration of the nasal olfactory epithelium |\n| NTP 1995 |  |  |  |  |  |  |  |  | Cadmium oxide aerosol |\n| 20 | Mouse (Swiss) 33 F | 14 days GDs 4–17 6.27 hours/day (WB) | 0, 0.04, 0.4, 1.7 | LE, CS, BW, OW, DX | Bd wt Develop | 0.4 | 0.04 | 1.7 | 22% decrease in maternal body weight on GD 18 Increased total litter resorption; decreased fetal body weight (29–30%); reduced ossification of sternebrae Decreased male (9%) and female (8%) fetal body weight |\n| Friberg 1950 |  |  |  |  |  |  |  |  | Cadmium metal dust |\n| 21 | Rabbit (NS) 8 NS | 4 hours (H) | 11.5 - 48.4 | LE | Death |  |  | 28.4 | LC50 at 14 days |\n| Henderson et al. 1979 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 22 | Hamster (Golden Syrian) 30 B | 30 minutes (N) | 0, 1.1, 10.1 | LE, BI, HP | Resp |  | 1.1 | 10.1 | LOAEL: Increased BALF PMN and AP levels SLOAEL: Necrosis of bronchiolar epithelium 1 day post-exposure; severe pneumonitis 7 days post-exposure |\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| INTERMEDIATE EXPOSURE |  |  |  |  |  |  |  |  |  |\n| Baranski 1984 |  |  |  |  |  |  |  |  | Cadmium oxide aerosol |\n| 23 | Rat (Wistar) 7–15 F | 6-7 months (5 months premating, up to 3 weeks mating, GDs 1–20) 5 hours/day 5 days/week (WB) | 0, 0.02, 0.16 | RX, DX | Repro Develop | 0.16 | 0.02 | 0.16 | LOAEL: Age- and sex-dependent changes in offspring motor activity; impaired avoidance acquisition in 3- and 7-month-old females SLOAEL: 25% mortality by PND 4 (decreased viability index); 15% decrease in weanling body weight |\n| Baranski 1985 |  |  |  |  |  |  |  |  | Cadmium oxide dust |\n| 24 | Rat (Wistar) 5–16 F | 5–7 months (4–5 months premating, mating, GDs 1–20) 5 days/week 5 hours/day (WB) | 0, 0.02, 0.16, 1.0 | LE, BW, RX, DX | Death Bd wt Repro Develop | 1 1 | 0.02 | 1 | 55.1% mortality |\n| Baranski and Sitarek 1987 |  |  |  |  |  |  |  |  | LOAEL: Decreased motor activity in 3-month-old males and decreased conditioned reflexes in 5-month-old females SLOAEL: 23% decrease in pup viability index; unspecified decrease in pup weight during first 2 months |\n| 25 | Rat (Wistar) 13–14 F | 20 weeks 5 days/week 5 hours/day (WB) | 0, 0.02, 0.16, 1.0 | LE, CS, BW, RX | Death Bd wt Repro | 0.16 | 0.02 | 1 | Cadmium oxide dust 38% mortality by week 13; 100% mortality by week 20 30–50% decrease in body weight gain starting at week 4 Increased duration of estrous cycle |\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Glaser et al. 1986 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 26 | Rat (Wistar) 12 M | 30 days 7 days/week 22 hours/day (WB) | 0, 0.105 | LE, CS, BW, HE, BC, BI, UR | Bd wt Resp | 0.105 | 0.105 |  | Increase in BALF cellularity (PMNs, macrophages, leukocytes) and markers of cytotoxicity (LDH, total protein levels); macrophages, total protein and LDH remained elevated at 2-months post-exposure |\n| 26 | Rat (Wistar) 12 M | 30 days 7 days/week 22 hours/day (WB) | 0, 0.105 | LE, CS, BW, HE, BC, BI, UR | Hemato | 0.105 | 0.105 |  | Increased WBC counts at terminal sacrifice |\n| 26 | Rat (Wistar) 12 M | 30 days 7 days/week 22 hours/day (WB) | 0, 0.105 | LE, CS, BW, HE, BC, BI, UR | Renal | 0.105 |  |  |  |\n| Rats were sacrificed immediately following exposure (terminal sacrifice) or 2 months post-exposure (6/group/timepoint) |  |  |  |  |  |  |  |  |  |\n| Glaser et al. 1986 |  |  |  |  |  |  |  |  | Cadmium sulfide |\n| 27 | Rat (Wistar) 12 M | 30 days 7 days/week 22 hours/day (WB) | 0, 1.034 | LE, CS, BW, HE, BC, BI, OW | Bd wt Resp | 1.034 | 1.034 |  | Increase in BALF cellularity (PMNs, macrophages, leukocytes) and markers of cytotoxicity (LDH, total protein levels); macrophages, total protein and LDH remained elevated at 2-months post-exposure |\n| 27 | Rat (Wistar) 12 M | 30 days 7 days/week 22 hours/day (WB) | 0, 1.034 | LE, CS, BW, HE, BC, BI, OW | Hemato | 1.034 |  |  |  |\n| 27 | Rat (Wistar) 12 M | 30 days 7 days/week 22 hours/day (WB) | 0, 1.034 | LE, CS, BW, HE, BC, BI, OW | Renal | 1.034 |  |  |  |\n| Rats were sacrificed immediately following exposure (terminal sacrifice) or 2 months post-exposure (6/group/timepoint) |  |  |  |  |  |  |  |  |  |\n| Glaser et al. 1986 |  |  |  |  |  |  |  |  | Cadmium oxide dust |\n| 28 | Rat (Wistar) 12 M | 30 days 7 days/week 22 hours/day (WB) | 0, 0.098 | LE, CS, BW, HE, BC, BI, OW | Bd wt Resp | 0.098 | 0.098 |  | Increase in BALF cellularity (PMNs, macrophages, leukocytes) and markers of cytotoxicity (LDH, total protein levels); total protein remained elevated at 2-months post-exposure |\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n|  |  |  |  |  | Hemato |  | 0.098 |  | Increased WBC count at terminal sacrifice |\n|  |  |  |  |  | Renal | 0.098 |  |  |  |\n\n| Rats were sacrificed immediately following exposure (terminal sacrifice) or 2 months post-exposure (6/group/timepoint) |  |  |  |  |  |  |  |  |  |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Hart 1986 |  |  |  |  |  |  |  | Cadmium acetate |  |\n| 29 | Rat (Lewis) 3 M | 3–6 weeks 5 days/week 3 hours/day (N) | 0, 1.6 | BI, OW, HP | Resp |  | 1.6 |  | Transient increase in BALF cellularity (macrophages, PMNs, lymphocytes) and markers of cytotoxicity (LDH, ALP, AP, total protein); resolving weeks 4–6 |\n| Kutzman et al. 1986 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 30 | Rat (Fischer 344) 20 M | 62 days 5 days/week 6 hours/day (WB) | 0, 0.33, 1.06, 2.13 | LE, CS, BW, BI, OW, HP | Death |  |  | 2.13 | 100% mortality by day 45 |\n| 30 | Rat (Fischer 344) 20 M | 62 days 5 days/week 6 hours/day (WB) | 0, 0.33, 1.06, 2.13 | LE, CS, BW, BI, OW, HP | Bd wt | 0.33 |  | 1.06 | 27% decrease in body weight |\n| Kutzman et al. 1986 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 31 | Rat (Fischer 344) 8 M, 8 F | 62 days 5 days/week 6 hours/day (WB) | 0, 0.33, 1.06, 2.13 | LE, BW, RX | Death |  |  | 2.13 | 100% mortality by day 45 |\n| 31 | Rat (Fischer 344) 8 M, 8 F | 62 days 5 days/week 6 hours/day (WB) | 0, 0.33, 1.06, 2.13 | LE, BW, RX | Bd wt | 0.33 | 1.03 | 2.13 | LOAEL: 14% decreased in body weight SLOAEL: Body weight loss (decreased 40% compared to starting body weight) |\n| Repro |  |  |  |  |  | 1.06 M |  |  |  |\n| Exposed rats were mated with both exposed and unexposed rats 6 days post-exposure |  |  |  |  |  |  |  |  |  |\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| NTP 1995 |  |  |  |  |  |  |  |  | Cadmium oxide aerosol |\n| 32 | Rat (Fischer-344) 10 M, 10 F | 13 weeks 5 days/week 6.33 hours/day (WB) | 0, 0.021, 0.046, 0.088, 0.212, 0.902 | LE, CS, BW, HE, BC, UR, OW, HP, OF, RX | Bd wt Resp | 0.902 | 0.021 F | 0.902 M | Minimal epithelial degeneration in the larynx LOAEL: Minimal alveolar histiocytic infiltrate and epithelial hyperplasia; minimal epithelial degeneration in the larynx SLOAEL: Marked inflammation and moderate fibrosis in interstitium around alveolar ducts and terminal bronchioles |\n| 32 | Rat (Fischer-344) 10 M, 10 F | 13 weeks 5 days/week 6.33 hours/day (WB) | 0, 0.021, 0.046, 0.088, 0.212, 0.902 | LE, CS, BW, HE, BC, UR, OW, HP, OF, RX | Cardio Gastro Hemato Musc/skel Hepatic Renal Endocr Immuno Neuro Repro | 0.902 0.902 0.902 0.902 0.902 0.902 0.902 | 0.021 M | 0.046 M | Minimal epithelial degeneration in the larynx LOAEL: Minimal alveolar histiocytic infiltrate and epithelial hyperplasia; minimal epithelial degeneration in the larynx SLOAEL: Marked inflammation and moderate fibrosis in interstitium around alveolar ducts and terminal bronchioles |\n| NTP 1995 |  |  |  |  |  |  |  |  | Decreased spermatid counts in males, increased estrous cycle length in females |\n| 33 | Rat (Sprague-Dawley) 32 F | 16 days GDs 4–19 6.27 hours/day (WB) | 0, 0.04, 0.4, 1.7 | LE, CS, BW,OW, DX | Bd wt | 0.4 | 1.7 | Cadmium oxide aerosol | 14% decrease in maternal body weight on GD 20 Decreased male (16%) and female (17%) fetal body weight; reduced ossification of pelvis and sternebrae |\n| 33 | Rat (Sprague-Dawley) 32 F | 16 days GDs 4–19 6.27 hours/day (WB) | 0, 0.04, 0.4, 1.7 | LE, CS, BW,OW, DX | Develop | 0.4 |  | 1.7 | 14% decrease in maternal body weight on GD 20 Decreased male (16%) and female (17%) fetal body weight; reduced ossification of pelvis and sternebrae |\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects | Cadmium chloride |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Oberdörster et al. 1994 |  |  |  |  |  |  |  |  |  |  |\n| 34 | Rat (Fischer 344) 48 M | 4 weeks 5 days/week 6 hours/day (WB) | 0, 0.100 | BI | Resp |  | 0.1 |  | Increase in BALF PMNs (1 day post-exposure) |  |\n\n| Rats were sacrificed at 1, 7, or 28 days post-exposure (≥4/group/timepoint per endpoint) |  |  |  |  |  |  |  |\n| --- | --- | --- | --- | --- | --- | --- | --- |\n| Oldiges and Glaser 1986 |  |  |  |  |  |  | Cadmium oxide dust |\n| 35 | Rat (Wistar) 20 M, 20 F | 218–343 days 7 days/week 22 hours/day (WB) | M: 0, 0.030, 0.090 F: 0, 0.026, 0.081 | LE, GN, BW, Death FI, WI, HE, OW |  | 0.081 F 0.09 M | 6/20 died 6/20 died |\n| Oldiges and Glaser 1986 |  |  |  |  |  |  | Cadmium sulfide |\n| 36 | Rat (Wistar) 20–24 M, 20–24 F | 105–298 days 7 days/week 22 hours/day (WB) | M: 0, 0.843, 2.270 F: 0, 0.841, 2.247 | LE, GN, BW, Death FI, WI, HE, OW |  | 0.841 F 0.843 M | 7/20 died by day 298 6/20 died by day 208 |\n| Oldiges et al. 1989 |  |  |  |  |  |  | Cadmium chloride |\n| 37 | Rat (Wistar) 20 M, 18–20 F | 6 months 7 days/week 22 hours/day (WB) | 0, 0.090 | LE, GN, HP Death Cancer |  | 0.09 0.09 M | 25% mortality at 6 months CEL: Lung tumors (bronchioalveolar adenoma, adenocarcinoma, or squamous cell carcinoma) |\n| Scheduled sacrifice at 31 months; surviving Cd-exposed rats sacrificed at 29–30 months due to mortality ≥75% |  |  |  |  |  |  |  |\n| Oldiges et al. 1989 |  |  |  |  |  |  | Cadmium sulfide |\n| 38 | Rat (Wistar) 20 M, 20 F | 6 months 40 hours/week (WB) | 0, 0.270 | LE, GN, HP Death |  | 0.27 | 75% mortality at 27–29 months |\n| Scheduled sacrifice at 31 months; surviving Cd-exposed rats sacrificed at 27–29 months due to mortality ≥75% |  |  |  |  |  |  |  |\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Oldiges et al. 1989 |  |  |  |  |  |  |  |  | Cadmium sulfide |\n| 39 | Rat (Wistar) 16–20 M, 19–20 F | 3–10 months 7 days/week 22 hours/day (WB) | 0, 0.810, 2.430 | LE, GN, HP | Death Cancer |  |  | 0.81 | 25% mortality at 7–10 months CEL: Lung tumors (bronchioalveolar adenoma, adenocarcinoma, squamous cell carcinoma, or mixed tumor type) |\n\nScheduled sacrifice at 31 months; most surviving Cd-exposed rats sacrificed at 29-30 months due to mortality ≥75%\n\n| Oldiges et al. 1989 |  |  |  |  |  |  |  | Cadmium oxide dust |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| 40 | Rat (Wistar) 17–20 M, 16–20 F | 7–11 months 7 days/week 22 hours/day (WB) | 0, 0.090 | LE, GN, HP | Death Cancer | 0.09 | 0.09 | 25% mortality at 7–11 months CEL: Lung tumors (bronchioalveolar adenoma, adenocarcinoma, squamous cell carcinoma, or mixed tumor type) |\n\n| Scheduled sacrifice at 31 months |  |  |  |  |  |  |  |  |  |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Prigge 1978a |  |  |  |  |  |  |  | Cadmium oxide dust |  |\n| 41 | Rat (Wistar) 12 F | 90 days 24 hours/day (WB) | 0, 0.025, 0.052 | LE, BW, HE, BC, UR, OW, HP | Bd wt Resp | 0.025 | 0.025 | 0.052 | 23% decrease in body weight gain Proliferative lung lesions, histiocytic cell granulomas Increased hemoglobin and hematocrit |\n| 41 | Rat (Wistar) 12 F | 90 days 24 hours/day (WB) | 0, 0.025, 0.052 | LE, BW, HE, BC, UR, OW, HP | Hematoc | 0.025 | 0.052 | 0.052 | 23% decrease in body weight gain Proliferative lung lesions, histiocytic cell granulomas Increased hemoglobin and hematocrit |\n| 41 | Rat (Wistar) 12 F | 90 days 24 hours/day (WB) | 0, 0.025, 0.052 | LE, BW, HE, BC, UR, OW, HP | Hepatic Renal | 0.052 | 0.052 | 0.052 | 23% decrease in body weight gain Proliferative lung lesions, histiocytic cell granulomas Increased hemoglobin and hematocrit |\n\n| Prigge 1978a |  |  |  |  |  |  |  | Cadmium oxide dust |  |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| 42 | Rat (Wistar) 12 F | 63 days 24 hours/day (WB) | 0, 0.105 | LE, BW, HE, BC, UR | Death |  |  | 0.105 | 5/12 died |\n| 42 | Rat (Wistar) 12 F | 63 days 24 hours/day (WB) | 0, 0.105 | LE, BW, HE, BC, UR | Bd wt Hematoc |  |  | 0.105 | 51% decrease in body weight gain Increased hemoglobin and hematocrit |\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Prigge 1978b |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 43 | Rat (Wistar) 12–13 F | 21 days 24 hours/day (WB) | 0, 0.204, 0.394, 0.581 | BW, HE, BC, UR, OW, HP | Bd wt Hemato | 0.581 | 0.204 |  | Increase in hemoglobin and hematocrit |\n|  |  |  |  |  | Renal | 0.581 |  |  |  |\n| Prigge 1978b |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 44 | Rat (Wistar) 12–13 F | 21 days GDs 1–21 24 hours/day (WB) | 0, 0.204, 0.394, 0.581 | BW, HE, BC, UR, OW, HP, DX | Bd wt |  | 0.204 | 0.394 | LOAEL: 12% decrease in maternal body weight gain SLOAEL: 35% decrease in maternal body weight gain Increased hemoglobin and hematocrit; elevated total (but not direct) bilirubin |\n|  |  |  |  |  | Hemato | 0.394 | 0.581 |  |  |\n|  |  |  |  |  | Renal | 0.581 |  |  |  |\n|  |  |  |  |  | Develop | 0.394 |  | 0.581 | 19% decrease in fetal body weight; decreased fetal hemoglobin |\n| NTP 1995 |  |  |  |  |  |  |  |  | Cadmium oxide aerosol |\n| 45 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week 6.33 hours/day (WB) | 0, 0.021, 0.046, 0.088, 0.211, 0.910 | LE, CS, BW, OW, HP, RX | Bd wt Resp | 0.91 | 0.021 |  | Minimal alveolar histiocytic infiltrates and squamous metaplasia of the larynx |\n|  |  |  |  |  | Cardio | 0.91 |  |  |  |\n|  |  |  |  |  | Gastro | 0.91 |  |  |  |\n|  |  |  |  |  | Musc/skel | 0.91 |  |  |  |\n|  |  |  |  |  | Hepatic | 0.91 |  |  |  |\n|  |  |  |  |  | Renal | 0.91 |  |  |  |\n|  |  |  |  |  | Endocr | 0.91 |  |  |  |\n|  |  |  |  |  | Immuno | 0.91 |  |  |  |\n|  |  |  |  |  | Neuro | 0.91 |  |  |  |\n|  |  |  |  |  | Repro | 0.91 |  |  |  |\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Oberdörster et al. 1994 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 46 | Mouse (BALB/c) 72 M | 4 weeks 5 days/week 6 hours/day (WB) | 0, 0.100 | BI | Resp |  | 0.1 |  | Increase in BALF PMNs and LDH levels (1, 7, and 28 days post-exposure); increase cell proliferation in alveolar epithelium and macrophage infiltration (1 and 7 days post-exposure) |\n| Mice were sacrificed at 1, 7, or 28 days post-exposure (≥4/group/timepoint per endpoint) |  |  |  |  |  |  |  |  |  |\n| Johansson et al. 1984 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 47 | Rabbit (NS) 8 M | 4–6 weeks 5 days/week 6 hours/day (WB) | 0, 0.4 | BI, OW, HP | Resp |  | 0.4 |  | Lung interstitial inflammation, type 2 cell hyperplasia |\n| CHRONIC EXPOSURE |  |  |  |  |  |  |  |  |  |\n| Buchet et al. 1990; Hoo et al. 2004; Järup and Elinder 1994; Järup et al. 2000; Kobayashi et al. 2008; Lei et al. 2007; Shao et al. 2007; Suwazono et al. 2006; Uno et al. 2005; Wu et al. 2001; Zhang et al. 2016a |  |  |  |  |  |  |  |  | Cadmium |\n| 48 | Human 85–3,454 per dataset | 17 datasets (3 occupational and 8 general population cohorts) | UR | Renal |  |  |  | LMW proteinuria; 95% LCL weighted median of 17 UC10 values = 0.00106 mg Cd/m3 c |  |\n| Oldiges and Glaser 1986 |  |  |  |  |  |  |  |  | Cadmium sulfate |\n| 49 | Rat (Wistar) 20–40 M, 20 F | 413–455 days 7 days/week 22 hours/day (WB) | M: 0, 0.095 F: 0, 0.092 | LE, BW, FI, WI, HE, OW, GN | Death |  |  | 0.095 M | 6/20 died |\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Oldiges et al. 1989 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 50 | Rat (Wistar) 20 M, 18–20 F | 18 months 7 days/week 22 hours/day (WB) | 0, 0.030 | LE, GN, HP | Death Cancer |  |  | 0.03 M 0.03 | 75% mortality at 30 months CEL: Lung tumors (bronchioalveolar adenoma, adenocarcinoma, squamous cell carcinoma, or mixed tumor type) |\n| Scheduled sacrifice at 31 months; surviving Cd-exposed males sacrificed at 30 months due to mortality ≥75% |  |  |  |  |  |  |  |  |  |\n| Oldiges et al. 1989 |  |  |  |  |  |  |  |  | Cadmium sulfide |\n| 51 | Rat (Wistar) 19–20 M, 19–20 F | 16–18 months 7 days/week 22 hours/day (WB) | 0, 0.090, 0.270 | LE, GN, HP | Death Cancer |  |  | 0.09 0.270 | 75% mortality at 30 months in males 25% mortality at 16 months in females CEL: Lung tumors (bronchioalveolar adenoma, adenocarcinoma, squamous cell carcinoma, or mixed tumor type) |\n| Scheduled sacrifice at 31 months; surviving Cd-exposed rats sacrificed at 30 months due to mortality ≥75% |  |  |  |  |  |  |  |  |  |\n| Oldiges et al. 1989 |  |  |  |  |  |  |  |  | Cadmium oxide dust |\n| 52 | Rat (Wistar) 20 M, 20 F | 18 months 7 days/week 22 hours/day (WB) | 0, 0.030 | LE, GN, HP | Cancer |  |  | 0.03 | CEL: Lung tumors (bronchioalveolar adenoma, adenocarcinoma, squamous cell carcinoma, or mixed tumor type) |\n| Scheduled sacrifice at 31 months |  |  |  |  |  |  |  |  |  |\n| Oldiges et al. 1989 |  |  |  |  |  |  |  |  | Cadmium sulfate |\n| 53 | Rat (Wistar) 20 M, 20 F | 14–18 months 7 days/week 22 hours/day (WB) | 0, 0.09 | LE, GN, HP | Death Cancer |  |  | 0.09 | 25% mortality in males by 14 months; 75% mortality in females by 29 months CEL: Lung tumors (bronchioalveolar adenoma, adenocarcinoma, squamous cell carcinoma, or mixed tumor type) |\n\nScheduled sacrifice at 31 months; surviving Cd-exposed females sacrificed at 29 months due to mortality ≥75%\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Oldiges et al. 1989 |  |  |  |  |  |  |  |  | Cadmium oxide fume |\n| 54 | Rat (Wistar) 17–20 M | 18 months 7 days/week 22 hours/day (WB) | 0, 0.01, 0.03 | LE, GN, HP | Cancer |  |  | 0.03 | CEL: Lung tumors (bronchioalveolar adenoma, adenocarcinoma) |\n| Takenaka et al. 1983 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 55 | Rat (Wistar) 40–41 M | 18 months 7 days/week 23 hours/day (WB) | 0, 0.0134, 0.0257, 0.0508 | LE, BW, HP | Bd wt Cancer | 0.0508 |  | 0.0134 | CEL: Lung tumors (lung epidermoid carcinomas, or adenocarcinomas) |\n| Scheduled sacrifice at 31 months |  |  |  |  |  |  |  |  |  |\n\n<sup>a</sup>The number corresponds to entries in Figure 2-2; differences in levels of health effects between male and females are not indicated in Figure 2-2.  Where such \ndifferences exist, only the levels of effect for the most sensitive sex are presented.\n\n<sup>b</sup>Concentrations are expressed as mg Cd/m<sup>3</sup>. If concentrations were reported by the study authors in terms of the administered compound (e.g., cadmium chloride \n[CdCl2]), they were converted to the equivalent concentration in terms of the metal (i.e., cadmium [Cd])) for easy comparison across studies.  Conversion was based on \nthe ratio of the molecular weights using the following equation: Concentration in terms of administered compound x (molecular weight Cd/molecular weight administered \ncompound).\n\n<sup>c</sup>Used to derive a chronic-duration inhalation MRL of 0.0001 mg Cd/m<sup>3</sup> (0.1 μg Cd/m<sup>3</sup>).  The point of departure (POD) is based on the 95% lower confidence limit (LCL) \non the weighted median of the UC10 values from 17 datasets from 11 human studies; the weighted median and 95% LCL were 2.04 and 1.57 μg Cd/g Cr, respectively.  \nThese values were converted into inhalation concentration equivalents of 0.00141 and 0.00106 mg Cd/m<sup>3</sup>, respectively, using PBPK modeling.  The POD of 0.00106 mg \nCd/m<sup>3</sup> was divided by an uncertainty factor of 3 for human variability and a modifying factor of 3 for database deficiencies.  See Appendix A for more detailed information \nregarding the MRL.\n\n## Principal studies for the MRL\n\nALP = alkaline phosphatase; AP = acid phosphatase; BALF = bronchoalveolar lavage fluid; BC = serum (blood) chemistry; Bd wt or BW = body weight; BI = biochemical \nchanges; Cardio = cardiovascular; Cd = cadmium; CEL = cancer effect level; Cr = creatinine; CS = clinical signs; Develop = developmental; DX = developmental toxicity; \nEndocr = endocrine; F = female(s); FI = food intake; Gastro = gastrointestinal; GD = gestation day; GN = gross necropsy; (H) = head only; HE = hematology; \nHemato = hematological; HP = histopathology; Immuno = immunological; IX = immune function; LC50 = lethal concentration, 50% kill; LDH = lactate dehydrogenase; \nLE = lethality; LMW = low molecular weight; LOAEL = lowest-observed-adverse-effect level; M = male(s); MRL = Minimal Risk Level; Musc/skel = musculoskeletal; \n(N) = nose-only; Neuro = neurological; NOAEL = no-observed-adverse-effect level; NS = not specified; (occup) = occupational; OF = organ function; OW = organ weight; \nPMN = polymorphonuclear leukocyte; PND = postnatal day; Repro = reproductive; Resp = respiratory; RX = reproductive function; SLOAEL = serious lowest-observedadverse-effect level; UC10 = urinary cadmium level associated with 10% extra risk; UR = urinalysis; (WB) = whole body; WBC = white blood cell; WI = water intake\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Cadmium – Inhalation**\nAcute (≤14 days)\n\n**Figure 2-2. Levels of Significant Exposure to Cadmium – Inhalation, Acute (≤14 days) - Death**\n\n| Category | mg Cd/m3 |\n| --- | --- |\n| 1 | 9 |\n| 2R | 30 |\n| 9R | 9 |\n| 14R | 85 |\n| 15R | 65 |\n| 16M | 40 |\n| 19M | 9 |\n| 21H | 30 |\n\n**Figure 2-2. Levels of Significant Exposure to Cadmium – Inhalation, Acute (≤14 days) - Body Weight**\n\n| Category | Animal - NOAEL (mg Cd/m3) | Animal - LOAEL (mg Cd/m3) | Animal - SLOAEL (mg Cd/m3) |\n| --- | --- | --- | --- |\n| 3R | 0.4 | 4.5 |  |\n| 4R |  | 6.5 |  |\n| 5R | 0.23 | 4.5 |  |\n| 6R | 4.0 |  |  |\n| 8R | 17 |  |  |\n| 9R | 2.5 |  |  |\n| 10R | 6.0 |  |  |\n| 12R | 140 |  |  |\n| 13R | 110 |  |  |\n| 19M | 2.5 |  |  |\n| 20M | 0.4 | 1.7 |  |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Cadmium – Inhalation**\nAcute (≤14 days)\n\n| Category | Human - SLOAEL (mg Cd/m3) | Animal - NOAEL (mg Cd/m3) | Animal - LOAEL (mg Cd/m3) | Animal - SLOAEL (mg Cd/m3) |\n| --- | --- | --- | --- | --- |\n| 1 | 9 |  |  |  |\n| 4R |  | 6 |  |  |\n| 7R |  | 1.6 |  |  |\n| 9R |  | 0.08 |  | 9 |\n| 10R |  | 6 |  |  |\n| 11R |  |  |  | 100 |\n| 14R |  |  |  | 85 |\n| 15R |  |  |  | 65 |\n| 19M |  | 0.008 |  | 0.8 |\n| 22S |  | 1.1 |  | 10 |\n| 9R |  | 2.5 |  |  |\n| 19M |  | 2.7 |  |  |\n| 9R |  | 2.7 |  |  |\n| 19M |  | 2.7 |  |  |\n| 9R |  | 2.7 |  |  |\n| 19M |  | 2.7 |  |  |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Cadmium – Inhalation**\nAcute (≤14 days)\n\n**Figure 2-2. Levels of Significant Exposure to Cadmium – Inhalation (Acute ≤14 days)**\n\n| Category | Human - SLOAEL (mg Cd/m3) | Animal - NOAEL (mg Cd/m3) | Animal - SLOAEL (mg Cd/m3) | Animal - LOAEL (mg Cd/m3) | Animal - LD50/LC50 (mg Cd/m3) |\n| --- | --- | --- | --- | --- | --- |\n| Endocrine |  | 6 |  |  |  |\n| Immunological |  | 0.12 |  | 0.2 | 1.0 |\n| Neurolgical |  |  |  | 90 |  |\n| Reproductive |  |  |  | 17 |  |\n| Developmental |  | 0.045 | 1.7 | 0.35 |  |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Cadmium – Inhalation**\nIntermediate (15–364 days)\n\n**Figure 2-2. Levels of Significant Exposure to Cadmium – Inhalation Intermediate (15–364 days)**\n\n| Category | Death NOAEL (mg Cd/m3) | Death LOAEL (mg Cd/m3) | Body Weight NOAEL (mg Cd/m3) | Body Weight LOAEL (mg Cd/m3) |\n| --- | --- | --- | --- | --- |\n| 24R |  | 1.0 | 1.0 |  |\n| 25R |  | 1.0 | 0.17 | 1.0 |\n| 30R |  | 2.6 | 0.40 | 1.1 |\n| 31R |  | 2.6 | 0.40 | 1.1 |\n| 35R |  | 0.080 |  |  |\n| 36R |  | 0.80 |  |  |\n| 37R |  | 0.090 |  |  |\n| 38R |  | 0.33 |  |  |\n| 39R |  | 0.80 |  |  |\n| 40R |  | 0.090 |  |  |\n| 42R |  | 0.11 |  | 0.11 |\n| 26R |  |  | 0.11 |  |\n| 27R |  |  | 1.0 |  |\n| 28R |  |  | 0.10 |  |\n| 31R |  |  |  | 2.6 |\n| 32R |  |  | 0.90 |  |\n| 33R |  |  | 0.47 | 1.9 |\n| 41R |  |  | 0.028 | 0.055 |\n| 43R |  |  | 0.60 |  |\n| 44R |  |  |  | 0.44 |\n| 44R |  |  |  | 0.22 |\n| 45M |  |  | 0.90 |  |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Cadmium – Inhalation**\nIntermediate (15–364 days)\n\n**Figure 2-2. Levels of Significant Exposure to Cadmium – Inhalation Intermediate (15–364 days)**\n\n| Category | Respiratory Animal - NOAEL (mg Cd/m3) | Respiratory Animal - LOAEL (mg Cd/m3) | Respiratory Animal - SLOAEL (mg Cd/m3) | Respiratory Animal - Cancer Effect Level (mg Cd/m3) | Cardiovascular Animal - NOAEL (mg Cd/m3) | Cardiovascular Animal - LOAEL (mg Cd/m3) | Cardiovascular Animal - SLOAEL (mg Cd/m3) | Cardiovascular Animal - Cancer Effect Level (mg Cd/m3) | Gastrointestinal Animal - NOAEL (mg Cd/m3) | Gastrointestinal Animal - LOAEL (mg Cd/m3) | Gastrointestinal Animal - SLOAEL (mg Cd/m3) | Gastrointestinal Animal - Cancer Effect Level (mg Cd/m3) | Hematological Animal - NOAEL (mg Cd/m3) | Hematological Animal - LOAEL (mg Cd/m3) | Hematological Animal - SLOAEL (mg Cd/m3) | Hematological Animal - Cancer Effect Level (mg Cd/m3) |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| 26R | 0.11 |  |  |  |  |  |  |  |  |  |  |  | 0.11 |  |  |  |\n| 27R |  | 1.1 |  |  |  |  |  |  |  |  |  |  | 1.1 |  |  |  |\n| 28R |  | 0.10 |  |  |  |  |  |  |  |  |  |  |  | 0.10 |  |  |\n| 29R |  | 1.7 |  |  |  |  |  |  |  |  |  |  |  |  |  |  |\n| 32R |  | 0.023 | 0.90 |  | 0.90 |  |  |  | 0.90 |  |  |  | 0.90 |  |  |  |\n| 34R |  | 0.10 |  |  |  |  |  |  |  |  |  |  |  |  |  |  |\n| 41R |  | 0.026 |  |  |  |  |  |  |  |  |  |  | 0.026 | 0.050 |  |  |\n| 45M |  | 0.022 |  |  | 0.90 |  |  |  | 0.90 |  |  |  |  |  |  |  |\n| 46M |  | 0.10 |  |  |  |  |  |  |  |  |  |  |  |  |  |  |\n| 47H |  | 0.45 |  |  |  |  |  |  |  |  |  |  |  |  |  |  |\n| 42R |  |  |  |  |  |  |  |  |  |  |  |  |  | 0.11 |  |  |\n| 43R |  |  |  |  |  |  |  |  |  |  |  |  |  | 0.21 |  |  |\n| 44R |  |  |  |  |  |  |  |  |  |  |  |  | 0.45 |  | 0.60 |  |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Cadmium – Inhalation**\nIntermediate (15–364 days)\n\n**Figure 2-2. Levels of Significant Exposure to Cadmium – Inhalation Intermediate (15–364 days)**\n\n| Category | 32R (mg Cd/m3) | 45M (mg Cd/m3) | 41R (mg Cd/m3) | 26R (mg Cd/m3) | 27R (mg Cd/m3) | 28R (mg Cd/m3) | 32R (mg Cd/m3) | 43R (mg Cd/m3) | 44R (mg Cd/m3) | 45M (mg Cd/m3) | 32R (mg Cd/m3) | 45M (mg Cd/m3) | 32R (mg Cd/m3) | 45M (mg Cd/m3) |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Musculoskeletal | 0.9 | 0.9 |  |  |  |  |  |  |  |  |  |  |  |  |\n| Hepatic | 0.85 | 0.9 | 0.05 |  |  |  |  |  |  |  |  |  |  |  |\n| Renal |  |  |  | 0.11 | 1.1 | 0.1 | 0.9 | 0.55 | 0.55 | 0.85 |  |  |  |  |\n| Endocrine | 0.85 | 0.9 |  |  |  |  |  |  |  |  |  |  |  |  |\n| Immunological | 0.9 | 0.9 |  |  |  |  |  |  |  |  |  |  |  |  |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Cadmium – Inhalation**\nIntermediate (15–364 days)\n\n**Figure 2-2. Levels of Significant Exposure to Cadmium – Inhalation Intermediate (15–364 days)**\n\n| Category | Neurolgical mg Cd/m3 | Reproductive mg Cd/m3 | Developmental mg Cd/m3 | Cancer mg Cd/m3 |\n| --- | --- | --- | --- | --- |\n| 32R | 0.9 | 0.9 |  |  |\n| 45M | 0.9 | 0.9 |  |  |\n| 23R |  | 0.17 | 0.17 |  |\n| 24R |  | 1.0 | 0.17 |  |\n| 25R |  | 1.0 |  |  |\n| 25R |  | 0.18 |  |  |\n| 31R |  | 1.1 |  |  |\n| 32R |  | 0.24 |  |  |\n| 23R |  |  | 0.022 |  |\n| 24R |  |  | 0.022 |  |\n| 33R |  |  | 2.0 |  |\n| 33R |  |  | 0.53 |  |\n| 44R |  |  | 0.6 |  |\n| 44R |  |  | 0.5 |  |\n| 37R |  |  |  | 0.09 |\n| 39R |  |  |  | 0.75 |\n| 40R |  |  |  | 0.09 |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Cadmium – Inhalation**\nChronic (≥365 days)\n\n**Figure 2-2. Levels of Significant Exposure to Cadmium – Inhalation Chronic (≥365 days)**\n\n| Category | Death mg Cd/m3 | Body Weight mg Cd/m3 |\n| --- | --- | --- |\n| 49R | 0.095 |  |\n| 50R | 0.035 |  |\n| 51R | 0.090 |  |\n| 53R | 0.090 |  |\n| 55R |  | 0.050 |\n\n**Figure 2-2. Levels of Significant Exposure to Cadmium – Inhalation Chronic (≥365 days) - Renal**\n\n| Category | Human - Weighted median (mg Cd/m3) | Human - 95% lower confidence limit of weighted median (mg Cd/m3) |\n| --- | --- | --- |\n| 48 | 0.0014 | 0.00011 |\n\n**Figure 2-2. Levels of Significant Exposure to Cadmium – Inhalation Chronic (≥365 days) - Cancer**\n\n| Category | Animal - Cancer Effect Level (mg Cd/m3) |\n| --- | --- |\n| 50R | 0.033 |\n| 51R | 0.095 |\n| 52R | 0.033 |\n| 53R | 0.095 |\n| 54R | 0.033 |\n| 55R | 0.013 |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| ACUTE EXPOSURE |  |  |  |  |  |  |  |  |  |\n| Andjelkovic et al. 2019 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 1 | Rat (Wistar) 6–8 M | Once (GW) | 0, 15, 30 | HE, BC, HP | Hemato |  | 15 |  | Decreased RBC count, hemoglobin, hematocrit, lymphocyte, and serum iron levels; increased MCHC |\n| Baranski 1985 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 2 | Rat (Wistar) 6–18 F | 10 days GDs 7–16 (GW) | 0, 2, 12, 40 | BW, OW, DX | Bd wt |  | 2 | 12 | LOAEL: 14% decrease in maternal body weight gain SLOAEL: 34% decrease in maternal body weight gain |\n| 2 | Rat (Wistar) 6–18 F | 10 days GDs 7–16 (GW) | 0, 2, 12, 40 | BW, OW, DX | Develop | 2 | 12 | 40 | LOAEL: 9% decrease in fetal weight SLOAEL: 23% decrease in fetal weight, decreased live fetuses/litter, increased resorptions/litter, fetal malformations (fused lower limbs, absent limbs) |\n| Bomhard et al. 1987 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 3 | Rat (Wistar) 25–35 M | Once (GW) | 0, 50, 100, 200 | LE, BW, CS, FI, WI, HP | Death Repro | 50 |  | 100 | 28/35 died within 3 days Testicular necrosis, focal proliferation of Leydig cells (6 months post-exposure); hyperemia and slight hemorrhages in testes and epididymides in rats that died |\n| Surviving rats sacrificed 6–30 months post-exposure |  |  |  |  |  |  |  |  |  |\n| Borzelleca et al. 1989 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 4 | Rat (Sprague-Dawley) 10 M, 10 F | Once (GW) | 0, 15, 31, 65.6, 138 | LE, CS, BW, HE, BC, GN, OW | Death |  |  | 138 F 65.6 M | 2/10 died within 24 hours 3/10 died within 24 hours |\n| 4 | Rat (Sprague-Dawley) 10 M, 10 F | Once (GW) | 0, 15, 31, 65.6, 138 | LE, CS, BW, HE, BC, GN, OW | Bd wt Hemato Hepatic Renal | 138 138 138 |  |  |  |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Borzelleca et al. 1989 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 5 | Rat (Sprague-Dawley) 10 M, 10 F | 10 days (W) | M: 0, 1.1, 7.85, 11.2 F: 0, 1.1, 8.16, 13.9 | LE, CS, BW, HE, BC, UR, GN, OW, HP | Bd wt | 13.9 F 1.1 M | 7.85 M | 11.2 M | LOAEL: 14% decrease in body weight SLOAEL: 25% decrease in body weight |\n| 5 | Rat (Sprague-Dawley) 10 M, 10 F | 10 days (W) | M: 0, 1.1, 7.85, 11.2 F: 0, 1.1, 8.16, 13.9 | LE, CS, BW, HE, BC, UR, GN, OW, HP | Hematocrit | 13.9 F 11.2 M 13.9 F 11.2 M 13.9 F 11.2 M |  |  |  |\n| 5 | Rat (Sprague-Dawley) 10 M, 10 F | 10 days (W) | M: 0, 1.1, 7.85, 11.2 F: 0, 1.1, 8.16, 13.9 | LE, CS, BW, HE, BC, UR, GN, OW, HP | Renal | 13.9 F 11.2 M 13.9 F 11.2 M |  |  |  |\n| 5 | Rat (Sprague-Dawley) 10 M, 10 F | 10 days (W) | M: 0, 1.1, 7.85, 11.2 F: 0, 1.1, 8.16, 13.9 | LE, CS, BW, HE, BC, UR, GN, OW, HP | Repro | 13.9 F 11.2 M |  |  |  |\n| Borzelleca et al. 1989 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 6 | Rat (Sprague-Dawley) 10 M, 10 F | 10 days (GW) | 0, 15, 31, 65.6, 138 | LE, CS, BW, HE, BC, UR, GN, OW, HP | Death | 31 F | 65.6 F 15 M | 31 M | 3/10 males and 4/10 females died within 7 days 18% decrease in terminal body weight LOAEL: 18% decrease in terminal body weight SLOAEL: 23% decrease in terminal body weight Increased WBC and platelet counts Increased RBC count Elevated serum ALT, decreased serum cholesterol Mild focal necrosis of hepatocytes or congestion Mild focal necrosis of tubular epithelium |\n| 6 | Rat (Sprague-Dawley) 10 M, 10 F | 10 days (GW) | 0, 15, 31, 65.6, 138 | LE, CS, BW, HE, BC, UR, GN, OW, HP | Bd wt | 31 F | 65.6 F 15 M 31 F |  |  |\n| 6 | Rat (Sprague-Dawley) 10 M, 10 F | 10 days (GW) | 0, 15, 31, 65.6, 138 | LE, CS, BW, HE, BC, UR, GN, OW, HP | Hematocrit | 15 F | 65.6 F 15 M 31 F |  |  |\n| 6 | Rat (Sprague-Dawley) 10 M, 10 F | 10 days (GW) | 0, 15, 31, 65.6, 138 | LE, CS, BW, HE, BC, UR, GN, OW, HP | 65.6 M | 138 M 138 M |  |  |  |\n| 6 | Rat (Sprague-Dawley) 10 M, 10 F | 10 days (GW) | 0, 15, 31, 65.6, 138 | LE, CS, BW, HE, BC, UR, GN, OW, HP | Renal | 31 F | 65.6 F |  |  |\n\n***DRAFT FOR PUBLIC COMMENT***\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n|  |  |  |  |  | Repro | 65.6 M 138 F 31 M | 138 M |  | Mild focal necrosis of tubular epithelium |\n|  |  |  |  |  | Repro | 65.6 M 138 F 31 M | 138 M | 65.6 M | Necrotic changes in testes with atrophy and loss of spermatogenic elements |\n| Dixon et al. 1976 |  |  |  |  |  |  |  |  |  |\n| 7 | Rat (Sprague-Dawley) 10 M | Once (GW) | 0, 6.25, 12.5, 25 | RX | Repro | 25 |  |  | Cadmium chloride |\n| Males serially mated to untreated females for 70 days post-treatment |  |  |  |  |  |  |  |  |  |\n| Kostial et al. 1978 |  |  |  |  |  |  |  |  |  |\n| 8 | Rat (NS) 6 B | Once (G) | NS | LE | Death |  |  | 29 | Cadmium chloride LD50 calculated 8 days post-exposure |\n| Age at exposure: 2 weeks |  |  |  |  |  |  |  |  |  |\n| Kostial et al. 1978 |  |  |  |  |  |  |  |  |  |\n| 9 | Rat (NS) 6 B | Once (G) | NS | LE | Death |  |  | 147 | Cadmium chloride LD50 calculated 8 days post-exposure |\n| Age at exposure: 3 weeks |  |  |  |  |  |  |  |  |  |\n| Kostial et al. 1978 |  |  |  |  |  |  |  |  |  |\n| 10 | Rat (NS) 6 B | Once (G) | NS | LE | Death |  |  | 129 | Cadmium chloride LD50 calculated 8 days post-exposure |\n| Age at exposure: 6 weeks |  |  |  |  |  |  |  |  |  |\n| Kostial et al. 1978 |  |  |  |  |  |  |  |  |  |\n| 11 | Rat (NS) 6 B | Once (G) | NS | LE | Death |  |  | 104 | Cadmium chloride LD50 calculated 8 days post-exposure |\n| Age at exposure: 18 weeks |  |  |  |  |  |  |  |  |  |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Kostial et al. 1978 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 12 | Rat (NS) 6 B | Once (G) | NS | LE | Death |  |  | 66.8 | LD50 calculated 8 days post-exposure |\n| Age at exposure: 54 weeks |  |  |  |  |  |  |  |  |  |\n| Kotsonis and Klaassen 1977 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 13 | Rat (Sprague-Dawley) 6 M | Once (premating) (GW) | 0, 25, 50, 100, 150 | HP, RX, NX | Neuro Repro | 25 50 | 50 | 100 | Decreased motor activity Testicular necrosis; decreased spermatogenesis; decreased fertility (fewer females producing pups) |\n| Males mated to unexposed females |  |  |  |  |  |  |  |  |  |\n| Kotsonis and Klaassen 1977 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 14 | Rat (Sprague-Dawley) 6–12 M | Once (GW) | 0, 25, 50, 100, 150 | CS, BW, HE, BC, BI, UR, HP, OF | Bd wt Resp Cardio Gastro Hematoc Hepatic Renal Endocr | 100 150 150 150 150 150 |  | 150 | Initial body weight loss resulting in approximate 10% decrease in terminal body weight (2 weeks post-exposure) |\n| Kotsonis and Klaassen 1977 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 15 | Rat (Sprague-Dawley) 15–20 M | Once (GW) | NS | LE | Death |  |  | 225 | LD50 at 14 days |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Kotsonis and Klaassen 1978 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 16 | Rat (Sprague-Dawley) 9 M | 2 weeks (W) | 0, 42 | LE | Death |  |  | 42 | 7/9 died within 2 weeks |\n| Machemer and Lorke 1981 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 17 | Rat (Long-Evans) 22–28 F | 10 days GDs 6–15 (GW) | 0, 1.84, 6.13, 18.39, 61.32 | LE, CS, BW, DX | Death Bd wt | 1.84 |  | 61.32 6.13 | 15/25 dams died 27% decrease in maternal body weight gain during treatment period |\n| 17 | Rat (Long-Evans) 22–28 F | 10 days GDs 6–15 (GW) | 0, 1.84, 6.13, 18.39, 61.32 | LE, CS, BW, DX | Gastro | 18.39 |  | 61.32 | Intestinal necrosis, hemorrhage, ulcers, constipation/absence of defecation |\n| 17 | Rat (Long-Evans) 22–28 F | 10 days GDs 6–15 (GW) | 0, 1.84, 6.13, 18.39, 61.32 | LE, CS, BW, DX | Dermal Develop | 1.84 6.13 | 6.13 | 18.39 | Coarse fur Increased number of fetuses with malformations, increased number of runts (<3 g), 7% decrease in fetal body weight |\n| Machemer and Lorke 1981 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 18 | Rat (Long-Evans) 21–24 F | 10 days GDs 6–15 (F) | 0, 1.2, 3.5, 12.5 | LE, CS, BW, FI, DX | Bd wt | 3.5 | 12.5 |  | 19% decrease in maternal body weight gain during treatment period |\n| 18 | Rat (Long-Evans) 21–24 F | 10 days GDs 6–15 (F) | 0, 1.2, 3.5, 12.5 | LE, CS, BW, FI, DX | Develop | 12.5 |  |  |  |\n| Saedi et al. 2020a, 2020b |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 19 | Rat (Sprague-Dawley) 4 F | 13 days PNDs 21–33 (GW) | 0, 15, 31, 46 | BW, BC, HE, OW, HP, DX | Bd wt Hemato | Endocr Develop | 46 15 | 15 | 21% decrease in terminal body weight Decreased RBC and increased WBC levels |\n| 19 | Rat (Sprague-Dawley) 4 F | 13 days PNDs 21–33 (GW) | 0, 15, 31, 46 | BW, BC, HE, OW, HP, DX | Hemat | 15 | 46 15 | 15 | 21% decrease in terminal body weight Decreased RBC and increased WBC levels |\n| 19 | Rat (Sprague-Dawley) 4 F | 13 days PNDs 21–33 (GW) | 0, 15, 31, 46 | BW, BC, HE, OW, HP, DX | Develop | 46 15 | 31 | 15 | Increased atretic follicles and decreased secondary follicles in ovaries; decreased serum estradiol levels |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Samuel et al. 2011 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 20 | Rat (Wistar) 18 F | 13 days GDs 9–21 (W) | 0, 6, 18 | BW, FI, WI, DX | Bd wt | 6 | 18 |  | 11% decrease in maternal body weight on GD 21 |\n| 20 | Rat (Wistar) 18 F | 13 days GDs 9–21 (W) | 0, 6, 18 | BW, FI, WI, DX | Develop |  |  | 6 | Fetal effects: Increased resorption Postnatal effects (female offspring): Decreased postnatal weight on PND 10 (22%) and PND 21 (14%), ovarian follicular degeneration, decreased estradiol and testosterone, delayed vaginal opening, and altered estrous cycling |\n| 20 | Rat (Wistar) 18 F | 13 days GDs 9–21 (W) | 0, 6, 18 | BW, FI, WI, DX | Other noncancer | 6 | 18 |  | Decreased maternal food intake |\n| Three dams/group were sacrificed on GD 21; remaining offspring were sacrificed on PND 10, PND 21, or evaluated during puberty |  |  |  |  |  |  |  |  |  |\n| Shimizu and Morita 1990 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 21 | Rat (Sprague-Dawley) 10 M | Once (GW) | NS | LE | Death |  |  | 106.9 | LD50 at 24 hours (fasted rats) |\n| Shimizu and Morita 1990 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 22 | Rat (Sprague-Dawley) 10 M | Once (GW) | NS | LE | Death |  |  | 327.3 | LD50 at 24 hours (fed rats) |\n| Stacey et al. 1988 |  |  |  |  |  |  |  |  | Cadmium acetate |\n| 23 | Rat (Sprague-Dawley) 4 M | 6 weeks 5 days/week (G) | 0, 0.0025, 0.025, 0.250 | BW, OW, IX | Bd wt | 0.25 |  |  | Enhanced spleen cell proliferative responses |\n| 23 | Rat (Sprague-Dawley) 4 M | 6 weeks 5 days/week (G) | 0, 0.0025, 0.025, 0.250 | BW, OW, IX | Immuno | 0.025 | 0.25 |  | Enhanced spleen cell proliferative responses |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Stacey et al. 1988 |  |  |  |  |  |  |  |  | Cadmium acetate |\n| 24 | Rat (Sprague-Dawley) 4 M | 2 weeks 5 days/week (G) | 0, 0.0025, 0.025, 0.250 | BW, OW, IX | Bd wt Immuno | 0.25 0.25 |  |  |  |\n| Wan et al. 2022 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 25 | Rat (Sprague-Dawley) 3 M, 3 F | 2 weeks (G) | 0, 2, 4 | BW, WI, BC, UR, OW, HP | Bd wt Renal | 4 | 2c |  | Increased 24-hour urinary protein excretion, elevated urinary β 2M levels, increased serum BUN |\n| Andersen et al. 1988 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 26 | Mouse (CBA/Bom) 7–42 M | Once (GW) | 0, 0.6, 3.9, 7.9, 15.7, 30.3, 59.6, 88.8 | LE, HP | Death Gastro | 15.7 | 30.3 | 88.8 | 36/42 mice died within 10 days LOAEL: Gastritis and enteritis SLOAEL: Severe gastric necrosis Fatty infiltration of liver cells, occasional hepatocellular necrosis Proximal tubular necrosis with poor cell differentiation and irregular granulation of cells Testicular necrosis in most tubules and interstitial tissue |\n| 26 | Mouse (CBA/Bom) 7–42 M | Once (GW) | 0, 0.6, 3.9, 7.9, 15.7, 30.3, 59.6, 88.8 | LE, HP | Hepatic | 15.7 | 30.3 | 88.8 | 36/42 mice died within 10 days LOAEL: Gastritis and enteritis SLOAEL: Severe gastric necrosis Fatty infiltration of liver cells, occasional hepatocellular necrosis Proximal tubular necrosis with poor cell differentiation and irregular granulation of cells Testicular necrosis in most tubules and interstitial tissue |\n| 26 | Mouse (CBA/Bom) 7–42 M | Once (GW) | 0, 0.6, 3.9, 7.9, 15.7, 30.3, 59.6, 88.8 | LE, HP | Renal | 59.6 |  | 88.8 | 36/42 mice died within 10 days LOAEL: Gastritis and enteritis SLOAEL: Severe gastric necrosis Fatty infiltration of liver cells, occasional hepatocellular necrosis Proximal tubular necrosis with poor cell differentiation and irregular granulation of cells Testicular necrosis in most tubules and interstitial tissue |\n| 26 | Mouse (CBA/Bom) 7–42 M | Once (GW) | 0, 0.6, 3.9, 7.9, 15.7, 30.3, 59.6, 88.8 | LE, HP | Repro | 30.3 |  | 59.6 | 36/42 mice died within 10 days LOAEL: Gastritis and enteritis SLOAEL: Severe gastric necrosis Fatty infiltration of liver cells, occasional hepatocellular necrosis Proximal tubular necrosis with poor cell differentiation and irregular granulation of cells Testicular necrosis in most tubules and interstitial tissue |\n| Ara et al. 2016 |  |  |  |  |  |  |  |  | Form not specified |\n| 27 | Mouse (Swiss-Webster) 5 F | 7 days GDs 6–12 (GW) | 0, 3.13, 6.25, 12.5, 25.0 | RX, DX | Develop |  |  | 3.13 | 49% decrease in fetal body weight; decreased crown-rump length, head and eye circumference, and forelimb, hindlimb and tail length; anomalies in the brain, eyes, forelimbs, hindlimbs, and tail |\n| Baer and Benson 1987 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 28 | Mouse (Swiss-Webster) 10 M | Once (GW) | 100, 150 | LE | Death |  |  | 95.5 | LD50 at 96 hours |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Yi et al. 2021a |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 29 | Mouse (ICR) 13 F | 10 days GDs 8–17 (W) | 0, 8.1, 24 | DX | Develop |  | 8.1 |  | Impaired glucose tolerance in adult male offspring |\n| INTERMEDIATE EXPOSURE |  |  |  |  |  |  |  |  |  |\n| Chopra et al. 1984 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 30 | Monkey (Rhesus) 3–4 M | 6 months (F) | 0, 5 | CS, BW, IX | Bd wt Immuno | 5 5 |  |  |  |\n| Afolabi et al. 2012 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 31 | Rat (Wistar) 8 M | 7 weeks (W) | 0, 4.6, 9.1 | BW, BC, BI | Hepatic Immuno |  | 4.6 4.6 |  | Increased plasma lipid levels Increased plasma pro-inflammatory cytokines |\n| Ali et al. 1986 |  |  |  |  |  |  |  |  | Cadmium acetate |\n| 32 | Rat (Wistar) 10 F | 21 days GDs 1–21 (W) | 0, 0.706, 1.2 | BW, FI, WI, RX, DX | Bd wt Repro Develop | 1.2 1.2 | 0.706 | 1.2 | Decreased offspring body weight, persisting through PND 45 (~20%) Delayed development of sensory motor coordination reflexes; altered motor activity (increased PNDs 7–21; decreased PND 60) |\n| Aprioku et al. 2014 |  |  |  |  |  |  |  |  | Cadmium sulfate |\n| 33 | Rat (Wistar) 8 F | 21 days GDs 0–20 (W) | 0, 4, 8 | BW, OW, HP, RX, DX | Bd wt Repro Develop |  | 4 | 4 | 40% decrease in maternal body weight on GD 20 Increased abortions |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Baranski 1987 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 34 | Rat (Wistar) 12–16 F | 20 days GDs 1–20 (W) | 0, 4.6, 11.1 | LE, BW, FI, WI, HE, BC, DX | Bd wt Repro Develop | 11.1 |  | 4.6 | 37% decrease in maternal body weight gain |\n| 34 | Rat (Wistar) 12–16 F | 20 days GDs 1–20 (W) | 0, 4.6, 11.1 | LE, BW, FI, WI, HE, BC, DX | Bd wt Repro Develop | 11.1 |  | 4.6 | 12% decrease in fetal body weight and 7% decrease in fetal body length |\n| 34 | Rat (Wistar) 12–16 F | 20 days GDs 1–20 (W) | 0, 4.6, 11.1 | LE, BW, FI, WI, HE, BC, DX | Other noncancer |  | 4.6 |  | Decreased maternal food intake |\n| Baranski and Sitarek 1987 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 35 | Rat (Wistar) 11–13 F | 14 weeks 5 days/week (GW) | 0, 0.04, 0.4, 4, 40 | LE, CS, BW, RX | Death |  |  | 40 | 4/13 died by week 8; 7/13 by week 14 |\n| 35 | Rat (Wistar) 11–13 F | 14 weeks 5 days/week (GW) | 0, 0.04, 0.4, 4, 40 | LE, CS, BW, RX | Bd wt Repro | 0.4 |  | 4 | 40% decrease in body weight gain |\n| 35 | Rat (Wistar) 11–13 F | 14 weeks 5 days/week (GW) | 0, 0.04, 0.4, 4, 40 | LE, CS, BW, RX | Bd wt Repro | 4 |  | 40 | Increased duration of estrus cycle |\n| Baranski et al. 1983 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 36 | Rat (Wistar) NS F | 11 weeks (5 weeks premating, 3 weeks mating, 3 weeks gestation) 5 days/week (GW) | 0, 0.04, 0.4, 4 | RX, DX | Repro Develop | 4 |  |  | Decreased pup locomotor activity and impaired motor coordination at 2 months |\n| 36 | Rat (Wistar) NS F | 11 weeks (5 weeks premating, 3 weeks mating, 3 weeks gestation) 5 days/week (GW) | 0, 0.04, 0.4, 4 | RX, DX | Repro Develop | 4 | 0.04 |  | Decreased pup locomotor activity and impaired motor coordination at 2 months |\n| Half of dams were sacrificed on GD 21; half were allowed to deliver naturally and pups (8/sex/group) were assessed for 2 months after parturition |  |  |  |  |  |  |  |  |  |\n| Brzóska and Moniuszko-Jakoniuk 2005a, 2005b; 2010 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 37 | Rat (Wistar) 10 M | 12 months (W) | 0, 0.2, 0.5, 4 | BW, FI, WI, BC, BI, HP | Bd wt Musc/skel | 4 |  |  | Increased lumbar spine deformities, decreased in lumbar spine and femur mineralization, altered bone turnover parameters |\n| 37 | Rat (Wistar) 10 M | 12 months (W) | 0, 0.2, 0.5, 4 | BW, FI, WI, BC, BI, HP | Bd wt Musc/skel | 0.2 | 0.5 |  | Increased lumbar spine deformities, decreased in lumbar spine and femur mineralization, altered bone turnover parameters |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Brzóska and Moniuszko-Jakoniuk 2005c; Brzóska et al. 2005a, 2005c |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 38 | Rat (Wistar) 40 F | 12 months (W) | 0, 0.2, 0.5, 4 | BW, FI, WI, BC, BI, HP, OF | Bd wt Musc/skel | 4 | 0.2 |  | Decreased bone mineralization, mechanical properties of tibia and femur, and altered bone turnover parameters |\n| Brzóska et al. 2004, 2005b |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 39 | Rat (Wistar) 8–10 F | 12 months (W) | 0, 0.3, 0.7, 4, 8 | BW, FI, WI, BI, OF | Musc/skel |  | 0.3 |  | Alterations in bone mineral content and density and mechanical properties of lumbar vertebral and femoral bones |\n| Buha et al. 2013, 2019 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 40 | Rat (Wistar) 7 M | 28 days (G) | 0, 0.3, 0.6, 1.25, 2.5, 5, 10 | BW, BC, BI | Bd wt Musc/skel | 0.6 | 0.3 | 1.25 | 36% decrease in body weight gain Decreased bone mineral content in femur Increased serum creatinine and urea Decreased serum T3 levels |\n|  |  |  |  |  | Renal Endocr | 2.5 | 5 0.3 |  |  |\n| Caride et al. 2010 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 41 | Rat (Sprague-Dawley) 60 M | 30 days (W) | 0, 0.92, 1.8 | BC | Endocr |  | 0.92 |  | Altered daily secretory pattern of ACTH and growth hormone; increased median levels of ACTH and TSH |\n| Carmignani and Boscolo 1984 |  |  |  |  |  |  |  |  | Cadmium acetate |\n| 42 | Rat (Sprague-Dawley) 10 M | 190 days (W) | 0, 1.4, 2.8 | CS, BW, OF | Bd wt Cardio | 2.8 | 1.4 |  | Increased systolic and diastolic blood pressure |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Chen et al. 2013 |  |  |  |  |  |  |  |  | Form not specified |\n| 43 | Rat (Sprague-Dawley) 6 M | 12 weeks (W) | 0, 0.2, 1.1, 5.0 | BW, BC, BI, UR, HP | Bd wt Musc/skel | 5 | 0.2 |  | Trabecular bone damage in tibia (decreased number, thickness; increased separation, increased dissociated ends); altered bone turnover parameters |\n| Cifone et al. 1989 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 44 | Rat (Wistar) 4 F | 170 days (W) | 0, 29, 58 | CS, BW, FI, WI, OW, IX | Bd wt Immuno | 58 | 29 |  | Biphasic decrease (first 30–50 days) then increase in NK cell activity, splenic cellularity, and the number of large granular lymphocytes in the peripheral blood; increased total peripheral lymphocytes |\n| Desi et al. 1998 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 45 | Rat (Wistar) NS F | 94 days F0: GDs 5–15 + PNDs 2–28 F1: PNWs 5–12 5 days/week (GW) | 0, 3.5, 7.0, 14.0 | DX | Develop | 3.5 | 7 |  | Decreased peripheral nerve conduction velocity with increased refractory periods |\n| Locomotor and sensory function assessed in F1 males at 12 weeks of age |  |  |  |  |  |  |  |  |  |\n| Desi et al. 1998 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 46 | Rat (Wistar) NS F | 11 days GDs 5–15 (GW) | 0, 3.5, 7.0, 14.0 | DX | Develop | 14 |  |  |  |\n| Locomotor and sensory function assessed in F1 males at 12 weeks of age |  |  |  |  |  |  |  |  |  |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Desi et al. 1998 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 47 | Rat (Wistar) NS F | 38 days GDs 5–15 plus PNDs 2–28 (GW) | 0, 3.5, 7.0, 14.0 | DX | Develop | 3.5 | 7 |  | Decreased horizontal ambulation and rearing activity |\n| Locomotor and sensory function assessed in F1 males at 12 weeks of age |  |  |  |  |  |  |  |  |  |\n| Dixon et al. 1976 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 48 | Rat (Sprague-Dawley) 10 M | 30–90 days (W) | 0, 0.00014, 0.0014, 0.014 | BC, OW, RX | Repro | 0.014 |  |  |  |\n| Males mated to untreated females |  |  |  |  |  |  |  |  |  |\n| Feng et al. 2019 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 49 | Rat (Sprague-Dawley) NS F | 6 weeks GD 0 to PND 21 (W) | 0, 0.6, 3 | DX | Develop |  | 0.6 |  | Impaired learning and memory in F1 males at PNDs 35 and 56 |\n| Huang et al. 2020 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 50 | Rat (Sprague-Dawley) <10 F | 3 weeks GD 1 to birth (GW) | 0, 0.3, 1.2, 4.9 | DX | Develop |  | 0.3 |  | F1 males: Decreased serum testosterone and increased seminiferous tubule diameter at PND 21; decreased Johnsen score (decreased testicular maturity) on PND 56 |\n| Iqbal et al. 2021 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 51 | Rat (Sprague-Dawley) 6 M | 17 days (GW) | 0, 5, 10, 15 | BW, OW, HP | Bd wt | 10 |  | 15 | 12% body weight loss during exposure (compared to 12% body weight gain in control) |\n|  |  |  |  |  | Repro | 5 | 10 |  | Structural changes in the testis and epididymis |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\nstimulated plasma insulin levels\n\nAltered glucose tolerance at PND 21\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects | Cadmium chloride |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Jacquet et al. 2018 |  |  |  |  |  |  |  |  |  |  |\n| 52 | Rat (Wistar) 9 M, 9 F | 12 weeks (W) | M: 0, 0.0053, 0.0558, 0.515; F: 0, 0.0055, 0.053, 0.4959 | LE, BW, BC, UR, OW, OF | Bd wt | 0.4959 F 0.515 M 0.4959 F 0.515 M Endocr | 0.053 F |  |  |  |\n| Jacquet et al. 2019 |  |  |  |  |  |  |  |  |  |  |\n| 53 | Rat (Wistar) 15–17 F | 11 weeks 3 weeks prior to mating GD 0–PND 35 (W) | 0, 0, 0.05, 0.5 | UR, RX, DX | Renal Repro Develop | 0.5 0.5 | 0.05 |  |  | Cadmium chloride |\n| Dams were sacrificed on PND 35; pups were sacrificed on PND 21, 26, and 60 |  |  |  |  |  |  |  |  |  |  |\n| Kelman et al. 1978 |  |  |  |  |  |  |  |  |  |  |\n| 54 | Rat (Sprague-Dawley) 15 F | 22 days GDs 0–21 (W) | 0, 1.5, 3.8 | HE, BI, DX | Hemato Musc/skel Develop | 3.8 | 1.5 | 1.5 | Decreased hematocrit | Form not specified |\n| Kotsonis and Klaassen 1978 |  |  |  |  |  |  |  |  |  |  |\n| 55 | Rat (Sprague-Dawley) 6 M | 24 weeks (W) | 0, 1.1, 2.92, 8.49 | CS, BW, FI, WI, HE, BC, BI, OW, HP, OF, RX, NX | Bd wt Resp Cardio Gastro Hemato Musc/skel Hepatic Renal Endocr | 8.49 8.49 8.49 8.49 8.49 1.1 | 8.49 8.49 8.49 1.1 | 8.49 8.49 8.49 1.1 | 8.49 8.49 8.49 1.1 | Cadmium chloride |\n\nProteinuria (starting at week 6)\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n|  |  |  |  |  | Immuno Neuro Repro | 8.49 1.1 8.49 | 2.92 |  | Decreased motor activity (starting at week 3) |\n| Males mated to unexposed females |  |  |  |  |  |  |  |  |  |\n| Kulas et al. 2019 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 56 | Rat (Dark Agouti) 8 M | 30 days (W) | 0, 0.35, 3.51 | OW, HP | Resp |  | 0.35 |  | Minimal to mild perivascular edema and respiratory epithelial desquamation in lungs |\n| Larregle et al. 2008 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 57 | Rat (Wistar) 8 M | 8 weeks daily (W) | 0, 18 | BC | Hepatic |  | 18 |  | Increased serum and liver triglyceride levels; increased serum cholesterol levels |\n| Li et al. 2018 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 58 | Rat (Sprague-Dawley) 10 F | 42 days GD 0-PND 21 (GW) | 0, 0.6, 3 | DX | Develop |  | 0.6 |  | F1 females: Decreased primordial follicles (PND 21) and increased serum estradiol (PND 21, PND 35) F2: females: Increased serum progesterone (PND 21) |\n| Liu et al. 2019 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 59 | Rat (Sprague-Dawley) 10 M | 60 days (G) | 0, 0.6, 1.5, 3 | CS, FI, WI, BW, BC, UR, OW, HP | Bd wt |  |  | 1.5 | 20% decrease in terminal body weights Decreased serum iron Increased BUN and serum creatinine |\n| Liu et al. 2020 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 60 | Rat (Sprague-Dawley) 5 F | 20 days GDs 1-21 (GW) | 0, 0.3, 1.2, 4.9 | DX | Develop |  | 0.3 |  | Decreased ovarian granulosa cell progesterone in F1 female offspring on PND 56 |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects | Cadmium chloride |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Loeser and Lorke 1977 |  |  |  |  |  |  |  |  |  |  |\n| 61 | Rat (Wistar) 20 M, 20 F | 3 months (F) | 0, 0.1, 0.3, 1, 3 | HP, BC, CS, UR, OW, OF, BW, FI | Bd wt Cardio Hematoc Hepatic Renal Endocr Immuno Repro | 3 3 3 3 3 3 | 0.439 | Decreased offspring body weights (by up to ~19% on PNW 9) | Cadmium chloride |  |\n| Luo et al. 2015 |  |  |  |  |  |  |  |  |  |  |\n| 62 | Rat (Sprague-Dawley) 10 F | 42 days GD 0-PND 21 (W) | 0, 0.089, 0.439, 0.955 | BW, RX, DX | Bd wt Repro Develop | 0.955 0.955 0.089 |  | 0.439 | Decreased offspring body weights (by up to ~19% on PNW 9) | Cadmium chloride |\n| McCalla et al. 2024 |  |  |  |  |  |  |  |  |  |  |\n| 63 | Rat (Sprague-Dawley) 10 M | 8 weeks 3 times/week (GW) | 0, 2.5, 5 | BW, HE, OF | Cardio Hematoc | 2.5 | 2.5 5 |  | Increased blood pressure Decreased mean cell volume and mean cell hemoglobin; increased red cell distribution width | Cadmium chloride |\n| Muller et al. 1988 |  |  |  |  |  |  |  |  |  |  |\n| 64 | Rat (Sprague-Dawley) 4 M | 6 weeks 5 days/week (GW) | 0, 0.0025, 0.025, 0.25 | BW, BC, BI, OW | Bd wt Hepatic | 0.25 0.25 |  |  |  | Cadmium acetate |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Nagymajtenyi et al. 1997 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 65 | Rat (Wistar) 5 M, 10 F | 3 generations ~16–18 weeks per generation (GW) | 0, 3.5, 7.0, 14.0 | CS, BW, RX, DX | Bd wt Repro Develop | 14 14 3.5 M | 7 M |  | Decreased tail nerve conduction velocity (all generations); prolonged latency and duration of somatosensory evoked potentials (F2, F3); increased frequency in auditory and visual evoked potentials (F3); 5% decrease in F3 body weight at PNW 12 |\n| Nasiadek et al. 2018 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 66 | Rat (Wistar) 20 F | 30 days (GW) | 0, 0.09, 1.8, 4.5 | CS, BW, BC, OW, HP | Bd wt Repro | 4.5 0.09 | 1.8 |  | Decreased plasma estradiol |\n| Nasiadek et al. 2019 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 67 | Rat (Wistar) 24 F | 90 days (GW) | 0, 0.09, 0.9, 1.8, 4.5 | LE, CS, BW, FI, WI, BC, OW, HP | Bd wt Repro | 4.5 0.09 | 0.9 |  | Decreased plasma estradiol |\n| Nation et al. 1984 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 68 | Rat (Sprague-Dawley) 9 M | 55 days (F) | 0, 1, 5 | CS, NX | Neuro | 1 | 5 |  | Increased anxiety-like behavior (passive avoidance) |\n| Ninkov et al. 2016 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 69 | Rat (Albino Oxford) 8–16 M | 30 days (W) | 0, 0.4, 4.1 | OW, HP, IX | Gastro Immuno | 4.1 | 0.4 |  | Increased intestinal lymphocyte counts, and mesenteric lymph node relative weight and cellularity; decreased spleen cell proliferative response |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Ogoshi et al. 1989 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 70 | Rat (NS) 19–22 F | 4 weeks (W) | 0, 1, 2.5 | BW, HE, BC, BI, OF | Bd wt Hemato | 2.5 | 1 |  | Decreased hematocrit, hemoglobin, MCHC, and MCV |\n|  |  |  |  |  | Musc/skel |  | 1 |  | Decreased bone strength |\n| Weanling rats (21-day-old) |  |  |  |  |  |  |  |  |  |\n| Ogoshi et al. 1989 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 71 | Rat (NS) 18–25 NS | 4 weeks (W) | 0, 1.6, 3.3, 6.6, 13, 26.2 | BW, HE, BC, BI, OF | Bd wt Hemato | 26.2 | 13 |  | Decreased hematocrit and MCV |\n|  |  |  |  |  | Musc/skel | 6.6 |  |  |  |\n| Adult rats (24-week-old) |  |  |  |  |  |  |  |  |  |\n| Ogoshi et al. 1989 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 72 | Rat (NS) 25–27 NS | 4 weeks (W) | 0, 11, 21.5 | BW, HE, BC, BI, OF | Bd wt Hemato | 11 | 21.5 |  | 10% decrease in body weight gain |\n|  |  |  |  |  | Musc/skel | 21.5 |  |  | Decreased hemoglobin and MCHC |\n| Aged rats (1.5-year-old) |  |  |  |  |  |  |  |  |  |\n| Oluranti et al. 2021 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 73 | Rat (Wistar) 5 M | 21 days (G) | 0, 3, 18 | BC, BI, OW | Endocr |  | 3 |  | Decreased plasma insulin and glucose levels |\n| Petering et al. 1979 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 74 | Rat (Sprague-Dawley) 5 F | 111 days (90 days prior mating through GD 21) (W) | 0, 0.56, 1.3, 2.61, 5.23 | HE, RX, DX | Repro Develop | 5.23 | 1.3 | 2.61 | 10% decrease in birth weight |\n| Prigge 1978a |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 75 | Rat (Wistar) 12 F | 90 days (W) | 0, 3.8, 7.6, 15.2 | LE, BW, HE, BC, BI, UR, OW | Bd wt Hemato | 3.8 | 3.8 | 7.6 | 28% decrease in body weight gain |\n|  |  |  |  |  | Renal | 3.8 | 7.6 |  | Decreased serum iron |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Sarmiento-Ortega et al. 2017 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 76 | Rat (Wistar) 10 M | 3, 4, or 5 months (W) | 0, 2.94 | BC, OF | Hepatic |  | 2.94 |  | Increased serum and hepatic lipid concentrations |\n| 76 | Rat (Wistar) 10 M | 3, 4, or 5 months (W) | 0, 2.94 | BC, OF | Endocr |  | 2.94 |  | Increased serum glucose and insulin levels following administration of an oral glucose load |\n| 76 | Rat (Wistar) 10 M | 3, 4, or 5 months (W) | 0, 2.94 | BC, OF | Other noncancer |  | 2.94 |  | Increased abdominal circumference, body mass index, and percentage of body fat |\n| Sorell and Graziano 1990 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 77 | Rat (Sprague-Dawley) 42–66 F | 15 days GDs 6–20 (W) | 0, 0.629, 4.714, 8.171 | BW, WI, HE, DX | Bd wt | 0.629 | 4.714 | 8.171 | LOAEL: 13% decrease in maternal weight gain SLOAEL: 30% decrease in maternal body weight gain |\n| 77 | Rat (Sprague-Dawley) 42–66 F | 15 days GDs 6–20 (W) | 0, 0.629, 4.714, 8.171 | BW, WI, HE, DX | Hemato | 4.714 | 8.171 |  | Reduced maternal hemoglobin levels |\n| 77 | Rat (Sprague-Dawley) 42–66 F | 15 days GDs 6–20 (W) | 0, 0.629, 4.714, 8.171 | BW, WI, HE, DX | Develop | 0.629 | 4.714 |  | 8% decrease in fetal body weight |\n| Sun et al. 2023 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 78 | Rat (Sprague-Dawley) 10 M | 29 days (GW) | 0, 0.3, 1, 5 | DX | Develop | 0.3 | 1 |  | Decreased serum estradiol and progesterone in adult F1 females |\n| F0 males were mated to unexposed females; reproductive development was assessed in F1 and F2 female offspring |  |  |  |  |  |  |  |  |  |\n| Sutou et al. 1980 |  |  |  |  |  |  |  |  | Form not specified |\n| 79 | Rat (Sprague-Dawley) 14 M, 14 F | 9 weeks (premating through GD 20) (GW) | 0, 0.1, 1.0, 10 | RX, DX | Repro | 1 |  | 10 | Decreased number of copulating and pregnant females; 49% reduction in number of live fetuses/litter; decreased total implants/litter, increased resorptions/litter |\n| 79 | Rat (Sprague-Dawley) 14 M, 14 F | 9 weeks (premating through GD 20) (GW) | 0, 0.1, 1.0, 10 | RX, DX | Develop | 1 |  | 10 | Decreased fetal body weight in males (34%) and females (33%); decreased body and tail length; delayed ossification |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Tang et al. 2016 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 80 | Rat (Sprague-Dawley) 6 M | 3 months (W) | 0, 0.28, 1.41, 7.07 | HP | Musc/skel | 1.41 | 7.07 |  | Decreased bone density and trabecular bone loss and damage in tibia (decreased trabecular volume and number, increased trabecular separation) |\n| Tian et al. 2017 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 81 | Rat (Sprague-Dawley) NS F | 6 weeks GD 0 to PND 21 (GW) | 0, 0.6, 3 | DX | Develop |  | 0.6 |  | Decreased serum progesterone and testosterone and in male offspring on PND 35 and 56, respectively; decreased relative testis weight on PND 21 |\n| Tucovic et al. 2018 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 82 | Rat (Dark Agouti) 4–6 M | 30 days (W) | 0, 0.7, 6.6 | BW, FI, WI, HE BC, UR, HP | Bd wt Hemato | 6.6 |  |  | Increased percent neutrophil leukocytes and eosinophil leukocytes |\n| 82 | Rat (Dark Agouti) 4–6 M | 30 days (W) | 0, 0.7, 6.6 | BW, FI, WI, HE BC, UR, HP | Hepatic Immuno | 6.6 0.7 | 6.6 |  | Increased IL-6 and TNF in skin |\n| Wan et al. 2022 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 83 | Rat (Sprague-Dawley) 3 M, 3 F | 4 weeks (G) | 0, 2, 4 | BW, WI, BC, UR, OW, HP | Bd wt Renal | 4 |  |  | Increased 24-hour urinary protein excretion, elevated urinary β 2M levels, increased serum BUN |\n| Wan et al. 2022 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 84 | Rat (Sprague-Dawley) 3 M, 3 F | 8 weeks (G) | 0, 2, 4 | BW, WI, BC, UR, OW, HP | Bd wt Renal | 4 |  |  | Increased 24-hour urinary protein excretion, elevated urinary β 2M levels, increased serum BUN |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Wang et al. 2014 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 85 | Rat (Sprague-Dawley) 8 M, 8 F | 28 days (GW) | 0, 1, 2.5, 5, 10, 20 | LE, CS, BW, FI, HE, BC, UR, GN, OW, HP | Bd wt | 5 | 10 |  | Decrease in terminal body weight in males (12%) and females (11%) |\n| 85 | Rat (Sprague-Dawley) 8 M, 8 F | 28 days (GW) | 0, 1, 2.5, 5, 10, 20 | LE, CS, BW, FI, HE, BC, UR, GN, OW, HP | Cardio | 20 |  |  | Decrease in terminal body weight in males (12%) and females (11%) |\n| 85 | Rat (Sprague-Dawley) 8 M, 8 F | 28 days (GW) | 0, 1, 2.5, 5, 10, 20 | LE, CS, BW, FI, HE, BC, UR, GN, OW, HP | Hemat | 10 F | 20 F |  | Increased platelets |\n| 85 | Rat (Sprague-Dawley) 8 M, 8 F | 28 days (GW) | 0, 1, 2.5, 5, 10, 20 | LE, CS, BW, FI, HE, BC, UR, GN, OW, HP | Hepatic | 2.5 M | 5 M |  | Increased platelets |\n| 85 | Rat (Sprague-Dawley) 8 M, 8 F | 28 days (GW) | 0, 1, 2.5, 5, 10, 20 | LE, CS, BW, FI, HE, BC, UR, GN, OW, HP | Renal | 10 F | 20 F |  | Increased serum ALT |\n| 85 | Rat (Sprague-Dawley) 8 M, 8 F | 28 days (GW) | 0, 1, 2.5, 5, 10, 20 | LE, CS, BW, FI, HE, BC, UR, GN, OW, HP | Endocr | 20 |  |  |  |\n| 85 | Rat (Sprague-Dawley) 8 M, 8 F | 28 days (GW) | 0, 1, 2.5, 5, 10, 20 | LE, CS, BW, FI, HE, BC, UR, GN, OW, HP | Immuno | 20 |  |  |  |\n| 85 | Rat (Sprague-Dawley) 8 M, 8 F | 28 days (GW) | 0, 1, 2.5, 5, 10, 20 | LE, CS, BW, FI, HE, BC, UR, GN, OW, HP | Neuro | 20 |  |  |  |\n| 85 | Rat (Sprague-Dawley) 8 M, 8 F | 28 days (GW) | 0, 1, 2.5, 5, 10, 20 | LE, CS, BW, FI, HE, BC, UR, GN, OW, HP | Repro | 5 | 10 |  | Decreased serum LH and testosterone in males; increased absolute and relative uterine weight |\n| 85 | Rat (Sprague-Dawley) 8 M, 8 F | 28 days (GW) | 0, 1, 2.5, 5, 10, 20 | LE, CS, BW, FI, HE, BC, UR, GN, OW, HP | Other | 1 F | 2.5 F |  | Decreased food intake |\n| 85 | Rat (Sprague-Dawley) 8 M, 8 F | 28 days (GW) | 0, 1, 2.5, 5, 10, 20 | LE, CS, BW, FI, HE, BC, UR, GN, OW, HP | noncancer |  |  |  |  |\n| Weng et al. 2014 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 86 | Rat (Wistar) 12 F | 8 weeks (G) | 0, 0.3, 1.2, 4.9 | BW, OW, HP | Bd wt | 4.9 |  |  |  |\n| 86 | Rat (Wistar) 12 F | 8 weeks (G) | 0, 0.3, 1.2, 4.9 | BW, OW, HP | Repro | 0.3 | 1.2 |  | Decreased absolute and relative ovary weight, increased atretic follicles, follicular cell apoptosis |\n| Xu et al. 2015 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 87 | Rat (Sprague-Dawley) 6 M | 90 days (GW) | 0, 0.7, 2.0, 6.0 | LE, CS, BW, HP | Bd wt | 6 |  |  |  |\n| 87 | Rat (Sprague-Dawley) 6 M | 90 days (GW) | 0, 0.7, 2.0, 6.0 | LE, CS, BW, HP | Neuro | 0.7 | 2 |  | Neuronal degeneration in cortex |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Yang et al. 2021a |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 88 | Rat (Sprague-Dawley) 9 NR | 8 weeks 5 days/week (GW) | 0, 0.15, 0.61, 2.5 | BC | Hepatic | 0.15 | 0.61 |  | Increased serum triglycerides, total cholesterol, and LDL cholesterol; decreased serum HDL cholesterol |\n|  |  |  |  |  | Renal | 0.61 | 2.5 |  | Increased serum urea nitrogen |\n| Yi et al. 2021b |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 89 | Rat (Sprague-Dawley) 6 M | 28 days (GO) | 0, 1, 3 | BW, BC, OW, HP, RX | Bd wt Repro | 3 | 1 |  | Decreased serum testosterone levels |\n| Zenick et al. 1982 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 90 | Rat (Long-Evans) 5 M | 70–80 days (W) | 0, 1.16, 2.32, 4.64 | BW, FI, WI, HP, RX, DX | Bd wt Repro Develop for fetal effects | 4.64 4.64 4.64 | 25 | 12 | LOAEL: 13% decrease in terminal body weight SLOAEL: 25% decrease in terminal body weight |\n| Males were mated with three untreated females; one litter evaluated for fetal effects and two litters evaluated for neurobehavior on PND 21 or 90 |  |  |  |  |  |  |  |  |  |\n| Zhang et al. 2022a |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 91 | Rat (Sprague-Dawley) 8 M | 12 weeks (G) | 0, 1.5, 3, 6.1, 12, 25 | LE, CS, BW, BC, OW, HP | Bd wt | 6.1 | 12 | 25 | LOAEL: 13% decrease in terminal body weight SLOAEL: 25% decrease in terminal body weight |\n|  |  |  |  |  | Hepatic | 1.5 | 3 | 12 | LOAEL: Hepatic fibrosis SLOAEL: Hepatic fibrous tissue proliferation |\n| Zhang et al. 2023a |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 92 | Rat (Sprague-Dawley) 6 M | 4 weeks (GW) | 0, 2.5, 5 | BC, HP, RX | Repro | 2.5 |  | 5 | Decreased serum testosterone, LH, and GnRH; decreased sperm count and motility; decreased seminiferous tubule diameter and seminiferous epithelial thickness |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Zhang et al. 2024a |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 93 | Rat (Sprague-Dawley) 10–30 M | 4 weeks (GW) | 0, 5 | BW, RX, DX | Bd wt Repro |  | 5 | 5 | 13% decrease in body weight Decreased fertility and percent live births, sperm quality, and levels of serum testosterone and gonad releasing hormone; decreased seminiferous tubule diameter and area, seminiferous epithelium thickness, and Johnsen score; decreased number of cells in interstitial region of testes and disordered cellular arrangement |\n| Males were mated with unexposed females. |  |  |  |  | Develop |  |  | 5 | 21% decrease in male fetal weight |\n| Blakley 1985 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 94 | Mouse (BDF1) 22 F | 3 weeks (W) | 0, 1.4, 2.8, 14 | CS, BW, GN, IX | Bd wt Immuno | 14 1.4 | 2.8 |  | Decreased humoral immune response |\n| Blakley 1988 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 95 | Mouse (BDF1) 14–16 F | 26 days (W) | 0, 2.5, 12.5 | BW, WI, IX | Immuno | 12.5 |  |  |  |\n| Aged mice (12-month-old) |  |  |  |  |  |  |  |  |  |\n| Chatterjee and Saxena 2015 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 96 | Mouse (C57BL/6) 10–15 M | 6 weeks (W) | 0, 7.6, 150 | HE, BC | Hemato Immuno | 150 | 7.6 |  | Decreased RBC count and hemoglobin |\n| Chou et al. 2023 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 97 | Mouse (C57BL/6) 11–18 M | 12 weeks (W) | 0, 11, 21 | BW, OF, HP | Bd wt Cardio | 21 |  | 11 | Cardiomyocyte apoptosis |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects | Cadmium chloride |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Exon et al. 1986 |  |  |  |  |  |  |  |  |  |  |\n| 98 | Mouse (Swiss-Webster) 20 M | 10 weeks (W) | 0, 0.57, 5.7, 57 | LE, BW, GN, HP, IX | Bd wt Immuno | 57 57 |  |  |  |  |\n| Exon et al. 1986 |  |  |  |  |  |  |  |  |  |  |\n| 99 | Mouse (Swiss-Webster) 20 M | 10 weeks (W) | 0, 0.57, 5.7, 57 | LE, BW, GN, HP, IX | Bd wt Immuno | 0.57 57 | 5.7 |  | Cadmium acetate | 14% decrease in body weight |\n| Exon et al. 1986 |  |  |  |  |  |  |  |  |  |  |\n| 100 | Mouse (Swiss-Webster) 20 M | 10 weeks (W) | 0, 0.57, 5.7, 57 | LE, BW, GN, HP, IX | Bd wt Immuno | 57 57 |  |  |  | Cadmium sulfate |\n| Gathwan and Albir 2020 |  |  |  |  |  |  |  |  |  |  |\n| 101 | Mouse (Swiss) 6 M | 30 days (G) | 0, 6.1, 12.3, 19.5 | BW, FI, WI, OW, HP | Bd wt | 6.1 | 12.3 | 19.5 | LOAEL: 13% decrease in terminal body weight SLOAEL: 23% decrease in terminal body weight | Cadmium oxide |\n| He et al. 2019a |  |  |  |  |  |  |  |  |  |  |\n| 102 | Mouse (C57BL/6) 10 M | 20 weeks (W) | 0, 1.475, 6.566 | LE, CS, WI, BC, BI, OW, HP | Bd wt Hepatic | Endocr | 6.566 | 1.475 | 6.566 | Cadmium chloride 22% decrease in body weight gain NAFLD; increased hepatic triglyceride levels |\n| He et al. 2019b |  |  |  |  |  |  |  |  |  |  |\n| 103 | Mouse (BALB/c) 12 F | 16 weeks (W) | 0, 2, 6.5 | BW, FI, BC, BI, HP | Bd wt Musc/skel | 6.5 | 2 |  |  | Cadmium chloride |\n\nTrabecular bone damage\n(decreased number, thickness;\nincreased separation, fat cells);\naltered bone turnover parameters\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| He et al. 2020 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 104 | Mouse (C57BL/6) 10 M | 20 weeks (W) | 0, 1.5, 7.6 | LE, CS, BW, HP | Bd wt Gastro | 7.6 1.5 | 7.6 |  | Decreased length of intestinal villus and thickness of intestinal wall |\n| Hudson et al. 2019 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 105 | Mouse (C57BL/6J) NS F | 8 weeks 5 weeks prior to mating until birth (W) | 0, 0.3, 13 | RX, DX | Repro Develop | 13 | 0.3 | 13 | LOAEL: Increased absolute and relative heart weight in female pups at birth; increased tail blood volume and tail blood flow in female offspring at 5.5 months of age SLOAEL: 12% decrease in birth weight in both sexes; increased absolute and relative heart weight in male pups at birth; increased systolic, diastolic, and mean arterial blood pressure in female offspring at 5.5 months of age |\n| C57BL/6J dams mated to unexposed CAST/EiJ males, to generate F1 hybrid mice |  |  |  |  |  |  |  |  |  |\n| Hudson et al. 2019 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 106 | Mouse (CAST/EiJ) NS F | 8 weeks 5 weeks prior to mating until birth (W) | 0, 0.3, 13 | RX, DX | Repro Develop | 13 | 0.3 | 13 | LOAEL: Decreased body weight at birth in males; increased absolute heart weight in females SLOAEL: 22% decrease in birth weight |\n| CAST/EiJ dams mated to unexposed C57BL/6J males, to generate F1 hybrid mice |  |  |  |  |  |  |  |  |  |\n| Krzystyniak et al. 1987 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 107 | Mouse (C57BL/6) 10 F | 12–16 weeks (W) | 0, 0.6, 17, 52 | IX | Immuno | 17 | 52 |  | Reduced humoral immune response |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Kurita et al. 2018 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 108 | Mouse (C57BL/6J) 3–10 F | 18 days GDs 1–18 (G) | 0, 5, 10 | DX | Develop | 5 |  | 10 | 34% decrease in fetal weight, decreased fetal length |\n| Li et al. 2022 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 109 | Mouse (ICR) 10 F | 70 days 4 weeks premating to PND 21 (W) | 0, 2.6, 19.7 | WI, DX | Develop |  | 2.6 | 19.7 | LOAEL: Decreased serum estradiol and increased primordial follicles and decreased secondary follicles at PND 21 in female offspring; increased prevalence of irregular estrous cycles SLOAEL: 40% decreased in PND 21 body weight in female offspring; delayed vaginal opening |\n| Liu et al. 2023 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 110 | Mouse F0: 9–12 F F1: 5-7 M, 5–7 F | ~220 days F0: 1 week premating through PND 21 F1: PND 21 to 6 months of age (W) | F0: 0, 0.1, 1.5 F1: 0, 0.2, 1.6 | BC, OW, HP, NX | Immuno Neuro | 1.6 | 0.2 |  | Increased locomotor activity, impaired spatial memory (Y-maze test) in adult F1 mice |\n| Mei et al. 2017 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 111 | Mouse (C57BL/6) 5 M | 8 weeks (W) | 0, 1.5, 4.5, 7.6 | IX | Immuno |  | 1.5 |  | Delayed wound healing |\n| Ohsawa et al. 1988 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 112 | Mouse (BALB/c) 9–10 M | 10 weeks (W) | 0, 0.75, 7.5, 75 | IX | Immuno | 7.5 | 75 |  | Induction of anti-nuclear autoantibodies |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Ohsawa et al. 1988 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 113 | Mouse (ICR) 5–12 M | 10 weeks (W) | 0, 0.75, 7.5, 75 | IX | Immuno |  | 0.75 |  | Induction of anti-nuclear autoantibodies; biphasic immune response (stimulation at low dose, suppression at high dose) |\n| Tan et al. 2023 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 114 | Mouse (C57BL/6) 20 M | 10 weeks (W) | 0, 1.5, 15 | DX | Develop | 1.5 | 15 |  | Impaired growth in both sexes (10% at terminal sacrifice on PND 125); impaired glucose metabolism in adult female offspring |\n| Males mated to untreated females after 10-week exposure |  |  |  |  |  |  |  |  |  |\n| Valois and Webster 1989 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 115 | Mouse (QS) 25 F | 22 weeks (W) | 0, 0.20, 1.4, 11 | CS, BW, WI, HP | Bd wt | 0.2 | 1.4 | 11 | LOAEL: 19% decrease in body weight SLOAEL: 28% decrease in body weight |\n|  |  |  |  |  | Neuro | 0.2 |  | 1.4 | Degenerative and necrotic cellular changes in choroid plexus |\n| Marked decreases in water consumption at 1.4 and 11 mg Cd/kg/day |  |  |  |  |  |  |  |  |  |\n| Wang et al. 2016a |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 116 | Mouse (CD-1) 10 F | 19 days GDs 0–18 (W) | 0, 1.3, 9.3, 26.9 | BW, WI, RX, DX | Bd wt Repro Develop | 26.9 26.9 9.3 |  | 26.9 | 17% decrease in fetal weight; decreased crown-rump length |\n| Xiong et al. 2022a |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 117 | Mouse (C57BL/6) F0: 6–7 M, 17 F F1: 4 M | 32 weeks F0: 2 weeks premating–PNW 3 F1: PNWs 3–27 (W) | 0, 0.1, 1.3 | BW, WI, OW, HP | Bd wt Repro | 1.3 M 0.1 M | 1.3 M |  | Decreased absolute testis weight, germ cell loss |\n| Endpoints reported for F1 males (evaluated at PNW 27) |  |  |  |  |  |  |  |  |  |\n\nEndpoints reported for F1 males (evaluated at PNW 27)\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects | Cadmium chloride |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Zhang et al. 2019a |  |  |  |  |  |  |  |  |  |  |\n| 118 | Mouse (C57BL/6J) F0: 10 M, 10 F F1: 6 M, 6 F | 17-18 weeks F0: 1 month premating to PNW 3 F1: PNWs 3–10 (W) | 0, 0.001089, 0.01003, 0.10012 | DX | Develop | 0.10012 |  |  |  |  |\n| F1 pups examined for developmental landmarks, neurobehavior (PNWs 8-9), endocrine, and reproductive endpoints at PNW 10 |  |  |  |  |  |  |  |  |  |  |\n| Zhang et al. 2019a |  |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 119 | Mouse (C57BL/6J) F0: 10 M, 10 F F1: 6 M, 6 F | 25-26 weeks F0: 3 months premating to PNW 3 F1: PNWs 3–10 (W) | 0, 0.001089, 0.01003, 0.10012 | DX | Develop | 0.10012 |  |  |  |  |\n| F1 pups examined for developmental landmarks, neurobehavior (PNWs 8-9), endocrine, and reproductive endpoints at PNW 10 |  |  |  |  |  |  |  |  |  | Cadmium chloride |\n| Zhang et al. 2019a |  |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 120 | Mouse (C57BL/6J) F0: 10 M, 10 F F1: 6 M, 6 F | 33–34 weeks F0: 5 months premating to PNW 3 F1: PNWs 3–10 (W) | 0, 0.001089, 0.01003, 0.10012 | DX | Develop | 0.01003 | 0.10012 |  | Increased anxiety-like behavior in open field; elevated corticosterone levels |  |\n| F1 pups examined for developmental landmarks, neurobehavior (PNWs 8-9), endocrine, and reproductive endpoints at PNW 10 |  |  |  |  |  |  |  |  |  | Cadmium chloride |\n| Zhang et al. 2024b |  |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 121 | Mouse (ICR) 9–11 M | 21 days PNDs 22–42 (W) | 0, 0.9, 1.5 | DX | Develop | 0.9 | 1.5 |  | Altered socioemotional behaviors during adolescence (immobility in forced swim and tail suspension, decreased social interaction/preference for novelty) |  |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Boscolo and Carmignani 1986 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 122 | Rabbit (New Zealand) 8 M | 9 months (W) | 0, 1.6 | CS, BW, HP, OF | Bd wt Cardio Renal | 1.6 | 1.6 |  | Increased aortic resistance, reduced contractility |\n| Stowe et al. 1972 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 123 | Rabbit (New Zealand) 5 M | 200 days (W) | 0, 14.9 | CS, BW, WI, HE | Bd wt Hemato |  | 14.9 | 14.9 | 20% decrease in body weight Decreased hematocrit and hemoglobin; elevated neutrophils and decreased lymphocytes |\n| Stowe et al. 1972 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 124 | Rabbit (Belgian Giant) 5 M | 200 days (W) | 0, 14.9 | CS, BW, WI, HE | Bd wt Hemato |  | 14.9 | 14.9 | 15% decrease in body weight Decreased hematocrit and hemoglobin; elevated neutrophils and decreased lymphocytes |\n| CHRONIC EXPOSURE |  |  |  |  |  |  |  |  |  |\n| Buchet et al. 1990; Shao et al. 2007; Suwazono et al. 2006; Uno et al. 2005; Wu et al. 2001; Zhang et al. 2016a |  |  |  |  |  |  |  |  | Cadmium |\n| 125 | Human 85–3,454 per dataset | 17 datasets (3 occupational and 8 general population cohorts) | UR | Renal |  |  |  | LMW proteinuria; 95% LCL weighted median of 17 UC10 values = 0.000760 mg Cd/kg/dayd |  |\n| Bernard et al. 1992 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 126 | Rat (Sprague-Dawley) 50 F | up to 18 months (W) | 0, 13 | BI, BC, UR, HP, OF | Renal |  |  | 13 | Loss of glomerular polyanion charge barrier, proteinuria |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Bomhard et al. 1984 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 127 | Rat (Wistar) 12 M, 12 F | 72 weeks (F) | M: 0, 0.7, 3.5, 17.5 F: 0, 0.8, 4.0, 20.0 | BC, UR | Renal | 4 F | 20 F |  | Increase in urinary LDH and GST levels Increase in urinary LDH and GST levels |\n| 127 | Rat (Wistar) 12 M, 12 F | 72 weeks (F) | M: 0, 0.7, 3.5, 17.5 F: 0, 0.8, 4.0, 20.0 | BC, UR | Renal | 3.5 M | 17.5 M |  | Increase in urinary LDH and GST levels Increase in urinary LDH and GST levels |\n| Brzóska 2012; Brzóska and Moniuszko-Jakoniuk 2004a, 2004b |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 128 | Rat (Wistar) 10 F | 24 months (W) | 0, 0.08 | BW, FI, WI, BC, BI, UR, HP, OF | Bd wt Musc/skel | 0.08 |  | 0.08 | Decreases in bone mineral content and density of lumbar spine, altered bone turnover parameters, increases in deformed and fractured vertebral bodies |\n| Decker et al. 1958 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 129 | Rat (Sprague-Dawley) 8–10 M, 8–10 F | 12 months (W) | M: 0, 0.008, 0.036, 0.197, 0.386, 0.696 F: 0, 0.012, 0.062, 0.315, 0.578, 1.052 | LE, BW, FI, WI, HE, HP | Bd wt Gastro | 1.052 F 0.696 M 1.052 F 0.696 M 1.052 F 0.696 M 1.052 F 0.696 M 1.052 F 0.696 M 1.052 F 0.696 M 0.696 M 0.696 M 0.696 M 0.696 M |  |  |  |\n| 129 | Rat (Sprague-Dawley) 8–10 M, 8–10 F | 12 months (W) | M: 0, 0.008, 0.036, 0.197, 0.386, 0.696 F: 0, 0.012, 0.062, 0.315, 0.578, 1.052 | LE, BW, FI, WI, HE, HP | Renal | 1.052 F 0.696 M 0.696 M |  |  |  |\n| 129 | Rat (Sprague-Dawley) 8–10 M, 8–10 F | 12 months (W) | M: 0, 0.008, 0.036, 0.197, 0.386, 0.696 F: 0, 0.012, 0.062, 0.315, 0.578, 1.052 | LE, BW, FI, WI, HE, HP | Endocrinoma | 1.052 F 0.696 M 0.696 M 0.696 M |  |  |  |\n| 129 | Rat (Sprague-Dawley) 8–10 M, 8–10 F | 12 months (W) | M: 0, 0.008, 0.036, 0.197, 0.386, 0.696 F: 0, 0.012, 0.062, 0.315, 0.578, 1.052 | LE, BW, FI, WI, HE, HP | Neuro | 1.052 F 0.696 M 0.696 M |  |  |  |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects | Cadmium chloride |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Fingerle et al. 1982 |  |  |  |  |  |  |  |  |  |  |\n| 130 | Rat (Sprague-Dawley) 10 M, 10 F | M: 92 weeks F: 84 weeks (W) | M: 0, 0.6, 1.51, 3.78 F: 0, 0.8, 1.64, 4.01 | HP, BW, OW, OF, FI, WI, CS, LE | Bd wt Cardio | 4.01 4.01 |  |  |  |  |\n| Mangler et al. 1988 |  |  |  |  |  |  |  |  |  |  |\n| 131 | Rat (Sprague-Dawley) 12 F | 18 months (W) | 0, 2.301 | LE, BW, HP | Bd wt Renal | 2.301 | 2.301 |  | Cloudy swelling of renal tubular cells | Cadmium chloride |\n| Mangler et al. 1988 |  |  |  |  |  |  |  |  |  |  |\n| 132 | Rat (Sprague-Dawley) 12 F | 12 months (W) | 0, 2.337 | LE, BW, HP | Bd wt Renal | 2.337 | 2.337 |  | Cloudy swelling of renal tubular cells | Cadmium chloride |\n| Sato et al. 1978 |  |  |  |  |  |  |  |  |  |  |\n| 133 | Rat (Wistar) 11 NS | 31 months (W) | 0, 2.7 | CS, BW, WI, HP | Bd wt Musc/skel Neuro | 2.7 |  | 2.7 2.7 | Muscle weakness and atrophy Peripheral neuropathy | Cadmium chloride |\n| Waalkes and Rehm 1992 |  |  |  |  |  |  |  |  |  |  |\n| 134 | Rat (Wistar) 24–28 M | 77 weeks (F) | 0, 1.1, 2.3, 5.28, 10.9 | LE, CS, BW, FI, GN, HP | Bd wt Cancer | 2.3 | 5.28 | 2.3 | 10% decrease in body weight CEL: Large granular lymphocyte leukemia | Cadmium chloride |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Hays and Margaretten 1985 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 135 | Mouse (CBA/H) 5–13 M; 5 F | 12 months (W) | 0, 40 | BW, FI, WI, HE, BC, HP | Bd wt Hematocrit | 40 |  | 40 | 21% decreased terminal body weight Decreased hematocrit and neutrophils; bone marrow hypoplasia |\n|  |  |  |  |  | Renal | 40 |  |  |  |\n\n<sup>a</sup>The number corresponds to entries in Figure 2-3; differences in levels of health effects between male and females are not indicated in Figure 2-3.  Where such \ndifferences exist, only the levels of effect for the most sensitive sex are presented.\n\n<sup>b</sup>Doses are expressed as mg Cd/kg/day.  If doses were reported by study authors in terms of the administered compound (e.g., cadmium chloride [CdCl2]), they were \nconverted to the equivalent dose in terms of the metal (i.e., cadmium [Cd])) for easy comparison across studies. Conversion was based on the ratio of the molecular \nweights using the following equation: Dose in terms of administered compound × (molecular weight Cd/molecular weight administered compound).\n\n<sup>c</sup>Used to derive an acute-duration oral MRL of 0.002 mg Cd/kg/day (2 μg Cd/kg/day).  The LOAEL of 2 mg Cd/kg/day divided by an uncertainty factor of 1,000 (10 for use \nof a LOAEL, 10 for animal to human, and 10 for human variability).\n\n<sup>d</sup>Used to derive a chronic-duration oral MRL of 0.0003 mg Cd/kg/day (0.3 μg Cd/kg/day).  The point of departure (POD) is based on the 95% lower confidence limit (LCL) \non the weighted median of the UC10 values from 17 datasets from 11 human studies; the weighted median and 95% LCL were 2.04 and 1.57 μg Cd/g Cr, respectively.  \nThese values were converted into oral dose equivalents of 9.88x10<sup>-4</sup> and 7.60x10<sup>-4</sup> mg Cd/kg/day, respectively, using PBPK modeling. The POD of 7.60x10<sup>-4</sup> mg \nCd/kg/day was divided by an uncertainty factor of 3 for human variability and a modifying factor of 3 for database deficiencies. See Appendix A for more detailed \ninformation regarding the MRL.\n\n## Principal studies for the MRLs\n\nACTH = adrenocorticotrophic hormone; ALT = alanine aminotransferase; β2M = β2-microglobulin; BC = serum (blood) chemistry; Bd wt or BW = body weight; \nBI = biochemical changes; BUN = blood urea nitrogen; Cardio = cardiovascular; Cd = cadmium; CEL = cancer effect level; Cr = creatinine; CS = clinical signs; Develop \n= developmental; DX = developmental toxicity; Endocr = endocrine; (F) = feed (dietary); F = female(s); FI = food intake; (G) = gavage; (GO) = gavage in oil; \n(GW) = gavage in water; Gastro = gastrointestinal; GD = gestation day; GN = gross necropsy; GnRH = gonadotropin releasing hormone; GST = glutathione \nS-transferase; HDL = high-density lipoprotein; HE = hematology; Hemato = hematological; HP = histopathology; IL-6 = interleukin-6; Immuno = immunological; \nIX = immune function; LD50 = lethal dose, 50% kill; LDH = lactate dehydrogenase; LDL = low-density lipoprotein; LE = lethality; LH = luteinizing hormone; LMW = low \nmolecular weight; LOAEL = lowest-observed-adverse-effect level; M = male(s); MCHC = mean corpuscular hemoglobin concentration; MCV = mean corpuscular volume; \nMRL = Minimal Risk Level; Musc/skel = musculoskeletal; NAFLD = non-alcoholic fatty liver disease; Neuro = neurological; NK = natural killer; NOAEL = no-observedadverse-effect level; NS = not specified; NX = neurological function; OF = organ function; OW = organ weight; PBPK = physiologically based pharmacokinetic; \nPND = postnatal day; PNW = postnatal week; RBC = red blood cell; Repro = reproductive; Resp = respiratory; RX = reproductive function; SLOAEL = serious lowestobserved-adverse-effect level; T3 = triiodothyronine; TNF = tumor necrosis factor; TSH = thyroid-stimulating hormone; UC10 = urinary cadmium level associated with \n10% extra risk; UR = urinalysis; (W) = drinking water; WBC = white blood cell; WI = water intake\n\n---\n\n**Figure 2-3.  Levels of Significant Exposure to Cadmium – Oral**\nAcute (≤14 days)\n\n**Figure 2-3. Levels of Significant Exposure to Cadmium – Oral Acute (≤14 days) - Death**\n\n| Category | Animal - LD50/LC50 (mg Cd/kg/day) | Animal - NOAEL (mg Cd/kg/day) | Animal - LOAEL (mg Cd/kg/day) | Animal - SLOAEL (mg Cd/kg/day) |\n| --- | --- | --- | --- | --- |\n| 3R |  |  |  | 100 |\n| 4R |  |  |  | 70 |\n| 6R |  |  |  | 30 |\n| 8R | 28 |  |  |  |\n| 9R | 140 |  |  |  |\n| 10R | 130 |  |  |  |\n| 11R | 100 |  |  |  |\n| 12R | 70 |  |  |  |\n| 15R | 230 |  |  |  |\n| 16R |  |  |  | 45 |\n| 17R |  |  |  | 65 |\n| 21R | 110 |  |  |  |\n| 22R | 340 |  |  |  |\n| 26M |  |  |  | 85 |\n| 28M | 95 |  |  |  |\n\n---\n\n**Figure 2-3.  Levels of Significant Exposure to Cadmium – Oral**\nAcute (≤14 days)\n\n**Figure 2-3. Levels of Significant Exposure to Cadmium – Oral Acute (≤14 days) - Body Weight**\n\n| Category | Animal - LD50/LC50 (mg Cd/kg/day) | Animal - LOAEL (mg Cd/kg/day) | Animal - NOAEL (mg Cd/kg/day) | Animal - SLOAEL (mg Cd/kg/day) |\n| --- | --- | --- | --- | --- |\n| 2R |  |  |  | 12 |\n| 2R |  |  | 2.0 |  |\n| 4R |  |  | 150 |  |\n| 5R |  | 8.0 |  |  |\n| 5R |  |  | 1.2 |  |\n| 5R |  |  |  | 11 |\n| 6R |  |  |  | 30 |\n| 6R |  |  |  | 15 |\n| 14R |  |  |  | 150 |\n| 14R |  |  | 100 |  |\n| 17R |  |  |  | 6.0 |\n| 17R |  |  | 1.8 |  |\n| 18R |  |  |  | 13 |\n| 18R |  |  | 3.3 |  |\n| 19R |  |  |  | 14 |\n| 20R |  |  |  | 18 |\n| 20R |  |  | 6.0 |  |\n| 23R |  |  | 0.20 |  |\n| 24R |  |  | 0.25 |  |\n| 25R |  |  | 4.0 |  |\n\n---\n\n**Figure 2-3.  Levels of Significant Exposure to Cadmium – Oral**\nAcute (≤14 days)\n\n| Category | Animal - NOAEL (mg Cd/kg/day) | Animal - LOAEL (mg Cd/kg/day) | Animal - SLOAEL (mg Cd/kg/day) |\n| --- | --- | --- | --- |\n| Respiratory | 14R: 160 |  |  |\n| Cardiovascular | 14R: 160 |  |  |\n| Gastrointestinal | 14R: 160 |  |  |\n|  |  | 17R: 65 |  |\n|  |  | 17R: 19 |  |\n|  |  | 26M: 30 |  |\n|  |  | 26M: 16 |  |\n|  |  | 26M: 85 |  |\n| Hematological | 1R: 15 |  |  |\n|  |  | 4R: 150 |  |\n|  |  | 5R: 14 |  |\n|  |  | 6R: 16 |  |\n|  |  | 14R: 160 |  |\n|  |  | 19R: 16 |  |\n| Hepatic | 4R: 150 |  |  |\n|  |  | 5R: 13 |  |\n|  |  | 6R: 16 |  |\n|  |  | 6R: 33 |  |\n|  |  | 14R: 160 |  |\n|  |  | 26M: 33 |  |\n|  |  | 26M: 16 |  |\n\n---\n\n**Figure 2-3.  Levels of Significant Exposure to Cadmium – Oral**\nAcute (≤14 days)\n\n**Figure 2-3. Levels of Significant Exposure to Cadmium – Oral Acute (≤14 days)**\n\n| Category | Animal - LD50/LC50 (mg Cd/kg/day) | Animal - LOAEL (mg Cd/kg/day) | Animal - NOAEL (mg Cd/kg/day) | Animal - SLOAEL (mg Cd/kg/day) | MRL for effect other than cancer (mg Cd/kg/day) |\n| --- | --- | --- | --- | --- | --- |\n| Renal |  |  | 4R: 150 |  |  |\n| Renal |  |  | 5R: 13 |  |  |\n| Renal |  |  | 6R: 70 | 6R: 70 |  |\n| Renal |  |  | 6R: 30 |  |  |\n| Renal |  |  | 14R: 160 |  |  |\n| Renal |  |  | 25R: 2.0 | 25R: 2.0 | 0.0022 |\n| Renal |  |  | 26M: 65 | 26M: 90 |  |\n| Dermal |  |  | 17R: 2.3 | 17R: 7.0 |  |\n| Endocrine |  |  | 14R: 150 |  |  |\n| Endocrine |  |  | 19R: 50 |  |  |\n| Immunological |  |  | 23R: 0.26 | 23R: 0.26 |  |\n| Immunological |  |  | 23R: 0.028 |  |  |\n| Immunological |  |  | 24R: 0.28 |  |  |\n| Neurolgical |  |  | 13R: 26 | 13R: 50 |  |\n| Neurolgical |  |  | 13R: 2.3 |  |  |\n\n---\n\n**Figure 2-3.  Levels of Significant Exposure to Cadmium – Oral**\nAcute (≤14 days)\n\n**Figure 2-3. Levels of Significant Exposure to Cadmium – Oral Acute (≤14 days)**\n\n| Category | Reproductive Animal - LD50/LC50 (mg Cd/kg/day) | Reproductive Animal - LOAEL (mg Cd/kg/day) | Reproductive Animal - NOAEL (mg Cd/kg/day) | Reproductive Animal - SLOAEL (mg Cd/kg/day) | Developmental Animal - LD50/LC50 (mg Cd/kg/day) | Developmental Animal - LOAEL (mg Cd/kg/day) | Developmental Animal - NOAEL (mg Cd/kg/day) | Developmental Animal - SLOAEL (mg Cd/kg/day) |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| 3R |  |  |  | 1', 'pages': None, 'truncated': True, 'extraction': 'firecrawl-public-document-markdown', 'request_id': '293c7827-ff96-4db1-b5ad-c97da5c1aeef', 'source_url': 'https://downloads.regulations.gov/ATSDR-2026-0133-0002/attachment_1.pdf', 'observed_at': '2026-10-04T00:38:44.750111+00:00', 'content_hash': '19390979349ee9f90ebdd60e3716b58502ea8d916d0b4add252a923c7eb753e3'}, 'title': 'Draft Toxicological Profile for Cadmium'}, {'url': 'https://downloads.regulations.gov/ATSDR-2026-0133-0002/content.pdf', 'body': {'text': '## Toxicological Profile for Cadmium\nDraft for Public Comment\nOctober 2026\n\nATSDR\nU.S. Department of Health and Human Services\nAgency for Toxic Substances and Disease Registry\n\nCS274127-A\n\n---\n\n## DISCLAIMER\n\nUse of trade names is for identification only and does not imply endorsement by the Agency for Toxic \nSubstances and Disease Registry, the Public Health Service, or the U.S. Department of Health and Human \nServices.\n\nThis information is distributed solely for the purpose of pre-dissemination for public comment under \napplicable information quality guidelines.  It has not been formally disseminated by the Agency for Toxic \nSubstances and Disease Registry.  It does not represent and should not be construed to represent any \nagency determination or policy.\n\n---\n\n## FOREWORD\n\nThis toxicological profile is prepared in accordance with guidelines developed by the Agency for Toxic \nSubstances and Disease Registry (ATSDR) and the Environmental Protection Agency (EPA).  The \noriginal guidelines were published in the *Federal Register* on April 17, 1987.  Each profile will be revised \nand republished as necessary.\n\nThe ATSDR toxicological profile succinctly characterizes the toxicologic and adverse health effects \ninformation for these toxic substances described therein.  Each peer-reviewed profile identifies and \nreviews the key literature that describes a substance\'s toxicologic properties.  Other pertinent literature is \nalso presented but is described in less detail than the key studies.  The profile is not intended to be an \nexhaustive document; however, more comprehensive sources of specialty information are referenced.\n\nThe focus of the profiles is on health and toxicologic information; therefore, each toxicological profile \nbegins with a relevance to public health discussion which would allow a public health professional to \nmake a real-time determination of whether the presence of a particular substance in the environment \nposes a potential threat to human health.  The adequacy of information to determine a substance\'s health \neffects is described in a health effects summary.  Data needs that are of significance to the protection of \npublic health are identified by ATSDR.\n\nEach profile includes the following:\n\n(A) The examination, summary, and interpretation of available toxicologic information and \nepidemiologic evaluations on a toxic substance to ascertain the levels of significant \nhuman exposure for the substance due to associated acute-, intermediate-, and chronicduration exposures;\n\n(B) A determination of whether adequate information on the health effects of each substance \nis available or in the process of development to determine the levels of exposure that \npresent a significant risk to human health due to acute-, intermediate-, and chronicduration exposures; and\n\n(C) Where appropriate, identification of toxicologic testing needed to identify the types or \nlevels of exposure that may present significant risk of adverse health effects in humans.\n\nThe principal audiences for the toxicological profiles are health professionals at the Federal, State, and \nlocal levels; interested private sector organizations and groups; and members of the public.  ATSDR plans \nto revise these documents in response to public comments and as additional data become available.  \nTherefore, we encourage comments that will make the toxicological profile series of the greatest use.\n\nElectronic comments may be submitted via: www.regulations.gov. Follow the on-line instructions for \nsubmitting comments.\n\nWritten comments may also be sent to:\n\nWritten comments may also be sent to:  Agency for Toxic Substances and Disease Registry\n\nOffice of Innovation and Analytics\n\nToxicology Section\n\n1600 Clifton Road, N.E.\n\nMail Stop S106-5\n\nAtlanta, Georgia 30329-4027\n\n---\n\nThe toxicological profiles are developed under the Comprehensive Environmental Response, \nCompensation, and Liability Act of 1980, as amended (CERCLA or Superfund).  CERCLA \nSection 104(i)(1) directs the Administrator of ATSDR to “…effectuate and implement the health-related \nauthorities” of the statute.  This includes the preparation of toxicological profiles for hazardous \nsubstances most commonly found at facilities on the CERCLA National Priorities List (NPL) and that \npose the most significant potential threat to human health, as determined by ATSDR and the EPA.  \nSection 104(i)(3) of CERCLA, as amended, directs the Administrator of ATSDR to prepare a \ntoxicological profile for each substance on the list.  In addition, ATSDR has the authority to prepare \ntoxicological profiles for substances not found at sites on the NPL, in an effort to “…establish and \nmaintain inventory of literature, research, and studies on the health effects of toxic substances” under \nCERCLA Section 104(i)(1)(B), to respond to requests for consultation under Section 104(i)(4), and as \notherwise necessary to support the site-specific response actions conducted by ATSDR.\n\nThis profile reflects ATSDR’s assessment of all relevant toxicologic testing and information that has been \npeer-reviewed.  Staffs of the Centers for Disease Control and Prevention and other Federal scientists have \nalso reviewed the profile.  In addition, this profile has been peer-reviewed by a nongovernmental panel \nand is being made available for public review.  Final responsibility for the contents and views expressed \nin this toxicological profile resides with ATSDR.\n\nChristopher M. Reh, Ph.D. \nAssociate Director,\nAgency for Toxic Substances and Disease Registry \nCenters for Disease Control and Prevention\n\n---\n\n**VERSION HISTORY**\n\n| Date | Description |\n| --- | --- |\n| October 2026 | Draft for public comment toxicological profile released |\n| September 2012 | Final toxicological profile released |\n| July 1999 | Final toxicological profile released |\n| April 1993 | Final toxicological profile released |\n| March 1989 | Final toxicological profile released |\n\n---\n\n# CONTRIBUTORS & REVIEWERS\n\n# CHEMICAL MANAGER TEAM\n\nBrittany Szafran, D.V.M, Ph.D., D.A.B.T. (lead)\nCustodio Muianga, M.P.H., Ph.D., C.H.M.M.\nMohammad Shoeb, Ph.D.\nBreanna Alman, M.P.H.\nFranco Scinicariello, M.D., M.P.H.\n\nKimberly Zaccaria, Ph.D., D.A.B.T.\nFrances Belmonte, Ph.D., D.A.B.T.\nHeather Carlson-Lynch, M.S., D.A.B.T.\nMario Citra, Ph.D.\nGary L. Diamond, Ph.D.\nZach Guerrette, Ph.D., D.A.B.T\nDeborah M. Herber, Ph.D.\nClaire Heit, Ph.D.\nLisa Ingerman, Ph.D., D.A.B.T.\nConnor McGuire, Ph.D.\nJennifer Rhoades, B.S.\n\nATSDR, Office of Innovation and Analytics, \nToxicology Section, Atlanta, GA\n\nSRC, Inc., North Syracuse, NY\n\n## REVIEWERS\n\n## Interagency Minimal Risk Level Workgroup:\n\nIncludes ATSDR; National Center for Environmental Health (NCEH); U.S. Environmental Protection \nAgency (EPA); National Toxicology Program (NTP).\n\n## Additional reviews for science and/or policy:\n\nATSDR, Office of Community Health Hazard Assessment; ATSDR, Office of Capacity Development \nand Applied Prevention Science; ATSDR, Office of Science; NCEH, Division of Laboratory Sciences; \nNCEH, Division of Environmental Health Science and Practice; National Institute for Occupational \nSafety and Health (NIOSH); EPA, Office of Research and Development; EPA, Office of Water.\n\n## PEER REVIEWERS\n\n1. Kristen Upson, Ph.D., M.P.H.; Associate Professor of Epidemiology and Biostatistics; Michigan \nState University; Department of Epidemiology and Biostatistics; 909 Wilson Road Room B601; \nEast Lansing, MI\n\n2. Zahir Shaikh, Ph.D.; Professor Emeritus and Former Founding Director of RI-INBRE; The \nUniversity of Rhode Island, College of Pharmacy; Kingston, RI\n\n3. Curtis D. Klaassen, M.S., Ph.D., FATS, FAASLD, FASPET; Director of the Mid-America \nToxicology Course; Previously University Distinguished Professor and Chair at The University \nof Kansas School of Medicine; Kansas City, KS (retired)\n\nThese experts collectively have knowledge of toxicology, chemistry, and/or health effects.  All reviewers \nwere selected in conformity with Section 104(I)(13) of the Comprehensive Environmental Response, \nCompensation, and Liability Act, as amended.\n\n---\n\nATSDR scientists review peer reviewers’ comments and determine whether changes will be made to the \nprofile based on comments.  The peer reviewers’ comments and responses to these comments are part of \nthe administrative record for this compound.\n\nThe listing of peer reviewers should not be understood to imply their approval of the profile\'s final \ncontent.  The responsibility for the content of this profile lies with ATSDR.\n\n---\n\n## CONTENTS\n\nDISCLAIMER .............................................................................................................................................. ii\nFOREWORD ............................................................................................................................................... iii\nVERSION HISTORY ................................................................................................................................... v\nCONTRIBUTORS & REVIEWERS ........................................................................................................... vi\nCONTENTS ............................................................................................................................................... viii\nLIST OF FIGURES ...................................................................................................................................... x\nLIST OF TABLES ....................................................................................................................................... xi\nCHAPTER 1. RELEVANCE TO PUBLIC HEALTH ................................................................................. 1\n1.1 OVERVIEW AND U.S. EXPOSURES ......................................................................................... 1\n1.2 SUMMARY OF HEALTH EFFECTS........................................................................................... 2\n1.3 MINIMAL RISK LEVELS (MRLs) .............................................................................................. 8\nCHAPTER 2. HEALTH EFFECTS ............................................................................................................ 12\n2.1 INTRODUCTION ........................................................................................................................ 12\n2.2 DEATH ........................................................................................................................................ 92\n2.3 BODY WEIGHT .......................................................................................................................... 99\n2.4 RESPIRATORY ........................................................................................................................ 104\n2.5 CARDIOVASCULAR ............................................................................................................... 113\n2.6 GASTROINTESTINAL ............................................................................................................. 124\n2.7 HEMATOLOGICAL ................................................................................................................. 125\n2.8 MUSCULOSKELETAL ............................................................................................................ 131\n2.9 HEPATIC ................................................................................................................................... 143\n2.10 RENAL ...................................................................................................................................... 151\n2.11 DERMAL ................................................................................................................................... 171\n2.12 OCULAR ................................................................................................................................... 172\n2.13 ENDOCRINE ............................................................................................................................. 172\n2.14 IMMUNOLOGICAL ................................................................................................................. 182\n2.15 NEUROLOGICAL..................................................................................................................... 189\n2.16 REPRODUCTIVE ..................................................................................................................... 196\n2.17 DEVELOPMENTAL ................................................................................................................. 213\n2.18 OTHER NONCANCER ............................................................................................................. 239\n2.19 CANCER .................................................................................................................................... 241\n2.20 GENOTOXICITY ...................................................................................................................... 256\n2.21 MECHANISMS OF ACTION ................................................................................................... 266\nCHAPTER 3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, \nCHEMICAL INTERACTIONS ......................................................................................... 269\n3.1 TOXICOKINETICS................................................................................................................... 269\n3.1.1 Absorption ........................................................................................................................... 269\n3.1.2 Distribution ......................................................................................................................... 274\n3.1.3 Metabolism .......................................................................................................................... 277\n3.1.4 Excretion ............................................................................................................................. 278\n3.1.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models ........... 278\n3.1.6 Animal-to-Human Extrapolations ....................................................................................... 285\n3.2 CHILDREN AND OTHER POPULATIONS THAT ARE UNUSUALLY \nSUSCEPTIBLE .......................................................................................................................... 286\n\n---\n\n3.3 BIOMARKERS OF EXPOSURE AND EFFECT ..................................................................... 290\n3.3.1 Biomarkers of Exposure ...................................................................................................... 291\n3.3.2 Biomarkers of Effect ........................................................................................................... 294\n3.4 INTERACTIONS WITH OTHER CHEMICALS ..................................................................... 297\nCHAPTER 4. CHEMICAL AND PHYSICAL INFORMATION ........................................................... 303\n4.1 CHEMICAL IDENTITY ........................................................................................................... 303\n4.2 PHYSICAL AND CHEMICAL PROPERTIES ........................................................................ 304\nCHAPTER 5. POTENTIAL FOR HUMAN EXPOSURE ....................................................................... 307\n5.1 OVERVIEW .............................................................................................................................. 307\n5.2 PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL ................................................ 310\n5.2.1 Production ........................................................................................................................... 310\n5.2.2 Import/Export ...................................................................................................................... 313\n5.2.3 Use ...................................................................................................................................... 314\n5.2.4 Disposal ............................................................................................................................... 314\n5.3 RELEASES TO THE ENVIRONMENT ................................................................................... 315\n5.3.1 Air ....................................................................................................................................... 315\n5.3.2 Water ................................................................................................................................... 319\n5.3.3 Soil ...................................................................................................................................... 320\n5.4 ENVIRONMENTAL FATE ...................................................................................................... 321\n5.4.1 Transport and Partitioning ................................................................................................... 321\n5.4.2 Transformation and Degradation ........................................................................................ 325\n5.5 LEVELS IN THE ENVIRONMENT ......................................................................................... 326\n5.5.1 Air ....................................................................................................................................... 327\n5.5.2 Water ................................................................................................................................... 328\n5.5.3 Sediment and Soil ............................................................................................................... 330\n5.5.4 Other Media ........................................................................................................................ 332\n5.6 GENERAL POPULATION EXPOSURE.................................................................................. 335\n5.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES .............................................. 362\nCHAPTER 6. ADEQUACY OF THE DATABASE ................................................................................ 363\n6.1 EXISTING INFORMATION ON HEALTH EFFECTS ........................................................... 363\n6.2 IDENTIFICATION OF DATA NEEDS .................................................................................... 365\n6.3 ONGOING STUDIES ................................................................................................................ 372\nCHAPTER 7. REGULATIONS AND GUIDELINES ............................................................................. 376\nCHAPTER 8. REFERENCES .................................................................................................................. 380\nAPPENDICES\nAPPENDIX A.  ATSDR MINIMAL RISK LEVEL WORKSHEETS .................................................... A-1 \nAPPENDIX B.  LITERATURE SEARCH FRAMEWORK FOR CADMIUM ...................................... B-1 \nAPPENDIX C.  FRAMEWORK FOR ATSDR’S SYSTEMATIC REVIEW OF HEALTH EFFECTS \nDATA FOR CADMIUM ................................................................................................ C-1 \nAPPENDIX D.  USER’S GUIDE ............................................................................................................. D-1 \nAPPENDIX E.  QUICK REFERENCE FOR HEALTH CARE PROVIDERS ....................................... E-1 \nAPPENDIX F.  GLOSSARY .................................................................................................................... F-1 \nAPPENDIX G.  ACRONYMS, ABBREVIATIONS, AND SYMBOLS................................................. G-1\n\n---\n\n## LIST OF FIGURES\n\n1-1.  Health Effects Found in Animals Following Inhalation Exposure to Cadmium .................................. 4\n1-2.  Health Effects Found in Animals Following Oral Exposure to Cadmium ........................................... 5\n1-3.  Summary of Sensitive Targets of Cadmium – Inhalation ..................................................................... 9\n1-4.  Summary of Sensitive Targets of Cadmium – Oral ............................................................................ 10\n2-1.  Overview of the Number of Studies Examining Cadmium Health Effects ........................................ 17\n2-2.  Levels of Significant Exposure to Cadmium – Inhalation .................................................................. 33\n2-3.  Levels of Significant Exposure to Cadmium – Oral ........................................................................... 72\n3-1.  Structure of Kjellström-Nordberg Cadmium Biokinetic Model ....................................................... 280\n3-2.  Structure of Diamond and Klotzbach Cadmium Biokinetics Model ................................................ 283\n5-1.  Number of NPL Sites with Cadmium Contamination ...................................................................... 307\n6-1.  Summary of Existing Health Effects Studies on Cadmium by Route and Endpoint ........................ 364\n\n---\n\n## LIST OF TABLES\n\n1-1.  Minimal Risk Levels (MRLs) for Cadmium ...................................................................................... 11\n2-1.  Levels of Significant Exposure to Cadmium – Inhalation .................................................................. 18\n2-2.  Levels of Significant Exposure to Cadmium – Oral ........................................................................... 41\n2-3.  Levels of Significant Exposure to Cadmium – Dermal ...................................................................... 90\n2-4.  Results of Meta-Analyses Evaluating Exposure to Cadmium and Mortality Endpoints .................... 93\n2-5.  Studies Included in Meta-Analyses Evaluating Exposure to Cadmium and Mortality \nEndpoints ............................................................................................................................................ 94\n2-6.  Results of General Population Studies Evaluating Urinary Cadmium Levels and All-Cause \nMortality ............................................................................................................................................. 94\n2-7.  Results of Meta-Analysis Evaluating Exposure to Cadmium and Respiratory Endpoints ............... 106\n2-8.  Results of Epidemiological Studies Evaluating Urinary Cadmium Levels and Respiratory \nEffects ............................................................................................................................................... 108\n2-9.  Results of Meta-Analyses Evaluating Exposure to Cadmium and Cardiovascular Endpoints ......... 113\n2-10.  Studies Included in Meta-Analyses Evaluating Exposure to Cadmium and Cardiovascular \nEndpoints ........................................................................................................................................ 116\n2-11.  Results of General Population Studies Evaluating Urinary Cadmium Levels and Blood \nPressure or Hypertension ................................................................................................................ 118\n2-12.  Results of General Population Studies Evaluating Urinary Cadmium Levels and \nCardiovascular Disease-Related Effects ......................................................................................... 122\n2-13.  Results of General Population Epidemiological Studies Evaluating Urinary Cadmium \nLevels and Hematological Effects .................................................................................................. 126\n2-14.  Results of Meta-Analyses Evaluating Exposure to Cadmium and Skeletal Endpoints .................. 132\n2-15.  Studies Included in Meta Analyses Evaluating Exposure to Cadmium and Skeletal \nEndpoints ........................................................................................................................................ 133\n2-16.  Results of General Population Epidemiological Studies Evaluating Urinary Cadmium \nLevels and Musculoskeletal Effects ............................................................................................... 136\n2-17.  Results of Meta-Analyses Evaluating Exposure to Cadmium and Serum Lipids .......................... 143\n2-18.  Studies Included in Meta-Analyses Evaluating Exposure to Cadmium and Serum Lipids ............ 144\n2-19.  Results of General Population Studies Evaluating Urinary Cadmium Levels and Blood \nLipid Levels .................................................................................................................................... 145\n\n---\n\n2-20.  Results of General Population Studies Evaluating Exposure to Urinary Cadmium Levels \nand Hepatic Disease and Clinical Chemistry ................................................................................. 147\n2-21.  Results of Occupational Studies Evaluating Urine Cadmium Levels and Renal Outcomes .......... 154\n2-22.  Results of Meta-Analyses Evaluating Exposure to Cadmium and Renal Endpoints ...................... 157\n2-23.  Studies Included in Meta-Analyses Evaluating Exposure to Cadmium and Renal Endpoints ....... 158\n2-24.  Results of Epidemiological Studies of General Populations Evaluating Urine Cadmium \nLevels and Renal Effects ................................................................................................................ 161\n2-25.  Results of Meta-Analysis Evaluating Exposure to Cadmium and Thyroid Endpoints ................... 173\n2-26.  Results of General Population Studies Evaluating Urinary Cadmium Levels and Thyroid \nEffects ............................................................................................................................................. 174\n2-27.  Results of Meta-Analyses Evaluating Exposure to Cadmium and Diabetes Endpoints ................. 175\n2-28.  Studies Included in Meta Analyses Evaluating Exposure to Cadmium and Diabetes \nEndpoints ........................................................................................................................................ 177\n2-29.  Results of Epidemiological Studies Evaluating Exposure to Cadmium and Diabetes-\nRelated Effects ................................................................................................................................ 179\n2-30.  Results of Epidemiological Studies Evaluating Urinary Cadmium Levels and \nImmunological Effects ................................................................................................................... 182\n2-31.  Results of Meta-Analyses Evaluating Exposure to Cadmium and Neurological Endpoints .......... 190\n2-32.  Studies Included in Meta-Analyses Evaluating Exposure to Cadmium and Neurological \nEndpoints ........................................................................................................................................ 191\n2-33.  Results of General Population Studies Evaluating Exposure to Urinary Cadmium and \nNeurological Effects ....................................................................................................................... 192\n2-34.  Results of Meta-Analyses Evaluating Exposure to Cadmium and Male Reproductive \nEndpoints ........................................................................................................................................ 196\n2-35.  Studies Included in Meta-Analyses Evaluating Exposure to Cadmium and Male \nReproductive Endpoints ................................................................................................................. 197\n2-36.  Results of General Population Studies Evaluating Urinary Cadmium Levels and \nReproductive Effects in Men .......................................................................................................... 199\n2-37.  Results of Meta-Analyses Evaluating Exposure to Cadmium and Female Reproductive \nEndpoints ........................................................................................................................................ 202\n2-38.  Studies Included in Meta-Analyses Evaluating Exposure to Cadmium and Female \nReproductive Endpoints ................................................................................................................. 203\n2-39.  Results of General Population Studies Evaluating Urinary Cadmium Levels and \nReproductive Effects in Women..................................................................................................... 204\n\n---\n\n2-40.  Results of Meta-Analyses Evaluating Exposure to Cadmium and Neurodevelopmental \nEndpoints ........................................................................................................................................ 213\n2-41.  Studies Included in Meta-Analyses Evaluating Exposure to Cadmium and \nNeurodevelopmental Endpoints ..................................................................................................... 214\n2-42.  Results of General Population Studies Evaluating Exposure to Cadmium and \nNeurodevelopmental Effects .......................................................................................................... 217\n2-43.  Results of General Population Studies Evaluating Urinary Cadmium Levels and Growth \nand Metabolism During Infancy, Childhood, and Adolescence ..................................................... 228\n2-44.  Results of General Population Studies Evaluating Urinary Cadmium Levels and \nReproductive Developmental Effects ............................................................................................. 233\n2-45.  Results of Meta-Analyses Evaluating Exposure to Cadmium and Metabolic Syndrome \nEndpoints ........................................................................................................................................ 240\n2-46.  Studies Included in Meta Analyses Evaluating Exposure to Cadmium and Metabolic \nSyndrome Endpoints ...................................................................................................................... 240\n2-47.  Results of Meta-Analyses Evaluating Exposure to Cadmium and Cancer ..................................... 242\n2-48.  Studies Included in Meta-Analyses Evaluating Exposure to Cadmium and Cancer ...................... 245\n2-49.  Results of Epidemiological Studies Evaluating Exposure to Cadmium and Cancer ...................... 250\n2-50.  Genotoxicity of Cadmium *In Vivo* .................................................................................................. 257\n2-51.  Genotoxicity of Cadmium *In Vitro* ................................................................................................. 259\n4-1.  Chemical Identity of Cadmium and Compounds ............................................................................. 303\n4-2.  Physical and Chemical Properties of Cadmium and Compounds .................................................... 304\n5-1.  Facilities that Produce, Process, or Use Cadmium ........................................................................... 310\n5-2.  Facilities that Produce, Process, or Use Cadmium Compounds ....................................................... 311\n5-3.  Releases to the Environment from Facilities that Produce, Process, or Use Cadmium .................... 316\n5-4.  Releases to the Environment from Facilities that Produce, Process, or Use Cadmium \nCompounds ....................................................................................................................................... 317\n5-5.  Lowest Limit of Detection Based on Standards ............................................................................... 326\n5-6.  Summary of Environmental Levels of Cadmium ............................................................................. 327\n5-7.  Range of Arithmetic Means for Cadmium from the AQS ................................................................ 327\n5-8.  Total Cadmium Levels in Groundwater and Surface Water in U.S. Samples Collected in \n2022–2024 ........................................................................................................................................ 329\n5-9.  Total Cadmium Levels in Ambient Sediment Collected in 2022–2024 ........................................... 331\n\n---\n\n5-10.  Mean Concentrations of Cadmium for FDA’s Total Diet Study Market Baskets 2006-1\nthrough 2008-4 ............................................................................................................................... 333\n5-11.  Geometric Mean and Selected Percentile Blood Concentrations (μg/L) of Cadmium in the\nU.S. Population, 1999–2018 ........................................................................................................... 336\n5-12.  Geometric Mean and Selected Percentile Urine Concentrations (Creatinine Corrected)\n(μg/g Creatinine) of Cadmium in the U.S. Population, 1999––2018 ............................................. 343\n5-13.  Geometric Mean and Selected Percentile Urine Concentrations (μg/L) of Cadmium in the\nU.S. Population, 1999–2018 ........................................................................................................... 350\n5-14.  Blood Cadmium Concentrations, Geometric Means, Adjusted Proportional Change in\nMeans, and 95<sup>th</sup> Percentiles in New York City Adults in Population \nSubgroups....................................................................................................................................... 357\n5-15.  Occupations with Potential Exposure to Cadmium and Cadmium Compounds ............................ 361\n6-1.  Ongoing Studies on Cadmium .......................................................................................................... 372\n7-1.  Regulations and Guidelines Applicable to Cadmium ....................................................................... 376\n\n---\n\n## CHAPTER 1. RELEVANCE TO PUBLIC HEALTH\n\n### 1.1 OVERVIEW AND U.S. EXPOSURES\n\nCadmium (Cd) occurs in the earth’s crust at a concentration of roughly 0.1–0.5 ppm and is commonly \nassociated with zinc, lead, and copper ores.  It is also a natural constituent of ocean water with average \nlevels between <5 and 110 ng/L, with higher levels reported near coastal areas and in marine phosphates \nand phosphorites (Morrow 2010).  The cadmium concentration of natural surface water and groundwater \nis usually <1 μg/L (Elinder 1985a, 1992).  Surface soil concentrations will depend on several factors such \nas its mobility, natural geochemistry, and magnitude of contamination from sources such as fertilizers and \natmospheric deposition.  Natural emissions of cadmium to the environment can result from volcanic \neruptions, forest fires, generation of sea salt aerosols, or other natural phenomena (EPA 1985; Morrow \n2010; Shevchenko et al. 2003).\n\n$$\n<1\\;\\mu g/L\n$$\n\nIn the environment, cadmium exists in only one oxidation state (Cd<sup>+2</sup>) and does not undergo oxidationreduction reactions.  In surface water and groundwater, cadmium can exist as the hydrated ion or as ionic \ncomplexes with other inorganic or organic substances.  Soluble forms of cadmium can migrate in water.  \nInsoluble forms of cadmium will settle and adsorb to sediments.  Cadmium’s fate in soil depends on \nseveral factors such as pH of the soil and availability of organic matter.  Generally, cadmium will bind \nstrongly to organic matter and this will, for the most part, immobilize it (Autier and White 2004).  \nHowever, cadmium’s behavior in soil will vary depending on the environmental conditions.  It is not \nlikely that cadmium will undergo significant transformation in the atmosphere (EPA 1980).  It will exist \nin particulate form and sometimes vapor form (emitted from high-temperature processes) where it will \nundergo atmospheric transport and eventually deposit onto soils and surface waters.\n\n$$\n\\left(\\mathrm{Cd^{+2}}\\right)\n$$\n\nNon-ferrous metal mining and refining, manufacture and application of phosphate fertilizers, fossil fuel \ncombustion, and waste incineration and disposal are the main anthropogenic sources of cadmium in the \nenvironment.  Except for those who live near cadmium-emitting industries, inhalation of cadmium in the \nambient air may occur but is not a major source of exposure.  Similarly, cadmium exposure through the \ndrinking water supply is of minor concern for the majority of the U.S. population.  However, water \nsources near cadmium-emitting industries, both with historic and current operations, have shown a \nmarked elevation of cadmium in water sediments and aquatic organisms (Angelo et al. 2007; Arnason and \nFletcher 2003; Brumbaugh et al. 2005; Mason et al. 2000; Paulson 1997).  Concentrations of cadmium in these polluted waters have ranged from <1.0 to 77 μg/L.  Cadmium from polluted soil and water can \naccumulate in plants and organisms, thus entering the food supply (Morrow 2010).\n\n$$\n7 7 \\mu \\mathrm {g} / \\mathrm {L}\n$$\n\nIn the United States, the largest source of cadmium exposure for nonsmoking adults and children is \nthrough dietary intake (NTP 2005).  The average daily intake of cadmium for children and adults \n(≥2 years of age) in the United States was estimated as 4.63 µg/day (Kim et al. 2019).  In general, leafy \nvegetables such as lettuce and spinach and staples such as potatoes and grains contain relatively high \nvalues of cadmium.  Peanuts, soybeans, and sunflower seeds have naturally high levels of cadmium \n(Morrow 2010).  Shellfish and organ meats (liver and kidney) also have relatively high concentrations of \ncadmium (Elinder 1985a).\n\nMean values of cadmium in the blood and urine of the U.S. population were reported in the National \nHealth and Nutrition Examination Survey (NHANES) 1999–2018 (CDC 2024).  Blood cadmium tends to \nreflect recent exposures, and urinary cadmium reflects cumulative cadmium exposure and body burden \n(particularly, kidney cadmium levels).  The geometric mean blood cadmium levels for the total population \n(≥1 year of age) have decreased nearly 50% from survey years 1999–2000 (0.412 µg/L) to survey years \n2017–2018 (0.241 µg/L).\n\n$$\n1999-2000\\left(0.412\\ \\mu g/L\\right)\n$$\n\n$$\n2017-2018\\left(0.241\\ \\mu g/L\\right)\n$$\n\nSmoking greatly increases exposure to cadmium, as tobacco leaves naturally accumulate high amounts of \ncadmium (Morrow 2010).  It has been estimated that tobacco smokers are exposed to 0.5–2.0 μg \ncadmium per cigarette, and about 10% is inhaled when smoked (Morrow 2010; Nordberg et al. 2015; \nNTP 2005).  A geometric mean blood cadmium level for a heavy smoker has been reported as high as \n1.58 μg/L (McKelvey et al. 2007), compared to the estimated national mean of 0.295 μg/L for all adults\n≥20 years of age, based on survey years 2017–2018 (CDC 2024).  Nonsmokers may also be exposed to \ncadmium in cigarettes via second-hand smoke.\n\n$$\n1. 5 8 \\mu \\mathrm {g} / \\mathrm {L}\n$$\n\n### 1.2 SUMMARY OF HEALTH EFFECTS\n\nSince the early 1950s, when the hazards of occupational cadmium exposure were recognized (Friberg \n1950), a large amount of information has been generated concerning the toxic effects of cadmium \nexposure in humans and laboratory animals.  Toxicological properties of cadmium are similar for the \nseveral different salts and oxides of cadmium that have been investigated, although differences in \nabsorption and distribution lead to different effect levels.  For inhalation exposure, particle size and \nsolubility in biological fluids (in contrast to solubility in water) appear to be the more important determinants of the toxicokinetics (Hirano et al. 1989a, 1989b; Oldiges and Glaser 1986; Rusch et al. \n1986).  For oral exposure, most experimental studies have used soluble cadmium, which exists as the Cd<sup>+2</sup>\nion regardless of the initial salt.  Absorption appears to be similar for cadmium ion and cadmium \ncomplexed with proteins in food, except for a few specific types of foods such as Bluff oysters and seal \nmeat.  Also, poorly soluble cadmium pigments may be absorbed to a lesser extent than soluble cadmium \nion (ILZRO 1977; Oldiges and Glaser 1986).\n\nThe database on the toxicity of cadmium in humans and animals following inhalation or oral exposure is \nextensive.  Target organs are similar among species and, in general, toxicokinetics following systemic \nabsorption from the gastrointestinal and respiratory tracts are similar.  Most of the human data involve \nevaluation of health effects associated with chronic-duration exposure in occupational studies, \ncommunity-based studies of populations living in cadmium-polluted areas, or epidemiological studies in \nthe general population.  When adequate exposure characterization is available, human studies generally \nreport exposure levels in terms of an internal biomarker of exposure (e.g., urinary cadmium).  Numerous \nstudies have conducted dose-response analyses between urinary cadmium levels and biomarkers of renal \ndysfunction (see Section 2.10); similar rigorous dose-response analyses are not available for other targets \nof toxicity in humans.  In animals, evaluation of available dose-response data by route and duration \nindicates that sensitive noncancer targets of cadmium toxicity are respiratory and neurodevelopmental \neffects following inhalation exposure (Figure 1-1) and renal, skeletal, and neurodevelopmental effects \nfollowing oral exposure (Figure 1-2).\n\nA systematic review of these sensitive noncancer endpoints resulted in the following hazard identification \nconclusions:\n\n• Respiratory effects are a known effect for humans following inhalation exposure.\n\n• Skeletal effects are a known effect for humans.\n\n• Renal effects are a known effect for humans.\n\n• Neurodevelopmental effects are a presumed effect for humans.\n\n---\n\n**Figure 1-1.  Health Effects Found in Animals Following Inhalation Exposure to** \n**Cadmium**\n\nConcentration (mg Cd/m<sup>3</sup>) Effects in Animals\n>8 Acute:  Mortality; clinical signs of neurotoxicity, female reproductive effects\n0.9-1.7 Acute:  Decreased body weight\nIntermediate:  Male and female reproductive effects\n0.19-0.4 Acute:  Developmental and immune effects\n0.05-0.1 Acute:  Respiratory effects\nIntermediate:  Death\n0.02-0.03 Intermediate:  Respiratory and neurodevelopmental effects\nChronic:  Cancer, mortality\n1x10<sup>-4</sup> mg Cd/m<sup>3</sup> Provisional Chronic MRL (based on human data and exposure levels predicted from biomarkers)\n\nCd = cadmium; MRL = minimal risk level\n\n---\n\n**Figure 1-2.  Health Effects Found in Animals Following Oral Exposure to** \n**Cadmium**\n\n## Dose (mg Cd/kg/day)\n\n## Effects in Animals\n\n**Acute:**  Death; hepatic, gastrointestinal, neurological, and male \nreproductive effects\n\n**5.28-15**\n\n**Intermediate:**  Death\n\n**Chronic:**  Hematological effects\n\n**Acute:**  Hematological effects; altered reproductive development\n\n**0.6-3.13**\n\n**Intermediate:**  Gastrointestinal effects\n\n**Chronic:**  Decreased body weight\n\n**Acute:**  Renal and developmental effects, decreased body weight\n\n**0.2-0.4**\n\n**Intermediate:**  Renal, hepatic, hematological, and male and female \nreproductive effects; increased blood pressure; decreased body weight\n\n**Chronic:**  Renal and neurological effects; cancer\n\n**0.04-0.08**\n\n**Intermediate:**  Skeletal, neurological, respiratory, and immunological \neffects; decreased birth weight and altered reproductive development\n\n## 0.002 mg Cd/kg/day 3x10<sup>-4</sup> mg Cd/kg/day\n\n3x10 -4 mg Cd/kg/day\n\n**Intermediate:**  Neurodevelopmental and endocrine effects\n\n**Chronic:**  Skeletal effects\n\n**Provisional Acute MRL**\n\n**Provisional Chronic MRL (based on human data and exposure levels predicted from biomarkers)**\n\nCd = cadmium; MRL = minimal risk level\n\n---\n\n**_Respiratory Effects._** A meta-analysis of 12 studies reported an association between chronic-duration \ninhalation exposure to cadmium and reduced forced expiratory volume in the first second to forced vital \ncapacity (FEV1/FVC), which is indicative of an increased risk of chronic obstructive pulmonary disease \n(Wang et al. 2024a).  A limited number of occupational studies not included in the meta-analysis also \nreported associations between impaired lung function and urinary cadmium levels in workers (Moitra et \nal. 2013, 2015; Zhou et al. 2022).  These findings are supported by occupational case reports of clinical \nsigns of respiratory distress and pulmonary damage after acute-duration exposure to fatal concentrations \n(Beton et al. 1966; Townshend 1982).  In animal acute- and intermediate-duration inhalation studies, the \nrespiratory tract is the most sensitive target of toxicity in animals (NTP 1995).  Available studies \nconsistently report histopathological and inflammatory reactions in the respiratory tract of multiple \nspecies; in studies that provide quantitative data, findings are clearly concentration-related \n(see Section 2.4).\n\n**_Skeletal Effects._** Cadmium-associated bone effects were first described in 1955 in the Jinzu River Basin, \na cadmium-contaminated area in Japan, following the development of a bone disease called Itai-Itai\n("ouch-ouch") disease, characterized by multiple fractures of the long bones, osteomalacia, and \nosteoporosis in combination with proteinuria (Järup et al. 1998; Nordberg et al. 1997; Shigematsu 1984).  \nFour meta-analyses evaluating 41 unique references confirm the association between cadmium exposure \nand adverse bone effects, including fractures, osteoporosis, and decreased bone mineral density (Cheng et \nal. 2016; Kunioka et al. 2022; Li et al. 2021; Qing et al. 2021), as do several studies published since the \nmeta-analyses (Lv et al. 2021; Wang et al. 2021a; Xie et al. 2023a, 2023b).  Occupational case studies \nindicate that calcium deficiency, osteoporosis, or osteomalacia can develop in some workers after longterm occupational exposure to high levels of cadmium (Adams et al. 1969; Blainey et al. 1980; Bonnell \n1955; Kazantzis 1979; Scott et al. 1980).  In rodents, decreases in bone mineralization, bone mineral \ndensity, and mechanical properties have been consistently observed following oral exposure to cadmium \nchloride (see Section 2.8).  While bone effects may be secondary to cadmium-associated renal damage \n(Bhattacharyya et al. 2023; Shevchenko et al. 2021; Zhang et al. 2020a), there is also evidence for a direct \neffect of cadmium on bone, and acceleration of bone resorption can occur in the absence of renal \ndysfunction (Reyes-Hinojosa et al. 2019; Shevchenko et al. 2021; Zhang et al. 2020a).\n\n**_Renal Effects._** The kidney is a well-established target of cadmium toxicity in humans following \noccupational or dietary exposure.  Available meta-analyses consistently reported associations between \none or more biomarkers of cadmium exposure and risk of proteinuria, urolithiasis, chronic kidney disease, \nhyperuricemia, renal cytotoxicity, and low glomerular filtration rate (GFR) (Chen et al. 2024; Doccioli et al. 2024; Gu et al. 2022; Jalili et al. 2021; Liu et al. 2016a; Woo et al. 2015; Zhu et al. 2024a).  These \nfindings are supported by several studies conducted since the meta-analyses were published (see \nSection 2.10).  In animals, there is no evidence for renal effects in acute- and intermediate-duration \ninhalation studies; however, exposure duration and concentration may not have been enough to reach the \ncritical kidney concentration to induce renal effects and chronic-duration inhalation studies evaluating \nrenal toxicity were not identified.  In oral studies, some studies reported adverse changes in sensitive \nbiomarkers of kidney damage, such as a β2-microglobulin (β2M) or N-acetyl-β-d-glucosaminidase \n(NAG) (Bernard et al. 1992; Liu et al. 2019; Wan et al. 2022).  However, other studies did not find this \neffect at similar or higher doses (Wang et al. 2014).  Similar inconsistencies were observed for serum \nclinical chemistry values and histopathological findings (see Section 2.10).\n\n**_Neurodevelopmental Effects._** While several general population studies are available, findings are mixed.  \nAvailable meta-analysis reported mixed conclusions regarding the potential association between cadmium \nexposure and autism spectrum disorder (ASD) (Ding et al. 2023; Dou et al. 2023; Ramazani et al. 2024; \nSaghazadeh and Rezaei 2017; Sulaiman et al. 2020) and did not find an association with attention deficit \nhyperactivity disorder (ADHD) (Dimitrov et al. 2023).  Some studies reported associations between \ncadmium exposure and decreased measures of cognitive development in children and adolescents (Gustin \net al. 2018; Kippler et al. 2016; Rodríguez-Barranco et al. 2014; Zhou et al. 2020); however, other studies \ndid not support this finding (Forns et al. 2014; Lucchini et al. 2019; Pan et al. 2018; Yang et al. 2020).  \nNo consistent findings were observed regarding potential associations between cadmium exposure and \nneurobehavioral or neurosensory evaluations during childhood or adolescence (see Section 2.17).  In \ncontrast, available animal studies collectively indicate that developmental cadmium exposure can cause \nalterations in sensorimotor function (including nerve conduction) and activity, socioemotional behavior, \nand learning and memory in rodents; however, the timing and duration of exposure and assessment \ninfluence findings (see Section 2.17).\n\n**_Cancer Effects._** The carcinogenicity of cadmium has been studied extensively in humans in studies \ninvolving workers and general populations and in animals after inhalation or oral exposures.  The \nInternational Agency for Research on Cancer (IARC) classified cadmium and cadmium compounds as \ncarcinogenic to humans (Group 1) based on sufficient evidence in humans for the carcinogenicity of \ncadmium and cadmium compounds, sufficient evidence in animals for the carcinogenicity of cadmium \ncompounds, and limited evidence in animals for the carcinogenicity of cadmium metal (IARC \n2012).  Similarly, the Department of Health and Human Services (HHS) classified cadmium and \ncadmium compounds as substances known to be human carcinogens based on sufficient evidence of carcinogenicity in humans, including epidemiological and mechanistic studies (NTP 2021).  In 1989, the \nU.S. Environmental Protection Agency (EPA) classified cadmium as a probable human carcinogen by \ninhalation (Group B1) based on limited evidence in humans and sufficient evidence in animals (IRIS \n1989).\n\n### 1.3 MINIMAL RISK LEVELS (MRLs)\n\nMRLs for inhalation and oral exposures to cadmium were derived.  As presented in Figure 1-3, the most \nsensitive effects following inhalation exposure to cadmium are respiratory and developmental \n(specifically neurodevelopmental effects) following acute- and intermediate-duration exposure and renal \nfollowing chronic-duration exposure.  A provisional chronic-duration inhalation MRL was derived based \non renal effects in humans; the inhalation database was considered inadequate for the derivation of acuteor intermediate-duration MRLs.  The lack of renal toxicity at shorter durations in animal inhalation\nstudies is attributed to inadequate exposure duration to meet the critical renal burden required to elicit \nadverse renal effects.  The relationship between renal and urinary cadmium appears to be nearly linear at \nchronic-duration intakes and kidney burdens that do not produce nephrotoxicity (i.e., elimination halftime is independent of dose).  However, at high kidney cadmium burdens, associated with renal damage \n(>50 μg Cd/g cortex), the elimination half-time increases with increasing severity of renal damage.  \nLinearity in the dose-urinary excretion relationship also does not appear to apply following an acuteduration, high exposure to cadmium.  Multicompartment, physiologically based pharmacokinetic (PBPK) \nmodels (described in detail in Section 3.1.5) can be used to estimate cadmium intakes (inhalation and oral \nexposure) associated with a given urinary cadmium level and/or kidney cadmium burden.  These models \nhave been extensively evaluated for predicting dose-kidney-urinary cadmium relationships within the \nlinear range of the dose-urinary cadmium relationship, and PBPK modeling was used in the derivation of \nthe provisional inhalation chronic-duration MRL.\n\nAs presented in Figure 1-4, the most sensitive effects following oral exposure are renal, developmental \n(specifically neurodevelopmental), and skeletal effects.  Provisional acute- and chronic-duration oral \nMRLs were derived based on renal effects in animals and humans, respectively; the oral database was \nconsidered inadequate for the derivation an intermediate-duration oral MRL.  As discussed for the provisional chronic-duration inhalation MRL, PBPK modeling was used in the derivation of the \nprovisional oral chronic-duration MRL.\n\nMRLs derived for both the inhalation and oral exposure routes for cadmium are summarized in Table 1-1\nand are discussed in greater detail in Appendix A.\n\n**Figure 1-3.  Summary of Sensitive Targets of Cadmium – Inhalation**\n\n**Available data indicate that the respiratory system and developing nervous system are the most \nsensitive targets following acute- and intermediate-duration exposure and the renal system is the \nmost sensitive target following chronic-duration exposure to cadmium via inhalation.**\n\nNumbers in circles are the lowest lowest-observed-adverse-effect levels (LOAELs) for all health effects in \nanimals and the number in the triangle is the point of departure (POD) for the chronic-duration inhalation \nMRL based on human data.*\n\n**Acute (mg Cd/m³ )**\n\n| Category | Acute (mg Cd/m³) | Intermediate (mg Cd/m³) | Chronic (mg Cd/m³) |\n| --- | --- | --- | --- |\n| Respiratory | 0.081 | 0.021 |  |\n| Immunological | 0.19 |  |  |\n| Developmental | 0.4 | 0.02 |  |\n| Hematological |  | 0.052 |  |\n| Body weight |  | 0.052 | 0.03 |\n| Renal |  |  | 0.00106 |\n| Death |  |  | 0.03 |\n\n*See Table 2-1 for animal studies identifying the LOAELs in circles.  The value of 0.00106 mg Cd/m<sup>3</sup> represented by \nthe triangle (human data) is the renal POD used for the provisional chronic-duration MRL; the value represents the \nlower 95% confidence limit on the weighted median of the urinary cadmium level associated with a 10% extra risk \nassociated with low-molecular weight proteinuria in 17 datasets from 11 human studies (see Appendix A for details).\n\n---\n\n## Figure 1-4. Summary of Sensitive Targets of Cadmium – Oral\n\n**Available data indicate that the renal, skeletal, and developing nervous system are the most \nsensitive targets of cadmium oral exposure.**\n\nNumbers in circles are the lowest lowest-observed-adverse-effect levels (LOAELs) for all health effects in \nanimals and the number in the triangle is the point of departure (POD) for the chronic-duration oral MRL \nbased on human data.*\n\n**Acute (mg Cd/kg/day)**\n\n| Category | LOAEL (mg Cd/kg/day) |\n| --- | --- |\n| Acute - Renal | 2 |\n| Acute - Body weight | 2 |\n| Acute - Developmental | 3.13 |\n| Intermediate - Developmental | 0.04 |\n| Intermediate - Endocrine | 0.053 |\n| Intermediate - Musculoskeletal | 0.2 |\n| Chronic - Renal (POD) | 0.00076 |\n| Chronic - Musculoskeletal | 0.08 |\n| Chronic - Renal | 2.301 |\n| Chronic - Cancer | 2.3 |\n\n*See Table 2-2 for animal studies identifying the LOAELs in circles.  The value of 7.60x10<sup>-4</sup> mg Cd/kg/day \nrepresented by a triangle (human data) is the renal POD used for the provisional chronic-duration MRL; the value \nrepresents the lower 95% confidence limit on the weighted median of the urinary cadmium level associated with a \n10% extra risk associated with low-molecular weight proteinuria in 17 datasets from 11 human studies \n(see Appendix A for details).\n\n$$\n7.60\\times10^{-4}\n$$\n\n---\n\n**Table 1-1.**\n\n**Minimal Risk Levels (MRLs) for Cadmium**\n\n| Exposure route | Exposure duration | Provisional MRL | Critical effect (species) | POD type | POD value | Uncertainty/modifying factor | Reference |\n| --- | --- | --- | --- | --- | --- | --- | --- |\n| Inhalation | Acute | None | - | - | - | - | - |\n| Inhalation | Intermediate | None | - | - | - | - | - |\n| Inhalation | Chronic | 1 × 10-4 mg CD/m3 | LMW proteinuria (humans) | 95% LCL of weighted median of UC10 from 17 datasets | 0.00106 mg Cd/m3 | UF: 3 MF: 3 | Weighted median from 17 datasetsb |\n| Oral | Acute | 0.002 mg Cd/kg/day | Total and LMW proteinuria; increased serum BUN (rats) | LOAEL | 2 mg Cd/kg/day | UF: 1,000 | Wan et al. 2022 |\n| Oral | Intermediate | None | - | - | - | - | - |\n| Oral | Chronic | 3 × 10-4 mg CD/kg/day | LMW proteinuria (humans) | 95% LCL of weighted median of UC10 from 17 datasets | 7.60 × 10-4 mg Cd/kg/day | UF: 3 | Weighted median from 17 datasetsb |\n\n<sup>a</sup>See Appendix A for additional information.\n\n<sup>b</sup>17 datasets from 3 occupational cohorts (Järup and Elinder 1994; Lei et al. 2007; Shao et al. 2007) and 8 general population cohorts (Buchet et al. 1990; Hong et \nal. 2004; Järup et al. 2000; Kobayashi et al. 2008; Suwazono et al. 2006; Uno et al. 2005; Wu et al. 2001; Zhang et al. 2016a).\n\nBUN = blood urea nitrogen; LCL = lower confidence limit; LMW = low molecular weight; LOAEL = lowest-observed-adverse-effect level; MF = modifying factor; \nPOD = point of departure; UC10 = urinary concentration associated with 10% extra risk; UF = uncertainty factor\n\n---\n\n## CHAPTER 2. HEALTH EFFECTS\n\n### 2.1 INTRODUCTION\n\nThe primary purpose of this chapter is to provide public health officials, physicians, toxicologists, and \nother interested individuals and groups with an overall perspective on the toxicology of cadmium.  It \ncontains descriptions and evaluations of toxicological studies and epidemiological investigations and \nprovides conclusions, where possible, on the relevance of toxicity and toxicokinetic data to public health.  \nWhen available, mechanisms of action specific to target organs are discussed along with the health effects \ndata, while general mechanisms of action are discussed in Section 2.21; toxicokinetic mechanistic data are \ndiscussed in Section 3.1.\n\nA glossary and list of acronyms, abbreviations, and symbols can be found at the end of this profile.\n\nTo help public health professionals and others address the needs of persons living or working near hazardous \nwaste sites, the information in this section is organized by health effect.  These data are discussed in terms of \nroute of exposure (inhalation, oral, and dermal) and three exposure periods:  acute (≤14 days), intermediate \n(15–364 days), and chronic (≥365 days).\n\nAs discussed in Appendix B, a literature search was conducted to identify relevant studies examining health \neffect endpoints.  Figure 2-1 provides an overview of the database of studies in humans or experimental \nanimals included in this chapter of the profile.  These studies evaluate the potential health effects associated \nwith inhalation, oral, or dermal exposure to cadmium, but may not be inclusive of the entire body of \nliterature.  As discussed in *Prioritization of Human Data* in Appendix B, the epidemiological database for \ncadmium is extensive, including thousands of primary studies and dozens of meta-analyses of available \nstudies.  To focus the profile review and discussion on the weight-of-evidence, recent evidence, and most \nrelevant data for hazard identification, ATSDR focused the discussion in Chapter 2 on meta-analyses \nconducted within the past 15 years.  To supplement discussion, any epidemiological study published since \nthe most recent meta-analysis for an endpoint was included if it provided: (1) reliable and reported estimates \nof cadmium exposure (measured levels in air or via urinary cadmium levels, as this is the most reliable \nbiomarker [see Section 3.3.1]); (2) analysis of potential confounders of the measures of association; and \n(3) appropriate statistical analysis.  For endpoints without a published meta-analysis, any study meeting these \ninclusion criteria were included, regardless of publication date.  Studies were excluded if they did not \nprovide quantitative evidence for associations, relied on semi-quantitative measures of exposure (e.g., food frequency questionnaires), or evaluated cadmium exposure from medical implants.  Exceptions to the above \ncriteria included studies reporting rare effects, inclusion of select older studies to provide historical context \n(e.g., Itai-Itai disease in the Jinzu River Basin region of Japan, early case reports and investigations of \nworkers exposed to cadmium that established targets of toxicity, etc.), and studies that fill data gaps (e.g., \nlower quality occupational studies in less-studied organ systems/tissues). The animal database for cadmium \nis also extensive.  As discussed in *Prioritization of Animal Data* in Appendix B, animal studies evaluating \nadverse effects were prioritized for efficient review.  Since cadmium is a well-established model of renal \ntoxicity, there are hundreds of studies describing administration of cadmium via oral or other routes (e.g., \nintraperitoneal) at known toxic doses to evaluate potential interventions to rescue (or prevent) renal toxicity \nor other cadmium-associated adverse effects at higher exposure levels.  Studies of this nature were excluded \nfrom the profile, as they do not inform dose-response effects at low, environmentally-relevant \ndoses. Similarly, acute- and intermediate-duration oral studies in rats or mice utilizing only one cadmium \ndose group were excluded due to lack of dose-response data; exceptions were made for acute-lethality \nstudies or studies addressing data-poor endpoints (e.g., lipid homeostasis studies).  All chronic-duration oral \nstudies and all inhalation and dermal studies of adequate quality were included in the profile.  A systematic \nreview of the scientific evidence of the most sensitive health effects associated with exposure to cadmium\nwas also conducted; the results of this review are presented in Appendix C.\n\nHuman and animal inhalation studies are presented together in Table 2-1 and Figure 2-2 and human and \nanimal oral studies are presented in Table 2-2 and Figure 2-3; limited dermal data were identified for \ncadmium and are presented in Table 2-3.\n\nLevels of significant exposure (LSEs) for each route and duration are presented in tables and illustrated in \nfigures.  The points in the figures showing no-observed-adverse-effect levels (NOAELs) or lowestobserved-adverse-effect levels (LOAELs) reflect the actual doses (levels of exposure) used in the studies.  \nEffects have been classified into “less serious LOAELs” or “serious LOAELs (SLOAELs).”  “Serious” \neffects are those that evoke failure in a biological system and can lead to morbidity or mortality (e.g., \nacute respiratory distress or death).  “Less serious” effects are those that are not expected to cause \nsignificant dysfunction or death, or those whose significance to the organism is not entirely clear.  \nATSDR acknowledges that a considerable amount of judgment may be required in establishing whether \nan endpoint should be classified as a NOAEL, “less serious” LOAEL, or “serious” LOAEL, and that in \nsome cases, there will be insufficient data to decide whether the effect is indicative of significant \ndysfunction.  However, the Agency has established guidelines and policies that are used to classify these \nendpoints.  ATSDR believes that there is sufficient merit in this approach to warrant an attempt at distinguishing between “less serious” and “serious” effects.  The distinction between “less serious” effects \nand “serious” effects is considered to be important because it helps the users of the profiles to identify \nlevels of exposure at which major health effects start to appear.  LOAELs or NOAELs should also help in \ndetermining whether or not the effects vary with dose and/or duration, and place into perspective the \npossible significance of these effects to human health.  Levels of exposure associated with cancer (Cancer \nEffect Levels, CELs) of cadmium are indicated in Tables 2-1 and 2-2 and Figures 2-2 and 2-3.\n\nA User\'s Guide has been provided at the end of this profile (see Appendix D).  This guide should aid in \nthe interpretation of the tables and figures for LSEs and MRLs.\n\nThis section provides information regarding potential adverse health effects of cadmium and cadmium \ncompounds.  To appropriately compare doses following exposures to various cadmium compounds, \ninhalation exposures are expressed throughout the profile as mg Cd/m<sup>3</sup> and oral exposures are expressed as \nmg Cd/kg/day, when possible.  This allows for evaluation of relative toxicities and determination of whether \ncertain chemical properties (e.g., solubility) impact toxicity.  When available, information pertaining to \nrelative toxicity of different cadmium compounds is discussed throughout Chapter 2.\n\nThe health effects of cadmium and cadmium compounds have been extensively evaluated in human and \nanimal studies.  As discussed above, due to the vast amount of available data, studies were prioritized for \ninclusion in Chapter 2 based on criteria defined in Appendix B.  A total of 69 meta-analyses of human \ndata were included.  An additional 219 human studies and 192 animal studies meeting inclusion criteria \nwere identified.  Most of the human data involve evaluation of health effects associated with chronicduration exposure in occupational studies, community-based studies of populations living in cadmiumpolluted areas, or epidemiological studies in the general population.  For workers, the predominant \nexposure route is inhalation; however, some gastrointestinal tract exposure may also occur when dust is \nremoved from the lungs by mucociliary clearance and subsequently swallowed, or by ingestion of dust on \nhands, cigarettes, or food (Adamsson et al. 1979).  For the nonsmoking general population, dietary \nexposure to cadmium is the most likely route of exposure (Kim et al. 2018; Nordberg et al. 2018; Zhu et \nal. 2024a).  However, since cadmium is present in tobacco leaves, tobacco smoking can contribute \nsignificantly to cadmium exposure in general populations (Diamond and Klotzbach 2025; Ellis et al. \n1979; Friis et al. 1998).  Therefore, both occupational and general population studies are classified as \nmulti-route exposure in Figure 2-1.  In animal studies, most of the health effects data in animals come \nfrom oral exposure studies (Figure 2-1).\n\n---\n\nHuman studies are available for nearly every organ system, with the predominant focus on renal, cancer, \ndevelopmental, musculoskeletal, and cardiovascular endpoints.  Animal studies predominantly focused on \nrespiratory endpoints following inhalation exposure and examined a comprehensive set of endpoints \nfollowing oral exposure.  For oral studies, the most well-studied effects include body weight, developmental, \nand reproductive endpoints.  Data from dermal exposure are very limited.\n\nAs outlined in Chapter 1, the most sensitive effects following exposure to cadmium appear to be respiratory, \nrenal, and neurodevelopmental following inhalation exposure and renal, skeletal, and neurodevelopmental \nfollowing oral exposure.  A systematic review was conducted on the available human and animal studies for \nthese endpoints.  The information in these studies indicates the following on the potential targets of cadmium\ntoxicity:\n\n• **Respiratory Endpoints.**  Respiratory effects are a known effect of cadmium toxicity following \ninhalation exposure based on a low level of evidence in human occupational studies, a high level \nof evidence in laboratory animal inhalation studies, and other relevant data including a metaanalysis, occupational case reports, and a plausible mechanism of action.  In humans, \noccupational exposure has been associated with respiratory irritation and impaired respiratory \nfunction.  In animals, inhalation exposure is consistently associated with inflammatory changes in \nthe lung and upper and lower respiratory tract lesions with increasing concentration and duration \nin multiple species.\n\n• **Skeletal Endpoints.**  Adverse effects on the skeletal system (e.g., decreased bone density, \nstrength, and mineralization) are a known effect of cadmium toxicity based on a moderate level of \nevidence from human epidemiological studies, a high level of evidence from laboratory animals, \nand other relevant data including several meta-analyses, older studies and case reports of high \ndietary or occupational exposure, and plausible mechanisms of action.  In humans, cadmium \nexposure is associated with adverse bone effects, including fractures, osteoporosis, and decreased \nbone mineral density.  Bone effects associated with cadmium exposure were first described in \ncadmium-contaminated communities in Japan with high dietary intake; the disease called Itai-Itai \n(“ouch-ouch”) disease was characterized by multiple fractures of the long bones, osteomalacia, \nand osteoporosis.  Bone effects have been confirmed in animal studies following oral exposure; \nthese endpoints have not been assessed following inhalation exposure in animals.\n\n• **Renal Endpoints.** Renal effects are a known effect of cadmium toxicity based on a high level of \nevidence from human epidemiological studies, a moderate level of evidence in laboratory animal \ninhalation studies, and other relevant data including several meta-analyses and a well-defined \nmechanism of action. The kidney has been a well-established target of cadmium toxicity in \nhumans following occupational and dietary exposure for decades.  Several studies have \ndeveloped dose-response analyses of sensitive biomarkers of cadmium exposure and renal \ntoxicity (e.g., urinary cadmium levels and low molecular weight [LMW] proteinuria).  Data in \nanimals following inhalation exposure are inadequate.  While findings in multi-dose oral studies \nin animals meeting inclusion criteria are mixed, several studies reported alterations in biomarkers \nof renal functions (e.g., LMW proteinuria, serum blood urea nitrogen [BUN]) and \nhistopathological changes.\n\n---\n\n## 2. HEALTH EFFECTS\n\n• **Neurodevelopmental Endpoints.** Neurodevelopmental effects are a presumed effect in humans \nbased on a low level of evidence in humans and a high level of evidence in animals.  Available \nepidemiological data from general population studies are mixed.  A limited number of inhalation \nstudies and numerous oral studies in animals indicate that developmental cadmium exposure can \ncause alterations in sensorimotor function (including nerve conduction) and activity, \nsocioemotional behavior, and learning and memory in rodents; however, the timing and duration \nof exposure and assessment influence findings.  Available data indicate that neurodevelopmental \neffects are the most sensitive indicator of developmental toxicity of cadmium (occur at lower \nexposures than those associated with standard developmental outcomes or specialized evaluations \nof other systems, such as reproductive development).\n\n---\n\n**Figure 2-1.  Overview of the Number of Studies Examining Cadmium Health Effects***\n\n## Most studies examined the potential body weight, renal, and developmental effects of cadmium\n\nNumerous studies are available in both **humans** and **animals** (counts represent studies examining endpoint)\n\n| Category | humans (count) | animals (count) |\n| --- | --- | --- |\n| Death | 11 | 42 |\n| Body weight |  | 98 |\n| Respiratory | 15 | 29 |\n| Cardiovascular | 28 | 13 |\n| Gastrointestinal | 6 | 9 |\n| Hematological | 5 | 31 |\n| Musculoskeletal | 30 | 16 |\n| Hepatic | 21 | 23 |\n| Renal | 54 | 34 |\n| Dermal | 2 | 1 |\n| Ocular | 2 | 2 |\n| Endocrine | 19 | 15 |\n| Immunological | 14 | 26 |\n| Neurolgical | 12 | 12 |\n| Reproductive | 30 | 39 |\n| Developmental | 33 | 45 |\n| Other Noncancer | 4 | 4 |\n| Cancer | 34 | 10 |\n\n**Exposure Route**\n\n| Category | Share of studies (%) |\n| --- | --- |\n| Multi-route | 56 |\n| Oral | 30 |\n| Dermal | 1 |\n| Inhalation | 13 |\n\n**Exposure Duration**\n\n| Category | Share of studies (%) |\n| --- | --- |\n| Chronic | 60 |\n| Intermediate | 25 |\n| Acute | 15 |\n\n*Includes studies discussed in Chapter 2.  A total of 69 meta-analyses and 411 studies meeting inclusion criteria (including those finding no effect) have examined \ntoxicity; most studies examined multiple endpoints. Note: Meta-analyses are counted as a single data-point in the figure above because only the overall results of \nthe meta-analysis, not the individual studies included in the meta-analyses, were included in Chapter 2.\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| ACUTE EXPOSURE |  |  |  |  |  |  |  |  |  |\n| Beton et al. 1966 |  |  |  |  |  |  |  |  | Cadmium oxide fume |\n| 1 | Human 5 M | 5 hours (occup) | 8.63 | LE, CS | Death Resp |  |  | 8.63 | 1/5 exposed workers died Severe dyspnea, wheezing, chest pain and precordial constriction, persistent cough (lasting up to 7 days post-exposure); severe pulmonary edema and alveolar cell metaplasia in the worker that died |\n| Barrett et al. 1947 |  |  |  |  |  |  |  |  | Cadmium oxide fume |\n| 2 | Rat (NS) 10–25 NS | 10–15 minutes (WB) | 8.8, 13, 18, 19, 22, 25, 31, 41, 79.2, 110 | LE | Death |  |  | 30 | LC50 at 7 days |\n| Buckley and Bassett 1987 |  |  |  |  |  |  |  |  | Cadmium oxide dust |\n| 3 | Rat (Wistar) 20 M | 3 hours (WB) | 0, 0.4, 4.6 | BW | Bd wt | 0.4 | 4.6 |  | 15% decrease in body weight 7 days post-exposure |\n| Bus et al. 1978 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 4 | Rat (Sprague-Dawley) 18 M | 1 hour (WB) | 0, 6.5 | LE, BW, BI, OW, OF | Bd wt |  | 6.5 |  | 11% decrease in body weight 11 days post-exposure |\n|  |  |  |  |  | Resp |  | 6.5 |  | Decreased tidal volume and increased respiratory frequency 1 and 5 days post-exposure |\n| Rats were examined at 1, 5, and 11 days post-exposure (6/group/timepoint) |  |  |  |  |  |  |  |  |  |\n| Grose et al. 1987 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 5 | Rat (Sprague-Dawley) 40 M | 2 hours (H) | 0, 0.25, 0.48, 4.50 | LE, CS, BW | Bd wt | 0.25 |  | 4.5 | 20% decrease in body weight 72 hours post-exposure |\n\nRats were examined immediately and 72 hours post-exposure (20/group/timepoint)\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects | Cadmium oxide dust |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Grose et al. 1987 |  |  |  |  |  |  |  |  |  |  |\n| 6 | Rat (Sprague-Dawley) 40 M | 2 hours (H) | 0, 0.25, 0.44, 4.45 | LE, CS, BW | Bd wt | 4.45 |  |  |  |  |\n| Rats were examined immediately and 72 hours post-exposure (20/group/timepoint) |  |  |  |  |  |  |  |  |  |  |\n| Hart 1986 |  |  |  |  |  |  |  |  |  |  |\n| 7 | Rat (Lewis) 3 M | 1 or 2 weeks 5 days/week 3 hours/day (N) | 0, 1.6 | BI, OW, HP | Resp |  | 1.6 |  |  | Cadmium acetate Increase in BALF cellularity (macrophages, PMNs, lymphocytes) and markers of cytotoxicity (LDH, ALP, AP, total protein) |\n| Jacobo-Estrada et al. 2016 |  |  |  |  |  |  |  |  |  |  |\n| 8 | Rat (Wistar) 6 F | 13 days GDs 8–20 2 hours/day (WB) | 0, 17.43 | BW, OW, DX | Bd wt Repro Develop | 17.43 | 17.43 | 17.43 |  | Cadmium chloride Decreased absolute placental weight Fetal kidney injury (decreased fetal plasma creatinine levels, increased total histopathological lesion score in fetal kidney); decreased fetal body weight (8%) |\n| NTP 1995 |  |  |  |  |  |  |  |  |  |  |\n| 9 | Rat (Fischer-344) 5 M, 5 F | 2 weeks 5 days/week 6.2 hours/day (WB) | 0, 0.081, 0.249, 0.844, 2.49, 8.60 | LE, CS, BW, OW, HP | Death Bd wt Resp | 2.49 | 0.081 | 8.6 |  | Cadmium oxide aerosol 100% mortality by day 6 |\n|  |  |  |  |  | Cardio | 2.49 |  |  |  | SLOAEL: Marked necrosis of alveolar ducts LOAEL: Minimal-to-mild alveolar histiocytic infiltrate and focal inflammation in alveolar septa |\n|  |  |  |  |  | Hepatic | 2.49 |  |  |  |  |\n|  |  |  |  |  | Renal | 2.49 |  |  |  |  |\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects | Cadmium chloride |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Palmer et al. 1986 |  |  |  |  |  |  |  |  |  |  |\n| 10 | Rat (Sprague-Dawley) 20–30 M | 2 hours (WB) | 0, 6.0 | BW, BC, BI, OW | Bd wt | 6 |  |  |  |  |\n| 10 | Rat (Sprague-Dawley) 20–30 M | 2 hours (WB) | 0, 6.0 | BW, BC, BI, OW | Resp |  | 6 |  |  | Increased BALF cellularity (primarily macrophages) 3 days post-exposure |\n| 10 | Rat (Sprague-Dawley) 20–30 M | 2 hours (WB) | 0, 6.0 | BW, BC, BI, OW | Endocr | 6 |  |  |  |  |\n| Rats were sacrificed |  | 1, 3, 7, or 10 days post-exposure (≥4/group/timepoint) |  |  |  |  |  |  |  |  |\n| Rusch et al. 1986 |  |  |  |  |  |  |  |  |  | Cadmium carbonate |\n| 11 | Rat (Sprague-Dawley) 26 M, 26 F | 2 hours (WB) | 0, 94 | LE, CS, GN | Resp |  |  | 94 |  | Rales persisting up to 4 hours post-exposure |\n| Rats were sacrificed immediately or 1, 3, 7, or 30 days post-exposure (10/group/timepoint); extra two rats were replacement animals |  |  |  |  |  |  |  |  |  |  |\n| Rusch et al. 1986 |  |  |  |  |  |  |  |  |  | Cadmium sulfide |\n| 12 | Rat (Sprague-Dawley) 26 M, 26 F | 2 hours (WB) | 0, 140 | LE, CS, BW | Bd wt | 140 |  |  |  |  |\n| Rats were sacrificed immediately or 1, 3, 7, or 30 days post-exposure (10/group/timepoint); extra two rats were replacement animals |  |  |  |  |  |  |  |  |  |  |\n| Rusch et al. 1986 |  |  |  |  |  |  |  |  |  | Cadmium selenide |\n| 13 | Rat (Sprague-Dawley) 26 M, 26 F | 2 hours (WB) | 0, 105 | LE, CS, BW | Bd wt | 105 |  |  |  |  |\n| Rats were sacrificed immediately or 1, 3, 7, or 30 days post-exposure (10/group/timepoint); extra two rats were replacement animals |  |  |  |  |  |  |  |  |  |  |\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Rusch et al. 1986 |  |  |  |  |  |  |  |  | Cadmium acetate |\n| 14 | Rat (Sprague-Dawley) 26 M, 26 F | 2 hours (WB) | 0, 83 | LE, CS | Death |  |  | 83 | 25/32 died between 1 and 7 days post-exposure |\n| 14 | Rat (Sprague-Dawley) 26 M, 26 F | 2 hours (WB) | 0, 83 | LE, CS | Resp |  |  | 83 | Labored breathing and rales persisting up to 4 hours post-exposure |\n| 14 | Rat (Sprague-Dawley) 26 M, 26 F | 2 hours (WB) | 0, 83 | LE, CS | Neuro |  | 83 |  | Reduced activity during exposure |\n| Rats were sacrificed immediately or 1, 3, 7, or 30 days post-exposure (10/group/timepoint); extra two rats were replacement animals |  |  |  |  |  |  |  |  |  |\n| Snider et al. 1973 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 15 | Rat (Sprague-Dawley) 18 M | 3 days 1 hour/day (WB) | 61 | LE, GN | Death |  |  | 61 | 17/18 died within 3 days |\n| 15 | Rat (Sprague-Dawley) 18 M | 3 days 1 hour/day (WB) | 61 | LE, GN | Resp |  |  | 61 | Pulmonary hemorrhage |\n| Barrett et al. 1947 |  |  |  |  |  |  |  |  | Cadmium oxide fume |\n| 16 | Mouse (NS) 10 NS | 15 minutes (WB) | 39, 61.3, 65.9 | LE | Death |  |  | 39 | 9/10 died within 7 days |\n| Graham et al. 1978 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 17 | Mouse (CD-1) 16–20 F | 2 hours (WB) | 0, 0.110, 0.190 | IX | Immuno | 0.11 | 0.19 |  | Decreased humoral immune response |\n| Krzystyniak et al. 1987 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 18 | Mouse (C57BL/6) 4–5 F | 60 minutes (N) | 0, 0.88 | IX | Immuno |  | 0.88 |  | Reduced humoral and cell-mediated immune responses |\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| NTP 1995 |  |  |  |  |  |  |  |  | Cadmium oxide aerosol |\n| 19 | Mouse (B6C3F1) 5 M, 5 F | 2 weeks 5 days/week 6.2 hours/day (WB) | 0, 0.081, 0.249, 0.844, 2.49, 8.60 | LE, CS, BW, OW, HP | Death Bd wt Resp | 2.49 | 0.081 | 8.6 | 100% mortality by day 7 |\n| 19 | Mouse (B6C3F1) 5 M, 5 F | 2 weeks 5 days/week 6.2 hours/day (WB) | 0, 0.081, 0.249, 0.844, 2.49, 8.60 | LE, CS, BW, OW, HP | Cardio Hepatic Renal | 2.49 2.49 2.49 | 0.081 | 0.844 | LOAEL: Minimal-to-mild alveolar histiocytic infiltrates SLOAEL: Fibrosis, inflammation, and mild necrosis of the alveolar ducts; degeneration of the nasal olfactory epithelium |\n| NTP 1995 |  |  |  |  |  |  |  |  | Cadmium oxide aerosol |\n| 20 | Mouse (Swiss) 33 F | 14 days GDs 4–17 6.27 hours/day (WB) | 0, 0.04, 0.4, 1.7 | LE, CS, BW, OW, DX | Bd wt Develop | 0.4 | 0.04 | 1.7 | 22% decrease in maternal body weight on GD 18 Increased total litter resorption; decreased fetal body weight (29–30%); reduced ossification of sternebrae Decreased male (9%) and female (8%) fetal body weight |\n| Friberg 1950 |  |  |  |  |  |  |  |  | Cadmium metal dust |\n| 21 | Rabbit (NS) 8 NS | 4 hours (H) | 11.5 - 48.4 | LE | Death |  |  | 28.4 | LC50 at 14 days |\n| Henderson et al. 1979 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 22 | Hamster (Golden Syrian) 30 B | 30 minutes (N) | 0, 1.1, 10.1 | LE, BI, HP | Resp |  | 1.1 | 10.1 | LOAEL: Increased BALF PMN and AP levels SLOAEL: Necrosis of bronchiolar epithelium 1 day post-exposure; severe pneumonitis 7 days post-exposure |\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| INTERMEDIATE EXPOSURE |  |  |  |  |  |  |  |  |  |\n| Baranski 1984 |  |  |  |  |  |  |  |  | Cadmium oxide aerosol |\n| 23 | Rat (Wistar) 7–15 F | 6-7 months (5 months premating, up to 3 weeks mating, GDs 1–20) 5 hours/day 5 days/week (WB) | 0, 0.02, 0.16 | RX, DX | Repro Develop | 0.16 | 0.02 | 0.16 | LOAEL: Age- and sex-dependent changes in offspring motor activity; impaired avoidance acquisition in 3- and 7-month-old females SLOAEL: 25% mortality by PND 4 (decreased viability index); 15% decrease in weanling body weight |\n| Baranski 1985 |  |  |  |  |  |  |  |  | Cadmium oxide dust |\n| 24 | Rat (Wistar) 5–16 F | 5–7 months (4–5 months premating, mating, GDs 1–20) 5 days/week 5 hours/day (WB) | 0, 0.02, 0.16, 1.0 | LE, BW, RX, DX | Death Bd wt Repro Develop | 1 1 | 0.02 | 1 | 55.1% mortality |\n| Baranski and Sitarek 1987 |  |  |  |  |  |  |  |  | LOAEL: Decreased motor activity in 3-month-old males and decreased conditioned reflexes in 5-month-old females SLOAEL: 23% decrease in pup viability index; unspecified decrease in pup weight during first 2 months |\n| 25 | Rat (Wistar) 13–14 F | 20 weeks 5 days/week 5 hours/day (WB) | 0, 0.02, 0.16, 1.0 | LE, CS, BW, RX | Death Bd wt Repro | 0.16 | 0.02 | 1 | Cadmium oxide dust 38% mortality by week 13; 100% mortality by week 20 30–50% decrease in body weight gain starting at week 4 Increased duration of estrous cycle |\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Glaser et al. 1986 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 26 | Rat (Wistar) 12 M | 30 days 7 days/week 22 hours/day (WB) | 0, 0.105 | LE, CS, BW, HE, BC, BI, UR | Bd wt Resp | 0.105 | 0.105 |  | Increase in BALF cellularity (PMNs, macrophages, leukocytes) and markers of cytotoxicity (LDH, total protein levels); macrophages, total protein and LDH remained elevated at 2-months post-exposure |\n| 26 | Rat (Wistar) 12 M | 30 days 7 days/week 22 hours/day (WB) | 0, 0.105 | LE, CS, BW, HE, BC, BI, UR | Hemato | 0.105 | 0.105 |  | Increased WBC counts at terminal sacrifice |\n| 26 | Rat (Wistar) 12 M | 30 days 7 days/week 22 hours/day (WB) | 0, 0.105 | LE, CS, BW, HE, BC, BI, UR | Renal | 0.105 |  |  |  |\n| Rats were sacrificed immediately following exposure (terminal sacrifice) or 2 months post-exposure (6/group/timepoint) |  |  |  |  |  |  |  |  |  |\n| Glaser et al. 1986 |  |  |  |  |  |  |  |  | Cadmium sulfide |\n| 27 | Rat (Wistar) 12 M | 30 days 7 days/week 22 hours/day (WB) | 0, 1.034 | LE, CS, BW, HE, BC, BI, OW | Bd wt Resp | 1.034 | 1.034 |  | Increase in BALF cellularity (PMNs, macrophages, leukocytes) and markers of cytotoxicity (LDH, total protein levels); macrophages, total protein and LDH remained elevated at 2-months post-exposure |\n| 27 | Rat (Wistar) 12 M | 30 days 7 days/week 22 hours/day (WB) | 0, 1.034 | LE, CS, BW, HE, BC, BI, OW | Hemato | 1.034 |  |  |  |\n| 27 | Rat (Wistar) 12 M | 30 days 7 days/week 22 hours/day (WB) | 0, 1.034 | LE, CS, BW, HE, BC, BI, OW | Renal | 1.034 |  |  |  |\n| Rats were sacrificed immediately following exposure (terminal sacrifice) or 2 months post-exposure (6/group/timepoint) |  |  |  |  |  |  |  |  |  |\n| Glaser et al. 1986 |  |  |  |  |  |  |  |  | Cadmium oxide dust |\n| 28 | Rat (Wistar) 12 M | 30 days 7 days/week 22 hours/day (WB) | 0, 0.098 | LE, CS, BW, HE, BC, BI, OW | Bd wt Resp | 0.098 | 0.098 |  | Increase in BALF cellularity (PMNs, macrophages, leukocytes) and markers of cytotoxicity (LDH, total protein levels); total protein remained elevated at 2-months post-exposure |\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n|  |  |  |  |  | Hemato |  | 0.098 |  | Increased WBC count at terminal sacrifice |\n|  |  |  |  |  | Renal | 0.098 |  |  |  |\n\n| Rats were sacrificed immediately following exposure (terminal sacrifice) or 2 months post-exposure (6/group/timepoint) |  |  |  |  |  |  |  |  |  |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Hart 1986 |  |  |  |  |  |  |  | Cadmium acetate |  |\n| 29 | Rat (Lewis) 3 M | 3–6 weeks 5 days/week 3 hours/day (N) | 0, 1.6 | BI, OW, HP | Resp |  | 1.6 |  | Transient increase in BALF cellularity (macrophages, PMNs, lymphocytes) and markers of cytotoxicity (LDH, ALP, AP, total protein); resolving weeks 4–6 |\n| Kutzman et al. 1986 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 30 | Rat (Fischer 344) 20 M | 62 days 5 days/week 6 hours/day (WB) | 0, 0.33, 1.06, 2.13 | LE, CS, BW, BI, OW, HP | Death |  |  | 2.13 | 100% mortality by day 45 |\n| 30 | Rat (Fischer 344) 20 M | 62 days 5 days/week 6 hours/day (WB) | 0, 0.33, 1.06, 2.13 | LE, CS, BW, BI, OW, HP | Bd wt | 0.33 |  | 1.06 | 27% decrease in body weight |\n| Kutzman et al. 1986 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 31 | Rat (Fischer 344) 8 M, 8 F | 62 days 5 days/week 6 hours/day (WB) | 0, 0.33, 1.06, 2.13 | LE, BW, RX | Death |  |  | 2.13 | 100% mortality by day 45 |\n| 31 | Rat (Fischer 344) 8 M, 8 F | 62 days 5 days/week 6 hours/day (WB) | 0, 0.33, 1.06, 2.13 | LE, BW, RX | Bd wt | 0.33 | 1.03 | 2.13 | LOAEL: 14% decreased in body weight SLOAEL: Body weight loss (decreased 40% compared to starting body weight) |\n| Repro |  |  |  |  |  | 1.06 M |  |  |  |\n| Exposed rats were mated with both exposed and unexposed rats 6 days post-exposure |  |  |  |  |  |  |  |  |  |\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| NTP 1995 |  |  |  |  |  |  |  |  | Cadmium oxide aerosol |\n| 32 | Rat (Fischer-344) 10 M, 10 F | 13 weeks 5 days/week 6.33 hours/day (WB) | 0, 0.021, 0.046, 0.088, 0.212, 0.902 | LE, CS, BW, HE, BC, UR, OW, HP, OF, RX | Bd wt Resp | 0.902 | 0.021 F | 0.902 M | Minimal epithelial degeneration in the larynx LOAEL: Minimal alveolar histiocytic infiltrate and epithelial hyperplasia; minimal epithelial degeneration in the larynx SLOAEL: Marked inflammation and moderate fibrosis in interstitium around alveolar ducts and terminal bronchioles |\n| 32 | Rat (Fischer-344) 10 M, 10 F | 13 weeks 5 days/week 6.33 hours/day (WB) | 0, 0.021, 0.046, 0.088, 0.212, 0.902 | LE, CS, BW, HE, BC, UR, OW, HP, OF, RX | Cardio Gastro Hemato Musc/skel Hepatic Renal Endocr Immuno Neuro Repro | 0.902 0.902 0.902 0.902 0.902 0.902 0.902 | 0.021 M | 0.046 M | Minimal epithelial degeneration in the larynx LOAEL: Minimal alveolar histiocytic infiltrate and epithelial hyperplasia; minimal epithelial degeneration in the larynx SLOAEL: Marked inflammation and moderate fibrosis in interstitium around alveolar ducts and terminal bronchioles |\n| NTP 1995 |  |  |  |  |  |  |  |  | Decreased spermatid counts in males, increased estrous cycle length in females |\n| 33 | Rat (Sprague-Dawley) 32 F | 16 days GDs 4–19 6.27 hours/day (WB) | 0, 0.04, 0.4, 1.7 | LE, CS, BW,OW, DX | Bd wt | 0.4 | 1.7 | Cadmium oxide aerosol | 14% decrease in maternal body weight on GD 20 Decreased male (16%) and female (17%) fetal body weight; reduced ossification of pelvis and sternebrae |\n| 33 | Rat (Sprague-Dawley) 32 F | 16 days GDs 4–19 6.27 hours/day (WB) | 0, 0.04, 0.4, 1.7 | LE, CS, BW,OW, DX | Develop | 0.4 |  | 1.7 | 14% decrease in maternal body weight on GD 20 Decreased male (16%) and female (17%) fetal body weight; reduced ossification of pelvis and sternebrae |\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects | Cadmium chloride |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Oberdörster et al. 1994 |  |  |  |  |  |  |  |  |  |  |\n| 34 | Rat (Fischer 344) 48 M | 4 weeks 5 days/week 6 hours/day (WB) | 0, 0.100 | BI | Resp |  | 0.1 |  | Increase in BALF PMNs (1 day post-exposure) |  |\n\n| Rats were sacrificed at 1, 7, or 28 days post-exposure (≥4/group/timepoint per endpoint) |  |  |  |  |  |  |  |\n| --- | --- | --- | --- | --- | --- | --- | --- |\n| Oldiges and Glaser 1986 |  |  |  |  |  |  | Cadmium oxide dust |\n| 35 | Rat (Wistar) 20 M, 20 F | 218–343 days 7 days/week 22 hours/day (WB) | M: 0, 0.030, 0.090 F: 0, 0.026, 0.081 | LE, GN, BW, Death FI, WI, HE, OW |  | 0.081 F 0.09 M | 6/20 died 6/20 died |\n| Oldiges and Glaser 1986 |  |  |  |  |  |  | Cadmium sulfide |\n| 36 | Rat (Wistar) 20–24 M, 20–24 F | 105–298 days 7 days/week 22 hours/day (WB) | M: 0, 0.843, 2.270 F: 0, 0.841, 2.247 | LE, GN, BW, Death FI, WI, HE, OW |  | 0.841 F 0.843 M | 7/20 died by day 298 6/20 died by day 208 |\n| Oldiges et al. 1989 |  |  |  |  |  |  | Cadmium chloride |\n| 37 | Rat (Wistar) 20 M, 18–20 F | 6 months 7 days/week 22 hours/day (WB) | 0, 0.090 | LE, GN, HP Death Cancer |  | 0.09 0.09 M | 25% mortality at 6 months CEL: Lung tumors (bronchioalveolar adenoma, adenocarcinoma, or squamous cell carcinoma) |\n| Scheduled sacrifice at 31 months; surviving Cd-exposed rats sacrificed at 29–30 months due to mortality ≥75% |  |  |  |  |  |  |  |\n| Oldiges et al. 1989 |  |  |  |  |  |  | Cadmium sulfide |\n| 38 | Rat (Wistar) 20 M, 20 F | 6 months 40 hours/week (WB) | 0, 0.270 | LE, GN, HP Death |  | 0.27 | 75% mortality at 27–29 months |\n| Scheduled sacrifice at 31 months; surviving Cd-exposed rats sacrificed at 27–29 months due to mortality ≥75% |  |  |  |  |  |  |  |\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Oldiges et al. 1989 |  |  |  |  |  |  |  |  | Cadmium sulfide |\n| 39 | Rat (Wistar) 16–20 M, 19–20 F | 3–10 months 7 days/week 22 hours/day (WB) | 0, 0.810, 2.430 | LE, GN, HP | Death Cancer |  |  | 0.81 | 25% mortality at 7–10 months CEL: Lung tumors (bronchioalveolar adenoma, adenocarcinoma, squamous cell carcinoma, or mixed tumor type) |\n\nScheduled sacrifice at 31 months; most surviving Cd-exposed rats sacrificed at 29-30 months due to mortality ≥75%\n\n| Oldiges et al. 1989 |  |  |  |  |  |  |  | Cadmium oxide dust |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| 40 | Rat (Wistar) 17–20 M, 16–20 F | 7–11 months 7 days/week 22 hours/day (WB) | 0, 0.090 | LE, GN, HP | Death Cancer | 0.09 | 0.09 | 25% mortality at 7–11 months CEL: Lung tumors (bronchioalveolar adenoma, adenocarcinoma, squamous cell carcinoma, or mixed tumor type) |\n\n| Scheduled sacrifice at 31 months |  |  |  |  |  |  |  |  |  |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Prigge 1978a |  |  |  |  |  |  |  | Cadmium oxide dust |  |\n| 41 | Rat (Wistar) 12 F | 90 days 24 hours/day (WB) | 0, 0.025, 0.052 | LE, BW, HE, BC, UR, OW, HP | Bd wt Resp | 0.025 | 0.025 | 0.052 | 23% decrease in body weight gain Proliferative lung lesions, histiocytic cell granulomas Increased hemoglobin and hematocrit |\n| 41 | Rat (Wistar) 12 F | 90 days 24 hours/day (WB) | 0, 0.025, 0.052 | LE, BW, HE, BC, UR, OW, HP | Hematoc | 0.025 | 0.052 | 0.052 | 23% decrease in body weight gain Proliferative lung lesions, histiocytic cell granulomas Increased hemoglobin and hematocrit |\n| 41 | Rat (Wistar) 12 F | 90 days 24 hours/day (WB) | 0, 0.025, 0.052 | LE, BW, HE, BC, UR, OW, HP | Hepatic Renal | 0.052 | 0.052 | 0.052 | 23% decrease in body weight gain Proliferative lung lesions, histiocytic cell granulomas Increased hemoglobin and hematocrit |\n\n| Prigge 1978a |  |  |  |  |  |  |  | Cadmium oxide dust |  |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| 42 | Rat (Wistar) 12 F | 63 days 24 hours/day (WB) | 0, 0.105 | LE, BW, HE, BC, UR | Death |  |  | 0.105 | 5/12 died |\n| 42 | Rat (Wistar) 12 F | 63 days 24 hours/day (WB) | 0, 0.105 | LE, BW, HE, BC, UR | Bd wt |  |  | 0.105 | 51% decrease in body weight gain |\n| 42 | Rat (Wistar) 12 F | 63 days 24 hours/day (WB) | 0, 0.105 | LE, BW, HE, BC, UR | Hematoc |  | 0.105 |  | Increased hemoglobin and hematocrit |\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Prigge 1978b |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 43 | Rat (Wistar) 12–13 F | 21 days 24 hours/day (WB) | 0, 0.204, 0.394, 0.581 | BW, HE, BC, UR, OW, HP | Bd wt Hemato | 0.581 | 0.204 |  | Increase in hemoglobin and hematocrit |\n|  |  |  |  |  | Renal | 0.581 |  |  |  |\n| Prigge 1978b |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 44 | Rat (Wistar) 12–13 F | 21 days GDs 1–21 24 hours/day (WB) | 0, 0.204, 0.394, 0.581 | BW, HE, BC, UR, OW, HP, DX | Bd wt |  | 0.204 | 0.394 | LOAEL: 12% decrease in maternal body weight gain SLOAEL: 35% decrease in maternal body weight gain Increased hemoglobin and hematocrit; elevated total (but not direct) bilirubin |\n|  |  |  |  |  | Hemato | 0.394 | 0.581 |  |  |\n|  |  |  |  |  | Renal | 0.581 |  |  |  |\n|  |  |  |  |  | Develop | 0.394 |  | 0.581 | 19% decrease in fetal body weight; decreased fetal hemoglobin |\n| NTP 1995 |  |  |  |  |  |  |  |  | Cadmium oxide aerosol |\n| 45 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week 6.33 hours/day (WB) | 0, 0.021, 0.046, 0.088, 0.211, 0.910 | LE, CS, BW, OW, HP, RX | Bd wt Resp | 0.91 | 0.021 |  | Minimal alveolar histiocytic infiltrates and squamous metaplasia of the larynx |\n|  |  |  |  |  | Cardio | 0.91 |  |  |  |\n|  |  |  |  |  | Gastro | 0.91 |  |  |  |\n|  |  |  |  |  | Musc/skel | 0.91 |  |  |  |\n|  |  |  |  |  | Hepatic | 0.91 |  |  |  |\n|  |  |  |  |  | Renal | 0.91 |  |  |  |\n|  |  |  |  |  | Endocr | 0.91 |  |  |  |\n|  |  |  |  |  | Immuno | 0.91 |  |  |  |\n|  |  |  |  |  | Neuro | 0.91 |  |  |  |\n|  |  |  |  |  | Repro | 0.91 |  |  |  |\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Oberdörster et al. 1994 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 46 | Mouse (BALB/c) 72 M | 4 weeks 5 days/week 6 hours/day (WB) | 0, 0.100 | BI | Resp |  | 0.1 |  | Increase in BALF PMNs and LDH levels (1, 7, and 28 days post-exposure); increase cell proliferation in alveolar epithelium and macrophage infiltration (1 and 7 days post-exposure) |\n| Mice were sacrificed at 1, 7, or 28 days post-exposure (≥4/group/timepoint per endpoint) |  |  |  |  |  |  |  |  |  |\n| Johansson et al. 1984 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 47 | Rabbit (NS) 8 M | 4–6 weeks 5 days/week 6 hours/day (WB) | 0, 0.4 | BI, OW, HP | Resp |  | 0.4 |  | Lung interstitial inflammation, type 2 cell hyperplasia |\n| CHRONIC EXPOSURE |  |  |  |  |  |  |  |  |  |\n| Buchet et al. 1990; Hoo et al. 2004; Järup and Elinder 1994; Järup et al. 2000; Kobayashi et al. 2008; Lei et al. 2007; Shao et al. 2007; Suwazono et al. 2006; Uno et al. 2005; Wu et al. 2001; Zhang et al. 2016a |  |  |  |  |  |  |  |  | Cadmium |\n| 48 | Human 85–3,454 per dataset | 17 datasets (3 occupational and 8 general population cohorts) | UR | Renal |  |  |  | LMW proteinuria; 95% LCL weighted median of 17 UC10 values = 0.00106 mg Cd/m3 c |  |\n| Oldiges and Glaser 1986 |  |  |  |  |  |  |  |  | Cadmium sulfate |\n| 49 | Rat (Wistar) 20–40 M, 20 F | 413–455 days 7 days/week 22 hours/day (WB) | M: 0, 0.095 F: 0, 0.092 | LE, BW, FI, WI, HE, OW, GN | Death |  |  | 0.095 M | 6/20 died |\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Oldiges et al. 1989 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 50 | Rat (Wistar) 20 M, 18–20 F | 18 months 7 days/week 22 hours/day (WB) | 0, 0.030 | LE, GN, HP | Death Cancer |  |  | 0.03 M 0.03 | 75% mortality at 30 months CEL: Lung tumors (bronchioalveolar adenoma, adenocarcinoma, squamous cell carcinoma, or mixed tumor type) |\n| Scheduled sacrifice at 31 months; surviving Cd-exposed males sacrificed at 30 months due to mortality ≥75% |  |  |  |  |  |  |  |  |  |\n| Oldiges et al. 1989 |  |  |  |  |  |  |  |  | Cadmium sulfide |\n| 51 | Rat (Wistar) 19–20 M, 19–20 F | 16–18 months 7 days/week 22 hours/day (WB) | 0, 0.090, 0.270 | LE, GN, HP | Death Cancer |  |  | 0.09 0.270 | 75% mortality at 30 months in males 25% mortality at 16 months in females CEL: Lung tumors (bronchioalveolar adenoma, adenocarcinoma, squamous cell carcinoma, or mixed tumor type) |\n| Scheduled sacrifice at 31 months; surviving Cd-exposed rats sacrificed at 30 months due to mortality ≥75% |  |  |  |  |  |  |  |  |  |\n| Oldiges et al. 1989 |  |  |  |  |  |  |  |  | Cadmium oxide dust |\n| 52 | Rat (Wistar) 20 M, 20 F | 18 months 7 days/week 22 hours/day (WB) | 0, 0.030 | LE, GN, HP | Cancer |  |  | 0.03 | CEL: Lung tumors (bronchioalveolar adenoma, adenocarcinoma, squamous cell carcinoma, or mixed tumor type) |\n| Scheduled sacrifice at 31 months |  |  |  |  |  |  |  |  |  |\n| Oldiges et al. 1989 |  |  |  |  |  |  |  |  | Cadmium sulfate |\n| 53 | Rat (Wistar) 20 M, 20 F | 14–18 months 7 days/week 22 hours/day (WB) | 0, 0.09 | LE, GN, HP | Death Cancer |  |  | 0.09 | 25% mortality in males by 14 months; 75% mortality in females by 29 months CEL: Lung tumors (bronchioalveolar adenoma, adenocarcinoma, squamous cell carcinoma, or mixed tumor type) |\n\nScheduled sacrifice at 31 months; surviving Cd-exposed females sacrificed at 29 months due to mortality ≥75%\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Oldiges et al. 1989 |  |  |  |  |  |  |  |  | Cadmium oxide fume |\n| 54 | Rat (Wistar) 17–20 M | 18 months 7 days/week 22 hours/day (WB) | 0, 0.01, 0.03 | LE, GN, HP | Cancer |  |  | 0.03 | CEL: Lung tumors (bronchioalveolar adenoma, adenocarcinoma) |\n| Takenaka et al. 1983 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 55 | Rat (Wistar) 40–41 M | 18 months 7 days/week 23 hours/day (WB) | 0, 0.0134, 0.0257, 0.0508 | LE, BW, HP | Bd wt Cancer | 0.0508 |  | 0.0134 | CEL: Lung tumors (lung epidermoid carcinomas, or adenocarcinomas) |\n| Scheduled sacrifice at 31 months |  |  |  |  |  |  |  |  |  |\n\n<sup>a</sup>The number corresponds to entries in Figure 2-2; differences in levels of health effects between male and females are not indicated in Figure 2-2.  Where such \ndifferences exist, only the levels of effect for the most sensitive sex are presented.\n\n<sup>b</sup>Concentrations are expressed as mg Cd/m<sup>3</sup>. If concentrations were reported by the study authors in terms of the administered compound (e.g., cadmium chloride \n[CdCl2]), they were converted to the equivalent concentration in terms of the metal (i.e., cadmium [Cd])) for easy comparison across studies.  Conversion was based on \nthe ratio of the molecular weights using the following equation: Concentration in terms of administered compound x (molecular weight Cd/molecular weight administered \ncompound).\n\n<sup>c</sup>Used to derive a chronic-duration inhalation MRL of 0.0001 mg Cd/m<sup>3</sup> (0.1 μg Cd/m<sup>3</sup>).  The point of departure (POD) is based on the 95% lower confidence limit (LCL) \non the weighted median of the UC10 values from 17 datasets from 11 human studies; the weighted median and 95% LCL were 2.04 and 1.57 μg Cd/g Cr, respectively.  \nThese values were converted into inhalation concentration equivalents of 0.00141 and 0.00106 mg Cd/m<sup>3</sup>, respectively, using PBPK modeling.  The POD of 0.00106 mg \nCd/m<sup>3</sup> was divided by an uncertainty factor of 3 for human variability and a modifying factor of 3 for database deficiencies.  See Appendix A for more detailed information \nregarding the MRL.\n\n## Principal studies for the MRL\n\nALP = alkaline phosphatase; AP = acid phosphatase; BALF = bronchoalveolar lavage fluid; BC = serum (blood) chemistry; Bd wt or BW = body weight; BI = biochemical \nchanges; Cardio = cardiovascular; Cd = cadmium; CEL = cancer effect level; Cr = creatinine; CS = clinical signs; Develop = developmental; DX = developmental toxicity; \nEndocr = endocrine; F = female(s); FI = food intake; Gastro = gastrointestinal; GD = gestation day; GN = gross necropsy; (H) = head only; HE = hematology; \nHemato = hematological; HP = histopathology; Immuno = immunological; IX = immune function; LC50 = lethal concentration, 50% kill; LDH = lactate dehydrogenase; \nLE = lethality; LMW = low molecular weight; LOAEL = lowest-observed-adverse-effect level; M = male(s); MRL = Minimal Risk Level; Musc/skel = musculoskeletal; \n(N) = nose-only; Neuro = neurological; NOAEL = no-observed-adverse-effect level; NS = not specified; (occup) = occupational; OF = organ function; OW = organ weight; \nPMN = polymorphonuclear leukocyte; PND = postnatal day; Repro = reproductive; Resp = respiratory; RX = reproductive function; SLOAEL = serious lowest-observedadverse-effect level; UC10 = urinary cadmium level associated with 10% extra risk; UR = urinalysis; (WB) = whole body; WBC = white blood cell; WI = water intake\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Cadmium – Inhalation**\nAcute (≤14 days)\n\n**Figure 2-2. Levels of Significant Exposure to Cadmium – Inhalation, Acute (≤14 days) - Death**\n\n| Category | mg Cd/m3 |\n| --- | --- |\n| 1 | 9 |\n| 2R | 30 |\n| 9R | 9 |\n| 14R | 85 |\n| 15R | 65 |\n| 16M | 40 |\n| 19M | 9 |\n| 21H | 30 |\n\n**Figure 2-2. Levels of Significant Exposure to Cadmium – Inhalation, Acute (≤14 days) - Body Weight**\n\n| Category | Animal - NOAEL (mg Cd/m3) | Animal - LOAEL (mg Cd/m3) | Animal - SLOAEL (mg Cd/m3) |\n| --- | --- | --- | --- |\n| 3R | 0.4 | 4.5 |  |\n| 4R |  | 6.5 |  |\n| 5R | 0.23 | 4.5 |  |\n| 6R | 4.0 |  |  |\n| 8R | 17 |  |  |\n| 9R | 2.6 |  |  |\n| 10R | 6.0 |  |  |\n| 12R | 140 |  |  |\n| 13R | 110 |  |  |\n| 19M | 2.6 |  |  |\n| 20M | 0.4 |  | 1.7 |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Cadmium – Inhalation**\nAcute (≤14 days)\n\n| Category | Human - SLOAEL (mg Cd/m3) | Animal - NOAEL (mg Cd/m3) | Animal - LOAEL (mg Cd/m3) | Animal - SLOAEL (mg Cd/m3) |\n| --- | --- | --- | --- | --- |\n| 1 | 9 |  |  |  |\n| 4R |  | 6 |  |  |\n| 7R |  | 1.6 |  |  |\n| 9R |  | 0.08 |  | 9 |\n| 10R |  | 6 |  |  |\n| 11R |  |  |  | 100 |\n| 14R |  |  |  | 85 |\n| 15R |  |  |  | 65 |\n| 19M |  | 0.008 | 0.8 |  |\n| 22S |  | 1.1 |  | 10 |\n| 9R |  | 2.5 |  |  |\n| 19M |  | 2.7 |  |  |\n| 9R |  | 2.7 |  |  |\n| 19M |  | 2.7 |  |  |\n| 9R |  | 2.7 |  |  |\n| 19M |  | 2.7 |  |  |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Cadmium – Inhalation**\nAcute (≤14 days)\n\n**Figure 2-2. Levels of Significant Exposure to Cadmium – Inhalation (Acute ≤14 days)**\n\n| Category | Animal - NOAEL (mg Cd/m3) | Animal - LOAEL (mg Cd/m3) | Animal - SLOAEL (mg Cd/m3) |\n| --- | --- | --- | --- |\n| Endocrine | 6 |  |  |\n| Immunological | 0.11 | 0.19 |  |\n| Neuropsychological |  | 85 |  |\n| Reproductive |  | 16 |  |\n| Developmental | 0.043 | 0.35 | 1.7 |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Cadmium – Inhalation**\nIntermediate (15–364 days)\n\n**Figure 2-2. Levels of Significant Exposure to Cadmium – Inhalation Intermediate (15–364 days) - Death**\n\n| Category | mg Cd/m3 |\n| --- | --- |\n| 24R | 1.0 |\n| 25R | 1.0 |\n| 30R | 2.6 |\n| 31R | 2.6 |\n| 35R | 0.080 |\n| 36R | 0.80 |\n| 37R | 0.090 |\n| 38R | 0.33 |\n| 39R | 0.80 |\n| 40R | 0.090 |\n| 42R | 0.11 |\n\n**Figure 2-2. Levels of Significant Exposure to Cadmium – Inhalation Intermediate (15–364 days) - Body Weight**\n\n| Category | Animal - NOAEL (mg Cd/m3) | Animal - LOAEL (mg Cd/m3) | Animal - SLOAEL (mg Cd/m3) |\n| --- | --- | --- | --- |\n| 24R | 1.0 |  |  |\n| 25R | 0.17 | 1.0 |  |\n| 26R | 0.11 |  |  |\n| 27R | 1.1 |  |  |\n| 28R | 0.10 |  |  |\n| 30R | 0.40 | 1.1 |  |\n| 31R | 0.40 | 1.1 |  |\n| 31R |  |  | 2.6 |\n| 32R | 0.90 |  |  |\n| 33R | 0.50 | 1.8 |  |\n| 33R |  |  | 1.8 |\n| 41R | 0.030 | 0.055 |  |\n| 42R |  |  | 0.11 |\n| 43R | 0.60 |  |  |\n| 44R |  | 0.23 | 0.44 |\n| 45M | 0.90 |  |  |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Cadmium – Inhalation**\nIntermediate (15–364 days)\n\n**Figure 2-2. Levels of Significant Exposure to Cadmium – Inhalation Intermediate (15–364 days)**\n\n| Category | Respiratory Animal - NOAEL (mg Cd/m3) | Respiratory Animal - LOAEL (mg Cd/m3) | Respiratory Animal - SLOAEL (mg Cd/m3) | Respiratory Animal - Cancer Effect Level (mg Cd/m3) | Cardiovascular Animal - NOAEL (mg Cd/m3) | Cardiovascular Animal - LOAEL (mg Cd/m3) | Cardiovascular Animal - SLOAEL (mg Cd/m3) | Cardiovascular Animal - Cancer Effect Level (mg Cd/m3) | Gastrointestinal Animal - NOAEL (mg Cd/m3) | Gastrointestinal Animal - LOAEL (mg Cd/m3) | Gastrointestinal Animal - SLOAEL (mg Cd/m3) | Gastrointestinal Animal - Cancer Effect Level (mg Cd/m3) | Hematological Animal - NOAEL (mg Cd/m3) | Hematological Animal - LOAEL (mg Cd/m3) | Hematological Animal - SLOAEL (mg Cd/m3) | Hematological Animal - Cancer Effect Level (mg Cd/m3) |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| 26R | 0.11 |  |  |  |  |  |  |  |  |  |  |  | 0.11 |  |  |  |\n| 27R |  | 1.1 |  |  |  |  |  |  |  |  |  |  | 1.1 |  |  |  |\n| 28R |  | 0.10 |  |  |  |  |  |  |  |  |  |  |  | 0.10 |  |  |\n| 29R |  | 1.7 |  |  |  |  |  |  |  |  |  |  |  |  |  |  |\n| 32R |  | 0.023 | 0.90 |  | 0.90 |  |  |  | 0.90 |  |  |  | 0.90 |  |  |  |\n| 34R |  | 0.10 |  |  |  |  |  |  |  |  |  |  |  |  |  |  |\n| 41R |  | 0.026 |  |  |  |  |  |  |  |  |  |  | 0.026 | 0.053 |  |  |\n| 45M |  | 0.022 |  |  | 0.90 |  |  |  | 0.90 |  |  |  |  |  |  |  |\n| 46M |  | 0.10 |  |  |  |  |  |  |  |  |  |  |  |  |  |  |\n| 47H |  | 0.45 |  |  |  |  |  |  |  |  |  |  |  |  |  |  |\n| 42R |  |  |  |  |  |  |  |  |  |  |  |  |  | 0.11 |  |  |\n| 43R |  |  |  |  |  |  |  |  |  |  |  |  |  | 0.21 |  |  |\n| 44R |  |  |  |  |  |  |  |  |  |  |  |  | 0.45 |  | 0.60 |  |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Cadmium – Inhalation**\nIntermediate (15–364 days)\n\n**Figure 2-2. Levels of Significant Exposure to Cadmium – Inhalation Intermediate (15–364 days)**\n\n| Category | 32R (mg Cd/m3) | 45M (mg Cd/m3) | 41R (mg Cd/m3) | 26R (mg Cd/m3) | 27R (mg Cd/m3) | 28R (mg Cd/m3) | 32R (mg Cd/m3) | 43R (mg Cd/m3) | 44R (mg Cd/m3) | 45M (mg Cd/m3) | 32R (mg Cd/m3) | 45M (mg Cd/m3) | 32R (mg Cd/m3) | 45M (mg Cd/m3) |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Musculoskeletal | 0.9 | 0.9 |  |  |  |  |  |  |  |  |  |  |  |  |\n| Hepatic | 0.85 | 0.9 | 0.05 |  |  |  |  |  |  |  |  |  |  |  |\n| Renal |  |  |  | 0.11 | 1.1 | 0.1 | 0.9 | 0.55 | 0.55 | 0.85 |  |  |  |  |\n| Endocrine | 0.85 | 0.9 |  |  |  |  |  |  |  |  |  |  |  |  |\n| Immunological | 0.9 | 0.9 |  |  |  |  |  |  |  |  |  |  |  |  |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Cadmium – Inhalation**\nIntermediate (15–364 days)\n\n**Figure 2-2. Levels of Significant Exposure to Cadmium – Inhalation Intermediate (15–364 days)**\n\n| Category | Neurolgical mg Cd/m3 | Reproductive mg Cd/m3 | Developmental mg Cd/m3 | Cancer mg Cd/m3 |\n| --- | --- | --- | --- | --- |\n| 32R | 0.9 | 0.9 |  |  |\n| 45M | 0.9 | 0.9 |  |  |\n| 23R |  | 0.17 | 0.17 |  |\n| 24R |  | 1.0 | 0.17 |  |\n| 25R |  | 1.0 |  |  |\n| 25R |  | 0.18 |  |  |\n| 31R |  | 1.1 |  |  |\n| 32R |  | 0.24 |  |  |\n| 23R |  |  | 0.022 |  |\n| 24R |  |  | 0.022 |  |\n| 33R |  |  | 2.0 |  |\n| 33R |  |  | 0.53 |  |\n| 44R |  |  | 0.6 |  |\n| 44R |  |  | 0.5 |  |\n| 37R |  |  |  | 0.09 |\n| 39R |  |  |  | 0.75 |\n| 40R |  |  |  | 0.09 |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Cadmium – Inhalation**\nChronic (≥365 days)\n\n**Figure 2-2. Levels of Significant Exposure to Cadmium – Inhalation (Chronic ≥365 days)**\n\n| Category | Death mg Cd/m3 | Body Weight mg Cd/m3 |\n| --- | --- | --- |\n| 49R | 0.095 |  |\n| 50R | 0.033 |  |\n| 51R | 0.088 |  |\n| 53R | 0.088 |  |\n| 55R |  | 0.050 |\n\n**Figure 2-2. Levels of Significant Exposure to Cadmium – Inhalation (Chronic ≥365 days) - Renal**\n\n| Category | Human - Weighted median (mg Cd/m3) | Human - 95% lower confidence limit of weighted median (mg Cd/m3) |\n| --- | --- | --- |\n| 48 | 0.0014 | 0.00011 |\n\n**Figure 2-2. Levels of Significant Exposure to Cadmium – Inhalation (Chronic ≥365 days) - Cancer**\n\n| Category | Animal - Cancer Effect Level (mg Cd/m3) |\n| --- | --- |\n| 50R | 0.033 |\n| 51R | 0.092 |\n| 52R | 0.033 |\n| 53R | 0.092 |\n| 54R | 0.033 |\n| 55R | 0.013 |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| ACUTE EXPOSURE |  |  |  |  |  |  |  |  |  |\n| Andjelkovic et al. 2019 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 1 | Rat (Wistar) 6–8 M | Once (GW) | 0, 15, 30 | HE, BC, HP | Hemato |  | 15 |  | Decreased RBC count, hemoglobin, hematocrit, lymphocyte, and serum iron levels; increased MCHC |\n| Baranski 1985 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 2 | Rat (Wistar) 6–18 F | 10 days GDs 7–16 (GW) | 0, 2, 12, 40 | BW, OW, DX | Bd wt |  | 2 | 12 | LOAEL: 14% decrease in maternal body weight gain SLOAEL: 34% decrease in maternal body weight gain |\n| 2 | Rat (Wistar) 6–18 F | 10 days GDs 7–16 (GW) | 0, 2, 12, 40 | BW, OW, DX | Develop | 2 | 12 | 40 | LOAEL: 9% decrease in fetal weight SLOAEL: 23% decrease in fetal weight, decreased live fetuses/litter, increased resorptions/litter, fetal malformations (fused lower limbs, absent limbs) |\n| Bomhard et al. 1987 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 3 | Rat (Wistar) 25–35 M | Once (GW) | 0, 50, 100, 200 | LE, BW, CS, FI, WI, HP | Death Repro | 50 |  | 100 | 28/35 died within 3 days Testicular necrosis, focal proliferation of Leydig cells (6 months post-exposure); hyperemia and slight hemorrhages in testes and epididymides in rats that died |\n| Surviving rats sacrificed 6–30 months post-exposure |  |  |  |  |  |  |  |  |  |\n| Borzelleca et al. 1989 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 4 | Rat (Sprague-Dawley) 10 M, 10 F | Once (GW) | 0, 15, 31, 65.6, 138 | LE, CS, BW, HE, BC, GN, OW | Death |  |  | 138 F 65.6 M | 2/10 died within 24 hours 3/10 died within 24 hours |\n| 4 | Rat (Sprague-Dawley) 10 M, 10 F | Once (GW) | 0, 15, 31, 65.6, 138 | LE, CS, BW, HE, BC, GN, OW | Bd wt Hemato Hepatic Renal | 138 138 138 |  |  |  |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Borzelleca et al. 1989 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 5 | Rat (Sprague-Dawley) 10 M, 10 F | 10 days (W) | M: 0, 1.1, 7.85, 11.2 F: 0, 1.1, 8.16, 13.9 | LE, CS, BW, HE, BC, UR, GN, OW, HP | Bd wt | 13.9 F 1.1 M | 7.85 M | 11.2 M | LOAEL: 14% decrease in body weight SLOAEL: 25% decrease in body weight |\n| 5 | Rat (Sprague-Dawley) 10 M, 10 F | 10 days (W) | M: 0, 1.1, 7.85, 11.2 F: 0, 1.1, 8.16, 13.9 | LE, CS, BW, HE, BC, UR, GN, OW, HP | Hematocrit | 13.9 F 11.2 M 13.9 F 11.2 M 13.9 F 11.2 M |  |  |  |\n| 5 | Rat (Sprague-Dawley) 10 M, 10 F | 10 days (W) | M: 0, 1.1, 7.85, 11.2 F: 0, 1.1, 8.16, 13.9 | LE, CS, BW, HE, BC, UR, GN, OW, HP | Renal | 13.9 F 11.2 M 13.9 F 11.2 M |  |  |  |\n| 5 | Rat (Sprague-Dawley) 10 M, 10 F | 10 days (W) | M: 0, 1.1, 7.85, 11.2 F: 0, 1.1, 8.16, 13.9 | LE, CS, BW, HE, BC, UR, GN, OW, HP | Repro | 13.9 F 11.2 M |  |  |  |\n| Borzelleca et al. 1989 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 6 | Rat (Sprague-Dawley) 10 M, 10 F | 10 days (GW) | 0, 15, 31, 65.6, 138 | LE, CS, BW, HE, BC, UR, GN, OW, HP | Death | 31 F | 65.6 F 15 M | 31 M | 3/10 males and 4/10 females died within 7 days 18% decrease in terminal body weight LOAEL: 18% decrease in terminal body weight SLOAEL: 23% decrease in terminal body weight Increased WBC and platelet counts Increased RBC count Elevated serum ALT, decreased serum cholesterol Mild focal necrosis of hepatocytes or congestion Mild focal necrosis of tubular epithelium |\n| 6 | Rat (Sprague-Dawley) 10 M, 10 F | 10 days (GW) | 0, 15, 31, 65.6, 138 | LE, CS, BW, HE, BC, UR, GN, OW, HP | Bd wt | 31 F | 65.6 F 15 M 31 F |  |  |\n| 6 | Rat (Sprague-Dawley) 10 M, 10 F | 10 days (GW) | 0, 15, 31, 65.6, 138 | LE, CS, BW, HE, BC, UR, GN, OW, HP | Hematocrit | 15 F | 65.6 F 15 M 31 F |  |  |\n| 6 | Rat (Sprague-Dawley) 10 M, 10 F | 10 days (GW) | 0, 15, 31, 65.6, 138 | LE, CS, BW, HE, BC, UR, GN, OW, HP | Renal | 65.6 M | 138 M 65.6 F |  |  |\n\n***DRAFT FOR PUBLIC COMMENT***\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n|  |  |  |  |  | Repro | 65.6 M 138 F 31 M | 138 M |  | Mild focal necrosis of tubular epithelium |\n|  |  |  |  |  | Repro | 65.6 M 138 F 31 M | 138 M | 65.6 M | Necrotic changes in testes with atrophy and loss of spermatogenic elements |\n| Dixon et al. 1976 |  |  |  |  |  |  |  |  |  |\n| 7 | Rat (Sprague-Dawley) 10 M | Once (GW) | 0, 6.25, 12.5, 25 | RX | Repro | 25 |  |  | Cadmium chloride |\n| Males serially mated to untreated females for 70 days post-treatment |  |  |  |  |  |  |  |  |  |\n| Kostial et al. 1978 |  |  |  |  |  |  |  |  |  |\n| 8 | Rat (NS) 6 B | Once (G) | NS | LE | Death |  |  | 29 | Cadmium chloride LD50 calculated 8 days post-exposure |\n| Age at exposure: 2 weeks |  |  |  |  |  |  |  |  |  |\n| Kostial et al. 1978 |  |  |  |  |  |  |  |  |  |\n| 9 | Rat (NS) 6 B | Once (G) | NS | LE | Death |  |  | 147 | Cadmium chloride LD50 calculated 8 days post-exposure |\n| Age at exposure: 3 weeks |  |  |  |  |  |  |  |  |  |\n| Kostial et al. 1978 |  |  |  |  |  |  |  |  |  |\n| 10 | Rat (NS) 6 B | Once (G) | NS | LE | Death |  |  | 129 | Cadmium chloride LD50 calculated 8 days post-exposure |\n| Age at exposure: 6 weeks |  |  |  |  |  |  |  |  |  |\n| Kostial et al. 1978 |  |  |  |  |  |  |  |  |  |\n| 11 | Rat (NS) 6 B | Once (G) | NS | LE | Death |  |  | 104 | Cadmium chloride LD50 calculated 8 days post-exposure |\n| Age at exposure: 18 weeks |  |  |  |  |  |  |  |  |  |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Kostial et al. 1978 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 12 | Rat (NS) 6 B | Once (G) | NS | LE | Death |  |  | 66.8 | LD50 calculated 8 days post-exposure |\n| Age at exposure: 54 weeks |  |  |  |  |  |  |  |  |  |\n| Kotsonis and Klaassen 1977 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 13 | Rat (Sprague-Dawley) 6 M | Once (premating) (GW) | 0, 25, 50, 100, 150 | HP, RX, NX | Neuro Repro | 25 50 | 50 | 100 | Decreased motor activity Testicular necrosis; decreased spermatogenesis; decreased fertility (fewer females producing pups) |\n| Males mated to unexposed females |  |  |  |  |  |  |  |  |  |\n| Kotsonis and Klaassen 1977 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 14 | Rat (Sprague-Dawley) 6–12 M | Once (GW) | 0, 25, 50, 100, 150 | CS, BW, HE, BC, BI, UR, HP, OF | Bd wt Resp Cardio Gastro Hematoc Hepatic Renal Endocr | 100 150 150 150 150 150 |  | 150 | Initial body weight loss resulting in approximate 10% decrease in terminal body weight (2 weeks post-exposure) |\n| Kotsonis and Klaassen 1977 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 15 | Rat (Sprague-Dawley) 15–20 M | Once (GW) | NS | LE | Death |  |  | 225 | LD50 at 14 days |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Kotsonis and Klaassen 1978 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 16 | Rat (Sprague-Dawley) 9 M | 2 weeks (W) | 0, 42 | LE | Death |  |  | 42 | 7/9 died within 2 weeks |\n| Machemer and Lorke 1981 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 17 | Rat (Long-Evans) 22–28 F | 10 days GDs 6–15 (GW) | 0, 1.84, 6.13, 18.39, 61.32 | LE, CS, BW, DX | Death Bd wt | 1.84 |  | 61.32 6.13 | 15/25 dams died 27% decrease in maternal body weight gain during treatment period |\n| 17 | Rat (Long-Evans) 22–28 F | 10 days GDs 6–15 (GW) | 0, 1.84, 6.13, 18.39, 61.32 | LE, CS, BW, DX | Gastro | 18.39 |  | 61.32 | Intestinal necrosis, hemorrhage, ulcers, constipation/absence of defecation |\n| 17 | Rat (Long-Evans) 22–28 F | 10 days GDs 6–15 (GW) | 0, 1.84, 6.13, 18.39, 61.32 | LE, CS, BW, DX | Dermal Develop | 1.84 6.13 | 6.13 | 18.39 | Coarse fur Increased number of fetuses with malformations, increased number of runts (<3 g), 7% decrease in fetal body weight |\n| Machemer and Lorke 1981 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 18 | Rat (Long-Evans) 21–24 F | 10 days GDs 6–15 (F) | 0, 1.2, 3.5, 12.5 | LE, CS, BW, FI, DX | Bd wt | 3.5 | 12.5 |  | 19% decrease in maternal body weight gain during treatment period |\n| 18 | Rat (Long-Evans) 21–24 F | 10 days GDs 6–15 (F) | 0, 1.2, 3.5, 12.5 | LE, CS, BW, FI, DX | Develop | 12.5 |  |  |  |\n| Saedi et al. 2020a, 2020b |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 19 | Rat (Sprague-Dawley) 4 F | 13 days PNDs 21–33 (GW) | 0, 15, 31, 46 | BW, BC, HE, OW, HP, DX | Bd wt Hemato | Endocr Develop | 46 15 | 15 | 21% decrease in terminal body weight Decreased RBC and increased WBC levels |\n| 19 | Rat (Sprague-Dawley) 4 F | 13 days PNDs 21–33 (GW) | 0, 15, 31, 46 | BW, BC, HE, OW, HP, DX | Hemat | 15 | 46 15 | 15 | 21% decrease in terminal body weight Decreased RBC and increased WBC levels |\n| 19 | Rat (Sprague-Dawley) 4 F | 13 days PNDs 21–33 (GW) | 0, 15, 31, 46 | BW, BC, HE, OW, HP, DX | Develop | 46 15 | 31 | 15 | Increased atretic follicles and decreased secondary follicles in ovaries; decreased serum estradiol levels |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Samuel et al. 2011 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 20 | Rat (Wistar) 18 F | 13 days GDs 9–21 (W) | 0, 6, 18 | BW, FI, WI, DX | Bd wt | 6 | 18 |  | 11% decrease in maternal body weight on GD 21 |\n| 20 | Rat (Wistar) 18 F | 13 days GDs 9–21 (W) | 0, 6, 18 | BW, FI, WI, DX | Develop |  |  | 6 | Fetal effects: Increased resorption Postnatal effects (female offspring): Decreased postnatal weight on PND 10 (22%) and PND 21 (14%), ovarian follicular degeneration, decreased estradiol and testosterone, delayed vaginal opening, and altered estrous cycling |\n| 20 | Rat (Wistar) 18 F | 13 days GDs 9–21 (W) | 0, 6, 18 | BW, FI, WI, DX | Other noncancer | 6 | 18 |  | Decreased maternal food intake |\n| Three dams/group were sacrificed on GD 21; remaining offspring were sacrificed on PND 10, PND 21, or evaluated during puberty |  |  |  |  |  |  |  |  |  |\n| Shimizu and Morita 1990 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 21 | Rat (Sprague-Dawley) 10 M | Once (GW) | NS | LE | Death |  |  | 106.9 | LD50 at 24 hours (fasted rats) |\n| Shimizu and Morita 1990 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 22 | Rat (Sprague-Dawley) 10 M | Once (GW) | NS | LE | Death |  |  | 327.3 | LD50 at 24 hours (fed rats) |\n| Stacey et al. 1988 |  |  |  |  |  |  |  |  | Cadmium acetate |\n| 23 | Rat (Sprague-Dawley) 4 M | 6 weeks 5 days/week (G) | 0, 0.0025, 0.025, 0.250 | BW, OW, IX | Bd wt | 0.25 |  |  | Enhanced spleen cell proliferative responses |\n| 23 | Rat (Sprague-Dawley) 4 M | 6 weeks 5 days/week (G) | 0, 0.0025, 0.025, 0.250 | BW, OW, IX | Immuno | 0.025 | 0.25 |  | Enhanced spleen cell proliferative responses |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Stacey et al. 1988 |  |  |  |  |  |  |  |  | Cadmium acetate |\n| 24 | Rat (Sprague-Dawley) 4 M | 2 weeks 5 days/week (G) | 0, 0.0025, 0.025, 0.250 | BW, OW, IX | Bd wt Immuno | 0.25 0.25 |  |  |  |\n| Wan et al. 2022 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 25 | Rat (Sprague-Dawley) 3 M, 3 F | 2 weeks (G) | 0, 2, 4 | BW, WI, BC, UR, OW, HP | Bd wt Renal | 4 | 2c |  | Increased 24-hour urinary protein excretion, elevated urinary β 2M levels, increased serum BUN |\n| Andersen et al. 1988 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 26 | Mouse (CBA/Bom) 7–42 M | Once (GW) | 0, 0.6, 3.9, 7.9, 15.7, 30.3, 59.6, 88.8 | LE, HP | Death Gastro | 15.7 | 30.3 | 88.8 | 36/42 mice died within 10 days LOAEL: Gastritis and enteritis SLOAEL: Severe gastric necrosis Fatty infiltration of liver cells, occasional hepatocellular necrosis Proximal tubular necrosis with poor cell differentiation and irregular granulation of cells Testicular necrosis in most tubules and interstitial tissue |\n| 26 | Mouse (CBA/Bom) 7–42 M | Once (GW) | 0, 0.6, 3.9, 7.9, 15.7, 30.3, 59.6, 88.8 | LE, HP | Hepatic | 15.7 | 30.3 | 88.8 | 36/42 mice died within 10 days LOAEL: Gastritis and enteritis SLOAEL: Severe gastric necrosis Fatty infiltration of liver cells, occasional hepatocellular necrosis Proximal tubular necrosis with poor cell differentiation and irregular granulation of cells Testicular necrosis in most tubules and interstitial tissue |\n| 26 | Mouse (CBA/Bom) 7–42 M | Once (GW) | 0, 0.6, 3.9, 7.9, 15.7, 30.3, 59.6, 88.8 | LE, HP | Renal | 59.6 |  | 88.8 | 36/42 mice died within 10 days LOAEL: Gastritis and enteritis SLOAEL: Severe gastric necrosis Fatty infiltration of liver cells, occasional hepatocellular necrosis Proximal tubular necrosis with poor cell differentiation and irregular granulation of cells Testicular necrosis in most tubules and interstitial tissue |\n| 26 | Mouse (CBA/Bom) 7–42 M | Once (GW) | 0, 0.6, 3.9, 7.9, 15.7, 30.3, 59.6, 88.8 | LE, HP | Repro | 30.3 |  | 59.6 | 36/42 mice died within 10 days LOAEL: Gastritis and enteritis SLOAEL: Severe gastric necrosis Fatty infiltration of liver cells, occasional hepatocellular necrosis Proximal tubular necrosis with poor cell differentiation and irregular granulation of cells Testicular necrosis in most tubules and interstitial tissue |\n| Ara et al. 2016 |  |  |  |  |  |  |  |  | Form not specified |\n| 27 | Mouse (Swiss-Webster) 5 F | 7 days GDs 6–12 (GW) | 0, 3.13, 6.25, 12.5, 25.0 | RX, DX | Develop |  |  | 3.13 | 49% decrease in fetal body weight; decreased crown-rump length, head and eye circumference, and forelimb, hindlimb and tail length; anomalies in the brain, eyes, forelimbs, hindlimbs, and tail |\n| Baer and Benson 1987 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 28 | Mouse (Swiss-Webster) 10 M | Once (GW) | 100, 150 | LE | Death |  |  | 95.5 | LD50 at 96 hours |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Yi et al. 2021a |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 29 | Mouse (ICR) 13 F | 10 days GDs 8–17 (W) | 0, 8.1, 24 | DX | Develop |  | 8.1 |  | Impaired glucose tolerance in adult male offspring |\n| INTERMEDIATE EXPOSURE |  |  |  |  |  |  |  |  |  |\n| Chopra et al. 1984 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 30 | Monkey (Rhesus) 3–4 M | 6 months (F) | 0, 5 | CS, BW, IX | Bd wt Immuno | 5 5 |  |  |  |\n| Afolabi et al. 2012 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 31 | Rat (Wistar) 8 M | 7 weeks (W) | 0, 4.6, 9.1 | BW, BC, BI | Hepatic Immuno |  | 4.6 4.6 |  | Increased plasma lipid levels Increased plasma pro-inflammatory cytokines |\n| Ali et al. 1986 |  |  |  |  |  |  |  |  | Cadmium acetate |\n| 32 | Rat (Wistar) 10 F | 21 days GDs 1–21 (W) | 0, 0.706, 1.2 | BW, FI, WI, RX, DX | Bd wt Repro Develop | 1.2 1.2 | 0.706 | 1.2 | Decreased offspring body weight, persisting through PND 45 (~20%) Delayed development of sensory motor coordination reflexes; altered motor activity (increased PNDs 7–21; decreased PND 60) |\n| Aprioku et al. 2014 |  |  |  |  |  |  |  |  | Cadmium sulfate |\n| 33 | Rat (Wistar) 8 F | 21 days GDs 0–20 (W) | 0, 4, 8 | BW, OW, HP, RX, DX | Bd wt Repro Develop |  | 4 | 4 | 40% decrease in maternal body weight on GD 20 Increased abortions |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Baranski 1987 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 34 | Rat (Wistar) 12–16 F | 20 days GDs 1–20 (W) | 0, 4.6, 11.1 | LE, BW, FI, WI, HE, BC, DX | Bd wt Repro Develop | 11.1 |  | 4.6 | 37% decrease in maternal body weight gain |\n| 34 | Rat (Wistar) 12–16 F | 20 days GDs 1–20 (W) | 0, 4.6, 11.1 | LE, BW, FI, WI, HE, BC, DX | Bd wt Repro Develop | 11.1 |  | 4.6 | 12% decrease in fetal body weight and 7% decrease in fetal body length |\n| 34 | Rat (Wistar) 12–16 F | 20 days GDs 1–20 (W) | 0, 4.6, 11.1 | LE, BW, FI, WI, HE, BC, DX | Other noncancer |  | 4.6 |  | Decreased maternal food intake |\n| Baranski and Sitarek 1987 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 35 | Rat (Wistar) 11–13 F | 14 weeks 5 days/week (GW) | 0, 0.04, 0.4, 4, 40 | LE, CS, BW, RX | Death |  |  | 40 | 4/13 died by week 8; 7/13 by week 14 |\n| 35 | Rat (Wistar) 11–13 F | 14 weeks 5 days/week (GW) | 0, 0.04, 0.4, 4, 40 | LE, CS, BW, RX | Bd wt Repro | 0.4 |  | 4 | 40% decrease in body weight gain |\n| 35 | Rat (Wistar) 11–13 F | 14 weeks 5 days/week (GW) | 0, 0.04, 0.4, 4, 40 | LE, CS, BW, RX | Bd wt Repro | 4 |  | 40 | Increased duration of estrus cycle |\n| Baranski et al. 1983 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 36 | Rat (Wistar) NS F | 11 weeks (5 weeks premating, 3 weeks mating, 3 weeks gestation) 5 days/week (GW) | 0, 0.04, 0.4, 4 | RX, DX | Repro Develop | 4 |  |  | Decreased pup locomotor activity and impaired motor coordination at 2 months |\n| 36 | Rat (Wistar) NS F | 11 weeks (5 weeks premating, 3 weeks mating, 3 weeks gestation) 5 days/week (GW) | 0, 0.04, 0.4, 4 | RX, DX | Repro Develop | 4 | 0.04 |  | Decreased pup locomotor activity and impaired motor coordination at 2 months |\n| Half of dams were sacrificed on GD 21; half were allowed to deliver naturally and pups (8/sex/group) were assessed for 2 months after parturition |  |  |  |  |  |  |  |  |  |\n| Brzóska and Moniuszko-Jakoniuk 2005a, 2005b; 2010 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 37 | Rat (Wistar) 10 M | 12 months (W) | 0, 0.2, 0.5, 4 | BW, FI, WI, BC, BI, HP | Bd wt Musc/skel | 4 |  |  | Increased lumbar spine deformities, decreased in lumbar spine and femur mineralization, altered bone turnover parameters |\n| 37 | Rat (Wistar) 10 M | 12 months (W) | 0, 0.2, 0.5, 4 | BW, FI, WI, BC, BI, HP | Bd wt Musc/skel | 0.2 | 0.5 |  | Increased lumbar spine deformities, decreased in lumbar spine and femur mineralization, altered bone turnover parameters |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Brzóska and Moniuszko-Jakoniuk 2005c; Brzóska et al. 2005a, 2005c |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 38 | Rat (Wistar) 40 F | 12 months (W) | 0, 0.2, 0.5, 4 | BW, FI, WI, BC, BI, HP, OF | Bd wt Musc/skel | 4 | 0.2 |  | Decreased bone mineralization, mechanical properties of tibia and femur, and altered bone turnover parameters |\n| Brzóska et al. 2004, 2005b |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 39 | Rat (Wistar) 8–10 F | 12 months (W) | 0, 0.3, 0.7, 4, 8 | BW, FI, WI, BI, OF | Musc/skel |  | 0.3 |  | Alterations in bone mineral content and density and mechanical properties of lumbar vertebral and femoral bones |\n| Buha et al. 2013, 2019 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 40 | Rat (Wistar) 7 M | 28 days (G) | 0, 0.3, 0.6, 1.25, 2.5, 5, 10 | BW, BC, BI | Bd wt Musc/skel | 0.6 | 0.3 | 1.25 | 36% decrease in body weight gain Decreased bone mineral content in femur Increased serum creatinine and urea Decreased serum T3 levels |\n|  |  |  |  |  | Renal Endocr | 2.5 | 5 0.3 |  |  |\n| Caride et al. 2010 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 41 | Rat (Sprague-Dawley) 60 M | 30 days (W) | 0, 0.92, 1.8 | BC | Endocr |  | 0.92 |  | Altered daily secretory pattern of ACTH and growth hormone; increased median levels of ACTH and TSH |\n| Carmignani and Boscolo 1984 |  |  |  |  |  |  |  |  | Cadmium acetate |\n| 42 | Rat (Sprague-Dawley) 10 M | 190 days (W) | 0, 1.4, 2.8 | CS, BW, OF | Bd wt Cardio | 2.8 | 1.4 |  | Increased systolic and diastolic blood pressure |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Chen et al. 2013 |  |  |  |  |  |  |  |  | Form not specified |\n| 43 | Rat (Sprague-Dawley) 6 M | 12 weeks (W) | 0, 0.2, 1.1, 5.0 | BW, BC, BI, UR, HP | Bd wt Musc/skel | 5 | 0.2 |  | Trabecular bone damage in tibia (decreased number, thickness; increased separation, increased dissociated ends); altered bone turnover parameters |\n| Cifone et al. 1989 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 44 | Rat (Wistar) 4 F | 170 days (W) | 0, 29, 58 | CS, BW, FI, WI, OW, IX | Bd wt Immuno | 58 | 29 |  | Biphasic decrease (first 30–50 days) then increase in NK cell activity, splenic cellularity, and the number of large granular lymphocytes in the peripheral blood; increased total peripheral lymphocytes |\n| Desi et al. 1998 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 45 | Rat (Wistar) NS F | 94 days F0: GDs 5–15 + PNDs 2–28 F1: PNWs 5–12 5 days/week (GW) | 0, 3.5, 7.0, 14.0 | DX | Develop | 3.5 | 7 |  | Decreased peripheral nerve conduction velocity with increased refractory periods |\n| Locomotor and sensory function assessed in F1 males at 12 weeks of age |  |  |  |  |  |  |  |  |  |\n| Desi et al. 1998 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 46 | Rat (Wistar) NS F | 11 days GDs 5–15 (GW) | 0, 3.5, 7.0, 14.0 | DX | Develop | 14 |  |  |  |\n| Locomotor and sensory function assessed in F1 males at 12 weeks of age |  |  |  |  |  |  |  |  |  |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Desi et al. 1998 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 47 | Rat (Wistar) NS F | 38 days GDs 5–15 plus PNDs 2–28 (GW) | 0, 3.5, 7.0, 14.0 | DX | Develop | 3.5 | 7 |  | Decreased horizontal ambulation and rearing activity |\n| Locomotor and sensory function assessed in F1 males at 12 weeks of age |  |  |  |  |  |  |  |  |  |\n| Dixon et al. 1976 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 48 | Rat (Sprague-Dawley) 10 M | 30–90 days (W) | 0, 0.00014, 0.0014, 0.014 | BC, OW, RX | Repro | 0.014 |  |  |  |\n| Males mated to untreated females |  |  |  |  |  |  |  |  |  |\n| Feng et al. 2019 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 49 | Rat (Sprague-Dawley) NS F | 6 weeks GD 0 to PND 21 (W) | 0, 0.6, 3 | DX | Develop |  | 0.6 |  | Impaired learning and memory in F1 males at PNDs 35 and 56 |\n| Huang et al. 2020 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 50 | Rat (Sprague-Dawley) <10 F | 3 weeks GD 1 to birth (GW) | 0, 0.3, 1.2, 4.9 | DX | Develop |  | 0.3 |  | F1 males: Decreased serum testosterone and increased seminiferous tubule diameter at PND 21; decreased Johnsen score (decreased testicular maturity) on PND 56 |\n| Iqbal et al. 2021 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 51 | Rat (Sprague-Dawley) 6 M | 17 days (GW) | 0, 5, 10, 15 | BW, OW, HP | Bd wt | 10 |  | 15 | 12% body weight loss during exposure (compared to 12% body weight gain in control) |\n|  |  |  |  |  | Repro | 5 | 10 |  | Structural changes in the testis and epididymis |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\nstimulated plasma insulin levels\n\nAltered glucose tolerance at PND 21\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects | Cadmium chloride |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Jacquet et al. 2018 |  |  |  |  |  |  |  |  |  |  |\n| 52 | Rat (Wistar) 9 M, 9 F | 12 weeks (W) | M: 0, 0.0053, 0.0558, 0.515; F: 0, 0.0055, 0.053, 0.4959 | LE, BW, BC, UR, OW, OF | Bd wt | 0.4959 F 0.515 M 0.4959 F 0.515 M Endocr | 0.053 F |  |  |  |\n| Jacquet et al. 2019 |  |  |  |  |  |  |  |  |  |  |\n| 53 | Rat (Wistar) 15–17 F | 11 weeks 3 weeks prior to mating GD 0–PND 35 (W) | 0, 0, 0.05, 0.5 | UR, RX, DX | Renal Repro Develop | 0.5 0.5 | 0.05 |  |  | Cadmium chloride |\n| Dams were sacrificed on PND 35; pups were sacrificed on PND 21, 26, and 60 |  |  |  |  |  |  |  |  |  |  |\n| Kelman et al. 1978 |  |  |  |  |  |  |  |  |  |  |\n| 54 | Rat (Sprague-Dawley) 15 F | 22 days GDs 0–21 (W) | 0, 1.5, 3.8 | HE, BI, DX | Hemato Musc/skel Develop | 3.8 | 1.5 | 1.5 | Decreased hematocrit | Form not specified |\n| Kotsonis and Klaassen 1978 |  |  |  |  |  |  |  |  |  |  |\n| 55 | Rat (Sprague-Dawley) 6 M | 24 weeks (W) | 0, 1.1, 2.92, 8.49 | CS, BW, FI, WI, HE, BC, BI, OW, HP, OF, RX, NX | Bd wt Resp Cardio Gastro Hematocell Musc/skel Hepatic Renal Endocr | 8.49 8.49 8.49 8.49 | 8.49 8.49 8.49 | 8.49 8.49 | 8.49 | Cadmium chloride |\n\nProteinuria (starting at week 6)\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n|  |  |  |  |  | Immuno Neuro Repro | 8.49 1.1 8.49 | 2.92 |  | Decreased motor activity (starting at week 3) |\n| Males mated to unexposed females |  |  |  |  |  |  |  |  |  |\n| Kulas et al. 2019 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 56 | Rat (Dark Agouti) 8 M | 30 days (W) | 0, 0.35, 3.51 | OW, HP | Resp |  | 0.35 |  | Minimal to mild perivascular edema and respiratory epithelial desquamation in lungs |\n| Larregle et al. 2008 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 57 | Rat (Wistar) 8 M | 8 weeks daily (W) | 0, 18 | BC | Hepatic |  | 18 |  | Increased serum and liver triglyceride levels; increased serum cholesterol levels |\n| Li et al. 2018 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 58 | Rat (Sprague-Dawley) 10 F | 42 days GD 0-PND 21 (GW) | 0, 0.6, 3 | DX | Develop |  | 0.6 |  | F1 females: Decreased primordial follicles (PND 21) and increased serum estradiol (PND 21, PND 35) F2: females: Increased serum progesterone (PND 21) |\n| Liu et al. 2019 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 59 | Rat (Sprague-Dawley) 10 M | 60 days (G) | 0, 0.6, 1.5, 3 | CS, FI, WI, BW, BC, UR, OW, HP | Bd wt |  |  | 1.5 | 20% decrease in terminal body weights Decreased serum iron Increased BUN and serum creatinine |\n| Liu et al. 2020 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 60 | Rat (Sprague-Dawley) 5 F | 20 days GDs 1-21 (GW) | 0, 0.3, 1.2, 4.9 | DX | Develop |  | 0.3 |  | Decreased ovarian granulosa cell progesterone in F1 female offspring on PND 56 |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects | Cadmium chloride |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Loeser and Lorke 1977 |  |  |  |  |  |  |  |  |  |  |\n| 61 | Rat (Wistar) 20 M, 20 F | 3 months (F) | 0, 0.1, 0.3, 1, 3 | HP, BC, CS, UR, OW, OF, BW, FI | Bd wt Cardio Hematoc Hepatic Renal Endocr Immuno Repro | 3 3 3 3 3 3 | 0.439 | Decreased offspring body weights (by up to ~19% on PNW 9) | Cadmium chloride |  |\n| Luo et al. 2015 |  |  |  |  |  |  |  |  |  |  |\n| 62 | Rat (Sprague-Dawley) 10 F | 42 days GD 0-PND 21 (W) | 0, 0.089, 0.439, 0.955 | BW, RX, DX | Bd wt Repro Develop | 0.955 0.955 0.089 |  | 0.439 | Decreased offspring body weights (by up to ~19% on PNW 9) | Cadmium chloride |\n| McCalla et al. 2024 |  |  |  |  |  |  |  |  |  |  |\n| 63 | Rat (Sprague-Dawley) 10 M | 8 weeks 3 times/week (GW) | 0, 2.5, 5 | BW, HE, OF | Cardio Hematoc | 2.5 | 2.5 5 |  | Increased blood pressure Decreased mean cell volume and mean cell hemoglobin; increased red cell distribution width | Cadmium chloride |\n| Muller et al. 1988 |  |  |  |  |  |  |  |  |  |  |\n| 64 | Rat (Sprague-Dawley) 4 M | 6 weeks 5 days/week (GW) | 0, 0.0025, 0.025, 0.25 | BW, BC, BI, OW | Bd wt Hepatic | 0.25 0.25 |  |  |  | Cadmium acetate |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Nagymajtenyi et al. 1997 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 65 | Rat (Wistar) 5 M, 10 F | 3 generations ~16–18 weeks per generation (GW) | 0, 3.5, 7.0, 14.0 | CS, BW, RX, DX | Bd wt Repro Develop | 14 14 3.5 M | 7 M |  | Decreased tail nerve conduction velocity (all generations); prolonged latency and duration of somatosensory evoked potentials (F2, F3); increased frequency in auditory and visual evoked potentials (F3); 5% decrease in F3 body weight at PNW 12 |\n| Nasiadek et al. 2018 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 66 | Rat (Wistar) 20 F | 30 days (GW) | 0, 0.09, 1.8, 4.5 | CS, BW, BC, OW, HP | Bd wt Repro | 4.5 0.09 | 1.8 |  | Decreased plasma estradiol |\n| Nasiadek et al. 2019 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 67 | Rat (Wistar) 24 F | 90 days (GW) | 0, 0.09, 0.9, 1.8, 4.5 | LE, CS, BW, FI, WI, BC, OW, HP | Bd wt Repro | 4.5 0.09 | 0.9 |  | Decreased plasma estradiol |\n| Nation et al. 1984 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 68 | Rat (Sprague-Dawley) 9 M | 55 days (F) | 0, 1, 5 | CS, NX | Neuro | 1 | 5 |  | Increased anxiety-like behavior (passive avoidance) |\n| Ninkov et al. 2016 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 69 | Rat (Albino Oxford) 8–16 M | 30 days (W) | 0, 0.4, 4.1 | OW, HP, IX | Gastro Immuno | 4.1 | 0.4 |  | Increased intestinal lymphocyte counts, and mesenteric lymph node relative weight and cellularity; decreased spleen cell proliferative response |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Ogoshi et al. 1989 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 70 | Rat (NS) 19–22 F | 4 weeks (W) | 0, 1, 2.5 | BW, HE, BC, BI, OF | Bd wt Hemato | 2.5 | 1 |  | Decreased hematocrit, hemoglobin, MCHC, and MCV |\n|  |  |  |  |  | Musc/skel |  | 1 |  | Decreased bone strength |\n| Weanling rats (21-day-old) |  |  |  |  |  |  |  |  |  |\n| Ogoshi et al. 1989 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 71 | Rat (NS) 18–25 NS | 4 weeks (W) | 0, 1.6, 3.3, 6.6, 13, 26.2 | BW, HE, BC, BI, OF | Bd wt Hemato | 26.2 6.6 Musc/skel | 13 |  | Decreased hematocrit and MCV |\n| Adult rats (24-week-old) |  |  |  |  |  |  |  |  |  |\n| Ogoshi et al. 1989 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 72 | Rat (NS) 25–27 NS | 4 weeks (W) | 0, 11, 21.5 | BW, HE, BC, BI, OF | Bd wt Hemato | 11 21.5 | 11 21.5 |  | 10% decrease in body weight gain |\n|  |  |  |  |  | Musc/skel |  |  |  | Decreased hemoglobin and MCHC |\n| Aged rats (1.5-year-old) |  |  |  |  |  |  |  |  |  |\n| Oluranti et al. 2021 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 73 | Rat (Wistar) 5 M | 21 days (G) | 0, 3, 18 | BC, BI, OW | Endocr |  | 3 |  | Decreased plasma insulin and glucose levels |\n| Petering et al. 1979 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 74 | Rat (Sprague-Dawley) 5 F | 111 days (90 days prior mating through GD 21) (W) | 0, 0.56, 1.3, 2.61, 5.23 | HE, RX, DX | Repro Develop | 5.23 1.3 |  | 2.61 | 10% decrease in birth weight |\n| Prigge 1978a |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 75 | Rat (Wistar) 12 F | 90 days (W) | 0, 3.8, 7.6, 15.2 | LE, BW, HE, BC, BI, UR, OW | Bd wt Hemato | 3.8 3.8 Renal | 3.8 7.6 | 7.6 | 28% decrease in body weight gain |\n|  |  |  |  |  |  |  |  |  | Decreased serum iron |\n|  |  |  |  |  |  |  |  |  | Proteinuria |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Sarmiento-Ortega et al. 2017 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 76 | Rat (Wistar) 10 M | 3, 4, or 5 months (W) | 0, 2.94 | BC, OF | Hepatic |  | 2.94 |  | Increased serum and hepatic lipid concentrations |\n| 76 | Rat (Wistar) 10 M | 3, 4, or 5 months (W) | 0, 2.94 | BC, OF | Endocr |  | 2.94 |  | Increased serum glucose and insulin levels following administration of an oral glucose load |\n| 76 | Rat (Wistar) 10 M | 3, 4, or 5 months (W) | 0, 2.94 | BC, OF | Other noncancer |  | 2.94 |  | Increased abdominal circumference, body mass index, and percentage of body fat |\n| Sorell and Graziano 1990 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 77 | Rat (Sprague-Dawley) 42–66 F | 15 days GDs 6–20 (W) | 0, 0.629, 4.714, 8.171 | BW, WI, HE, DX | Bd wt | 0.629 | 4.714 | 8.171 | LOAEL: 13% decrease in maternal weight gain SLOAEL: 30% decrease in maternal body weight gain |\n| 77 | Rat (Sprague-Dawley) 42–66 F | 15 days GDs 6–20 (W) | 0, 0.629, 4.714, 8.171 | BW, WI, HE, DX | Hemato | 4.714 | 8.171 |  | Reduced maternal hemoglobin levels |\n| 77 | Rat (Sprague-Dawley) 42–66 F | 15 days GDs 6–20 (W) | 0, 0.629, 4.714, 8.171 | BW, WI, HE, DX | Develop | 0.629 | 4.714 |  | 8% decrease in fetal body weight |\n| Sun et al. 2023 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 78 | Rat (Sprague-Dawley) 10 M | 29 days (GW) | 0, 0.3, 1, 5 | DX | Develop | 0.3 | 1 |  | Decreased serum estradiol and progesterone in adult F1 females |\n| F0 males were mated to unexposed females; reproductive development was assessed in F1 and F2 female offspring |  |  |  |  |  |  |  |  |  |\n| Sutou et al. 1980 |  |  |  |  |  |  |  |  | Form not specified |\n| 79 | Rat (Sprague-Dawley) 14 M, 14 F | 9 weeks (premating through GD 20) (GW) | 0, 0.1, 1.0, 10 | RX, DX | Repro | 1 |  | 10 | Decreased number of copulating and pregnant females; 49% reduction in number of live fetuses/litter; decreased total implants/litter, increased resorptions/litter |\n| 79 | Rat (Sprague-Dawley) 14 M, 14 F | 9 weeks (premating through GD 20) (GW) | 0, 0.1, 1.0, 10 | RX, DX | Develop | 1 |  | 10 | Decreased fetal body weight in males (34%) and females (33%); decreased body and tail length; delayed ossification |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Tang et al. 2016 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 80 | Rat (Sprague-Dawley) 6 M | 3 months (W) | 0, 0.28, 1.41, 7.07 | HP | Musc/skel | 1.41 | 7.07 |  | Decreased bone density and trabecular bone loss and damage in tibia (decreased trabecular volume and number, increased trabecular separation) |\n| Tian et al. 2017 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 81 | Rat (Sprague-Dawley) NS F | 6 weeks GD 0 to PND 21 (GW) | 0, 0.6, 3 | DX | Develop |  | 0.6 |  | Decreased serum progesterone and testosterone and in male offspring on PND 35 and 56, respectively; decreased relative testis weight on PND 21 |\n| Tucovic et al. 2018 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 82 | Rat (Dark Agouti) 4–6 M | 30 days (W) | 0, 0.7, 6.6 | BW, FI, WI, HE BC, UR, HP | Bd wt Hemato | 6.6 |  |  | Increased percent neutrophil leukocytes and eosinophil leukocytes |\n| 82 | Rat (Dark Agouti) 4–6 M | 30 days (W) | 0, 0.7, 6.6 | BW, FI, WI, HE BC, UR, HP | Hepatic Immuno | 6.6 0.7 | 6.6 |  | Increased IL-6 and TNF in skin |\n| Wan et al. 2022 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 83 | Rat (Sprague-Dawley) 3 M, 3 F | 4 weeks (G) | 0, 2, 4 | BW, WI, BC, UR, OW, HP | Bd wt Renal | 4 | 2 |  | Increased 24-hour urinary protein excretion, elevated urinary β 2M levels, increased serum BUN |\n| Wan et al. 2022 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 84 | Rat (Sprague-Dawley) 3 M, 3 F | 8 weeks (G) | 0, 2, 4 | BW, WI, BC, UR, OW, HP | Bd wt Renal | 4 | 2 |  | Increased 24-hour urinary protein excretion, elevated urinary β 2M levels, increased serum BUN |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Wang et al. 2014 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 85 | Rat (Sprague-Dawley) 8 M, 8 F | 28 days (GW) | 0, 1, 2.5, 5, 10, 20 | LE, CS, BW, FI, HE, BC, UR, GN, OW, HP | Bd wt | 5 | 10 |  | Decrease in terminal body weight in males (12%) and females (11%) |\n| 85 | Rat (Sprague-Dawley) 8 M, 8 F | 28 days (GW) | 0, 1, 2.5, 5, 10, 20 | LE, CS, BW, FI, HE, BC, UR, GN, OW, HP | Cardio | 20 |  |  | Decrease in terminal body weight in males (12%) and females (11%) |\n| 85 | Rat (Sprague-Dawley) 8 M, 8 F | 28 days (GW) | 0, 1, 2.5, 5, 10, 20 | LE, CS, BW, FI, HE, BC, UR, GN, OW, HP | Hemat | 10 F | 20 F |  | Increased platelets |\n| 85 | Rat (Sprague-Dawley) 8 M, 8 F | 28 days (GW) | 0, 1, 2.5, 5, 10, 20 | LE, CS, BW, FI, HE, BC, UR, GN, OW, HP | Hepatic | 2.5 M | 5 M |  | Increased platelets |\n| 85 | Rat (Sprague-Dawley) 8 M, 8 F | 28 days (GW) | 0, 1, 2.5, 5, 10, 20 | LE, CS, BW, FI, HE, BC, UR, GN, OW, HP | Renal | 10 F | 20 F |  | Increased serum ALT |\n| 85 | Rat (Sprague-Dawley) 8 M, 8 F | 28 days (GW) | 0, 1, 2.5, 5, 10, 20 | LE, CS, BW, FI, HE, BC, UR, GN, OW, HP | Endocr | 20 |  |  |  |\n| 85 | Rat (Sprague-Dawley) 8 M, 8 F | 28 days (GW) | 0, 1, 2.5, 5, 10, 20 | LE, CS, BW, FI, HE, BC, UR, GN, OW, HP | Immuno | 20 |  |  |  |\n| 85 | Rat (Sprague-Dawley) 8 M, 8 F | 28 days (GW) | 0, 1, 2.5, 5, 10, 20 | LE, CS, BW, FI, HE, BC, UR, GN, OW, HP | Neuro | 20 |  |  |  |\n| 85 | Rat (Sprague-Dawley) 8 M, 8 F | 28 days (GW) | 0, 1, 2.5, 5, 10, 20 | LE, CS, BW, FI, HE, BC, UR, GN, OW, HP | Repro | 5 | 10 |  | Decreased serum LH and testosterone in males; increased absolute and relative uterine weight |\n| 85 | Rat (Sprague-Dawley) 8 M, 8 F | 28 days (GW) | 0, 1, 2.5, 5, 10, 20 | LE, CS, BW, FI, HE, BC, UR, GN, OW, HP | Other | 1 F | 2.5 F |  | Decreased food intake |\n| 85 | Rat (Sprague-Dawley) 8 M, 8 F | 28 days (GW) | 0, 1, 2.5, 5, 10, 20 | LE, CS, BW, FI, HE, BC, UR, GN, OW, HP | noncancer |  |  |  |  |\n| Weng et al. 2014 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 86 | Rat (Wistar) 12 F | 8 weeks (G) | 0, 0.3, 1.2, 4.9 | BW, OW, HP | Bd wt | 4.9 |  |  |  |\n| 86 | Rat (Wistar) 12 F | 8 weeks (G) | 0, 0.3, 1.2, 4.9 | BW, OW, HP | Repro | 0.3 | 1.2 |  | Decreased absolute and relative ovary weight, increased atretic follicles, follicular cell apoptosis |\n| Xu et al. 2015 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 87 | Rat (Sprague-Dawley) 6 M | 90 days (GW) | 0, 0.7, 2.0, 6.0 | LE, CS, BW, HP | Bd wt | 6 |  |  |  |\n| 87 | Rat (Sprague-Dawley) 6 M | 90 days (GW) | 0, 0.7, 2.0, 6.0 | LE, CS, BW, HP | Neuro | 0.7 | 2 |  | Neuronal degeneration in cortex |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Yang et al. 2021a |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 88 | Rat (Sprague-Dawley) 9 NR | 8 weeks 5 days/week (GW) | 0, 0.15, 0.61, 2.5 | BC | Hepatic | 0.15 | 0.61 |  | Increased serum triglycerides, total cholesterol, and LDL cholesterol; decreased serum HDL cholesterol |\n|  |  |  |  |  | Renal | 0.61 | 2.5 |  | Increased serum urea nitrogen |\n| Yi et al. 2021b |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 89 | Rat (Sprague-Dawley) 6 M | 28 days (GO) | 0, 1, 3 | BW, BC, OW, HP, RX | Bd wt Repro | 3 | 1 |  | Decreased serum testosterone levels |\n| Zenick et al. 1982 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 90 | Rat (Long-Evans) 5 M | 70–80 days (W) | 0, 1.16, 2.32, 4.64 | BW, FI, WI, HP, RX, DX | Bd wt Repro Develop for fetal effects | 4.64 4.64 4.64 | 25 | 12 | LOAEL: 13% decrease in terminal body weight SLOAEL: 25% decrease in terminal body weight |\n| Males were mated with three untreated females; one litter evaluated for fetal effects and two litters evaluated for neurobehavior on PND 21 or 90 |  |  |  |  |  |  |  |  |  |\n| Zhang et al. 2022a |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 91 | Rat (Sprague-Dawley) 8 M | 12 weeks (G) | 0, 1.5, 3, 6.1, 12, 25 | LE, CS, BW, BC, OW, HP | Bd wt | 6.1 | 12 | 25 | LOAEL: 13% decrease in terminal body weight SLOAEL: 25% decrease in terminal body weight |\n|  |  |  |  |  | Hepatic | 1.5 | 3 | 12 | LOAEL: Hepatic fibrosis SLOAEL: Hepatic fibrous tissue proliferation |\n| Zhang et al. 2023a |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 92 | Rat (Sprague-Dawley) 6 M | 4 weeks (GW) | 0, 2.5, 5 | BC, HP, RX | Repro | 2.5 |  | 5 | Decreased serum testosterone, LH, and GnRH; decreased sperm count and motility; decreased seminiferous tubule diameter and seminiferous epithelial thickness |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Zhang et al. 2024a |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 93 | Rat (Sprague-Dawley) 10–30 M | 4 weeks (GW) | 0, 5 | BW, RX, DX | Bd wt Repro |  | 5 | 5 | 13% decrease in body weight Decreased fertility and percent live births, sperm quality, and levels of serum testosterone and gonad releasing hormone; decreased seminiferous tubule diameter and area, seminiferous epithelium thickness, and Johnsen score; decreased number of cells in interstitial region of testes and disordered cellular arrangement |\n| Males were mated with unexposed females. |  |  |  |  | Develop |  |  | 5 | 21% decrease in male fetal weight |\n| Blakley 1985 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 94 | Mouse (BDF1) 22 F | 3 weeks (W) | 0, 1.4, 2.8, 14 | CS, BW, GN, IX | Bd wt Immuno | 14 1.4 | 2.8 |  | Decreased humoral immune response |\n| Blakley 1988 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 95 | Mouse (BDF1) 14–16 F | 26 days (W) | 0, 2.5, 12.5 | BW, WI, IX | Immuno | 12.5 |  |  |  |\n| Aged mice (12-month-old) |  |  |  |  |  |  |  |  |  |\n| Chatterjee and Saxena 2015 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 96 | Mouse (C57BL/6) 10–15 M | 6 weeks (W) | 0, 7.6, 150 | HE, BC | Hemato Immuno | 150 | 7.6 |  | Decreased RBC count and hemoglobin |\n| Chou et al. 2023 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 97 | Mouse (C57BL/6) 11–18 M | 12 weeks (W) | 0, 11, 21 | BW, OF, HP | Bd wt Cardio | 21 |  | 11 | Cardiomyocyte apoptosis |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects | Cadmium chloride |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Exon et al. 1986 |  |  |  |  |  |  |  |  |  |  |\n| 98 | Mouse (Swiss-Webster) 20 M | 10 weeks (W) | 0, 0.57, 5.7, 57 | LE, BW, GN, HP, IX | Bd wt Immuno | 57 57 |  |  |  |  |\n| Exon et al. 1986 |  |  |  |  |  |  |  |  |  |  |\n| 99 | Mouse (Swiss-Webster) 20 M | 10 weeks (W) | 0, 0.57, 5.7, 57 | LE, BW, GN, HP, IX | Bd wt Immuno | 0.57 57 | 5.7 |  | Cadmium acetate | 14% decrease in body weight |\n| Exon et al. 1986 |  |  |  |  |  |  |  |  |  |  |\n| 100 | Mouse (Swiss-Webster) 20 M | 10 weeks (W) | 0, 0.57, 5.7, 57 | LE, BW, GN, HP, IX | Bd wt Immuno | 57 57 |  |  |  | Cadmium sulfate |\n| Gathwan and Albir 2020 |  |  |  |  |  |  |  |  |  |  |\n| 101 | Mouse (Swiss) 6 M | 30 days (G) | 0, 6.1, 12.3, 19.5 | BW, FI, WI, OW, HP | Bd wt | 6.1 | 12.3 | 19.5 | LOAEL: 13% decrease in terminal body weight SLOAEL: 23% decrease in terminal body weight | Cadmium oxide |\n| He et al. 2019a |  |  |  |  |  |  |  |  |  |  |\n| 102 | Mouse (C57BL/6) 10 M | 20 weeks (W) | 0, 1.475, 6.566 | LE, CS, WI, BC, BI, OW, HP | Bd wt Hepatic | Endocr | 6.566 | 1.475 | 6.566 | Cadmium chloride 22% decrease in body weight gain NAFLD; increased hepatic triglyceride levels |\n| He et al. 2019b |  |  |  |  |  |  |  |  |  |  |\n| 103 | Mouse (BALB/c) 12 F | 16 weeks (W) | 0, 2, 6.5 | BW, FI, BC, BI, HP | Bd wt Musc/skel | 6.5 | 2 |  |  | Cadmium chloride |\n\nTrabecular bone damage\n(decreased number, thickness;\nincreased separation, fat cells);\naltered bone turnover parameters\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| He et al. 2020 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 104 | Mouse (C57BL/6) 10 M | 20 weeks (W) | 0, 1.5, 7.6 | LE, CS, BW, HP | Bd wt Gastro | 7.6 1.5 | 7.6 |  | Decreased length of intestinal villus and thickness of intestinal wall |\n| Hudson et al. 2019 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 105 | Mouse (C57BL/6J) NS F | 8 weeks 5 weeks prior to mating until birth (W) | 0, 0.3, 13 | RX, DX | Repro Develop | 13 | 0.3 | 13 | LOAEL: Increased absolute and relative heart weight in female pups at birth; increased tail blood volume and tail blood flow in female offspring at 5.5 months of age SLOAEL: 12% decrease in birth weight in both sexes; increased absolute and relative heart weight in male pups at birth; increased systolic, diastolic, and mean arterial blood pressure in female offspring at 5.5 months of age |\n| C57BL/6J dams mated to unexposed CAST/EiJ males, to generate F1 hybrid mice |  |  |  |  |  |  |  |  |  |\n| Hudson et al. 2019 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 106 | Mouse (CAST/EiJ) NS F | 8 weeks 5 weeks prior to mating until birth (W) | 0, 0.3, 13 | RX, DX | Repro Develop | 13 | 0.3 | 13 | LOAEL: Decreased body weight at birth in males; increased absolute heart weight in females SLOAEL: 22% decrease in birth weight |\n| CAST/EiJ dams mated to unexposed C57BL/6J males, to generate F1 hybrid mice |  |  |  |  |  |  |  |  |  |\n| Krzystyniak et al. 1987 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 107 | Mouse (C57BL/6) 10 F | 12–16 weeks (W) | 0, 0.6, 17, 52 | IX | Immuno | 17 | 52 |  | Reduced humoral immune response |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Kurita et al. 2018 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 108 | Mouse (C57BL/6J) 3–10 F | 18 days GDs 1–18 (G) | 0, 5, 10 | DX | Develop | 5 |  | 10 | 34% decrease in fetal weight, decreased fetal length |\n| Li et al. 2022 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 109 | Mouse (ICR) 10 F | 70 days 4 weeks premating to PND 21 (W) | 0, 2.6, 19.7 | WI, DX | Develop |  | 2.6 | 19.7 | LOAEL: Decreased serum estradiol and increased primordial follicles and decreased secondary follicles at PND 21 in female offspring; increased prevalence of irregular estrous cycles SLOAEL: 40% decreased in PND 21 body weight in female offspring; delayed vaginal opening |\n| Liu et al. 2023 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 110 | Mouse F0: 9–12 F F1: 5-7 M, 5–7 F | ~220 days F0: 1 week premating through PND 21 F1: PND 21 to 6 months of age (W) | F0: 0, 0.1, 1.5 F1: 0, 0.2, 1.6 | BC, OW, HP, NX | Immuno Neuro | 1.6 | 0.2 |  | Increased locomotor activity, impaired spatial memory (Y-maze test) in adult F1 mice |\n| Mei et al. 2017 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 111 | Mouse (C57BL/6) 5 M | 8 weeks (W) | 0, 1.5, 4.5, 7.6 | IX | Immuno |  | 1.5 |  | Delayed wound healing |\n| Ohsawa et al. 1988 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 112 | Mouse (BALB/c) 9–10 M | 10 weeks (W) | 0, 0.75, 7.5, 75 | IX | Immuno | 7.5 | 75 |  | Induction of anti-nuclear autoantibodies |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Ohsawa et al. 1988 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 113 | Mouse (ICR) 5–12 M | 10 weeks (W) | 0, 0.75, 7.5, 75 | IX | Immuno |  | 0.75 |  | Induction of anti-nuclear autoantibodies; biphasic immune response (stimulation at low dose, suppression at high dose) |\n| Tan et al. 2023 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 114 | Mouse (C57BL/6) 20 M | 10 weeks (W) | 0, 1.5, 15 | DX | Develop | 1.5 | 15 |  | Impaired growth in both sexes (10% at terminal sacrifice on PND 125); impaired glucose metabolism in adult female offspring |\n| Males mated to untreated females after 10-week exposure |  |  |  |  |  |  |  |  |  |\n| Valois and Webster 1989 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 115 | Mouse (QS) 25 F | 22 weeks (W) | 0, 0.20, 1.4, 11 | CS, BW, WI, HP | Bd wt | 0.2 | 1.4 | 11 | LOAEL: 19% decrease in body weight SLOAEL: 28% decrease in body weight |\n|  |  |  |  |  | Neuro | 0.2 |  | 1.4 | Degenerative and necrotic cellular changes in choroid plexus |\n| Marked decreases in water consumption at 1.4 and 11 mg Cd/kg/day |  |  |  |  |  |  |  |  |  |\n| Wang et al. 2016a |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 116 | Mouse (CD-1) 10 F | 19 days GDs 0–18 (W) | 0, 1.3, 9.3, 26.9 | BW, WI, RX, DX | Bd wt Repro Develop | 26.9 26.9 9.3 |  | 26.9 | 17% decrease in fetal weight; decreased crown-rump length |\n| Xiong et al. 2022a |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 117 | Mouse (C57BL/6) F0: 6–7 M, 17 F F1: 4 M | 32 weeks F0: 2 weeks premating–PNW 3 F1: PNWs 3–27 (W) | 0, 0.1, 1.3 | BW, WI, OW, HP | Bd wt Repro | 1.3 M 0.1 M | 1.3 M |  | Decreased absolute testis weight, germ cell loss |\n| Endpoints reported for F1 males (evaluated at PNW 27) |  |  |  |  |  |  |  |  |  |\n\nEndpoints reported for F1 males (evaluated at PNW 27)\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects | Cadmium chloride |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Zhang et al. 2019a |  |  |  |  |  |  |  |  |  |  |\n| 118 | Mouse (C57BL/6J) F0: 10 M, 10 F F1: 6 M, 6 F | 17-18 weeks F0: 1 month premating to PNW 3 F1: PNWs 3–10 (W) | 0, 0.001089, 0.01003, 0.10012 | DX | Develop | 0.10012 |  |  |  |  |\n| F1 pups examined for developmental landmarks, neurobehavior (PNWs 8-9), endocrine, and reproductive endpoints at PNW 10 |  |  |  |  |  |  |  |  |  |  |\n| Zhang et al. 2019a |  |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 119 | Mouse (C57BL/6J) F0: 10 M, 10 F F1: 6 M, 6 F | 25-26 weeks F0: 3 months premating to PNW 3 F1: PNWs 3–10 (W) | 0, 0.001089, 0.01003, 0.10012 | DX | Develop | 0.10012 |  |  |  |  |\n| F1 pups examined for developmental landmarks, neurobehavior (PNWs 8-9), endocrine, and reproductive endpoints at PNW 10 |  |  |  |  |  |  |  |  |  | Cadmium chloride |\n| Zhang et al. 2019a |  |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 120 | Mouse (C57BL/6J) F0: 10 M, 10 F F1: 6 M, 6 F | 33–34 weeks F0: 5 months premating to PNW 3 F1: PNWs 3–10 (W) | 0, 0.001089, 0.01003, 0.10012 | DX | Develop | 0.01003 | 0.10012 |  | Increased anxiety-like behavior in open field; elevated corticosterone levels |  |\n| F1 pups examined for developmental landmarks, neurobehavior (PNWs 8-9), endocrine, and reproductive endpoints at PNW 10 |  |  |  |  |  |  |  |  |  | Cadmium chloride |\n| Zhang et al. 2024b |  |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 121 | Mouse (ICR) 9–11 M | 21 days PNDs 22–42 (W) | 0, 0.9, 1.5 | DX | Develop | 0.9 | 1.5 |  | Altered socioemotional behaviors during adolescence (immobility in forced swim and tail suspension, decreased social interaction/preference for novelty) |  |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Boscolo and Carmignani 1986 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 122 | Rabbit (New Zealand) 8 M | 9 months (W) | 0, 1.6 | CS, BW, HP, OF | Bd wt Cardio Renal | 1.6 | 1.6 |  | Increased aortic resistance, reduced contractility |\n| Stowe et al. 1972 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 123 | Rabbit (New Zealand) 5 M | 200 days (W) | 0, 14.9 | CS, BW, WI, HE | Bd wt Hemato |  | 14.9 | 14.9 | 20% decrease in body weight Decreased hematocrit and hemoglobin; elevated neutrophils and decreased lymphocytes |\n| Stowe et al. 1972 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 124 | Rabbit (Belgian Giant) 5 M | 200 days (W) | 0, 14.9 | CS, BW, WI, HE | Bd wt Hemato |  | 14.9 | 14.9 | 15% decrease in body weight Decreased hematocrit and hemoglobin; elevated neutrophils and decreased lymphocytes |\n| CHRONIC EXPOSURE |  |  |  |  |  |  |  |  |  |\n| Buchet et al. 1990; Shao et al. 2007; Suwazono et al. 2006; Uno et al. 2005; Wu et al. 2001; Zhang et al. 2016a |  |  |  |  |  |  |  |  | Cadmium |\n| 125 | Human 85–3,454 per dataset | 17 datasets (3 occupational and 8 general population cohorts) | UR | Renal |  |  |  | LMW proteinuria; 95% LCL weighted median of 17 UC10 values = 0.000760 mg Cd/kg/dayd |  |\n| Bernard et al. 1992 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 126 | Rat (Sprague-Dawley) 50 F | up to 18 months (W) | 0, 13 | BI, BC, UR, HP, OF | Renal |  |  | 13 | Loss of glomerular polyanion charge barrier, proteinuria |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Bomhard et al. 1984 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 127 | Rat (Wistar) 12 M, 12 F | 72 weeks (F) | M: 0, 0.7, 3.5, 17.5 F: 0, 0.8, 4.0, 20.0 | BC, UR | Renal | 4 F | 20 F |  | Increase in urinary LDH and GST levels Increase in urinary LDH and GST levels |\n| 127 | Rat (Wistar) 12 M, 12 F | 72 weeks (F) | M: 0, 0.7, 3.5, 17.5 F: 0, 0.8, 4.0, 20.0 | BC, UR | Renal | 3.5 M | 17.5 M |  | Increase in urinary LDH and GST levels Increase in urinary LDH and GST levels |\n| Brzóska 2012; Brzóska and Moniuszko-Jakoniuk 2004a, 2004b |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 128 | Rat (Wistar) 10 F | 24 months (W) | 0, 0.08 | BW, FI, WI, BC, BI, UR, HP, OF | Bd wt Musc/skel | 0.08 |  | 0.08 | Decreases in bone mineral content and density of lumbar spine, altered bone turnover parameters, increases in deformed and fractured vertebral bodies |\n| Decker et al. 1958 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 129 | Rat (Sprague-Dawley) 8–10 M, 8–10 F | 12 months (W) | M: 0, 0.008, 0.036, 0.197, 0.386, 0.696 F: 0, 0.012, 0.062, 0.315, 0.578, 1.052 | LE, BW, FI, WI, HE, HP | Bd wt Gastro | 1.052 F 0.696 M 1.052 F 0.696 M 1.052 F 0.696 M 1.052 F 0.696 M 1.052 F 0.696 M 1.052 F 0.696 M 0.696 M 0.696 M 0.696 M 0.696 M |  |  |  |\n| 129 | Rat (Sprague-Dawley) 8–10 M, 8–10 F | 12 months (W) | M: 0, 0.008, 0.036, 0.197, 0.386, 0.696 F: 0, 0.012, 0.062, 0.315, 0.578, 1.052 | LE, BW, FI, WI, HE, HP | Renal | 1.052 F 0.696 M 0.696 M |  |  |  |\n| 129 | Rat (Sprague-Dawley) 8–10 M, 8–10 F | 12 months (W) | M: 0, 0.008, 0.036, 0.197, 0.386, 0.696 F: 0, 0.012, 0.062, 0.315, 0.578, 1.052 | LE, BW, FI, WI, HE, HP | Endocrinoma | 1.052 F 0.696 M 0.696 M 0.696 M |  |  |  |\n| 129 | Rat (Sprague-Dawley) 8–10 M, 8–10 F | 12 months (W) | M: 0, 0.008, 0.036, 0.197, 0.386, 0.696 F: 0, 0.012, 0.062, 0.315, 0.578, 1.052 | LE, BW, FI, WI, HE, HP | Neuro | 1.052 F 0.696 M 0.696 M |  |  |  |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects | Cadmium chloride |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Fingerle et al. 1982 |  |  |  |  |  |  |  |  |  |  |\n| 130 | Rat (Sprague-Dawley) 10 M, 10 F | M: 92 weeks F: 84 weeks (W) | M: 0, 0.6, 1.51, 3.78 F: 0, 0.8, 1.64, 4.01 | HP, BW, OW, OF, FI, WI, CS, LE | Bd wt Cardio | 4.01 4.01 |  |  |  |  |\n| Mangler et al. 1988 |  |  |  |  |  |  |  |  |  |  |\n| 131 | Rat (Sprague-Dawley) 12 F | 18 months (W) | 0, 2.301 | LE, BW, HP | Bd wt Renal | 2.301 | 2.301 |  | Cloudy swelling of renal tubular cells | Cadmium chloride |\n| Mangler et al. 1988 |  |  |  |  |  |  |  |  |  |  |\n| 132 | Rat (Sprague-Dawley) 12 F | 12 months (W) | 0, 2.337 | LE, BW, HP | Bd wt Renal | 2.337 | 2.337 |  | Cloudy swelling of renal tubular cells | Cadmium chloride |\n| Sato et al. 1978 |  |  |  |  |  |  |  |  |  |  |\n| 133 | Rat (Wistar) 11 NS | 31 months (W) | 0, 2.7 | CS, BW, WI, HP | Bd wt Musc/skel Neuro | 2.7 |  | 2.7 2.7 | Muscle weakness and atrophy Peripheral neuropathy | Cadmium chloride |\n| Waalkes and Rehm 1992 |  |  |  |  |  |  |  |  |  |  |\n| 134 | Rat (Wistar) 24–28 M | 77 weeks (F) | 0, 1.1, 2.3, 5.28, 10.9 | LE, CS, BW, FI, GN, HP | Bd wt Cancer | 2.3 | 5.28 | 2.3 | 10% decrease in body weight CEL: Large granular lymphocyte leukemia | Cadmium chloride |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Hays and Margaretten 1985 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 135 | Mouse (CBA/H) 5–13 M; 5 F | 12 months (W) | 0, 40 | BW, FI, WI, HE, BC, HP | Bd wt Hematoc | 40 | 40 | 21% decreased terminal body weight Decreased hematocrit and neutrophils; bone marrow hypoplasia |  |\n|  |  |  |  |  | Renal | 40 |  |  |  |\n\n<sup>a</sup>The number corresponds to entries in Figure 2-3; differences in levels of health effects between male and females are not indicated in Figure 2-3.  Where such \ndifferences exist, only the levels of effect for the most sensitive sex are presented.\n\n<sup>b</sup>Doses are expressed as mg Cd/kg/day.  If doses were reported by study authors in terms of the administered compound (e.g., cadmium chloride [CdCl2]), they were \nconverted to the equivalent dose in terms of the metal (i.e., cadmium [Cd])) for easy comparison across studies. Conversion was based on the ratio of the molecular \nweights using the following equation: Dose in terms of administered compound × (molecular weight Cd/molecular weight administered compound).\n\n<sup>c</sup>Used to derive an acute-duration oral MRL of 0.002 mg Cd/kg/day (2 μg Cd/kg/day).  The LOAEL of 2 mg Cd/kg/day divided by an uncertainty factor of 1,000 (10 for use \nof a LOAEL, 10 for animal to human, and 10 for human variability).\n\n<sup>d</sup>Used to derive a chronic-duration oral MRL of 0.0003 mg Cd/kg/day (0.3 μg Cd/kg/day).  The point of departure (POD) is based on the 95% lower confidence limit (LCL) \non the weighted median of the UC10 values from 17 datasets from 11 human studies; the weighted median and 95% LCL were 2.04 and 1.57 μg Cd/g Cr, respectively.  \nThese values were converted into oral dose equivalents of 9.88x10<sup>-4</sup> and 7.60x10<sup>-4</sup> mg Cd/kg/day, respectively, using PBPK modeling. The POD of 7.60x10<sup>-4</sup> mg \nCd/kg/day was divided by an uncertainty factor of 3 for human variability and a modifying factor of 3 for database deficiencies. See Appendix A for more detailed \ninformation regarding the MRL.\n\n## Principal studies for the MRLs\n\nACTH = adrenocorticotrophic hormone; ALT = alanine aminotransferase; β2M = β2-microglobulin; BC = serum (blood) chemistry; Bd wt or BW = body weight; \nBI = biochemical changes; BUN = blood urea nitrogen; Cardio = cardiovascular; Cd = cadmium; CEL = cancer effect level; Cr = creatinine; CS = clinical signs; Develop \n= developmental; DX = developmental toxicity; Endocr = endocrine; (F) = feed (dietary); F = female(s); FI = food intake; (G) = gavage; (GO) = gavage in oil; \n(GW) = gavage in water; Gastro = gastrointestinal; GD = gestation day; GN = gross necropsy; GnRH = gonadotropin releasing hormone; GST = glutathione \nS-transferase; HDL = high-density lipoprotein; HE = hematology; Hemato = hematological; HP = histopathology; IL-6 = interleukin-6; Immuno = immunological; \nIX = immune function; LD50 = lethal dose, 50% kill; LDH = lactate dehydrogenase; LDL = low-density lipoprotein; LE = lethality; LH = luteinizing hormone; LMW = low \nmolecular weight; LOAEL = lowest-observed-adverse-effect level; M = male(s); MCHC = mean corpuscular hemoglobin concentration; MCV = mean corpuscular volume; \nMRL = Minimal Risk Level; Musc/skel = musculoskeletal; NAFLD = non-alcoholic fatty liver disease; Neuro = neurological; NK = natural killer; NOAEL = no-observedadverse-effect level; NS = not specified; NX = neurological function; OF = organ function; OW = organ weight; PBPK = physiologically based pharmacokinetic; \nPND = postnatal day; PNW = postnatal week; RBC = red blood cell; Repro = reproductive; Resp = respiratory; RX = reproductive function; SLOAEL = serious lowestobserved-adverse-effect level; T3 = triiodothyronine; TNF = tumor necrosis factor; TSH = thyroid-stimulating hormone; UC10 = urinary cadmium level associated with \n10% extra risk; UR = urinalysis; (W) = drinking water; WBC = white blood cell; WI = water intake\n\n---\n\n**Figure 2-3.  Levels of Significant Exposure to Cadmium – Oral**\nAcute (≤14 days)\n\n**Figure 2-3. Levels of Significant Exposure to Cadmium – Oral Acute (≤14 days) - Death**\n\n| Category | Animal - LD50/LC50 (mg Cd/kg/day) | Animal - NOAEL (mg Cd/kg/day) | Animal - LOAEL (mg Cd/kg/day) | Animal - SLOAEL (mg Cd/kg/day) |\n| --- | --- | --- | --- | --- |\n| 3R |  |  |  | 100 |\n| 4R |  |  |  | 70 |\n| 6R |  |  |  | 30 |\n| 8R | 30 |  |  |  |\n| 9R | 140 |  |  |  |\n| 10R | 130 |  |  |  |\n| 11R | 100 |  |  |  |\n| 12R | 70 |  |  |  |\n| 15R | 230 |  |  |  |\n| 16R |  |  |  | 45 |\n| 17R |  |  |  | 65 |\n| 21R | 110 |  |  |  |\n| 22R | 340 |  |  |  |\n| 26M |  |  |  | 85 |\n| 28M | 95 |  |  |  |\n\n---\n\n**Figure 2-3.  Levels of Significant Exposure to Cadmium – Oral**\nAcute (≤14 days)\n\n**Figure 2-3. Levels of Significant Exposure to Cadmium – Oral Acute (≤14 days) - Body Weight**\n\n| Category | Animal - LD50/LC50 (mg Cd/kg/day) | Animal - LOAEL (mg Cd/kg/day) | Animal - NOAEL (mg Cd/kg/day) | Animal - SLOAEL (mg Cd/kg/day) |\n| --- | --- | --- | --- | --- |\n| 2R |  |  |  | 12 |\n| 2R |  |  | 2.0 |  |\n| 4R |  |  | 150 |  |\n| 5R |  | 8.0 |  |  |\n| 5R |  |  | 1.2 |  |\n| 5R |  |  |  | 11 |\n| 6R |  |  |  | 30 |\n| 6R |  |  |  | 15 |\n| 6R |  |  | 14 |  |\n| 14R |  |  |  | 150 |\n| 14R |  |  | 100 |  |\n| 17R |  |  |  | 6.0 |\n| 17R |  |  | 1.8 |  |\n| 18R |  |  |  | 12 |\n| 18R |  |  | 3.3 |  |\n| 19R |  |  |  | 13 |\n| 20R |  |  |  | 18 |\n| 20R |  |  | 6.0 |  |\n| 23R |  |  | 0.20 |  |\n| 24R |  |  | 0.25 |  |\n| 25R |  |  | 4.0 |  |\n\n---\n\n**Figure 2-3.  Levels of Significant Exposure to Cadmium – Oral**\nAcute (≤14 days)\n\n| Category | Animal - NOAEL (mg Cd/kg/day) | Animal - LOAEL (mg Cd/kg/day) | Animal - SLOAEL (mg Cd/kg/day) |\n| --- | --- | --- | --- |\n| Respiratory | 14R: 160 |  |  |\n| Cardiovascular | 14R: 160 |  |  |\n| Gastrointestinal | 14R: 160 |  |  |\n|  |  | 17R: 65 |  |\n|  |  | 17R: 19 |  |\n|  |  | 26M: 30 |  |\n|  |  | 26M: 16 |  |\n|  |  | 26M: 85 |  |\n| Hematological | 1R: 15 |  |  |\n|  |  | 4R: 150 |  |\n|  |  | 5R: 14 |  |\n|  |  | 6R: 16 |  |\n|  |  | 14R: 160 |  |\n|  |  | 19R: 16 |  |\n| Hepatic | 4R: 150 |  |  |\n|  |  | 5R: 13 |  |\n|  |  | 6R: 16 |  |\n|  |  | 6R: 33 |  |\n|  |  | 14R: 160 |  |\n|  |  | 26M: 33 |  |\n|  |  | 26M: 16 |  |\n\n---\n\n**Figure 2-3.  Levels of Significant Exposure to Cadmium – Oral**\nAcute (≤14 days)\n\n**Figure 2-3. Levels of Significant Exposure to Cadmium – Oral Acute (≤14 days)**\n\n| Category | Animal - LD50/LC50 (mg Cd/kg/day) | Animal - LOAEL (mg Cd/kg/day) | Animal - NOAEL (mg Cd/kg/day) | Animal - SLOAEL (mg Cd/kg/day) | MRL for effect other than cancer (mg Cd/kg/day) |\n| --- | --- | --- | --- | --- | --- |\n| Renal |  |  | 160 |  |  |\n|  |  |  | 13 |  |  |\n|  |  |  | 65 |  |  |\n|  |  |  | 30 |  |  |\n|  |  |  | 160 |  |  |\n|  |  |  | 2.0 |  |  |\n|  |  |  | 90 |  |  |\n|  |  |  | 60 |  |  |\n|  |  |  | 1.8 |  |  |\n| Dermal |  |  | 6.5 |  |  |\n|  |  |  | 2.0 |  |  |\n| Endocrine |  |  | 160 |  |  |\n|  |  |  | 55 |  |  |\n| Immunological |  |  | 0.26 |  |  |\n|  |  |  | 0.030 |  |  |\n| Neurolgical |  |  | 50 |  |  |\n|  |  |  | 24 |  |  |\n\n---\n\n**Figure 2-3.  Levels of Significant Exposure to Cadmium – Oral**\nAcute (≤14 days)\n\n**Figure 2-3. Levels of Significant Exposure to Cadmium – Oral Acute (≤14 days)**\n\n| Category | Reproductive Animal - LD50/LC50 (mg Cd/kg/day) | Reproductive Animal - LOAEL (mg Cd/kg/day) | Reproductive Animal - NOAEL (mg Cd/kg/day) | Reproductive Animal - SLOAEL (mg Cd/kg/day) | Developmental Animal - LD50/LC50 (mg Cd/kg/day) | Developmental Animal - LOAEL (mg Cd/kg/day) | Developmental Animal - NOAEL (mg Cd/kg/day) | Developmental Animal - SLOAEL (mg Cd/kg/day) |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| 3R |  |  | 55 | 100 |  |  |  |  |\n| 5R |  |  | 13 |  |  |  |  |  |\n| 6R |  | 30 |  | 70 |  |  |  |  |\n| 7R |  |  | 26 |  |  |  |  |  |\n| 13R |  |  | 55 | 100 |  |  |  |  |\n| 26M |  | 34 |  | 65 |  |  |  |  |\n| 2R |  |  |  |  |  | 1.7 |  | 40 |\n| 17R |  |  |  |  ', 'pages': None, 'truncated': True, 'extraction': 'firecrawl-public-document-markdown', 'request_id': '6dbf2162-3841-4eb2-a566-2e2a25ac24a4', 'source_url': 'https://downloads.regulations.gov/ATSDR-2026-0133-0002/content.pdf', 'observed_at': '2026-10-04T00:39:30.279437+00:00', 'content_hash': '48479c728d0b8f13ff13edfd55d511d6e1fa5337c3b6b487129b37d5698c38f2'}, 'title': 'pdf'}]}

Oct. 4, 2026, 12:40 a.m.: attachments changed since Oct. 4, 2026, 12:36 a.m..

{'attachments': [{'url': 'https://downloads.regulations.gov/ATSDR-2026-0133-0002/attachment_1.pdf', 'title': 'Draft Toxicological Profile for Cadmium'}, {'url': 'https://downloads.regulations.gov/ATSDR-2026-0133-0002/content.pdf', 'title': 'pdf'}]}

{'attachments': [{'url': 'https://downloads.regulations.gov/ATSDR-2026-0133-0002/attachment_1.pdf', 'body': {'text': '## Toxicological Profile for Cadmium\nDraft for Public Comment\nOctober 2026\n\nATSDR\nU.S. Department of Health and Human Services\nAgency for Toxic Substances and Disease Registry\n\nCS274127-A\n\n---\n\n## DISCLAIMER\n\nUse of trade names is for identification only and does not imply endorsement by the Agency for Toxic \nSubstances and Disease Registry, the Public Health Service, or the U.S. Department of Health and Human \nServices.\n\nThis information is distributed solely for the purpose of pre-dissemination for public comment under \napplicable information quality guidelines.  It has not been formally disseminated by the Agency for Toxic \nSubstances and Disease Registry.  It does not represent and should not be construed to represent any \nagency determination or policy.\n\n---\n\n## FOREWORD\n\nThis toxicological profile is prepared in accordance with guidelines developed by the Agency for Toxic \nSubstances and Disease Registry (ATSDR) and the Environmental Protection Agency (EPA).  The \noriginal guidelines were published in the *Federal Register* on April 17, 1987.  Each profile will be revised \nand republished as necessary.\n\nThe ATSDR toxicological profile succinctly characterizes the toxicologic and adverse health effects \ninformation for these toxic substances described therein.  Each peer-reviewed profile identifies and \nreviews the key literature that describes a substance\'s toxicologic properties.  Other pertinent literature is \nalso presented but is described in less detail than the key studies.  The profile is not intended to be an \nexhaustive document; however, more comprehensive sources of specialty information are referenced.\n\nThe focus of the profiles is on health and toxicologic information; therefore, each toxicological profile \nbegins with a relevance to public health discussion which would allow a public health professional to \nmake a real-time determination of whether the presence of a particular substance in the environment \nposes a potential threat to human health.  The adequacy of information to determine a substance\'s health \neffects is described in a health effects summary.  Data needs that are of significance to the protection of \npublic health are identified by ATSDR.\n\nEach profile includes the following:\n\n(A) The examination, summary, and interpretation of available toxicologic information and \nepidemiologic evaluations on a toxic substance to ascertain the levels of significant \nhuman exposure for the substance due to associated acute-, intermediate-, and chronicduration exposures;\n\n(B) A determination of whether adequate information on the health effects of each substance \nis available or in the process of development to determine the levels of exposure that \npresent a significant risk to human health due to acute-, intermediate-, and chronicduration exposures; and\n\n(C) Where appropriate, identification of toxicologic testing needed to identify the types or \nlevels of exposure that may present significant risk of adverse health effects in humans.\n\nThe principal audiences for the toxicological profiles are health professionals at the Federal, State, and \nlocal levels; interested private sector organizations and groups; and members of the public.  ATSDR plans \nto revise these documents in response to public comments and as additional data become available.  \nTherefore, we encourage comments that will make the toxicological profile series of the greatest use.\n\nElectronic comments may be submitted via: www.regulations.gov. Follow the on-line instructions for \nsubmitting comments.\n\nWritten comments may also be sent to:\n\nWritten comments may also be sent to:  Agency for Toxic Substances and Disease Registry\n\nOffice of Innovation and Analytics\n\nToxicology Section\n\n1600 Clifton Road, N.E.\n\nMail Stop S106-5\n\nAtlanta, Georgia 30329-4027\n\n---\n\nThe toxicological profiles are developed under the Comprehensive Environmental Response, \nCompensation, and Liability Act of 1980, as amended (CERCLA or Superfund).  CERCLA \nSection 104(i)(1) directs the Administrator of ATSDR to “…effectuate and implement the health-related \nauthorities” of the statute.  This includes the preparation of toxicological profiles for hazardous \nsubstances most commonly found at facilities on the CERCLA National Priorities List (NPL) and that \npose the most significant potential threat to human health, as determined by ATSDR and the EPA.  \nSection 104(i)(3) of CERCLA, as amended, directs the Administrator of ATSDR to prepare a \ntoxicological profile for each substance on the list.  In addition, ATSDR has the authority to prepare \ntoxicological profiles for substances not found at sites on the NPL, in an effort to “…establish and \nmaintain inventory of literature, research, and studies on the health effects of toxic substances” under \nCERCLA Section 104(i)(1)(B), to respond to requests for consultation under Section 104(i)(4), and as \notherwise necessary to support the site-specific response actions conducted by ATSDR.\n\nThis profile reflects ATSDR’s assessment of all relevant toxicologic testing and information that has been \npeer-reviewed.  Staffs of the Centers for Disease Control and Prevention and other Federal scientists have \nalso reviewed the profile.  In addition, this profile has been peer-reviewed by a nongovernmental panel \nand is being made available for public review.  Final responsibility for the contents and views expressed \nin this toxicological profile resides with ATSDR.\n\nChristopher M. Reh, Ph.D. \nAssociate Director,\nAgency for Toxic Substances and Disease Registry \nCenters for Disease Control and Prevention\n\n---\n\n**VERSION HISTORY**\n\n| Date | Description |\n| --- | --- |\n| October 2026 | Draft for public comment toxicological profile released |\n| September 2012 | Final toxicological profile released |\n| July 1999 | Final toxicological profile released |\n| April 1993 | Final toxicological profile released |\n| March 1989 | Final toxicological profile released |\n\n---\n\n# CONTRIBUTORS & REVIEWERS\n\n# CHEMICAL MANAGER TEAM\n\nBrittany Szafran, D.V.M, Ph.D., D.A.B.T. (lead)\nCustodio Muianga, M.P.H., Ph.D., C.H.M.M.\nMohammad Shoeb, Ph.D.\nBreanna Alman, M.P.H.\nFranco Scinicariello, M.D., M.P.H.\n\nKimberly Zaccaria, Ph.D., D.A.B.T.\nFrances Belmonte, Ph.D., D.A.B.T.\nHeather Carlson-Lynch, M.S., D.A.B.T.\nMario Citra, Ph.D.\nGary L. Diamond, Ph.D.\nZach Guerrette, Ph.D., D.A.B.T\nDeborah M. Herber, Ph.D.\nClaire Heit, Ph.D.\nLisa Ingerman, Ph.D., D.A.B.T.\nConnor McGuire, Ph.D.\nJennifer Rhoades, B.S.\n\nATSDR, Office of Innovation and Analytics, \nToxicology Section, Atlanta, GA\n\nSRC, Inc., North Syracuse, NY\n\n## REVIEWERS\n\n## Interagency Minimal Risk Level Workgroup:\n\nIncludes ATSDR; National Center for Environmental Health (NCEH); U.S. Environmental Protection \nAgency (EPA); National Toxicology Program (NTP).\n\n## Additional reviews for science and/or policy:\n\nATSDR, Office of Community Health Hazard Assessment; ATSDR, Office of Capacity Development \nand Applied Prevention Science; ATSDR, Office of Science; NCEH, Division of Laboratory Sciences; \nNCEH, Division of Environmental Health Science and Practice; National Institute for Occupational \nSafety and Health (NIOSH); EPA, Office of Research and Development; EPA, Office of Water.\n\n## PEER REVIEWERS\n\n1. Kristen Upson, Ph.D., M.P.H.; Associate Professor of Epidemiology and Biostatistics; Michigan \nState University; Department of Epidemiology and Biostatistics; 909 Wilson Road Room B601; \nEast Lansing, MI\n\n2. Zahir Shaikh, Ph.D.; Professor Emeritus and Former Founding Director of RI-INBRE; The \nUniversity of Rhode Island, College of Pharmacy; Kingston, RI\n\n3. Curtis D. Klaassen, M.S., Ph.D., FATS, FAASLD, FASPET; Director of the Mid-America \nToxicology Course; Previously University Distinguished Professor and Chair at The University \nof Kansas School of Medicine; Kansas City, KS (retired)\n\nThese experts collectively have knowledge of toxicology, chemistry, and/or health effects.  All reviewers \nwere selected in conformity with Section 104(I)(13) of the Comprehensive Environmental Response, \nCompensation, and Liability Act, as amended.\n\n---\n\nATSDR scientists review peer reviewers’ comments and determine whether changes will be made to the \nprofile based on comments.  The peer reviewers’ comments and responses to these comments are part of \nthe administrative record for this compound.\n\nThe listing of peer reviewers should not be understood to imply their approval of the profile\'s final \ncontent.  The responsibility for the content of this profile lies with ATSDR.\n\n---\n\n## CONTENTS\n\nDISCLAIMER .............................................................................................................................................. ii\nFOREWORD ............................................................................................................................................... iii\nVERSION HISTORY ................................................................................................................................... v\nCONTRIBUTORS & REVIEWERS ........................................................................................................... vi\nCONTENTS ............................................................................................................................................... viii\nLIST OF FIGURES ...................................................................................................................................... x\nLIST OF TABLES ....................................................................................................................................... xi\nCHAPTER 1. RELEVANCE TO PUBLIC HEALTH ................................................................................. 1\n1.1 OVERVIEW AND U.S. EXPOSURES ......................................................................................... 1\n1.2 SUMMARY OF HEALTH EFFECTS........................................................................................... 2\n1.3 MINIMAL RISK LEVELS (MRLs) .............................................................................................. 8\nCHAPTER 2. HEALTH EFFECTS ............................................................................................................ 12\n2.1 INTRODUCTION ........................................................................................................................ 12\n2.2 DEATH ........................................................................................................................................ 92\n2.3 BODY WEIGHT .......................................................................................................................... 99\n2.4 RESPIRATORY ........................................................................................................................ 104\n2.5 CARDIOVASCULAR ............................................................................................................... 113\n2.6 GASTROINTESTINAL ............................................................................................................. 124\n2.7 HEMATOLOGICAL ................................................................................................................. 125\n2.8 MUSCULOSKELETAL ............................................................................................................ 131\n2.9 HEPATIC ................................................................................................................................... 143\n2.10 RENAL ...................................................................................................................................... 151\n2.11 DERMAL ................................................................................................................................... 171\n2.12 OCULAR ................................................................................................................................... 172\n2.13 ENDOCRINE ............................................................................................................................. 172\n2.14 IMMUNOLOGICAL ................................................................................................................. 182\n2.15 NEUROLOGICAL..................................................................................................................... 189\n2.16 REPRODUCTIVE ..................................................................................................................... 196\n2.17 DEVELOPMENTAL ................................................................................................................. 213\n2.18 OTHER NONCANCER ............................................................................................................. 239\n2.19 CANCER .................................................................................................................................... 241\n2.20 GENOTOXICITY ...................................................................................................................... 256\n2.21 MECHANISMS OF ACTION ................................................................................................... 266\nCHAPTER 3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, \nCHEMICAL INTERACTIONS ......................................................................................... 269\n3.1 TOXICOKINETICS................................................................................................................... 269\n3.1.1 Absorption ........................................................................................................................... 269\n3.1.2 Distribution ......................................................................................................................... 274\n3.1.3 Metabolism .......................................................................................................................... 277\n3.1.4 Excretion ............................................................................................................................. 278\n3.1.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models ........... 278\n3.1.6 Animal-to-Human Extrapolations ....................................................................................... 285\n3.2 CHILDREN AND OTHER POPULATIONS THAT ARE UNUSUALLY \nSUSCEPTIBLE .......................................................................................................................... 286\n\n---\n\n3.3 BIOMARKERS OF EXPOSURE AND EFFECT ..................................................................... 290\n3.3.1 Biomarkers of Exposure ...................................................................................................... 291\n3.3.2 Biomarkers of Effect ........................................................................................................... 294\n3.4 INTERACTIONS WITH OTHER CHEMICALS ..................................................................... 297\nCHAPTER 4. CHEMICAL AND PHYSICAL INFORMATION ........................................................... 303\n4.1 CHEMICAL IDENTITY ........................................................................................................... 303\n4.2 PHYSICAL AND CHEMICAL PROPERTIES ........................................................................ 304\nCHAPTER 5. POTENTIAL FOR HUMAN EXPOSURE ....................................................................... 307\n5.1 OVERVIEW .............................................................................................................................. 307\n5.2 PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL ................................................ 310\n5.2.1 Production ........................................................................................................................... 310\n5.2.2 Import/Export ...................................................................................................................... 313\n5.2.3 Use ...................................................................................................................................... 314\n5.2.4 Disposal ............................................................................................................................... 314\n5.3 RELEASES TO THE ENVIRONMENT ................................................................................... 315\n5.3.1 Air ....................................................................................................................................... 315\n5.3.2 Water ................................................................................................................................... 319\n5.3.3 Soil ...................................................................................................................................... 320\n5.4 ENVIRONMENTAL FATE ...................................................................................................... 321\n5.4.1 Transport and Partitioning ................................................................................................... 321\n5.4.2 Transformation and Degradation ........................................................................................ 325\n5.5 LEVELS IN THE ENVIRONMENT ......................................................................................... 326\n5.5.1 Air ....................................................................................................................................... 327\n5.5.2 Water ................................................................................................................................... 328\n5.5.3 Sediment and Soil ............................................................................................................... 330\n5.5.4 Other Media ........................................................................................................................ 332\n5.6 GENERAL POPULATION EXPOSURE.................................................................................. 335\n5.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES .............................................. 362\nCHAPTER 6. ADEQUACY OF THE DATABASE ................................................................................ 363\n6.1 EXISTING INFORMATION ON HEALTH EFFECTS ........................................................... 363\n6.2 IDENTIFICATION OF DATA NEEDS .................................................................................... 365\n6.3 ONGOING STUDIES ................................................................................................................ 372\nCHAPTER 7. REGULATIONS AND GUIDELINES ............................................................................. 376\nCHAPTER 8. REFERENCES .................................................................................................................. 380\nAPPENDICES\nAPPENDIX A.  ATSDR MINIMAL RISK LEVEL WORKSHEETS .................................................... A-1 \nAPPENDIX B.  LITERATURE SEARCH FRAMEWORK FOR CADMIUM ...................................... B-1 \nAPPENDIX C.  FRAMEWORK FOR ATSDR’S SYSTEMATIC REVIEW OF HEALTH EFFECTS \nDATA FOR CADMIUM ................................................................................................ C-1 \nAPPENDIX D.  USER’S GUIDE ............................................................................................................. D-1 \nAPPENDIX E.  QUICK REFERENCE FOR HEALTH CARE PROVIDERS ....................................... E-1 \nAPPENDIX F.  GLOSSARY .................................................................................................................... F-1 \nAPPENDIX G.  ACRONYMS, ABBREVIATIONS, AND SYMBOLS................................................. G-1\n\n---\n\n## LIST OF FIGURES\n\n1-1.  Health Effects Found in Animals Following Inhalation Exposure to Cadmium .................................. 4\n1-2.  Health Effects Found in Animals Following Oral Exposure to Cadmium ........................................... 5\n1-3.  Summary of Sensitive Targets of Cadmium – Inhalation ..................................................................... 9\n1-4.  Summary of Sensitive Targets of Cadmium – Oral ............................................................................ 10\n2-1.  Overview of the Number of Studies Examining Cadmium Health Effects ........................................ 17\n2-2.  Levels of Significant Exposure to Cadmium – Inhalation .................................................................. 33\n2-3.  Levels of Significant Exposure to Cadmium – Oral ........................................................................... 72\n3-1.  Structure of Kjellström-Nordberg Cadmium Biokinetic Model ....................................................... 280\n3-2.  Structure of Diamond and Klotzbach Cadmium Biokinetics Model ................................................ 283\n5-1.  Number of NPL Sites with Cadmium Contamination ...................................................................... 307\n6-1.  Summary of Existing Health Effects Studies on Cadmium by Route and Endpoint ........................ 364\n\n---\n\n## LIST OF TABLES\n\n1-1.  Minimal Risk Levels (MRLs) for Cadmium ...................................................................................... 11\n2-1.  Levels of Significant Exposure to Cadmium – Inhalation .................................................................. 18\n2-2.  Levels of Significant Exposure to Cadmium – Oral ........................................................................... 41\n2-3.  Levels of Significant Exposure to Cadmium – Dermal ...................................................................... 90\n2-4.  Results of Meta-Analyses Evaluating Exposure to Cadmium and Mortality Endpoints .................... 93\n2-5.  Studies Included in Meta-Analyses Evaluating Exposure to Cadmium and Mortality \nEndpoints ............................................................................................................................................ 94\n2-6.  Results of General Population Studies Evaluating Urinary Cadmium Levels and All-Cause \nMortality ............................................................................................................................................. 94\n2-7.  Results of Meta-Analysis Evaluating Exposure to Cadmium and Respiratory Endpoints ............... 106\n2-8.  Results of Epidemiological Studies Evaluating Urinary Cadmium Levels and Respiratory \nEffects ............................................................................................................................................... 108\n2-9.  Results of Meta-Analyses Evaluating Exposure to Cadmium and Cardiovascular Endpoints ......... 113\n2-10.  Studies Included in Meta-Analyses Evaluating Exposure to Cadmium and Cardiovascular \nEndpoints ........................................................................................................................................ 116\n2-11.  Results of General Population Studies Evaluating Urinary Cadmium Levels and Blood \nPressure or Hypertension ................................................................................................................ 118\n2-12.  Results of General Population Studies Evaluating Urinary Cadmium Levels and \nCardiovascular Disease-Related Effects ......................................................................................... 122\n2-13.  Results of General Population Epidemiological Studies Evaluating Urinary Cadmium \nLevels and Hematological Effects .................................................................................................. 126\n2-14.  Results of Meta-Analyses Evaluating Exposure to Cadmium and Skeletal Endpoints .................. 132\n2-15.  Studies Included in Meta Analyses Evaluating Exposure to Cadmium and Skeletal \nEndpoints ........................................................................................................................................ 133\n2-16.  Results of General Population Epidemiological Studies Evaluating Urinary Cadmium \nLevels and Musculoskeletal Effects ............................................................................................... 136\n2-17.  Results of Meta-Analyses Evaluating Exposure to Cadmium and Serum Lipids .......................... 143\n2-18.  Studies Included in Meta-Analyses Evaluating Exposure to Cadmium and Serum Lipids ............ 144\n2-19.  Results of General Population Studies Evaluating Urinary Cadmium Levels and Blood \nLipid Levels .................................................................................................................................... 145\n\n---\n\n2-20.  Results of General Population Studies Evaluating Exposure to Urinary Cadmium Levels \nand Hepatic Disease and Clinical Chemistry ................................................................................. 147\n2-21.  Results of Occupational Studies Evaluating Urine Cadmium Levels and Renal Outcomes .......... 154\n2-22.  Results of Meta-Analyses Evaluating Exposure to Cadmium and Renal Endpoints ...................... 157\n2-23.  Studies Included in Meta-Analyses Evaluating Exposure to Cadmium and Renal Endpoints ....... 158\n2-24.  Results of Epidemiological Studies of General Populations Evaluating Urine Cadmium \nLevels and Renal Effects ................................................................................................................ 161\n2-25.  Results of Meta-Analysis Evaluating Exposure to Cadmium and Thyroid Endpoints ................... 173\n2-26.  Results of General Population Studies Evaluating Urinary Cadmium Levels and Thyroid \nEffects ............................................................................................................................................. 174\n2-27.  Results of Meta-Analyses Evaluating Exposure to Cadmium and Diabetes Endpoints ................. 175\n2-28.  Studies Included in Meta Analyses Evaluating Exposure to Cadmium and Diabetes \nEndpoints ........................................................................................................................................ 177\n2-29.  Results of Epidemiological Studies Evaluating Exposure to Cadmium and Diabetes-\nRelated Effects ................................................................................................................................ 179\n2-30.  Results of Epidemiological Studies Evaluating Urinary Cadmium Levels and \nImmunological Effects ................................................................................................................... 182\n2-31.  Results of Meta-Analyses Evaluating Exposure to Cadmium and Neurological Endpoints .......... 190\n2-32.  Studies Included in Meta-Analyses Evaluating Exposure to Cadmium and Neurological \nEndpoints ........................................................................................................................................ 191\n2-33.  Results of General Population Studies Evaluating Exposure to Urinary Cadmium and \nNeurological Effects ....................................................................................................................... 192\n2-34.  Results of Meta-Analyses Evaluating Exposure to Cadmium and Male Reproductive \nEndpoints ........................................................................................................................................ 196\n2-35.  Studies Included in Meta-Analyses Evaluating Exposure to Cadmium and Male \nReproductive Endpoints ................................................................................................................. 197\n2-36.  Results of General Population Studies Evaluating Urinary Cadmium Levels and \nReproductive Effects in Men .......................................................................................................... 199\n2-37.  Results of Meta-Analyses Evaluating Exposure to Cadmium and Female Reproductive \nEndpoints ........................................................................................................................................ 202\n2-38.  Studies Included in Meta-Analyses Evaluating Exposure to Cadmium and Female \nReproductive Endpoints ................................................................................................................. 203\n2-39.  Results of General Population Studies Evaluating Urinary Cadmium Levels and \nReproductive Effects in Women..................................................................................................... 204\n\n---\n\n2-40.  Results of Meta-Analyses Evaluating Exposure to Cadmium and Neurodevelopmental \nEndpoints ........................................................................................................................................ 213\n2-41.  Studies Included in Meta-Analyses Evaluating Exposure to Cadmium and \nNeurodevelopmental Endpoints ..................................................................................................... 214\n2-42.  Results of General Population Studies Evaluating Exposure to Cadmium and \nNeurodevelopmental Effects .......................................................................................................... 217\n2-43.  Results of General Population Studies Evaluating Urinary Cadmium Levels and Growth \nand Metabolism During Infancy, Childhood, and Adolescence ..................................................... 228\n2-44.  Results of General Population Studies Evaluating Urinary Cadmium Levels and \nReproductive Developmental Effects ............................................................................................. 233\n2-45.  Results of Meta-Analyses Evaluating Exposure to Cadmium and Metabolic Syndrome \nEndpoints ........................................................................................................................................ 240\n2-46.  Studies Included in Meta Analyses Evaluating Exposure to Cadmium and Metabolic \nSyndrome Endpoints ...................................................................................................................... 240\n2-47.  Results of Meta-Analyses Evaluating Exposure to Cadmium and Cancer ..................................... 242\n2-48.  Studies Included in Meta-Analyses Evaluating Exposure to Cadmium and Cancer ...................... 245\n2-49.  Results of Epidemiological Studies Evaluating Exposure to Cadmium and Cancer ...................... 250\n2-50.  Genotoxicity of Cadmium *In Vivo* .................................................................................................. 257\n2-51.  Genotoxicity of Cadmium *In Vitro* ................................................................................................. 259\n4-1.  Chemical Identity of Cadmium and Compounds ............................................................................. 303\n4-2.  Physical and Chemical Properties of Cadmium and Compounds .................................................... 304\n5-1.  Facilities that Produce, Process, or Use Cadmium ........................................................................... 310\n5-2.  Facilities that Produce, Process, or Use Cadmium Compounds ....................................................... 311\n5-3.  Releases to the Environment from Facilities that Produce, Process, or Use Cadmium .................... 316\n5-4.  Releases to the Environment from Facilities that Produce, Process, or Use Cadmium \nCompounds ....................................................................................................................................... 317\n5-5.  Lowest Limit of Detection Based on Standards ............................................................................... 326\n5-6.  Summary of Environmental Levels of Cadmium ............................................................................. 327\n5-7.  Range of Arithmetic Means for Cadmium from the AQS ................................................................ 327\n5-8.  Total Cadmium Levels in Groundwater and Surface Water in U.S. Samples Collected in \n2022–2024 ........................................................................................................................................ 329\n5-9.  Total Cadmium Levels in Ambient Sediment Collected in 2022–2024 ........................................... 331\n\n---\n\n5-10.  Mean Concentrations of Cadmium for FDA’s Total Diet Study Market Baskets 2006-1\nthrough 2008-4 ............................................................................................................................... 333\n5-11.  Geometric Mean and Selected Percentile Blood Concentrations (μg/L) of Cadmium in the\nU.S. Population, 1999–2018 ........................................................................................................... 336\n5-12.  Geometric Mean and Selected Percentile Urine Concentrations (Creatinine Corrected)\n(μg/g Creatinine) of Cadmium in the U.S. Population, 1999––2018 ............................................. 343\n5-13.  Geometric Mean and Selected Percentile Urine Concentrations (μg/L) of Cadmium in the\nU.S. Population, 1999–2018 ........................................................................................................... 350\n5-14.  Blood Cadmium Concentrations, Geometric Means, Adjusted Proportional Change in\nMeans, and 95<sup>th</sup> Percentiles in New York City Adults in Population \nSubgroups....................................................................................................................................... 357\n5-15.  Occupations with Potential Exposure to Cadmium and Cadmium Compounds ............................ 361\n6-1.  Ongoing Studies on Cadmium .......................................................................................................... 372\n7-1.  Regulations and Guidelines Applicable to Cadmium ....................................................................... 376\n\n---\n\n## CHAPTER 1. RELEVANCE TO PUBLIC HEALTH\n\n### 1.1 OVERVIEW AND U.S. EXPOSURES\n\nCadmium (Cd) occurs in the earth’s crust at a concentration of roughly 0.1–0.5 ppm and is commonly \nassociated with zinc, lead, and copper ores.  It is also a natural constituent of ocean water with average \nlevels between <5 and 110 ng/L, with higher levels reported near coastal areas and in marine phosphates \nand phosphorites (Morrow 2010).  The cadmium concentration of natural surface water and groundwater \nis usually <1 μg/L (Elinder 1985a, 1992).  Surface soil concentrations will depend on several factors such \nas its mobility, natural geochemistry, and magnitude of contamination from sources such as fertilizers and \natmospheric deposition.  Natural emissions of cadmium to the environment can result from volcanic \neruptions, forest fires, generation of sea salt aerosols, or other natural phenomena (EPA 1985; Morrow \n2010; Shevchenko et al. 2003).\n\n$$\n<1\\;\\mu g/L\n$$\n\nIn the environment, cadmium exists in only one oxidation state (Cd<sup>+2</sup>) and does not undergo oxidationreduction reactions.  In surface water and groundwater, cadmium can exist as the hydrated ion or as ionic \ncomplexes with other inorganic or organic substances.  Soluble forms of cadmium can migrate in water.  \nInsoluble forms of cadmium will settle and adsorb to sediments.  Cadmium’s fate in soil depends on \nseveral factors such as pH of the soil and availability of organic matter.  Generally, cadmium will bind \nstrongly to organic matter and this will, for the most part, immobilize it (Autier and White 2004).  \nHowever, cadmium’s behavior in soil will vary depending on the environmental conditions.  It is not \nlikely that cadmium will undergo significant transformation in the atmosphere (EPA 1980).  It will exist \nin particulate form and sometimes vapor form (emitted from high-temperature processes) where it will \nundergo atmospheric transport and eventually deposit onto soils and surface waters.\n\n$$\n\\left(\\mathrm{Cd^{+2}}\\right)\n$$\n\nNon-ferrous metal mining and refining, manufacture and application of phosphate fertilizers, fossil fuel \ncombustion, and waste incineration and disposal are the main anthropogenic sources of cadmium in the \nenvironment.  Except for those who live near cadmium-emitting industries, inhalation of cadmium in the \nambient air may occur but is not a major source of exposure.  Similarly, cadmium exposure through the \ndrinking water supply is of minor concern for the majority of the U.S. population.  However, water \nsources near cadmium-emitting industries, both with historic and current operations, have shown a \nmarked elevation of cadmium in water sediments and aquatic organisms (Angelo et al. 2007; Arnason and \nFletcher 2003; Brumbaugh et al. 2005; Mason et al. 2000; Paulson 1997).  Concentrations of cadmium in these polluted waters have ranged from <1.0 to 77 μg/L.  Cadmium from polluted soil and water can \naccumulate in plants and organisms, thus entering the food supply (Morrow 2010).\n\n$$\n7 7 \\mu \\mathrm {g} / \\mathrm {L}\n$$\n\nIn the United States, the largest source of cadmium exposure for nonsmoking adults and children is \nthrough dietary intake (NTP 2005).  The average daily intake of cadmium for children and adults \n(≥2 years of age) in the United States was estimated as 4.63 µg/day (Kim et al. 2019).  In general, leafy \nvegetables such as lettuce and spinach and staples such as potatoes and grains contain relatively high \nvalues of cadmium.  Peanuts, soybeans, and sunflower seeds have naturally high levels of cadmium \n(Morrow 2010).  Shellfish and organ meats (liver and kidney) also have relatively high concentrations of \ncadmium (Elinder 1985a).\n\nMean values of cadmium in the blood and urine of the U.S. population were reported in the National \nHealth and Nutrition Examination Survey (NHANES) 1999–2018 (CDC 2024).  Blood cadmium tends to \nreflect recent exposures, and urinary cadmium reflects cumulative cadmium exposure and body burden \n(particularly, kidney cadmium levels).  The geometric mean blood cadmium levels for the total population \n(≥1 year of age) have decreased nearly 50% from survey years 1999–2000 (0.412 µg/L) to survey years \n2017–2018 (0.241 µg/L).\n\n$$\n1999-2000\\left(0.412\\ \\mu g/L\\right)\n$$\n\n$$\n2017-2018\\left(0.241\\ \\mu g/L\\right)\n$$\n\nSmoking greatly increases exposure to cadmium, as tobacco leaves naturally accumulate high amounts of \ncadmium (Morrow 2010).  It has been estimated that tobacco smokers are exposed to 0.5–2.0 μg \ncadmium per cigarette, and about 10% is inhaled when smoked (Morrow 2010; Nordberg et al. 2015; \nNTP 2005).  A geometric mean blood cadmium level for a heavy smoker has been reported as high as \n1.58 μg/L (McKelvey et al. 2007), compared to the estimated national mean of 0.295 μg/L for all adults\n≥20 years of age, based on survey years 2017–2018 (CDC 2024).  Nonsmokers may also be exposed to \ncadmium in cigarettes via second-hand smoke.\n\n$$\n1. 5 8 \\mu \\mathrm {g} / \\mathrm {L}\n$$\n\n### 1.2 SUMMARY OF HEALTH EFFECTS\n\nSince the early 1950s, when the hazards of occupational cadmium exposure were recognized (Friberg \n1950), a large amount of information has been generated concerning the toxic effects of cadmium \nexposure in humans and laboratory animals.  Toxicological properties of cadmium are similar for the \nseveral different salts and oxides of cadmium that have been investigated, although differences in \nabsorption and distribution lead to different effect levels.  For inhalation exposure, particle size and \nsolubility in biological fluids (in contrast to solubility in water) appear to be the more important determinants of the toxicokinetics (Hirano et al. 1989a, 1989b; Oldiges and Glaser 1986; Rusch et al. \n1986).  For oral exposure, most experimental studies have used soluble cadmium, which exists as the Cd<sup>+2</sup>\nion regardless of the initial salt.  Absorption appears to be similar for cadmium ion and cadmium \ncomplexed with proteins in food, except for a few specific types of foods such as Bluff oysters and seal \nmeat.  Also, poorly soluble cadmium pigments may be absorbed to a lesser extent than soluble cadmium \nion (ILZRO 1977; Oldiges and Glaser 1986).\n\nThe database on the toxicity of cadmium in humans and animals following inhalation or oral exposure is \nextensive.  Target organs are similar among species and, in general, toxicokinetics following systemic \nabsorption from the gastrointestinal and respiratory tracts are similar.  Most of the human data involve \nevaluation of health effects associated with chronic-duration exposure in occupational studies, \ncommunity-based studies of populations living in cadmium-polluted areas, or epidemiological studies in \nthe general population.  When adequate exposure characterization is available, human studies generally \nreport exposure levels in terms of an internal biomarker of exposure (e.g., urinary cadmium).  Numerous \nstudies have conducted dose-response analyses between urinary cadmium levels and biomarkers of renal \ndysfunction (see Section 2.10); similar rigorous dose-response analyses are not available for other targets \nof toxicity in humans.  In animals, evaluation of available dose-response data by route and duration \nindicates that sensitive noncancer targets of cadmium toxicity are respiratory and neurodevelopmental \neffects following inhalation exposure (Figure 1-1) and renal, skeletal, and neurodevelopmental effects \nfollowing oral exposure (Figure 1-2).\n\nA systematic review of these sensitive noncancer endpoints resulted in the following hazard identification \nconclusions:\n\n• Respiratory effects are a known effect for humans following inhalation exposure.\n\n• Skeletal effects are a known effect for humans.\n\n• Renal effects are a known effect for humans.\n\n• Neurodevelopmental effects are a presumed effect for humans.\n\n---\n\n**Figure 1-1.  Health Effects Found in Animals Following Inhalation Exposure to** \n**Cadmium**\n\nConcentration (mg Cd/m<sup>3</sup>) Effects in Animals\n>8 Acute:  Mortality; clinical signs of neurotoxicity, female reproductive effects\n0.9-1.7 Acute:  Decreased body weight\nIntermediate:  Male and female reproductive effects\n0.19-0.4 Acute:  Developmental and immune effects\n0.05-0.1 Acute:  Respiratory effects\nIntermediate:  Death\n0.02-0.03 Intermediate:  Respiratory and neurodevelopmental effects\nChronic:  Cancer, mortality\n1x10<sup>-4</sup> mg Cd/m<sup>3</sup> Provisional Chronic MRL (based on human data and exposure levels predicted from biomarkers)\n\nCd = cadmium; MRL = minimal risk level\n\n---\n\n**Figure 1-2.  Health Effects Found in Animals Following Oral Exposure to** \n**Cadmium**\n\n## Dose (mg Cd/kg/day)\n\n## Effects in Animals\n\n**Acute:**  Death; hepatic, gastrointestinal, neurological, and male \nreproductive effects\n\n**5.28-15**\n\n**Intermediate:**  Death\n\n**Chronic:**  Hematological effects\n\n**Acute:**  Hematological effects; altered reproductive development\n\n**0.6-3.13**\n\n**Intermediate:**  Gastrointestinal effects\n\n**Chronic:**  Decreased body weight\n\n**Acute:**  Renal and developmental effects, decreased body weight\n\n**0.2-0.4**\n\n**Intermediate:**  Renal, hepatic, hematological, and male and female \nreproductive effects; increased blood pressure; decreased body weight\n\n**Chronic:**  Renal and neurological effects; cancer\n\n**0.04-0.08**\n\n**Intermediate:**  Skeletal, neurological, respiratory, and immunological \neffects; decreased birth weight and altered reproductive development\n\n## 0.002 mg Cd/kg/day 3x10<sup>-4</sup> mg Cd/kg/day\n\n3x10 -4 mg Cd/kg/day\n\n**Intermediate:**  Neurodevelopmental and endocrine effects\n\n**Chronic:**  Skeletal effects\n\n**Provisional Acute MRL**\n\n**Provisional Chronic MRL (based on human data and exposure levels predicted from biomarkers)**\n\nCd = cadmium; MRL = minimal risk level\n\n---\n\n**_Respiratory Effects._** A meta-analysis of 12 studies reported an association between chronic-duration \ninhalation exposure to cadmium and reduced forced expiratory volume in the first second to forced vital \ncapacity (FEV1/FVC), which is indicative of an increased risk of chronic obstructive pulmonary disease \n(Wang et al. 2024a).  A limited number of occupational studies not included in the meta-analysis also \nreported associations between impaired lung function and urinary cadmium levels in workers (Moitra et \nal. 2013, 2015; Zhou et al. 2022).  These findings are supported by occupational case reports of clinical \nsigns of respiratory distress and pulmonary damage after acute-duration exposure to fatal concentrations \n(Beton et al. 1966; Townshend 1982).  In animal acute- and intermediate-duration inhalation studies, the \nrespiratory tract is the most sensitive target of toxicity in animals (NTP 1995).  Available studies \nconsistently report histopathological and inflammatory reactions in the respiratory tract of multiple \nspecies; in studies that provide quantitative data, findings are clearly concentration-related \n(see Section 2.4).\n\n**_Skeletal Effects._** Cadmium-associated bone effects were first described in 1955 in the Jinzu River Basin, \na cadmium-contaminated area in Japan, following the development of a bone disease called Itai-Itai\n("ouch-ouch") disease, characterized by multiple fractures of the long bones, osteomalacia, and \nosteoporosis in combination with proteinuria (Järup et al. 1998; Nordberg et al. 1997; Shigematsu 1984).  \nFour meta-analyses evaluating 41 unique references confirm the association between cadmium exposure \nand adverse bone effects, including fractures, osteoporosis, and decreased bone mineral density (Cheng et \nal. 2016; Kunioka et al. 2022; Li et al. 2021; Qing et al. 2021), as do several studies published since the \nmeta-analyses (Lv et al. 2021; Wang et al. 2021a; Xie et al. 2023a, 2023b).  Occupational case studies \nindicate that calcium deficiency, osteoporosis, or osteomalacia can develop in some workers after longterm occupational exposure to high levels of cadmium (Adams et al. 1969; Blainey et al. 1980; Bonnell \n1955; Kazantzis 1979; Scott et al. 1980).  In rodents, decreases in bone mineralization, bone mineral \ndensity, and mechanical properties have been consistently observed following oral exposure to cadmium \nchloride (see Section 2.8).  While bone effects may be secondary to cadmium-associated renal damage \n(Bhattacharyya et al. 2023; Shevchenko et al. 2021; Zhang et al. 2020a), there is also evidence for a direct \neffect of cadmium on bone, and acceleration of bone resorption can occur in the absence of renal \ndysfunction (Reyes-Hinojosa et al. 2019; Shevchenko et al. 2021; Zhang et al. 2020a).\n\n**_Renal Effects._** The kidney is a well-established target of cadmium toxicity in humans following \noccupational or dietary exposure.  Available meta-analyses consistently reported associations between \none or more biomarkers of cadmium exposure and risk of proteinuria, urolithiasis, chronic kidney disease, \nhyperuricemia, renal cytotoxicity, and low glomerular filtration rate (GFR) (Chen et al. 2024; Doccioli et al. 2024; Gu et al. 2022; Jalili et al. 2021; Liu et al. 2016a; Woo et al. 2015; Zhu et al. 2024a).  These \nfindings are supported by several studies conducted since the meta-analyses were published (see \nSection 2.10).  In animals, there is no evidence for renal effects in acute- and intermediate-duration \ninhalation studies; however, exposure duration and concentration may not have been enough to reach the \ncritical kidney concentration to induce renal effects and chronic-duration inhalation studies evaluating \nrenal toxicity were not identified.  In oral studies, some studies reported adverse changes in sensitive \nbiomarkers of kidney damage, such as a β2-microglobulin (β2M) or N-acetyl-β-d-glucosaminidase \n(NAG) (Bernard et al. 1992; Liu et al. 2019; Wan et al. 2022).  However, other studies did not find this \neffect at similar or higher doses (Wang et al. 2014).  Similar inconsistencies were observed for serum \nclinical chemistry values and histopathological findings (see Section 2.10).\n\n**_Neurodevelopmental Effects._** While several general population studies are available, findings are mixed.  \nAvailable meta-analysis reported mixed conclusions regarding the potential association between cadmium \nexposure and autism spectrum disorder (ASD) (Ding et al. 2023; Dou et al. 2023; Ramazani et al. 2024; \nSaghazadeh and Rezaei 2017; Sulaiman et al. 2020) and did not find an association with attention deficit \nhyperactivity disorder (ADHD) (Dimitrov et al. 2023).  Some studies reported associations between \ncadmium exposure and decreased measures of cognitive development in children and adolescents (Gustin \net al. 2018; Kippler et al. 2016; Rodríguez-Barranco et al. 2014; Zhou et al. 2020); however, other studies \ndid not support this finding (Forns et al. 2014; Lucchini et al. 2019; Pan et al. 2018; Yang et al. 2020).  \nNo consistent findings were observed regarding potential associations between cadmium exposure and \nneurobehavioral or neurosensory evaluations during childhood or adolescence (see Section 2.17).  In \ncontrast, available animal studies collectively indicate that developmental cadmium exposure can cause \nalterations in sensorimotor function (including nerve conduction) and activity, socioemotional behavior, \nand learning and memory in rodents; however, the timing and duration of exposure and assessment \ninfluence findings (see Section 2.17).\n\n**_Cancer Effects._** The carcinogenicity of cadmium has been studied extensively in humans in studies \ninvolving workers and general populations and in animals after inhalation or oral exposures.  The \nInternational Agency for Research on Cancer (IARC) classified cadmium and cadmium compounds as \ncarcinogenic to humans (Group 1) based on sufficient evidence in humans for the carcinogenicity of \ncadmium and cadmium compounds, sufficient evidence in animals for the carcinogenicity of cadmium \ncompounds, and limited evidence in animals for the carcinogenicity of cadmium metal (IARC \n2012).  Similarly, the Department of Health and Human Services (HHS) classified cadmium and \ncadmium compounds as substances known to be human carcinogens based on sufficient evidence of carcinogenicity in humans, including epidemiological and mechanistic studies (NTP 2021).  In 1989, the \nU.S. Environmental Protection Agency (EPA) classified cadmium as a probable human carcinogen by \ninhalation (Group B1) based on limited evidence in humans and sufficient evidence in animals (IRIS \n1989).\n\n### 1.3 MINIMAL RISK LEVELS (MRLs)\n\nMRLs for inhalation and oral exposures to cadmium were derived.  As presented in Figure 1-3, the most \nsensitive effects following inhalation exposure to cadmium are respiratory and developmental \n(specifically neurodevelopmental effects) following acute- and intermediate-duration exposure and renal \nfollowing chronic-duration exposure.  A provisional chronic-duration inhalation MRL was derived based \non renal effects in humans; the inhalation database was considered inadequate for the derivation of acuteor intermediate-duration MRLs.  The lack of renal toxicity at shorter durations in animal inhalation\nstudies is attributed to inadequate exposure duration to meet the critical renal burden required to elicit \nadverse renal effects.  The relationship between renal and urinary cadmium appears to be nearly linear at \nchronic-duration intakes and kidney burdens that do not produce nephrotoxicity (i.e., elimination halftime is independent of dose).  However, at high kidney cadmium burdens, associated with renal damage \n(>50 μg Cd/g cortex), the elimination half-time increases with increasing severity of renal damage.  \nLinearity in the dose-urinary excretion relationship also does not appear to apply following an acuteduration, high exposure to cadmium.  Multicompartment, physiologically based pharmacokinetic (PBPK) \nmodels (described in detail in Section 3.1.5) can be used to estimate cadmium intakes (inhalation and oral \nexposure) associated with a given urinary cadmium level and/or kidney cadmium burden.  These models \nhave been extensively evaluated for predicting dose-kidney-urinary cadmium relationships within the \nlinear range of the dose-urinary cadmium relationship, and PBPK modeling was used in the derivation of \nthe provisional inhalation chronic-duration MRL.\n\nAs presented in Figure 1-4, the most sensitive effects following oral exposure are renal, developmental \n(specifically neurodevelopmental), and skeletal effects.  Provisional acute- and chronic-duration oral \nMRLs were derived based on renal effects in animals and humans, respectively; the oral database was \nconsidered inadequate for the derivation an intermediate-duration oral MRL.  As discussed for the provisional chronic-duration inhalation MRL, PBPK modeling was used in the derivation of the \nprovisional oral chronic-duration MRL.\n\nMRLs derived for both the inhalation and oral exposure routes for cadmium are summarized in Table 1-1\nand are discussed in greater detail in Appendix A.\n\n**Figure 1-3.  Summary of Sensitive Targets of Cadmium – Inhalation**\n\n**Available data indicate that the respiratory system and developing nervous system are the most \nsensitive targets following acute- and intermediate-duration exposure and the renal system is the \nmost sensitive target following chronic-duration exposure to cadmium via inhalation.**\n\nNumbers in circles are the lowest lowest-observed-adverse-effect levels (LOAELs) for all health effects in \nanimals and the number in the triangle is the point of departure (POD) for the chronic-duration inhalation \nMRL based on human data.*\n\n**Acute (mg Cd/m³ )**\n\n| Category | Acute (mg Cd/m³) | Intermediate (mg Cd/m³) | Chronic (mg Cd/m³) |\n| --- | --- | --- | --- |\n| Respiratory | 0.081 | 0.021 |  |\n| Immunological | 0.19 |  |  |\n| Developmental | 0.4 | 0.02 |  |\n| Hematological |  | 0.052 |  |\n| Body weight |  | 0.052 | 0.03 |\n| Renal |  |  | 0.00106 |\n| Death |  |  | 0.03 |\n\n*See Table 2-1 for animal studies identifying the LOAELs in circles.  The value of 0.00106 mg Cd/m<sup>3</sup> represented by \nthe triangle (human data) is the renal POD used for the provisional chronic-duration MRL; the value represents the \nlower 95% confidence limit on the weighted median of the urinary cadmium level associated with a 10% extra risk \nassociated with low-molecular weight proteinuria in 17 datasets from 11 human studies (see Appendix A for details).\n\n---\n\n## Figure 1-4. Summary of Sensitive Targets of Cadmium – Oral\n\n**Available data indicate that the renal, skeletal, and developing nervous system are the most \nsensitive targets of cadmium oral exposure.**\n\nNumbers in circles are the lowest lowest-observed-adverse-effect levels (LOAELs) for all health effects in \nanimals and the number in the triangle is the point of departure (POD) for the chronic-duration oral MRL \nbased on human data.*\n\n**Acute (mg Cd/kg/day)**\n\n| Category | LOAEL (mg Cd/kg/day) |\n| --- | --- |\n| Acute - Renal | 2 |\n| Acute - Body weight | 2 |\n| Acute - Developmental | 3.13 |\n| Intermediate - Developmental | 0.04 |\n| Intermediate - Endocrine | 0.053 |\n| Intermediate - Musculoskeletal | 0.2 |\n| Chronic - Renal (POD) | 0.00076 |\n| Chronic - Musculoskeletal | 0.08 |\n| Chronic - Renal | 2.301 |\n| Chronic - Cancer | 2.3 |\n\n*See Table 2-2 for animal studies identifying the LOAELs in circles.  The value of 7.60x10<sup>-4</sup> mg Cd/kg/day \nrepresented by a triangle (human data) is the renal POD used for the provisional chronic-duration MRL; the value \nrepresents the lower 95% confidence limit on the weighted median of the urinary cadmium level associated with a \n10% extra risk associated with low-molecular weight proteinuria in 17 datasets from 11 human studies \n(see Appendix A for details).\n\n$$\n7.60\\times10^{-4}\n$$\n\n---\n\n**Table 1-1.**\n\n**Minimal Risk Levels (MRLs) for Cadmium**\n\n| Exposure route | Exposure duration | Provisional MRL | Critical effect (species) | POD type | POD value | Uncertainty/modifying factor | Reference |\n| --- | --- | --- | --- | --- | --- | --- | --- |\n| Inhalation | Acute | None | - | - | - | - | - |\n| Inhalation | Intermediate | None | - | - | - | - | - |\n| Inhalation | Chronic | 1 × 10-4 mg CD/m3 | LMW proteinuria (humans) | 95% LCL of weighted median of UC10 from 17 datasets | 0.00106 mg Cd/m3 | UF: 3 MF: 3 | Weighted median from 17 datasetsb |\n| Oral | Acute | 0.002 mg Cd/kg/day | Total and LMW proteinuria; increased serum BUN (rats) | LOAEL | 2 mg Cd/kg/day | UF: 1,000 | Wan et al. 2022 |\n| Oral | Intermediate | None | - | - | - | - | - |\n| Oral | Chronic | 3 × 10-4 mg CD/kg/day | LMW proteinuria (humans) | 95% LCL of weighted median of UC10 from 17 datasets | 7.60 × 10-4 mg Cd/kg/day | UF: 3 | Weighted median from 17 datasetsb |\n\n<sup>a</sup>See Appendix A for additional information.\n\n<sup>b</sup>17 datasets from 3 occupational cohorts (Järup and Elinder 1994; Lei et al. 2007; Shao et al. 2007) and 8 general population cohorts (Buchet et al. 1990; Hong et \nal. 2004; Järup et al. 2000; Kobayashi et al. 2008; Suwazono et al. 2006; Uno et al. 2005; Wu et al. 2001; Zhang et al. 2016a).\n\nBUN = blood urea nitrogen; LCL = lower confidence limit; LMW = low molecular weight; LOAEL = lowest-observed-adverse-effect level; MF = modifying factor; \nPOD = point of departure; UC10 = urinary concentration associated with 10% extra risk; UF = uncertainty factor\n\n---\n\n## CHAPTER 2. HEALTH EFFECTS\n\n### 2.1 INTRODUCTION\n\nThe primary purpose of this chapter is to provide public health officials, physicians, toxicologists, and \nother interested individuals and groups with an overall perspective on the toxicology of cadmium.  It \ncontains descriptions and evaluations of toxicological studies and epidemiological investigations and \nprovides conclusions, where possible, on the relevance of toxicity and toxicokinetic data to public health.  \nWhen available, mechanisms of action specific to target organs are discussed along with the health effects \ndata, while general mechanisms of action are discussed in Section 2.21; toxicokinetic mechanistic data are \ndiscussed in Section 3.1.\n\nA glossary and list of acronyms, abbreviations, and symbols can be found at the end of this profile.\n\nTo help public health professionals and others address the needs of persons living or working near hazardous \nwaste sites, the information in this section is organized by health effect.  These data are discussed in terms of \nroute of exposure (inhalation, oral, and dermal) and three exposure periods:  acute (≤14 days), intermediate \n(15–364 days), and chronic (≥365 days).\n\nAs discussed in Appendix B, a literature search was conducted to identify relevant studies examining health \neffect endpoints.  Figure 2-1 provides an overview of the database of studies in humans or experimental \nanimals included in this chapter of the profile.  These studies evaluate the potential health effects associated \nwith inhalation, oral, or dermal exposure to cadmium, but may not be inclusive of the entire body of \nliterature.  As discussed in *Prioritization of Human Data* in Appendix B, the epidemiological database for \ncadmium is extensive, including thousands of primary studies and dozens of meta-analyses of available \nstudies.  To focus the profile review and discussion on the weight-of-evidence, recent evidence, and most \nrelevant data for hazard identification, ATSDR focused the discussion in Chapter 2 on meta-analyses \nconducted within the past 15 years.  To supplement discussion, any epidemiological study published since \nthe most recent meta-analysis for an endpoint was included if it provided: (1) reliable and reported estimates \nof cadmium exposure (measured levels in air or via urinary cadmium levels, as this is the most reliable \nbiomarker [see Section 3.3.1]); (2) analysis of potential confounders of the measures of association; and \n(3) appropriate statistical analysis.  For endpoints without a published meta-analysis, any study meeting these \ninclusion criteria were included, regardless of publication date.  Studies were excluded if they did not \nprovide quantitative evidence for associations, relied on semi-quantitative measures of exposure (e.g., food frequency questionnaires), or evaluated cadmium exposure from medical implants.  Exceptions to the above \ncriteria included studies reporting rare effects, inclusion of select older studies to provide historical context \n(e.g., Itai-Itai disease in the Jinzu River Basin region of Japan, early case reports and investigations of \nworkers exposed to cadmium that established targets of toxicity, etc.), and studies that fill data gaps (e.g., \nlower quality occupational studies in less-studied organ systems/tissues). The animal database for cadmium \nis also extensive.  As discussed in *Prioritization of Animal Data* in Appendix B, animal studies evaluating \nadverse effects were prioritized for efficient review.  Since cadmium is a well-established model of renal \ntoxicity, there are hundreds of studies describing administration of cadmium via oral or other routes (e.g., \nintraperitoneal) at known toxic doses to evaluate potential interventions to rescue (or prevent) renal toxicity \nor other cadmium-associated adverse effects at higher exposure levels.  Studies of this nature were excluded \nfrom the profile, as they do not inform dose-response effects at low, environmentally-relevant \ndoses. Similarly, acute- and intermediate-duration oral studies in rats or mice utilizing only one cadmium \ndose group were excluded due to lack of dose-response data; exceptions were made for acute-lethality \nstudies or studies addressing data-poor endpoints (e.g., lipid homeostasis studies).  All chronic-duration oral \nstudies and all inhalation and dermal studies of adequate quality were included in the profile.  A systematic \nreview of the scientific evidence of the most sensitive health effects associated with exposure to cadmium\nwas also conducted; the results of this review are presented in Appendix C.\n\nHuman and animal inhalation studies are presented together in Table 2-1 and Figure 2-2 and human and \nanimal oral studies are presented in Table 2-2 and Figure 2-3; limited dermal data were identified for \ncadmium and are presented in Table 2-3.\n\nLevels of significant exposure (LSEs) for each route and duration are presented in tables and illustrated in \nfigures.  The points in the figures showing no-observed-adverse-effect levels (NOAELs) or lowestobserved-adverse-effect levels (LOAELs) reflect the actual doses (levels of exposure) used in the studies.  \nEffects have been classified into “less serious LOAELs” or “serious LOAELs (SLOAELs).”  “Serious” \neffects are those that evoke failure in a biological system and can lead to morbidity or mortality (e.g., \nacute respiratory distress or death).  “Less serious” effects are those that are not expected to cause \nsignificant dysfunction or death, or those whose significance to the organism is not entirely clear.  \nATSDR acknowledges that a considerable amount of judgment may be required in establishing whether \nan endpoint should be classified as a NOAEL, “less serious” LOAEL, or “serious” LOAEL, and that in \nsome cases, there will be insufficient data to decide whether the effect is indicative of significant \ndysfunction.  However, the Agency has established guidelines and policies that are used to classify these \nendpoints.  ATSDR believes that there is sufficient merit in this approach to warrant an attempt at distinguishing between “less serious” and “serious” effects.  The distinction between “less serious” effects \nand “serious” effects is considered to be important because it helps the users of the profiles to identify \nlevels of exposure at which major health effects start to appear.  LOAELs or NOAELs should also help in \ndetermining whether or not the effects vary with dose and/or duration, and place into perspective the \npossible significance of these effects to human health.  Levels of exposure associated with cancer (Cancer \nEffect Levels, CELs) of cadmium are indicated in Tables 2-1 and 2-2 and Figures 2-2 and 2-3.\n\nA User\'s Guide has been provided at the end of this profile (see Appendix D).  This guide should aid in \nthe interpretation of the tables and figures for LSEs and MRLs.\n\nThis section provides information regarding potential adverse health effects of cadmium and cadmium \ncompounds.  To appropriately compare doses following exposures to various cadmium compounds, \ninhalation exposures are expressed throughout the profile as mg Cd/m<sup>3</sup> and oral exposures are expressed as \nmg Cd/kg/day, when possible.  This allows for evaluation of relative toxicities and determination of whether \ncertain chemical properties (e.g., solubility) impact toxicity.  When available, information pertaining to \nrelative toxicity of different cadmium compounds is discussed throughout Chapter 2.\n\nThe health effects of cadmium and cadmium compounds have been extensively evaluated in human and \nanimal studies.  As discussed above, due to the vast amount of available data, studies were prioritized for \ninclusion in Chapter 2 based on criteria defined in Appendix B.  A total of 69 meta-analyses of human \ndata were included.  An additional 219 human studies and 192 animal studies meeting inclusion criteria \nwere identified.  Most of the human data involve evaluation of health effects associated with chronicduration exposure in occupational studies, community-based studies of populations living in cadmiumpolluted areas, or epidemiological studies in the general population.  For workers, the predominant \nexposure route is inhalation; however, some gastrointestinal tract exposure may also occur when dust is \nremoved from the lungs by mucociliary clearance and subsequently swallowed, or by ingestion of dust on \nhands, cigarettes, or food (Adamsson et al. 1979).  For the nonsmoking general population, dietary \nexposure to cadmium is the most likely route of exposure (Kim et al. 2018; Nordberg et al. 2018; Zhu et \nal. 2024a).  However, since cadmium is present in tobacco leaves, tobacco smoking can contribute \nsignificantly to cadmium exposure in general populations (Diamond and Klotzbach 2025; Ellis et al. \n1979; Friis et al. 1998).  Therefore, both occupational and general population studies are classified as \nmulti-route exposure in Figure 2-1.  In animal studies, most of the health effects data in animals come \nfrom oral exposure studies (Figure 2-1).\n\n---\n\nHuman studies are available for nearly every organ system, with the predominant focus on renal, cancer, \ndevelopmental, musculoskeletal, and cardiovascular endpoints.  Animal studies predominantly focused on \nrespiratory endpoints following inhalation exposure and examined a comprehensive set of endpoints \nfollowing oral exposure.  For oral studies, the most well-studied effects include body weight, developmental, \nand reproductive endpoints.  Data from dermal exposure are very limited.\n\nAs outlined in Chapter 1, the most sensitive effects following exposure to cadmium appear to be respiratory, \nrenal, and neurodevelopmental following inhalation exposure and renal, skeletal, and neurodevelopmental \nfollowing oral exposure.  A systematic review was conducted on the available human and animal studies for \nthese endpoints.  The information in these studies indicates the following on the potential targets of cadmium\ntoxicity:\n\n• **Respiratory Endpoints.**  Respiratory effects are a known effect of cadmium toxicity following \ninhalation exposure based on a low level of evidence in human occupational studies, a high level \nof evidence in laboratory animal inhalation studies, and other relevant data including a metaanalysis, occupational case reports, and a plausible mechanism of action.  In humans, \noccupational exposure has been associated with respiratory irritation and impaired respiratory \nfunction.  In animals, inhalation exposure is consistently associated with inflammatory changes in \nthe lung and upper and lower respiratory tract lesions with increasing concentration and duration \nin multiple species.\n\n• **Skeletal Endpoints.**  Adverse effects on the skeletal system (e.g., decreased bone density, \nstrength, and mineralization) are a known effect of cadmium toxicity based on a moderate level of \nevidence from human epidemiological studies, a high level of evidence from laboratory animals, \nand other relevant data including several meta-analyses, older studies and case reports of high \ndietary or occupational exposure, and plausible mechanisms of action.  In humans, cadmium \nexposure is associated with adverse bone effects, including fractures, osteoporosis, and decreased \nbone mineral density.  Bone effects associated with cadmium exposure were first described in \ncadmium-contaminated communities in Japan with high dietary intake; the disease called Itai-Itai \n(“ouch-ouch”) disease was characterized by multiple fractures of the long bones, osteomalacia, \nand osteoporosis.  Bone effects have been confirmed in animal studies following oral exposure; \nthese endpoints have not been assessed following inhalation exposure in animals.\n\n• **Renal Endpoints.** Renal effects are a known effect of cadmium toxicity based on a high level of \nevidence from human epidemiological studies, a moderate level of evidence in laboratory animal \ninhalation studies, and other relevant data including several meta-analyses and a well-defined \nmechanism of action. The kidney has been a well-established target of cadmium toxicity in \nhumans following occupational and dietary exposure for decades.  Several studies have \ndeveloped dose-response analyses of sensitive biomarkers of cadmium exposure and renal \ntoxicity (e.g., urinary cadmium levels and low molecular weight [LMW] proteinuria).  Data in \nanimals following inhalation exposure are inadequate.  While findings in multi-dose oral studies \nin animals meeting inclusion criteria are mixed, several studies reported alterations in biomarkers \nof renal functions (e.g., LMW proteinuria, serum blood urea nitrogen [BUN]) and \nhistopathological changes.\n\n---\n\n## 2. HEALTH EFFECTS\n\n• **Neurodevelopmental Endpoints.** Neurodevelopmental effects are a presumed effect in humans \nbased on a low level of evidence in humans and a high level of evidence in animals.  Available \nepidemiological data from general population studies are mixed.  A limited number of inhalation \nstudies and numerous oral studies in animals indicate that developmental cadmium exposure can \ncause alterations in sensorimotor function (including nerve conduction) and activity, \nsocioemotional behavior, and learning and memory in rodents; however, the timing and duration \nof exposure and assessment influence findings.  Available data indicate that neurodevelopmental \neffects are the most sensitive indicator of developmental toxicity of cadmium (occur at lower \nexposures than those associated with standard developmental outcomes or specialized evaluations \nof other systems, such as reproductive development).\n\n---\n\n**Figure 2-1.  Overview of the Number of Studies Examining Cadmium Health Effects***\n\n## Most studies examined the potential body weight, renal, and developmental effects of cadmium\n\nNumerous studies are available in both **humans** and **animals** (counts represent studies examining endpoint)\n\n| Category | Series 1 (unlabelled) (number of studies) | Series 2 (unlabelled) (number of studies) |\n| --- | --- | --- |\n| Death | 11 | 42 |\n| Body weight |  | 98 |\n| Respiratory | 15 | 29 |\n| Cardiovascular | 28 | 13 |\n| Gastrointestinal | 6 | 9 |\n| Hematological | 5 | 31 |\n| Musculoskeletal | 30 | 16 |\n| Hepatic | 21 | 23 |\n| Renal | 54 | 34 |\n| Dermal | 2 | 1 |\n| Ocular | 2 | 2 |\n| Endocrine | 19 | 15 |\n| Immunological | 14 | 26 |\n| Neurolgical | 12 | 12 |\n| Reproductive | 30 | 39 |\n| Developmental | 33 | 45 |\n| Other Noncancer | 4 | 4 |\n| Cancer | 34 | 10 |\n\n**Exposure Route**\n\n| Category | Share of studies (%) |\n| --- | --- |\n| Multi-route | 56 |\n| Oral | 30 |\n| Dermal | 1 |\n| Inhalation | 13 |\n\n**Exposure Duration**\n\n| Category | Share of studies (%) |\n| --- | --- |\n| Chronic | 60 |\n| Intermediate | 25 |\n| Acute | 15 |\n\n*Includes studies discussed in Chapter 2.  A total of 69 meta-analyses and 411 studies meeting inclusion criteria (including those finding no effect) have examined \ntoxicity; most studies examined multiple endpoints. Note: Meta-analyses are counted as a single data-point in the figure above because only the overall results of \nthe meta-analysis, not the individual studies included in the meta-analyses, were included in Chapter 2.\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| ACUTE EXPOSURE |  |  |  |  |  |  |  |  |  |\n| Beton et al. 1966 |  |  |  |  |  |  |  |  | Cadmium oxide fume |\n| 1 | Human 5 M | 5 hours (occup) | 8.63 | LE, CS | Death Resp |  |  | 8.63 | 1/5 exposed workers died Severe dyspnea, wheezing, chest pain and precordial constriction, persistent cough (lasting up to 7 days post-exposure); severe pulmonary edema and alveolar cell metaplasia in the worker that died |\n| Barrett et al. 1947 |  |  |  |  |  |  |  |  | Cadmium oxide fume |\n| 2 | Rat (NS) 10–25 NS | 10–15 minutes (WB) | 8.8, 13, 18, 19, 22, 25, 31, 41, 79.2, 110 | LE | Death |  |  | 30 | LC50 at 7 days |\n| Buckley and Bassett 1987 |  |  |  |  |  |  |  |  | Cadmium oxide dust |\n| 3 | Rat (Wistar) 20 M | 3 hours (WB) | 0, 0.4, 4.6 | BW | Bd wt | 0.4 | 4.6 |  | 15% decrease in body weight 7 days post-exposure |\n| Bus et al. 1978 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 4 | Rat (Sprague-Dawley) 18 M | 1 hour (WB) | 0, 6.5 | LE, BW, BI, OW, OF | Bd wt |  | 6.5 |  | 11% decrease in body weight 11 days post-exposure |\n|  |  |  |  |  | Resp |  | 6.5 |  | Decreased tidal volume and increased respiratory frequency 1 and 5 days post-exposure |\n| Rats were examined at 1, 5, and 11 days post-exposure (6/group/timepoint) |  |  |  |  |  |  |  |  |  |\n| Grose et al. 1987 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 5 | Rat (Sprague-Dawley) 40 M | 2 hours (H) | 0, 0.25, 0.48, 4.50 | LE, CS, BW | Bd wt | 0.25 |  | 4.5 | 20% decrease in body weight 72 hours post-exposure |\n\nRats were examined immediately and 72 hours post-exposure (20/group/timepoint)\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects | Cadmium oxide dust |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Grose et al. 1987 |  |  |  |  |  |  |  |  |  |  |\n| 6 | Rat (Sprague-Dawley) 40 M | 2 hours (H) | 0, 0.25, 0.44, 4.45 | LE, CS, BW | Bd wt | 4.45 |  |  |  |  |\n| Rats were examined immediately and 72 hours post-exposure (20/group/timepoint) |  |  |  |  |  |  |  |  |  |  |\n| Hart 1986 |  |  |  |  |  |  |  |  |  |  |\n| 7 | Rat (Lewis) 3 M | 1 or 2 weeks 5 days/week 3 hours/day (N) | 0, 1.6 | BI, OW, HP | Resp |  | 1.6 |  |  | Cadmium acetate Increase in BALF cellularity (macrophages, PMNs, lymphocytes) and markers of cytotoxicity (LDH, ALP, AP, total protein) |\n| Jacobo-Estrada et al. 2016 |  |  |  |  |  |  |  |  |  |  |\n| 8 | Rat (Wistar) 6 F | 13 days GDs 8–20 2 hours/day (WB) | 0, 17.43 | BW, OW, DX | Bd wt Repro Develop | 17.43 | 17.43 | 17.43 |  | Cadmium chloride Decreased absolute placental weight Fetal kidney injury (decreased fetal plasma creatinine levels, increased total histopathological lesion score in fetal kidney); decreased fetal body weight (8%) |\n| NTP 1995 |  |  |  |  |  |  |  |  |  |  |\n| 9 | Rat (Fischer-344) 5 M, 5 F | 2 weeks 5 days/week 6.2 hours/day (WB) | 0, 0.081, 0.249, 0.844, 2.49, 8.60 | LE, CS, BW, OW, HP | Death Bd wt Resp | 2.49 | 0.081 | 8.6 |  | Cadmium oxide aerosol 100% mortality by day 6 |\n|  |  |  |  |  | Cardio | 2.49 |  |  |  | SLOAEL: Marked necrosis of alveolar ducts LOAEL: Minimal-to-mild alveolar histiocytic infiltrate and focal inflammation in alveolar septa |\n|  |  |  |  |  | Hepatic | 2.49 |  |  |  |  |\n|  |  |  |  |  | Renal | 2.49 |  |  |  |  |\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects | Cadmium chloride |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Palmer et al. 1986 |  |  |  |  |  |  |  |  |  |  |\n| 10 | Rat (Sprague-Dawley) 20–30 M | 2 hours (WB) | 0, 6.0 | BW, BC, BI, OW | Bd wt | 6 |  |  |  |  |\n| 10 | Rat (Sprague-Dawley) 20–30 M | 2 hours (WB) | 0, 6.0 | BW, BC, BI, OW | Resp |  | 6 |  |  | Increased BALF cellularity (primarily macrophages) 3 days post-exposure |\n| 10 | Rat (Sprague-Dawley) 20–30 M | 2 hours (WB) | 0, 6.0 | BW, BC, BI, OW | Endocr | 6 |  |  |  |  |\n| Rats were sacrificed |  | 1, 3, 7, or 10 days post-exposure (≥4/group/timepoint) |  |  |  |  |  |  |  |  |\n| Rusch et al. 1986 |  |  |  |  |  |  |  |  |  | Cadmium carbonate |\n| 11 | Rat (Sprague-Dawley) 26 M, 26 F | 2 hours (WB) | 0, 94 | LE, CS, GN | Resp |  |  | 94 |  | Rales persisting up to 4 hours post-exposure |\n| Rats were sacrificed immediately or 1, 3, 7, or 30 days post-exposure (10/group/timepoint); extra two rats were replacement animals |  |  |  |  |  |  |  |  |  |  |\n| Rusch et al. 1986 |  |  |  |  |  |  |  |  |  | Cadmium sulfide |\n| 12 | Rat (Sprague-Dawley) 26 M, 26 F | 2 hours (WB) | 0, 140 | LE, CS, BW | Bd wt | 140 |  |  |  |  |\n| Rats were sacrificed immediately or 1, 3, 7, or 30 days post-exposure (10/group/timepoint); extra two rats were replacement animals |  |  |  |  |  |  |  |  |  |  |\n| Rusch et al. 1986 |  |  |  |  |  |  |  |  |  | Cadmium selenide |\n| 13 | Rat (Sprague-Dawley) 26 M, 26 F | 2 hours (WB) | 0, 105 | LE, CS, BW | Bd wt | 105 |  |  |  |  |\n| Rats were sacrificed immediately or 1, 3, 7, or 30 days post-exposure (10/group/timepoint); extra two rats were replacement animals |  |  |  |  |  |  |  |  |  |  |\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Rusch et al. 1986 |  |  |  |  |  |  |  |  | Cadmium acetate |\n| 14 | Rat (Sprague-Dawley) 26 M, 26 F | 2 hours (WB) | 0, 83 | LE, CS | Death |  |  | 83 | 25/32 died between 1 and 7 days post-exposure |\n| 14 | Rat (Sprague-Dawley) 26 M, 26 F | 2 hours (WB) | 0, 83 | LE, CS | Resp |  |  | 83 | Labored breathing and rales persisting up to 4 hours post-exposure |\n| 14 | Rat (Sprague-Dawley) 26 M, 26 F | 2 hours (WB) | 0, 83 | LE, CS | Neuro |  | 83 |  | Reduced activity during exposure |\n| Rats were sacrificed immediately or 1, 3, 7, or 30 days post-exposure (10/group/timepoint); extra two rats were replacement animals |  |  |  |  |  |  |  |  |  |\n| Snider et al. 1973 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 15 | Rat (Sprague-Dawley) 18 M | 3 days 1 hour/day (WB) | 61 | LE, GN | Death |  |  | 61 | 17/18 died within 3 days |\n| 15 | Rat (Sprague-Dawley) 18 M | 3 days 1 hour/day (WB) | 61 | LE, GN | Resp |  |  | 61 | Pulmonary hemorrhage |\n| Barrett et al. 1947 |  |  |  |  |  |  |  |  | Cadmium oxide fume |\n| 16 | Mouse (NS) 10 NS | 15 minutes (WB) | 39, 61.3, 65.9 | LE | Death |  |  | 39 | 9/10 died within 7 days |\n| Graham et al. 1978 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 17 | Mouse (CD-1) 16–20 F | 2 hours (WB) | 0, 0.110, 0.190 | IX | Immuno | 0.11 | 0.19 |  | Decreased humoral immune response |\n| Krzystyniak et al. 1987 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 18 | Mouse (C57BL/6) 4–5 F | 60 minutes (N) | 0, 0.88 | IX | Immuno |  | 0.88 |  | Reduced humoral and cell-mediated immune responses |\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| NTP 1995 |  |  |  |  |  |  |  |  | Cadmium oxide aerosol |\n| 19 | Mouse (B6C3F1) 5 M, 5 F | 2 weeks 5 days/week 6.2 hours/day (WB) | 0, 0.081, 0.249, 0.844, 2.49, 8.60 | LE, CS, BW, OW, HP | Death Bd wt Resp | 2.49 | 0.081 | 8.6 | 100% mortality by day 7 |\n| 19 | Mouse (B6C3F1) 5 M, 5 F | 2 weeks 5 days/week 6.2 hours/day (WB) | 0, 0.081, 0.249, 0.844, 2.49, 8.60 | LE, CS, BW, OW, HP | Cardio Hepatic Renal | 2.49 2.49 2.49 | 0.081 | 0.844 | LOAEL: Minimal-to-mild alveolar histiocytic infiltrates SLOAEL: Fibrosis, inflammation, and mild necrosis of the alveolar ducts; degeneration of the nasal olfactory epithelium |\n| NTP 1995 |  |  |  |  |  |  |  |  | Cadmium oxide aerosol |\n| 20 | Mouse (Swiss) 33 F | 14 days GDs 4–17 6.27 hours/day (WB) | 0, 0.04, 0.4, 1.7 | LE, CS, BW, OW, DX | Bd wt Develop | 0.4 | 0.04 | 1.7 | 22% decrease in maternal body weight on GD 18 Increased total litter resorption; decreased fetal body weight (29–30%); reduced ossification of sternebrae Decreased male (9%) and female (8%) fetal body weight |\n| Friberg 1950 |  |  |  |  |  |  |  |  | Cadmium metal dust |\n| 21 | Rabbit (NS) 8 NS | 4 hours (H) | 11.5 - 48.4 | LE | Death |  |  | 28.4 | LC50 at 14 days |\n| Henderson et al. 1979 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 22 | Hamster (Golden Syrian) 30 B | 30 minutes (N) | 0, 1.1, 10.1 | LE, BI, HP | Resp |  | 1.1 | 10.1 | LOAEL: Increased BALF PMN and AP levels SLOAEL: Necrosis of bronchiolar epithelium 1 day post-exposure; severe pneumonitis 7 days post-exposure |\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| INTERMEDIATE EXPOSURE |  |  |  |  |  |  |  |  |  |\n| Baranski 1984 |  |  |  |  |  |  |  |  | Cadmium oxide aerosol |\n| 23 | Rat (Wistar) 7–15 F | 6-7 months (5 months premating, up to 3 weeks mating, GDs 1–20) 5 hours/day 5 days/week (WB) | 0, 0.02, 0.16 | RX, DX | Repro Develop | 0.16 | 0.02 | 0.16 | LOAEL: Age- and sex-dependent changes in offspring motor activity; impaired avoidance acquisition in 3- and 7-month-old females SLOAEL: 25% mortality by PND 4 (decreased viability index); 15% decrease in weanling body weight |\n| Baranski 1985 |  |  |  |  |  |  |  |  | Cadmium oxide dust |\n| 24 | Rat (Wistar) 5–16 F | 5–7 months (4–5 months premating, mating, GDs 1–20) 5 days/week 5 hours/day (WB) | 0, 0.02, 0.16, 1.0 | LE, BW, RX, DX | Death Bd wt Repro Develop | 1 1 | 0.02 | 1 | 55.1% mortality |\n| Baranski and Sitarek 1987 |  |  |  |  |  |  |  |  | LOAEL: Decreased motor activity in 3-month-old males and decreased conditioned reflexes in 5-month-old females SLOAEL: 23% decrease in pup viability index; unspecified decrease in pup weight during first 2 months |\n| 25 | Rat (Wistar) 13–14 F | 20 weeks 5 days/week 5 hours/day (WB) | 0, 0.02, 0.16, 1.0 | LE, CS, BW, RX | Death Bd wt Repro | 0.16 | 0.02 | 1 | Cadmium oxide dust 38% mortality by week 13; 100% mortality by week 20 30–50% decrease in body weight gain starting at week 4 Increased duration of estrous cycle |\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Glaser et al. 1986 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 26 | Rat (Wistar) 12 M | 30 days 7 days/week 22 hours/day (WB) | 0, 0.105 | LE, CS, BW, HE, BC, BI, UR | Bd wt Resp | 0.105 | 0.105 |  | Increase in BALF cellularity (PMNs, macrophages, leukocytes) and markers of cytotoxicity (LDH, total protein levels); macrophages, total protein and LDH remained elevated at 2-months post-exposure |\n| 26 | Rat (Wistar) 12 M | 30 days 7 days/week 22 hours/day (WB) | 0, 0.105 | LE, CS, BW, HE, BC, BI, UR | Hemato | 0.105 | 0.105 |  | Increased WBC counts at terminal sacrifice |\n| 26 | Rat (Wistar) 12 M | 30 days 7 days/week 22 hours/day (WB) | 0, 0.105 | LE, CS, BW, HE, BC, BI, UR | Renal | 0.105 |  |  |  |\n| Rats were sacrificed immediately following exposure (terminal sacrifice) or 2 months post-exposure (6/group/timepoint) |  |  |  |  |  |  |  |  |  |\n| Glaser et al. 1986 |  |  |  |  |  |  |  |  | Cadmium sulfide |\n| 27 | Rat (Wistar) 12 M | 30 days 7 days/week 22 hours/day (WB) | 0, 1.034 | LE, CS, BW, HE, BC, BI, OW | Bd wt Resp | 1.034 | 1.034 |  | Increase in BALF cellularity (PMNs, macrophages, leukocytes) and markers of cytotoxicity (LDH, total protein levels); macrophages, total protein and LDH remained elevated at 2-months post-exposure |\n| 27 | Rat (Wistar) 12 M | 30 days 7 days/week 22 hours/day (WB) | 0, 1.034 | LE, CS, BW, HE, BC, BI, OW | Hemato | 1.034 |  |  |  |\n| 27 | Rat (Wistar) 12 M | 30 days 7 days/week 22 hours/day (WB) | 0, 1.034 | LE, CS, BW, HE, BC, BI, OW | Renal | 1.034 |  |  |  |\n| Rats were sacrificed immediately following exposure (terminal sacrifice) or 2 months post-exposure (6/group/timepoint) |  |  |  |  |  |  |  |  |  |\n| Glaser et al. 1986 |  |  |  |  |  |  |  |  | Cadmium oxide dust |\n| 28 | Rat (Wistar) 12 M | 30 days 7 days/week 22 hours/day (WB) | 0, 0.098 | LE, CS, BW, HE, BC, BI, OW | Bd wt Resp | 0.098 | 0.098 |  | Increase in BALF cellularity (PMNs, macrophages, leukocytes) and markers of cytotoxicity (LDH, total protein levels); total protein remained elevated at 2-months post-exposure |\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n|  |  |  |  |  | Hemato |  | 0.098 |  | Increased WBC count at terminal sacrifice |\n|  |  |  |  |  | Renal | 0.098 |  |  |  |\n\n| Rats were sacrificed immediately following exposure (terminal sacrifice) or 2 months post-exposure (6/group/timepoint) |  |  |  |  |  |  |  |  |  |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Hart 1986 |  |  |  |  |  |  |  | Cadmium acetate |  |\n| 29 | Rat (Lewis) 3 M | 3–6 weeks 5 days/week 3 hours/day (N) | 0, 1.6 | BI, OW, HP | Resp |  | 1.6 |  | Transient increase in BALF cellularity (macrophages, PMNs, lymphocytes) and markers of cytotoxicity (LDH, ALP, AP, total protein); resolving weeks 4–6 |\n| Kutzman et al. 1986 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 30 | Rat (Fischer 344) 20 M | 62 days 5 days/week 6 hours/day (WB) | 0, 0.33, 1.06, 2.13 | LE, CS, BW, BI, OW, HP | Death |  |  | 2.13 | 100% mortality by day 45 |\n| 30 | Rat (Fischer 344) 20 M | 62 days 5 days/week 6 hours/day (WB) | 0, 0.33, 1.06, 2.13 | LE, CS, BW, BI, OW, HP | Bd wt | 0.33 |  | 1.06 | 27% decrease in body weight |\n| Kutzman et al. 1986 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 31 | Rat (Fischer 344) 8 M, 8 F | 62 days 5 days/week 6 hours/day (WB) | 0, 0.33, 1.06, 2.13 | LE, BW, RX | Death |  |  | 2.13 | 100% mortality by day 45 |\n| 31 | Rat (Fischer 344) 8 M, 8 F | 62 days 5 days/week 6 hours/day (WB) | 0, 0.33, 1.06, 2.13 | LE, BW, RX | Bd wt | 0.33 | 1.03 | 2.13 | LOAEL: 14% decreased in body weight SLOAEL: Body weight loss (decreased 40% compared to starting body weight) |\n| Repro |  |  |  |  |  | 1.06 M |  |  |  |\n| Exposed rats were mated with both exposed and unexposed rats 6 days post-exposure |  |  |  |  |  |  |  |  |  |\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| NTP 1995 |  |  |  |  |  |  |  |  | Cadmium oxide aerosol |\n| 32 | Rat (Fischer-344) 10 M, 10 F | 13 weeks 5 days/week 6.33 hours/day (WB) | 0, 0.021, 0.046, 0.088, 0.212, 0.902 | LE, CS, BW, HE, BC, UR, OW, HP, OF, RX | Bd wt Resp | 0.902 | 0.021 F | 0.902 M | Minimal epithelial degeneration in the larynx LOAEL: Minimal alveolar histiocytic infiltrate and epithelial hyperplasia; minimal epithelial degeneration in the larynx SLOAEL: Marked inflammation and moderate fibrosis in interstitium around alveolar ducts and terminal bronchioles |\n| 32 | Rat (Fischer-344) 10 M, 10 F | 13 weeks 5 days/week 6.33 hours/day (WB) | 0, 0.021, 0.046, 0.088, 0.212, 0.902 | LE, CS, BW, HE, BC, UR, OW, HP, OF, RX | Cardio Gastro Hemato Musc/skel Hepatic Renal Endocr Immuno Neuro Repro | 0.902 0.902 0.902 0.902 0.902 0.902 0.902 | 0.021 M | 0.046 M | Minimal epithelial degeneration in the larynx LOAEL: Minimal alveolar histiocytic infiltrate and epithelial hyperplasia; minimal epithelial degeneration in the larynx SLOAEL: Marked inflammation and moderate fibrosis in interstitium around alveolar ducts and terminal bronchioles |\n| NTP 1995 |  |  |  |  |  |  |  |  | Decreased spermatid counts in males, increased estrous cycle length in females |\n| 33 | Rat (Sprague-Dawley) 32 F | 16 days GDs 4–19 6.27 hours/day (WB) | 0, 0.04, 0.4, 1.7 | LE, CS, BW,OW, DX | Bd wt | 0.4 | 1.7 | Cadmium oxide aerosol | 14% decrease in maternal body weight on GD 20 Decreased male (16%) and female (17%) fetal body weight; reduced ossification of pelvis and sternebrae |\n| 33 | Rat (Sprague-Dawley) 32 F | 16 days GDs 4–19 6.27 hours/day (WB) | 0, 0.04, 0.4, 1.7 | LE, CS, BW,OW, DX | Develop | 0.4 |  | 1.7 | 14% decrease in maternal body weight on GD 20 Decreased male (16%) and female (17%) fetal body weight; reduced ossification of pelvis and sternebrae |\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects | Cadmium chloride |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Oberdörster et al. 1994 |  |  |  |  |  |  |  |  |  |  |\n| 34 | Rat (Fischer 344) 48 M | 4 weeks 5 days/week 6 hours/day (WB) | 0, 0.100 | BI | Resp |  | 0.1 |  | Increase in BALF PMNs (1 day post-exposure) |  |\n\n| Rats were sacrificed at 1, 7, or 28 days post-exposure (≥4/group/timepoint per endpoint) |  |  |  |  |  |  |  |\n| --- | --- | --- | --- | --- | --- | --- | --- |\n| Oldiges and Glaser 1986 |  |  |  |  |  |  | Cadmium oxide dust |\n| 35 | Rat (Wistar) 20 M, 20 F | 218–343 days 7 days/week 22 hours/day (WB) | M: 0, 0.030, 0.090 F: 0, 0.026, 0.081 | LE, GN, BW, Death FI, WI, HE, OW |  | 0.081 F 0.09 M | 6/20 died 6/20 died |\n| Oldiges and Glaser 1986 |  |  |  |  |  |  | Cadmium sulfide |\n| 36 | Rat (Wistar) 20–24 M, 20–24 F | 105–298 days 7 days/week 22 hours/day (WB) | M: 0, 0.843, 2.270 F: 0, 0.841, 2.247 | LE, GN, BW, Death FI, WI, HE, OW |  | 0.841 F 0.843 M | 7/20 died by day 298 6/20 died by day 208 |\n| Oldiges et al. 1989 |  |  |  |  |  |  | Cadmium chloride |\n| 37 | Rat (Wistar) 20 M, 18–20 F | 6 months 7 days/week 22 hours/day (WB) | 0, 0.090 | LE, GN, HP Death Cancer |  | 0.09 0.09 M | 25% mortality at 6 months CEL: Lung tumors (bronchioalveolar adenoma, adenocarcinoma, or squamous cell carcinoma) |\n| Scheduled sacrifice at 31 months; surviving Cd-exposed rats sacrificed at 29–30 months due to mortality ≥75% |  |  |  |  |  |  |  |\n| Oldiges et al. 1989 |  |  |  |  |  |  | Cadmium sulfide |\n| 38 | Rat (Wistar) 20 M, 20 F | 6 months 40 hours/week (WB) | 0, 0.270 | LE, GN, HP Death |  | 0.27 | 75% mortality at 27–29 months |\n| Scheduled sacrifice at 31 months; surviving Cd-exposed rats sacrificed at 27–29 months due to mortality ≥75% |  |  |  |  |  |  |  |\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Oldiges et al. 1989 |  |  |  |  |  |  |  |  | Cadmium sulfide |\n| 39 | Rat (Wistar) 16–20 M, 19–20 F | 3–10 months 7 days/week 22 hours/day (WB) | 0, 0.810, 2.430 | LE, GN, HP | Death Cancer |  |  | 0.81 | 25% mortality at 7–10 months CEL: Lung tumors (bronchioalveolar adenoma, adenocarcinoma, squamous cell carcinoma, or mixed tumor type) |\n\nScheduled sacrifice at 31 months; most surviving Cd-exposed rats sacrificed at 29-30 months due to mortality ≥75%\n\n| Oldiges et al. 1989 |  |  |  |  |  |  |  | Cadmium oxide dust |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| 40 | Rat (Wistar) 17–20 M, 16–20 F | 7–11 months 7 days/week 22 hours/day (WB) | 0, 0.090 | LE, GN, HP | Death Cancer | 0.09 | 0.09 | 25% mortality at 7–11 months CEL: Lung tumors (bronchioalveolar adenoma, adenocarcinoma, squamous cell carcinoma, or mixed tumor type) |\n\n| Scheduled sacrifice at 31 months |  |  |  |  |  |  |  |  |  |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Prigge 1978a |  |  |  |  |  |  |  | Cadmium oxide dust |  |\n| 41 | Rat (Wistar) 12 F | 90 days 24 hours/day (WB) | 0, 0.025, 0.052 | LE, BW, HE, BC, UR, OW, HP | Bd wt Resp | 0.025 | 0.025 | 0.052 | 23% decrease in body weight gain Proliferative lung lesions, histiocytic cell granulomas Increased hemoglobin and hematocrit |\n| 41 | Rat (Wistar) 12 F | 90 days 24 hours/day (WB) | 0, 0.025, 0.052 | LE, BW, HE, BC, UR, OW, HP | Hematoc | 0.025 | 0.052 | 0.052 | 23% decrease in body weight gain Proliferative lung lesions, histiocytic cell granulomas Increased hemoglobin and hematocrit |\n| 41 | Rat (Wistar) 12 F | 90 days 24 hours/day (WB) | 0, 0.025, 0.052 | LE, BW, HE, BC, UR, OW, HP | Hepatic Renal | 0.052 | 0.052 | 0.052 | 23% decrease in body weight gain Proliferative lung lesions, histiocytic cell granulomas Increased hemoglobin and hematocrit |\n\n| Prigge 1978a |  |  |  |  |  |  |  | Cadmium oxide dust |  |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| 42 | Rat (Wistar) 12 F | 63 days 24 hours/day (WB) | 0, 0.105 | LE, BW, HE, BC, UR | Death |  |  | 0.105 | 5/12 died |\n| 42 | Rat (Wistar) 12 F | 63 days 24 hours/day (WB) | 0, 0.105 | LE, BW, HE, BC, UR | Bd wt Hematoc |  |  | 0.105 | 51% decrease in body weight gain Increased hemoglobin and hematocrit |\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Prigge 1978b |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 43 | Rat (Wistar) 12–13 F | 21 days 24 hours/day (WB) | 0, 0.204, 0.394, 0.581 | BW, HE, BC, UR, OW, HP | Bd wt Hemato | 0.581 | 0.204 |  | Increase in hemoglobin and hematocrit |\n|  |  |  |  |  | Renal | 0.581 |  |  |  |\n| Prigge 1978b |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 44 | Rat (Wistar) 12–13 F | 21 days GDs 1–21 24 hours/day (WB) | 0, 0.204, 0.394, 0.581 | BW, HE, BC, UR, OW, HP, DX | Bd wt |  | 0.204 | 0.394 | LOAEL: 12% decrease in maternal body weight gain SLOAEL: 35% decrease in maternal body weight gain Increased hemoglobin and hematocrit; elevated total (but not direct) bilirubin |\n|  |  |  |  |  | Hemato | 0.394 | 0.581 |  |  |\n|  |  |  |  |  | Renal | 0.581 |  |  |  |\n|  |  |  |  |  | Develop | 0.394 |  | 0.581 | 19% decrease in fetal body weight; decreased fetal hemoglobin |\n| NTP 1995 |  |  |  |  |  |  |  |  | Cadmium oxide aerosol |\n| 45 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week 6.33 hours/day (WB) | 0, 0.021, 0.046, 0.088, 0.211, 0.910 | LE, CS, BW, OW, HP, RX | Bd wt Resp | 0.91 | 0.021 |  | Minimal alveolar histiocytic infiltrates and squamous metaplasia of the larynx |\n|  |  |  |  |  | Cardio | 0.91 |  |  |  |\n|  |  |  |  |  | Gastro | 0.91 |  |  |  |\n|  |  |  |  |  | Musc/skel | 0.91 |  |  |  |\n|  |  |  |  |  | Hepatic | 0.91 |  |  |  |\n|  |  |  |  |  | Renal | 0.91 |  |  |  |\n|  |  |  |  |  | Endocr | 0.91 |  |  |  |\n|  |  |  |  |  | Immuno | 0.91 |  |  |  |\n|  |  |  |  |  | Neuro | 0.91 |  |  |  |\n|  |  |  |  |  | Repro | 0.91 |  |  |  |\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Oberdörster et al. 1994 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 46 | Mouse (BALB/c) 72 M | 4 weeks 5 days/week 6 hours/day (WB) | 0, 0.100 | BI | Resp |  | 0.1 |  | Increase in BALF PMNs and LDH levels (1, 7, and 28 days post-exposure); increase cell proliferation in alveolar epithelium and macrophage infiltration (1 and 7 days post-exposure) |\n| Mice were sacrificed at 1, 7, or 28 days post-exposure (≥4/group/timepoint per endpoint) |  |  |  |  |  |  |  |  |  |\n| Johansson et al. 1984 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 47 | Rabbit (NS) 8 M | 4–6 weeks 5 days/week 6 hours/day (WB) | 0, 0.4 | BI, OW, HP | Resp |  | 0.4 |  | Lung interstitial inflammation, type 2 cell hyperplasia |\n| CHRONIC EXPOSURE |  |  |  |  |  |  |  |  |  |\n| Buchet et al. 1990; Hoo et al. 2004; Järup and Elinder 1994; Järup et al. 2000; Kobayashi et al. 2008; Lei et al. 2007; Shao et al. 2007; Suwazono et al. 2006; Uno et al. 2005; Wu et al. 2001; Zhang et al. 2016a |  |  |  |  |  |  |  |  | Cadmium |\n| 48 | Human 85–3,454 per dataset | 17 datasets (3 occupational and 8 general population cohorts) | UR | Renal |  |  |  | LMW proteinuria; 95% LCL weighted median of 17 UC10 values = 0.00106 mg Cd/m3 c |  |\n| Oldiges and Glaser 1986 |  |  |  |  |  |  |  |  | Cadmium sulfate |\n| 49 | Rat (Wistar) 20–40 M, 20 F | 413–455 days 7 days/week 22 hours/day (WB) | M: 0, 0.095 F: 0, 0.092 | LE, BW, FI, WI, HE, OW, GN | Death |  |  | 0.095 M | 6/20 died |\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Oldiges et al. 1989 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 50 | Rat (Wistar) 20 M, 18–20 F | 18 months 7 days/week 22 hours/day (WB) | 0, 0.030 | LE, GN, HP | Death Cancer |  |  | 0.03 M 0.03 | 75% mortality at 30 months CEL: Lung tumors (bronchioalveolar adenoma, adenocarcinoma, squamous cell carcinoma, or mixed tumor type) |\n| Scheduled sacrifice at 31 months; surviving Cd-exposed males sacrificed at 30 months due to mortality ≥75% |  |  |  |  |  |  |  |  |  |\n| Oldiges et al. 1989 |  |  |  |  |  |  |  |  | Cadmium sulfide |\n| 51 | Rat (Wistar) 19–20 M, 19–20 F | 16–18 months 7 days/week 22 hours/day (WB) | 0, 0.090, 0.270 | LE, GN, HP | Death Cancer |  |  | 0.09 0.270 | 75% mortality at 30 months in males 25% mortality at 16 months in females CEL: Lung tumors (bronchioalveolar adenoma, adenocarcinoma, squamous cell carcinoma, or mixed tumor type) |\n| Scheduled sacrifice at 31 months; surviving Cd-exposed rats sacrificed at 30 months due to mortality ≥75% |  |  |  |  |  |  |  |  |  |\n| Oldiges et al. 1989 |  |  |  |  |  |  |  |  | Cadmium oxide dust |\n| 52 | Rat (Wistar) 20 M, 20 F | 18 months 7 days/week 22 hours/day (WB) | 0, 0.030 | LE, GN, HP | Cancer |  |  | 0.03 | CEL: Lung tumors (bronchioalveolar adenoma, adenocarcinoma, squamous cell carcinoma, or mixed tumor type) |\n| Scheduled sacrifice at 31 months |  |  |  |  |  |  |  |  |  |\n| Oldiges et al. 1989 |  |  |  |  |  |  |  |  | Cadmium sulfate |\n| 53 | Rat (Wistar) 20 M, 20 F | 14–18 months 7 days/week 22 hours/day (WB) | 0, 0.09 | LE, GN, HP | Death Cancer |  |  | 0.09 | 25% mortality in males by 14 months; 75% mortality in females by 29 months CEL: Lung tumors (bronchioalveolar adenoma, adenocarcinoma, squamous cell carcinoma, or mixed tumor type) |\n\nScheduled sacrifice at 31 months; surviving Cd-exposed females sacrificed at 29 months due to mortality ≥75%\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Oldiges et al. 1989 |  |  |  |  |  |  |  |  | Cadmium oxide fume |\n| 54 | Rat (Wistar) 17–20 M | 18 months 7 days/week 22 hours/day (WB) | 0, 0.01, 0.03 | LE, GN, HP | Cancer |  |  | 0.03 | CEL: Lung tumors (bronchioalveolar adenoma, adenocarcinoma) |\n| Takenaka et al. 1983 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 55 | Rat (Wistar) 40–41 M | 18 months 7 days/week 23 hours/day (WB) | 0, 0.0134, 0.0257, 0.0508 | LE, BW, HP | Bd wt Cancer | 0.0508 |  | 0.0134 | CEL: Lung tumors (lung epidermoid carcinomas, or adenocarcinomas) |\n| Scheduled sacrifice at 31 months |  |  |  |  |  |  |  |  |  |\n\n<sup>a</sup>The number corresponds to entries in Figure 2-2; differences in levels of health effects between male and females are not indicated in Figure 2-2.  Where such \ndifferences exist, only the levels of effect for the most sensitive sex are presented.\n\n<sup>b</sup>Concentrations are expressed as mg Cd/m<sup>3</sup>. If concentrations were reported by the study authors in terms of the administered compound (e.g., cadmium chloride \n[CdCl2]), they were converted to the equivalent concentration in terms of the metal (i.e., cadmium [Cd])) for easy comparison across studies.  Conversion was based on \nthe ratio of the molecular weights using the following equation: Concentration in terms of administered compound x (molecular weight Cd/molecular weight administered \ncompound).\n\n<sup>c</sup>Used to derive a chronic-duration inhalation MRL of 0.0001 mg Cd/m<sup>3</sup> (0.1 μg Cd/m<sup>3</sup>).  The point of departure (POD) is based on the 95% lower confidence limit (LCL) \non the weighted median of the UC10 values from 17 datasets from 11 human studies; the weighted median and 95% LCL were 2.04 and 1.57 μg Cd/g Cr, respectively.  \nThese values were converted into inhalation concentration equivalents of 0.00141 and 0.00106 mg Cd/m<sup>3</sup>, respectively, using PBPK modeling.  The POD of 0.00106 mg \nCd/m<sup>3</sup> was divided by an uncertainty factor of 3 for human variability and a modifying factor of 3 for database deficiencies.  See Appendix A for more detailed information \nregarding the MRL.\n\n## Principal studies for the MRL\n\nALP = alkaline phosphatase; AP = acid phosphatase; BALF = bronchoalveolar lavage fluid; BC = serum (blood) chemistry; Bd wt or BW = body weight; BI = biochemical \nchanges; Cardio = cardiovascular; Cd = cadmium; CEL = cancer effect level; Cr = creatinine; CS = clinical signs; Develop = developmental; DX = developmental toxicity; \nEndocr = endocrine; F = female(s); FI = food intake; Gastro = gastrointestinal; GD = gestation day; GN = gross necropsy; (H) = head only; HE = hematology; \nHemato = hematological; HP = histopathology; Immuno = immunological; IX = immune function; LC50 = lethal concentration, 50% kill; LDH = lactate dehydrogenase; \nLE = lethality; LMW = low molecular weight; LOAEL = lowest-observed-adverse-effect level; M = male(s); MRL = Minimal Risk Level; Musc/skel = musculoskeletal; \n(N) = nose-only; Neuro = neurological; NOAEL = no-observed-adverse-effect level; NS = not specified; (occup) = occupational; OF = organ function; OW = organ weight; \nPMN = polymorphonuclear leukocyte; PND = postnatal day; Repro = reproductive; Resp = respiratory; RX = reproductive function; SLOAEL = serious lowest-observedadverse-effect level; UC10 = urinary cadmium level associated with 10% extra risk; UR = urinalysis; (WB) = whole body; WBC = white blood cell; WI = water intake\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Cadmium – Inhalation**\nAcute (≤14 days)\n\n**Figure 2-2. Levels of Significant Exposure to Cadmium – Inhalation, Acute (≤14 days) - Death**\n\n| Category | mg Cd/m3 |\n| --- | --- |\n| 1 | 9 |\n| 2R | 30 |\n| 9R | 9 |\n| 14R | 85 |\n| 15R | 65 |\n| 16M | 40 |\n| 19M | 9 |\n| 21H | 30 |\n\n**Figure 2-2. Levels of Significant Exposure to Cadmium – Inhalation, Acute (≤14 days) - Body Weight**\n\n| Category | Animal - NOAEL (mg Cd/m3) | Animal - LOAEL (mg Cd/m3) | Animal - SLOAEL (mg Cd/m3) |\n| --- | --- | --- | --- |\n| 3R | 0.4 | 4.5 |  |\n| 4R |  | 6.5 |  |\n| 5R | 0.23 | 4.5 |  |\n| 6R | 4.0 |  |  |\n| 8R | 17 |  |  |\n| 9R | 2.5 |  |  |\n| 10R | 6.0 |  |  |\n| 12R | 140 |  |  |\n| 13R | 110 |  |  |\n| 19M | 2.5 |  |  |\n| 20M | 0.4 | 1.7 |  |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Cadmium – Inhalation**\nAcute (≤14 days)\n\n| Category | Human - SLOAEL (mg Cd/m3) | Animal - NOAEL (mg Cd/m3) | Animal - LOAEL (mg Cd/m3) | Animal - SLOAEL (mg Cd/m3) |\n| --- | --- | --- | --- | --- |\n| 1 | 9 |  |  |  |\n| 4R |  | 6 |  |  |\n| 7R |  | 1.6 |  |  |\n| 9R |  | 0.08 |  | 9 |\n| 10R |  | 6 |  |  |\n| 11R |  |  |  | 100 |\n| 14R |  |  |  | 85 |\n| 15R |  |  |  | 65 |\n| 19M |  | 0.008 |  | 0.8 |\n| 22S |  | 1.1 |  | 10 |\n| 9R |  | 2.5 |  |  |\n| 19M |  | 2.7 |  |  |\n| 9R |  | 2.7 |  |  |\n| 19M |  | 2.7 |  |  |\n| 9R |  | 2.7 |  |  |\n| 19M |  | 2.7 |  |  |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Cadmium – Inhalation**\nAcute (≤14 days)\n\n**Figure 2-2. Levels of Significant Exposure to Cadmium – Inhalation (Acute ≤14 days)**\n\n| Category | Human - SLOAEL (mg Cd/m3) | Animal - NOAEL (mg Cd/m3) | Animal - SLOAEL (mg Cd/m3) | Animal - LOAEL (mg Cd/m3) | Animal - LD50/LC50 (mg Cd/m3) |\n| --- | --- | --- | --- | --- | --- |\n| Endocrine |  | 6 |  |  |  |\n| Immunological |  | 0.12 |  | 0.2 | 1.0 |\n| Neurolgical |  |  |  | 90 |  |\n| Reproductive |  |  |  | 17 |  |\n| Developmental |  | 0.045 | 1.7 | 0.35 |  |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Cadmium – Inhalation**\nIntermediate (15–364 days)\n\n**Figure 2-2. Levels of Significant Exposure to Cadmium – Inhalation Intermediate (15–364 days)**\n\n| Category | Death NOAEL (mg Cd/m3) | Death LOAEL (mg Cd/m3) | Body Weight NOAEL (mg Cd/m3) | Body Weight LOAEL (mg Cd/m3) |\n| --- | --- | --- | --- | --- |\n| 24R |  | 1.0 | 1.0 |  |\n| 25R |  | 1.0 | 0.17 | 1.0 |\n| 30R |  | 2.6 | 0.40 | 1.1 |\n| 31R |  | 2.6 | 0.40 | 1.1 |\n| 35R |  | 0.080 |  |  |\n| 36R |  | 0.80 |  |  |\n| 37R |  | 0.090 |  |  |\n| 38R |  | 0.33 |  |  |\n| 39R |  | 0.80 |  |  |\n| 40R |  | 0.090 |  |  |\n| 42R |  | 0.11 |  | 0.11 |\n| 26R |  |  | 0.11 |  |\n| 27R |  |  | 1.0 |  |\n| 28R |  |  | 0.10 |  |\n| 31R |  |  |  | 2.6 |\n| 32R |  |  | 0.90 |  |\n| 33R |  |  | 0.47 | 1.9 |\n| 41R |  |  | 0.028 | 0.055 |\n| 43R |  |  | 0.60 |  |\n| 44R |  |  |  | 0.44 |\n| 44R |  |  |  | 0.22 |\n| 45M |  |  | 0.90 |  |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Cadmium – Inhalation**\nIntermediate (15–364 days)\n\n**Figure 2-2. Levels of Significant Exposure to Cadmium – Inhalation Intermediate (15–364 days)**\n\n| Category | Respiratory Animal - NOAEL (mg Cd/m3) | Respiratory Animal - LOAEL (mg Cd/m3) | Respiratory Animal - SLOAEL (mg Cd/m3) | Respiratory Animal - Cancer Effect Level (mg Cd/m3) | Cardiovascular Animal - NOAEL (mg Cd/m3) | Cardiovascular Animal - LOAEL (mg Cd/m3) | Cardiovascular Animal - SLOAEL (mg Cd/m3) | Cardiovascular Animal - Cancer Effect Level (mg Cd/m3) | Gastrointestinal Animal - NOAEL (mg Cd/m3) | Gastrointestinal Animal - LOAEL (mg Cd/m3) | Gastrointestinal Animal - SLOAEL (mg Cd/m3) | Gastrointestinal Animal - Cancer Effect Level (mg Cd/m3) | Hematological Animal - NOAEL (mg Cd/m3) | Hematological Animal - LOAEL (mg Cd/m3) | Hematological Animal - SLOAEL (mg Cd/m3) | Hematological Animal - Cancer Effect Level (mg Cd/m3) |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| 26R | 0.11 |  |  |  |  |  |  |  |  |  |  |  | 0.11 |  |  |  |\n| 27R |  | 1.1 |  |  |  |  |  |  |  |  |  |  | 1.1 |  |  |  |\n| 28R |  | 0.10 |  |  |  |  |  |  |  |  |  |  |  | 0.10 |  |  |\n| 29R |  | 1.7 |  |  |  |  |  |  |  |  |  |  |  |  |  |  |\n| 32R |  | 0.023 | 0.90 |  | 0.90 |  |  |  | 0.90 |  |  |  | 0.90 |  |  |  |\n| 34R |  | 0.10 |  |  |  |  |  |  |  |  |  |  |  |  |  |  |\n| 41R |  | 0.026 |  |  |  |  |  |  |  |  |  |  | 0.026 | 0.050 |  |  |\n| 45M |  | 0.022 |  |  | 0.90 |  |  |  | 0.90 |  |  |  |  |  |  |  |\n| 46M |  | 0.10 |  |  |  |  |  |  |  |  |  |  |  |  |  |  |\n| 47H |  | 0.45 |  |  |  |  |  |  |  |  |  |  |  |  |  |  |\n| 42R |  |  |  |  |  |  |  |  |  |  |  |  |  | 0.11 |  |  |\n| 43R |  |  |  |  |  |  |  |  |  |  |  |  |  | 0.21 |  |  |\n| 44R |  |  |  |  |  |  |  |  |  |  |  |  | 0.45 |  | 0.60 |  |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Cadmium – Inhalation**\nIntermediate (15–364 days)\n\n**Figure 2-2. Levels of Significant Exposure to Cadmium – Inhalation Intermediate (15–364 days)**\n\n| Category | 32R (mg Cd/m3) | 45M (mg Cd/m3) | 41R (mg Cd/m3) | 26R (mg Cd/m3) | 27R (mg Cd/m3) | 28R (mg Cd/m3) | 32R (mg Cd/m3) | 43R (mg Cd/m3) | 44R (mg Cd/m3) | 45M (mg Cd/m3) | 32R (mg Cd/m3) | 45M (mg Cd/m3) | 32R (mg Cd/m3) | 45M (mg Cd/m3) |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Musculoskeletal | 0.9 | 0.9 |  |  |  |  |  |  |  |  |  |  |  |  |\n| Hepatic | 0.85 | 0.9 | 0.05 |  |  |  |  |  |  |  |  |  |  |  |\n| Renal |  |  |  | 0.11 | 1.1 | 0.1 | 0.9 | 0.55 | 0.55 | 0.85 |  |  |  |  |\n| Endocrine | 0.85 | 0.9 |  |  |  |  |  |  |  |  |  |  |  |  |\n| Immunological | 0.9 | 0.9 |  |  |  |  |  |  |  |  |  |  |  |  |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Cadmium – Inhalation**\nIntermediate (15–364 days)\n\n**Figure 2-2. Levels of Significant Exposure to Cadmium – Inhalation Intermediate (15–364 days)**\n\n| Category | Neurolgical mg Cd/m3 | Reproductive mg Cd/m3 | Developmental mg Cd/m3 | Cancer mg Cd/m3 |\n| --- | --- | --- | --- | --- |\n| 32R | 0.9 | 0.9 |  |  |\n| 45M | 0.9 | 0.9 |  |  |\n| 23R |  | 0.17 | 0.17 |  |\n| 24R |  | 1.0 | 0.17 |  |\n| 25R |  | 1.0 |  |  |\n| 25R |  | 0.18 |  |  |\n| 31R |  | 1.1 |  |  |\n| 32R |  | 0.24 |  |  |\n| 23R |  |  | 0.022 |  |\n| 24R |  |  | 0.022 |  |\n| 33R |  |  | 2.0 |  |\n| 33R |  |  | 0.53 |  |\n| 44R |  |  | 0.6 |  |\n| 44R |  |  | 0.5 |  |\n| 37R |  |  |  | 0.09 |\n| 39R |  |  |  | 0.75 |\n| 40R |  |  |  | 0.09 |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Cadmium – Inhalation**\nChronic (≥365 days)\n\n**Figure 2-2. Levels of Significant Exposure to Cadmium – Inhalation Chronic (≥365 days)**\n\n| Category | Death mg Cd/m3 | Body Weight mg Cd/m3 |\n| --- | --- | --- |\n| 49R | 0.095 |  |\n| 50R | 0.035 |  |\n| 51R | 0.090 |  |\n| 53R | 0.090 |  |\n| 55R |  | 0.050 |\n\n**Figure 2-2. Levels of Significant Exposure to Cadmium – Inhalation Chronic (≥365 days) - Renal**\n\n| Category | Human - Weighted median (mg Cd/m3) | Human - 95% lower confidence limit of weighted median (mg Cd/m3) |\n| --- | --- | --- |\n| 48 | 0.0014 | 0.00011 |\n\n**Figure 2-2. Levels of Significant Exposure to Cadmium – Inhalation Chronic (≥365 days) - Cancer**\n\n| Category | Animal - Cancer Effect Level (mg Cd/m3) |\n| --- | --- |\n| 50R | 0.033 |\n| 51R | 0.095 |\n| 52R | 0.033 |\n| 53R | 0.095 |\n| 54R | 0.033 |\n| 55R | 0.013 |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| ACUTE EXPOSURE |  |  |  |  |  |  |  |  |  |\n| Andjelkovic et al. 2019 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 1 | Rat (Wistar) 6–8 M | Once (GW) | 0, 15, 30 | HE, BC, HP | Hemato |  | 15 |  | Decreased RBC count, hemoglobin, hematocrit, lymphocyte, and serum iron levels; increased MCHC |\n| Baranski 1985 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 2 | Rat (Wistar) 6–18 F | 10 days GDs 7–16 (GW) | 0, 2, 12, 40 | BW, OW, DX | Bd wt |  | 2 | 12 | LOAEL: 14% decrease in maternal body weight gain SLOAEL: 34% decrease in maternal body weight gain |\n| 2 | Rat (Wistar) 6–18 F | 10 days GDs 7–16 (GW) | 0, 2, 12, 40 | BW, OW, DX | Develop | 2 | 12 | 40 | LOAEL: 9% decrease in fetal weight SLOAEL: 23% decrease in fetal weight, decreased live fetuses/litter, increased resorptions/litter, fetal malformations (fused lower limbs, absent limbs) |\n| Bomhard et al. 1987 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 3 | Rat (Wistar) 25–35 M | Once (GW) | 0, 50, 100, 200 | LE, BW, CS, FI, WI, HP | Death Repro | 50 |  | 100 | 28/35 died within 3 days Testicular necrosis, focal proliferation of Leydig cells (6 months post-exposure); hyperemia and slight hemorrhages in testes and epididymides in rats that died |\n| Surviving rats sacrificed 6–30 months post-exposure |  |  |  |  |  |  |  |  |  |\n| Borzelleca et al. 1989 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 4 | Rat (Sprague-Dawley) 10 M, 10 F | Once (GW) | 0, 15, 31, 65.6, 138 | LE, CS, BW, HE, BC, GN, OW | Death |  |  | 138 F 65.6 M | 2/10 died within 24 hours 3/10 died within 24 hours |\n| 4 | Rat (Sprague-Dawley) 10 M, 10 F | Once (GW) | 0, 15, 31, 65.6, 138 | LE, CS, BW, HE, BC, GN, OW | Bd wt Hemato Hepatic Renal | 138 138 138 |  |  |  |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Borzelleca et al. 1989 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 5 | Rat (Sprague-Dawley) 10 M, 10 F | 10 days (W) | M: 0, 1.1, 7.85, 11.2 F: 0, 1.1, 8.16, 13.9 | LE, CS, BW, HE, BC, UR, GN, OW, HP | Bd wt | 13.9 F 1.1 M | 7.85 M | 11.2 M | LOAEL: 14% decrease in body weight SLOAEL: 25% decrease in body weight |\n| 5 | Rat (Sprague-Dawley) 10 M, 10 F | 10 days (W) | M: 0, 1.1, 7.85, 11.2 F: 0, 1.1, 8.16, 13.9 | LE, CS, BW, HE, BC, UR, GN, OW, HP | Hematocrit | 13.9 F 11.2 M 13.9 F 11.2 M 13.9 F 11.2 M |  |  |  |\n| 5 | Rat (Sprague-Dawley) 10 M, 10 F | 10 days (W) | M: 0, 1.1, 7.85, 11.2 F: 0, 1.1, 8.16, 13.9 | LE, CS, BW, HE, BC, UR, GN, OW, HP | Renal | 13.9 F 11.2 M 13.9 F 11.2 M |  |  |  |\n| 5 | Rat (Sprague-Dawley) 10 M, 10 F | 10 days (W) | M: 0, 1.1, 7.85, 11.2 F: 0, 1.1, 8.16, 13.9 | LE, CS, BW, HE, BC, UR, GN, OW, HP | Repro | 13.9 F 11.2 M |  |  |  |\n| Borzelleca et al. 1989 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 6 | Rat (Sprague-Dawley) 10 M, 10 F | 10 days (GW) | 0, 15, 31, 65.6, 138 | LE, CS, BW, HE, BC, UR, GN, OW, HP | Death | 31 F | 65.6 F 15 M | 31 M | 3/10 males and 4/10 females died within 7 days 18% decrease in terminal body weight LOAEL: 18% decrease in terminal body weight SLOAEL: 23% decrease in terminal body weight Increased WBC and platelet counts Increased RBC count Elevated serum ALT, decreased serum cholesterol Mild focal necrosis of hepatocytes or congestion Mild focal necrosis of tubular epithelium |\n| 6 | Rat (Sprague-Dawley) 10 M, 10 F | 10 days (GW) | 0, 15, 31, 65.6, 138 | LE, CS, BW, HE, BC, UR, GN, OW, HP | Bd wt | 31 F | 65.6 F 15 M 31 F |  |  |\n| 6 | Rat (Sprague-Dawley) 10 M, 10 F | 10 days (GW) | 0, 15, 31, 65.6, 138 | LE, CS, BW, HE, BC, UR, GN, OW, HP | Hematocrit | 15 F | 65.6 F 15 M 31 F |  |  |\n| 6 | Rat (Sprague-Dawley) 10 M, 10 F | 10 days (GW) | 0, 15, 31, 65.6, 138 | LE, CS, BW, HE, BC, UR, GN, OW, HP | 65.6 M | 138 M 138 M |  |  |  |\n| 6 | Rat (Sprague-Dawley) 10 M, 10 F | 10 days (GW) | 0, 15, 31, 65.6, 138 | LE, CS, BW, HE, BC, UR, GN, OW, HP | Renal | 31 F | 65.6 F |  |  |\n\n***DRAFT FOR PUBLIC COMMENT***\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n|  |  |  |  |  | Repro | 65.6 M 138 F 31 M | 138 M |  | Mild focal necrosis of tubular epithelium |\n|  |  |  |  |  | Repro | 65.6 M 138 F 31 M | 138 M | 65.6 M | Necrotic changes in testes with atrophy and loss of spermatogenic elements |\n| Dixon et al. 1976 |  |  |  |  |  |  |  |  |  |\n| 7 | Rat (Sprague-Dawley) 10 M | Once (GW) | 0, 6.25, 12.5, 25 | RX | Repro | 25 |  |  | Cadmium chloride |\n| Males serially mated to untreated females for 70 days post-treatment |  |  |  |  |  |  |  |  |  |\n| Kostial et al. 1978 |  |  |  |  |  |  |  |  |  |\n| 8 | Rat (NS) 6 B | Once (G) | NS | LE | Death |  |  | 29 | Cadmium chloride LD50 calculated 8 days post-exposure |\n| Age at exposure: 2 weeks |  |  |  |  |  |  |  |  |  |\n| Kostial et al. 1978 |  |  |  |  |  |  |  |  |  |\n| 9 | Rat (NS) 6 B | Once (G) | NS | LE | Death |  |  | 147 | Cadmium chloride LD50 calculated 8 days post-exposure |\n| Age at exposure: 3 weeks |  |  |  |  |  |  |  |  |  |\n| Kostial et al. 1978 |  |  |  |  |  |  |  |  |  |\n| 10 | Rat (NS) 6 B | Once (G) | NS | LE | Death |  |  | 129 | Cadmium chloride LD50 calculated 8 days post-exposure |\n| Age at exposure: 6 weeks |  |  |  |  |  |  |  |  |  |\n| Kostial et al. 1978 |  |  |  |  |  |  |  |  |  |\n| 11 | Rat (NS) 6 B | Once (G) | NS | LE | Death |  |  | 104 | Cadmium chloride LD50 calculated 8 days post-exposure |\n| Age at exposure: 18 weeks |  |  |  |  |  |  |  |  |  |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Kostial et al. 1978 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 12 | Rat (NS) 6 B | Once (G) | NS | LE | Death |  |  | 66.8 | LD50 calculated 8 days post-exposure |\n| Age at exposure: 54 weeks |  |  |  |  |  |  |  |  |  |\n| Kotsonis and Klaassen 1977 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 13 | Rat (Sprague-Dawley) 6 M | Once (premating) (GW) | 0, 25, 50, 100, 150 | HP, RX, NX | Neuro Repro | 25 50 | 50 | 100 | Decreased motor activity Testicular necrosis; decreased spermatogenesis; decreased fertility (fewer females producing pups) |\n| Males mated to unexposed females |  |  |  |  |  |  |  |  |  |\n| Kotsonis and Klaassen 1977 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 14 | Rat (Sprague-Dawley) 6–12 M | Once (GW) | 0, 25, 50, 100, 150 | CS, BW, HE, BC, BI, UR, HP, OF | Bd wt Resp Cardio Gastro Hematoc Hepatic Renal Endocr | 100 150 150 150 150 150 |  | 150 | Initial body weight loss resulting in approximate 10% decrease in terminal body weight (2 weeks post-exposure) |\n| Kotsonis and Klaassen 1977 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 15 | Rat (Sprague-Dawley) 15–20 M | Once (GW) | NS | LE | Death |  |  | 225 | LD50 at 14 days |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Kotsonis and Klaassen 1978 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 16 | Rat (Sprague-Dawley) 9 M | 2 weeks (W) | 0, 42 | LE | Death |  |  | 42 | 7/9 died within 2 weeks |\n| Machemer and Lorke 1981 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 17 | Rat (Long-Evans) 22–28 F | 10 days GDs 6–15 (GW) | 0, 1.84, 6.13, 18.39, 61.32 | LE, CS, BW, DX | Death Bd wt | 1.84 |  | 61.32 6.13 | 15/25 dams died 27% decrease in maternal body weight gain during treatment period |\n| 17 | Rat (Long-Evans) 22–28 F | 10 days GDs 6–15 (GW) | 0, 1.84, 6.13, 18.39, 61.32 | LE, CS, BW, DX | Gastro | 18.39 |  | 61.32 | Intestinal necrosis, hemorrhage, ulcers, constipation/absence of defecation |\n| 17 | Rat (Long-Evans) 22–28 F | 10 days GDs 6–15 (GW) | 0, 1.84, 6.13, 18.39, 61.32 | LE, CS, BW, DX | Dermal Develop | 1.84 6.13 | 6.13 | 18.39 | Coarse fur Increased number of fetuses with malformations, increased number of runts (<3 g), 7% decrease in fetal body weight |\n| Machemer and Lorke 1981 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 18 | Rat (Long-Evans) 21–24 F | 10 days GDs 6–15 (F) | 0, 1.2, 3.5, 12.5 | LE, CS, BW, FI, DX | Bd wt | 3.5 | 12.5 |  | 19% decrease in maternal body weight gain during treatment period |\n| 18 | Rat (Long-Evans) 21–24 F | 10 days GDs 6–15 (F) | 0, 1.2, 3.5, 12.5 | LE, CS, BW, FI, DX | Develop | 12.5 |  |  |  |\n| Saedi et al. 2020a, 2020b |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 19 | Rat (Sprague-Dawley) 4 F | 13 days PNDs 21–33 (GW) | 0, 15, 31, 46 | BW, BC, HE, OW, HP, DX | Bd wt Hemato | Endocr Develop | 46 15 | 15 | 21% decrease in terminal body weight Decreased RBC and increased WBC levels |\n| 19 | Rat (Sprague-Dawley) 4 F | 13 days PNDs 21–33 (GW) | 0, 15, 31, 46 | BW, BC, HE, OW, HP, DX | Hemat | 15 | 46 15 | 15 | 21% decrease in terminal body weight Decreased RBC and increased WBC levels |\n| 19 | Rat (Sprague-Dawley) 4 F | 13 days PNDs 21–33 (GW) | 0, 15, 31, 46 | BW, BC, HE, OW, HP, DX | Develop | 46 15 | 31 | 15 | Increased atretic follicles and decreased secondary follicles in ovaries; decreased serum estradiol levels |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Samuel et al. 2011 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 20 | Rat (Wistar) 18 F | 13 days GDs 9–21 (W) | 0, 6, 18 | BW, FI, WI, DX | Bd wt | 6 | 18 |  | 11% decrease in maternal body weight on GD 21 |\n| 20 | Rat (Wistar) 18 F | 13 days GDs 9–21 (W) | 0, 6, 18 | BW, FI, WI, DX | Develop |  |  | 6 | Fetal effects: Increased resorption Postnatal effects (female offspring): Decreased postnatal weight on PND 10 (22%) and PND 21 (14%), ovarian follicular degeneration, decreased estradiol and testosterone, delayed vaginal opening, and altered estrous cycling |\n| 20 | Rat (Wistar) 18 F | 13 days GDs 9–21 (W) | 0, 6, 18 | BW, FI, WI, DX | Other noncancer | 6 | 18 |  | Decreased maternal food intake |\n| Three dams/group were sacrificed on GD 21; remaining offspring were sacrificed on PND 10, PND 21, or evaluated during puberty |  |  |  |  |  |  |  |  |  |\n| Shimizu and Morita 1990 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 21 | Rat (Sprague-Dawley) 10 M | Once (GW) | NS | LE | Death |  |  | 106.9 | LD50 at 24 hours (fasted rats) |\n| Shimizu and Morita 1990 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 22 | Rat (Sprague-Dawley) 10 M | Once (GW) | NS | LE | Death |  |  | 327.3 | LD50 at 24 hours (fed rats) |\n| Stacey et al. 1988 |  |  |  |  |  |  |  |  | Cadmium acetate |\n| 23 | Rat (Sprague-Dawley) 4 M | 6 weeks 5 days/week (G) | 0, 0.0025, 0.025, 0.250 | BW, OW, IX | Bd wt | 0.25 |  |  | Enhanced spleen cell proliferative responses |\n| 23 | Rat (Sprague-Dawley) 4 M | 6 weeks 5 days/week (G) | 0, 0.0025, 0.025, 0.250 | BW, OW, IX | Immuno | 0.025 | 0.25 |  | Enhanced spleen cell proliferative responses |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Stacey et al. 1988 |  |  |  |  |  |  |  |  | Cadmium acetate |\n| 24 | Rat (Sprague-Dawley) 4 M | 2 weeks 5 days/week (G) | 0, 0.0025, 0.025, 0.250 | BW, OW, IX | Bd wt Immuno | 0.25 0.25 |  |  |  |\n| Wan et al. 2022 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 25 | Rat (Sprague-Dawley) 3 M, 3 F | 2 weeks (G) | 0, 2, 4 | BW, WI, BC, UR, OW, HP | Bd wt Renal | 4 | 2c |  | Increased 24-hour urinary protein excretion, elevated urinary β 2M levels, increased serum BUN |\n| Andersen et al. 1988 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 26 | Mouse (CBA/Bom) 7–42 M | Once (GW) | 0, 0.6, 3.9, 7.9, 15.7, 30.3, 59.6, 88.8 | LE, HP | Death Gastro | 15.7 | 30.3 | 88.8 | 36/42 mice died within 10 days LOAEL: Gastritis and enteritis SLOAEL: Severe gastric necrosis Fatty infiltration of liver cells, occasional hepatocellular necrosis Proximal tubular necrosis with poor cell differentiation and irregular granulation of cells Testicular necrosis in most tubules and interstitial tissue |\n| 26 | Mouse (CBA/Bom) 7–42 M | Once (GW) | 0, 0.6, 3.9, 7.9, 15.7, 30.3, 59.6, 88.8 | LE, HP | Hepatic | 15.7 | 30.3 | 88.8 | 36/42 mice died within 10 days LOAEL: Gastritis and enteritis SLOAEL: Severe gastric necrosis Fatty infiltration of liver cells, occasional hepatocellular necrosis Proximal tubular necrosis with poor cell differentiation and irregular granulation of cells Testicular necrosis in most tubules and interstitial tissue |\n| 26 | Mouse (CBA/Bom) 7–42 M | Once (GW) | 0, 0.6, 3.9, 7.9, 15.7, 30.3, 59.6, 88.8 | LE, HP | Renal | 59.6 |  | 88.8 | 36/42 mice died within 10 days LOAEL: Gastritis and enteritis SLOAEL: Severe gastric necrosis Fatty infiltration of liver cells, occasional hepatocellular necrosis Proximal tubular necrosis with poor cell differentiation and irregular granulation of cells Testicular necrosis in most tubules and interstitial tissue |\n| 26 | Mouse (CBA/Bom) 7–42 M | Once (GW) | 0, 0.6, 3.9, 7.9, 15.7, 30.3, 59.6, 88.8 | LE, HP | Repro | 30.3 |  | 59.6 | 36/42 mice died within 10 days LOAEL: Gastritis and enteritis SLOAEL: Severe gastric necrosis Fatty infiltration of liver cells, occasional hepatocellular necrosis Proximal tubular necrosis with poor cell differentiation and irregular granulation of cells Testicular necrosis in most tubules and interstitial tissue |\n| Ara et al. 2016 |  |  |  |  |  |  |  |  | Form not specified |\n| 27 | Mouse (Swiss-Webster) 5 F | 7 days GDs 6–12 (GW) | 0, 3.13, 6.25, 12.5, 25.0 | RX, DX | Develop |  |  | 3.13 | 49% decrease in fetal body weight; decreased crown-rump length, head and eye circumference, and forelimb, hindlimb and tail length; anomalies in the brain, eyes, forelimbs, hindlimbs, and tail |\n| Baer and Benson 1987 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 28 | Mouse (Swiss-Webster) 10 M | Once (GW) | 100, 150 | LE | Death |  |  | 95.5 | LD50 at 96 hours |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Yi et al. 2021a |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 29 | Mouse (ICR) 13 F | 10 days GDs 8–17 (W) | 0, 8.1, 24 | DX | Develop |  | 8.1 |  | Impaired glucose tolerance in adult male offspring |\n| INTERMEDIATE EXPOSURE |  |  |  |  |  |  |  |  |  |\n| Chopra et al. 1984 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 30 | Monkey (Rhesus) 3–4 M | 6 months (F) | 0, 5 | CS, BW, IX | Bd wt Immuno | 5 5 |  |  |  |\n| Afolabi et al. 2012 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 31 | Rat (Wistar) 8 M | 7 weeks (W) | 0, 4.6, 9.1 | BW, BC, BI | Hepatic Immuno |  | 4.6 4.6 |  | Increased plasma lipid levels Increased plasma pro-inflammatory cytokines |\n| Ali et al. 1986 |  |  |  |  |  |  |  |  | Cadmium acetate |\n| 32 | Rat (Wistar) 10 F | 21 days GDs 1–21 (W) | 0, 0.706, 1.2 | BW, FI, WI, RX, DX | Bd wt Repro Develop | 1.2 1.2 | 0.706 | 1.2 | Decreased offspring body weight, persisting through PND 45 (~20%) Delayed development of sensory motor coordination reflexes; altered motor activity (increased PNDs 7–21; decreased PND 60) |\n| Aprioku et al. 2014 |  |  |  |  |  |  |  |  | Cadmium sulfate |\n| 33 | Rat (Wistar) 8 F | 21 days GDs 0–20 (W) | 0, 4, 8 | BW, OW, HP, RX, DX | Bd wt Repro Develop |  | 4 | 4 | 40% decrease in maternal body weight on GD 20 Increased abortions |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Baranski 1987 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 34 | Rat (Wistar) 12–16 F | 20 days GDs 1–20 (W) | 0, 4.6, 11.1 | LE, BW, FI, WI, HE, BC, DX | Bd wt Repro Develop | 11.1 |  | 4.6 | 37% decrease in maternal body weight gain |\n| 34 | Rat (Wistar) 12–16 F | 20 days GDs 1–20 (W) | 0, 4.6, 11.1 | LE, BW, FI, WI, HE, BC, DX | Bd wt Repro Develop | 11.1 |  | 4.6 | 12% decrease in fetal body weight and 7% decrease in fetal body length |\n| 34 | Rat (Wistar) 12–16 F | 20 days GDs 1–20 (W) | 0, 4.6, 11.1 | LE, BW, FI, WI, HE, BC, DX | Other noncancer |  | 4.6 |  | Decreased maternal food intake |\n| Baranski and Sitarek 1987 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 35 | Rat (Wistar) 11–13 F | 14 weeks 5 days/week (GW) | 0, 0.04, 0.4, 4, 40 | LE, CS, BW, RX | Death |  |  | 40 | 4/13 died by week 8; 7/13 by week 14 |\n| 35 | Rat (Wistar) 11–13 F | 14 weeks 5 days/week (GW) | 0, 0.04, 0.4, 4, 40 | LE, CS, BW, RX | Bd wt Repro | 0.4 |  | 4 | 40% decrease in body weight gain |\n| 35 | Rat (Wistar) 11–13 F | 14 weeks 5 days/week (GW) | 0, 0.04, 0.4, 4, 40 | LE, CS, BW, RX | Bd wt Repro | 4 |  | 40 | Increased duration of estrus cycle |\n| Baranski et al. 1983 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 36 | Rat (Wistar) NS F | 11 weeks (5 weeks premating, 3 weeks mating, 3 weeks gestation) 5 days/week (GW) | 0, 0.04, 0.4, 4 | RX, DX | Repro Develop | 4 |  |  | Decreased pup locomotor activity and impaired motor coordination at 2 months |\n| 36 | Rat (Wistar) NS F | 11 weeks (5 weeks premating, 3 weeks mating, 3 weeks gestation) 5 days/week (GW) | 0, 0.04, 0.4, 4 | RX, DX | Repro Develop | 4 | 0.04 |  | Decreased pup locomotor activity and impaired motor coordination at 2 months |\n| Half of dams were sacrificed on GD 21; half were allowed to deliver naturally and pups (8/sex/group) were assessed for 2 months after parturition |  |  |  |  |  |  |  |  |  |\n| Brzóska and Moniuszko-Jakoniuk 2005a, 2005b; 2010 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 37 | Rat (Wistar) 10 M | 12 months (W) | 0, 0.2, 0.5, 4 | BW, FI, WI, BC, BI, HP | Bd wt Musc/skel | 4 |  |  | Increased lumbar spine deformities, decreased in lumbar spine and femur mineralization, altered bone turnover parameters |\n| 37 | Rat (Wistar) 10 M | 12 months (W) | 0, 0.2, 0.5, 4 | BW, FI, WI, BC, BI, HP | Bd wt Musc/skel | 0.2 | 0.5 |  | Increased lumbar spine deformities, decreased in lumbar spine and femur mineralization, altered bone turnover parameters |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Brzóska and Moniuszko-Jakoniuk 2005c; Brzóska et al. 2005a, 2005c |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 38 | Rat (Wistar) 40 F | 12 months (W) | 0, 0.2, 0.5, 4 | BW, FI, WI, BC, BI, HP, OF | Bd wt Musc/skel | 4 | 0.2 |  | Decreased bone mineralization, mechanical properties of tibia and femur, and altered bone turnover parameters |\n| Brzóska et al. 2004, 2005b |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 39 | Rat (Wistar) 8–10 F | 12 months (W) | 0, 0.3, 0.7, 4, 8 | BW, FI, WI, BI, OF | Musc/skel |  | 0.3 |  | Alterations in bone mineral content and density and mechanical properties of lumbar vertebral and femoral bones |\n| Buha et al. 2013, 2019 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 40 | Rat (Wistar) 7 M | 28 days (G) | 0, 0.3, 0.6, 1.25, 2.5, 5, 10 | BW, BC, BI | Bd wt Musc/skel | 0.6 | 0.3 | 1.25 | 36% decrease in body weight gain Decreased bone mineral content in femur Increased serum creatinine and urea Decreased serum T3 levels |\n|  |  |  |  |  | Renal Endocr | 2.5 | 5 0.3 |  |  |\n| Caride et al. 2010 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 41 | Rat (Sprague-Dawley) 60 M | 30 days (W) | 0, 0.92, 1.8 | BC | Endocr |  | 0.92 |  | Altered daily secretory pattern of ACTH and growth hormone; increased median levels of ACTH and TSH |\n| Carmignani and Boscolo 1984 |  |  |  |  |  |  |  |  | Cadmium acetate |\n| 42 | Rat (Sprague-Dawley) 10 M | 190 days (W) | 0, 1.4, 2.8 | CS, BW, OF | Bd wt Cardio | 2.8 | 1.4 |  | Increased systolic and diastolic blood pressure |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Chen et al. 2013 |  |  |  |  |  |  |  |  | Form not specified |\n| 43 | Rat (Sprague-Dawley) 6 M | 12 weeks (W) | 0, 0.2, 1.1, 5.0 | BW, BC, BI, UR, HP | Bd wt Musc/skel | 5 | 0.2 |  | Trabecular bone damage in tibia (decreased number, thickness; increased separation, increased dissociated ends); altered bone turnover parameters |\n| Cifone et al. 1989 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 44 | Rat (Wistar) 4 F | 170 days (W) | 0, 29, 58 | CS, BW, FI, WI, OW, IX | Bd wt Immuno | 58 | 29 |  | Biphasic decrease (first 30–50 days) then increase in NK cell activity, splenic cellularity, and the number of large granular lymphocytes in the peripheral blood; increased total peripheral lymphocytes |\n| Desi et al. 1998 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 45 | Rat (Wistar) NS F | 94 days F0: GDs 5–15 + PNDs 2–28 F1: PNWs 5–12 5 days/week (GW) | 0, 3.5, 7.0, 14.0 | DX | Develop | 3.5 | 7 |  | Decreased peripheral nerve conduction velocity with increased refractory periods |\n| Locomotor and sensory function assessed in F1 males at 12 weeks of age |  |  |  |  |  |  |  |  |  |\n| Desi et al. 1998 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 46 | Rat (Wistar) NS F | 11 days GDs 5–15 (GW) | 0, 3.5, 7.0, 14.0 | DX | Develop | 14 |  |  |  |\n| Locomotor and sensory function assessed in F1 males at 12 weeks of age |  |  |  |  |  |  |  |  |  |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Desi et al. 1998 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 47 | Rat (Wistar) NS F | 38 days GDs 5–15 plus PNDs 2–28 (GW) | 0, 3.5, 7.0, 14.0 | DX | Develop | 3.5 | 7 |  | Decreased horizontal ambulation and rearing activity |\n| Locomotor and sensory function assessed in F1 males at 12 weeks of age |  |  |  |  |  |  |  |  |  |\n| Dixon et al. 1976 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 48 | Rat (Sprague-Dawley) 10 M | 30–90 days (W) | 0, 0.00014, 0.0014, 0.014 | BC, OW, RX | Repro | 0.014 |  |  |  |\n| Males mated to untreated females |  |  |  |  |  |  |  |  |  |\n| Feng et al. 2019 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 49 | Rat (Sprague-Dawley) NS F | 6 weeks GD 0 to PND 21 (W) | 0, 0.6, 3 | DX | Develop |  | 0.6 |  | Impaired learning and memory in F1 males at PNDs 35 and 56 |\n| Huang et al. 2020 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 50 | Rat (Sprague-Dawley) <10 F | 3 weeks GD 1 to birth (GW) | 0, 0.3, 1.2, 4.9 | DX | Develop |  | 0.3 |  | F1 males: Decreased serum testosterone and increased seminiferous tubule diameter at PND 21; decreased Johnsen score (decreased testicular maturity) on PND 56 |\n| Iqbal et al. 2021 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 51 | Rat (Sprague-Dawley) 6 M | 17 days (GW) | 0, 5, 10, 15 | BW, OW, HP | Bd wt | 10 |  | 15 | 12% body weight loss during exposure (compared to 12% body weight gain in control) |\n|  |  |  |  |  | Repro | 5 | 10 |  | Structural changes in the testis and epididymis |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\nstimulated plasma insulin levels\n\nAltered glucose tolerance at PND 21\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects | Cadmium chloride |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Jacquet et al. 2018 |  |  |  |  |  |  |  |  |  |  |\n| 52 | Rat (Wistar) 9 M, 9 F | 12 weeks (W) | M: 0, 0.0053, 0.0558, 0.515; F: 0, 0.0055, 0.053, 0.4959 | LE, BW, BC, UR, OW, OF | Bd wt | 0.4959 F 0.515 M 0.4959 F 0.515 M Endocr | 0.053 F |  |  |  |\n| Jacquet et al. 2019 |  |  |  |  |  |  |  |  |  |  |\n| 53 | Rat (Wistar) 15–17 F | 11 weeks 3 weeks prior to mating GD 0–PND 35 (W) | 0, 0, 0.05, 0.5 | UR, RX, DX | Renal Repro Develop | 0.5 0.5 | 0.05 |  |  | Cadmium chloride |\n| Dams were sacrificed on PND 35; pups were sacrificed on PND 21, 26, and 60 |  |  |  |  |  |  |  |  |  |  |\n| Kelman et al. 1978 |  |  |  |  |  |  |  |  |  |  |\n| 54 | Rat (Sprague-Dawley) 15 F | 22 days GDs 0–21 (W) | 0, 1.5, 3.8 | HE, BI, DX | Hemato Musc/skel Develop | 3.8 | 1.5 | 1.5 | Decreased hematocrit | Form not specified |\n| Kotsonis and Klaassen 1978 |  |  |  |  |  |  |  |  |  |  |\n| 55 | Rat (Sprague-Dawley) 6 M | 24 weeks (W) | 0, 1.1, 2.92, 8.49 | CS, BW, FI, WI, HE, BC, BI, OW, HP, OF, RX, NX | Bd wt Resp Cardio Gastro Hemato Musc/skel Hepatic Renal Endocr | 8.49 8.49 8.49 8.49 8.49 1.1 | 8.49 8.49 8.49 1.1 | 8.49 8.49 8.49 1.1 | 8.49 8.49 8.49 1.1 | Cadmium chloride |\n\nProteinuria (starting at week 6)\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n|  |  |  |  |  | Immuno Neuro Repro | 8.49 1.1 8.49 | 2.92 |  | Decreased motor activity (starting at week 3) |\n| Males mated to unexposed females |  |  |  |  |  |  |  |  |  |\n| Kulas et al. 2019 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 56 | Rat (Dark Agouti) 8 M | 30 days (W) | 0, 0.35, 3.51 | OW, HP | Resp |  | 0.35 |  | Minimal to mild perivascular edema and respiratory epithelial desquamation in lungs |\n| Larregle et al. 2008 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 57 | Rat (Wistar) 8 M | 8 weeks daily (W) | 0, 18 | BC | Hepatic |  | 18 |  | Increased serum and liver triglyceride levels; increased serum cholesterol levels |\n| Li et al. 2018 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 58 | Rat (Sprague-Dawley) 10 F | 42 days GD 0-PND 21 (GW) | 0, 0.6, 3 | DX | Develop |  | 0.6 |  | F1 females: Decreased primordial follicles (PND 21) and increased serum estradiol (PND 21, PND 35) F2: females: Increased serum progesterone (PND 21) |\n| Liu et al. 2019 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 59 | Rat (Sprague-Dawley) 10 M | 60 days (G) | 0, 0.6, 1.5, 3 | CS, FI, WI, BW, BC, UR, OW, HP | Bd wt |  |  | 1.5 | 20% decrease in terminal body weights Decreased serum iron Increased BUN and serum creatinine |\n| Liu et al. 2020 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 60 | Rat (Sprague-Dawley) 5 F | 20 days GDs 1-21 (GW) | 0, 0.3, 1.2, 4.9 | DX | Develop |  | 0.3 |  | Decreased ovarian granulosa cell progesterone in F1 female offspring on PND 56 |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects | Cadmium chloride |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Loeser and Lorke 1977 |  |  |  |  |  |  |  |  |  |  |\n| 61 | Rat (Wistar) 20 M, 20 F | 3 months (F) | 0, 0.1, 0.3, 1, 3 | HP, BC, CS, UR, OW, OF, BW, FI | Bd wt Cardio Hematoc Hepatic Renal Endocr Immuno Repro | 3 3 3 3 3 3 | 0.439 | Decreased offspring body weights (by up to ~19% on PNW 9) | Cadmium chloride |  |\n| Luo et al. 2015 |  |  |  |  |  |  |  |  |  |  |\n| 62 | Rat (Sprague-Dawley) 10 F | 42 days GD 0-PND 21 (W) | 0, 0.089, 0.439, 0.955 | BW, RX, DX | Bd wt Repro Develop | 0.955 0.955 0.089 |  | 0.439 | Decreased offspring body weights (by up to ~19% on PNW 9) | Cadmium chloride |\n| McCalla et al. 2024 |  |  |  |  |  |  |  |  |  |  |\n| 63 | Rat (Sprague-Dawley) 10 M | 8 weeks 3 times/week (GW) | 0, 2.5, 5 | BW, HE, OF | Cardio Hematoc | 2.5 | 2.5 5 |  | Increased blood pressure Decreased mean cell volume and mean cell hemoglobin; increased red cell distribution width | Cadmium chloride |\n| Muller et al. 1988 |  |  |  |  |  |  |  |  |  |  |\n| 64 | Rat (Sprague-Dawley) 4 M | 6 weeks 5 days/week (GW) | 0, 0.0025, 0.025, 0.25 | BW, BC, BI, OW | Bd wt Hepatic | 0.25 0.25 |  |  |  | Cadmium acetate |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Nagymajtenyi et al. 1997 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 65 | Rat (Wistar) 5 M, 10 F | 3 generations ~16–18 weeks per generation (GW) | 0, 3.5, 7.0, 14.0 | CS, BW, RX, DX | Bd wt Repro Develop | 14 14 3.5 M | 7 M |  | Decreased tail nerve conduction velocity (all generations); prolonged latency and duration of somatosensory evoked potentials (F2, F3); increased frequency in auditory and visual evoked potentials (F3); 5% decrease in F3 body weight at PNW 12 |\n| Nasiadek et al. 2018 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 66 | Rat (Wistar) 20 F | 30 days (GW) | 0, 0.09, 1.8, 4.5 | CS, BW, BC, OW, HP | Bd wt Repro | 4.5 0.09 | 1.8 |  | Decreased plasma estradiol |\n| Nasiadek et al. 2019 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 67 | Rat (Wistar) 24 F | 90 days (GW) | 0, 0.09, 0.9, 1.8, 4.5 | LE, CS, BW, FI, WI, BC, OW, HP | Bd wt Repro | 4.5 0.09 | 0.9 |  | Decreased plasma estradiol |\n| Nation et al. 1984 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 68 | Rat (Sprague-Dawley) 9 M | 55 days (F) | 0, 1, 5 | CS, NX | Neuro | 1 | 5 |  | Increased anxiety-like behavior (passive avoidance) |\n| Ninkov et al. 2016 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 69 | Rat (Albino Oxford) 8–16 M | 30 days (W) | 0, 0.4, 4.1 | OW, HP, IX | Gastro Immuno | 4.1 | 0.4 |  | Increased intestinal lymphocyte counts, and mesenteric lymph node relative weight and cellularity; decreased spleen cell proliferative response |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Ogoshi et al. 1989 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 70 | Rat (NS) 19–22 F | 4 weeks (W) | 0, 1, 2.5 | BW, HE, BC, BI, OF | Bd wt Hemato | 2.5 | 1 |  | Decreased hematocrit, hemoglobin, MCHC, and MCV |\n|  |  |  |  |  | Musc/skel |  | 1 |  | Decreased bone strength |\n| Weanling rats (21-day-old) |  |  |  |  |  |  |  |  |  |\n| Ogoshi et al. 1989 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 71 | Rat (NS) 18–25 NS | 4 weeks (W) | 0, 1.6, 3.3, 6.6, 13, 26.2 | BW, HE, BC, BI, OF | Bd wt Hemato | 26.2 | 13 |  | Decreased hematocrit and MCV |\n|  |  |  |  |  | Musc/skel | 6.6 |  |  |  |\n| Adult rats (24-week-old) |  |  |  |  |  |  |  |  |  |\n| Ogoshi et al. 1989 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 72 | Rat (NS) 25–27 NS | 4 weeks (W) | 0, 11, 21.5 | BW, HE, BC, BI, OF | Bd wt Hemato | 11 | 21.5 |  | 10% decrease in body weight gain |\n|  |  |  |  |  | Musc/skel | 21.5 |  |  | Decreased hemoglobin and MCHC |\n| Aged rats (1.5-year-old) |  |  |  |  |  |  |  |  |  |\n| Oluranti et al. 2021 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 73 | Rat (Wistar) 5 M | 21 days (G) | 0, 3, 18 | BC, BI, OW | Endocr |  | 3 |  | Decreased plasma insulin and glucose levels |\n| Petering et al. 1979 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 74 | Rat (Sprague-Dawley) 5 F | 111 days (90 days prior mating through GD 21) (W) | 0, 0.56, 1.3, 2.61, 5.23 | HE, RX, DX | Repro Develop | 5.23 | 1.3 | 2.61 | 10% decrease in birth weight |\n| Prigge 1978a |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 75 | Rat (Wistar) 12 F | 90 days (W) | 0, 3.8, 7.6, 15.2 | LE, BW, HE, BC, BI, UR, OW | Bd wt Hemato | 3.8 | 3.8 | 7.6 | 28% decrease in body weight gain |\n|  |  |  |  |  | Renal | 3.8 | 7.6 |  | Decreased serum iron |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Sarmiento-Ortega et al. 2017 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 76 | Rat (Wistar) 10 M | 3, 4, or 5 months (W) | 0, 2.94 | BC, OF | Hepatic |  | 2.94 |  | Increased serum and hepatic lipid concentrations |\n| 76 | Rat (Wistar) 10 M | 3, 4, or 5 months (W) | 0, 2.94 | BC, OF | Endocr |  | 2.94 |  | Increased serum glucose and insulin levels following administration of an oral glucose load |\n| 76 | Rat (Wistar) 10 M | 3, 4, or 5 months (W) | 0, 2.94 | BC, OF | Other noncancer |  | 2.94 |  | Increased abdominal circumference, body mass index, and percentage of body fat |\n| Sorell and Graziano 1990 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 77 | Rat (Sprague-Dawley) 42–66 F | 15 days GDs 6–20 (W) | 0, 0.629, 4.714, 8.171 | BW, WI, HE, DX | Bd wt | 0.629 | 4.714 | 8.171 | LOAEL: 13% decrease in maternal weight gain SLOAEL: 30% decrease in maternal body weight gain |\n| 77 | Rat (Sprague-Dawley) 42–66 F | 15 days GDs 6–20 (W) | 0, 0.629, 4.714, 8.171 | BW, WI, HE, DX | Hemato | 4.714 | 8.171 |  | Reduced maternal hemoglobin levels |\n| 77 | Rat (Sprague-Dawley) 42–66 F | 15 days GDs 6–20 (W) | 0, 0.629, 4.714, 8.171 | BW, WI, HE, DX | Develop | 0.629 | 4.714 |  | 8% decrease in fetal body weight |\n| Sun et al. 2023 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 78 | Rat (Sprague-Dawley) 10 M | 29 days (GW) | 0, 0.3, 1, 5 | DX | Develop | 0.3 | 1 |  | Decreased serum estradiol and progesterone in adult F1 females |\n| F0 males were mated to unexposed females; reproductive development was assessed in F1 and F2 female offspring |  |  |  |  |  |  |  |  |  |\n| Sutou et al. 1980 |  |  |  |  |  |  |  |  | Form not specified |\n| 79 | Rat (Sprague-Dawley) 14 M, 14 F | 9 weeks (premating through GD 20) (GW) | 0, 0.1, 1.0, 10 | RX, DX | Repro | 1 |  | 10 | Decreased number of copulating and pregnant females; 49% reduction in number of live fetuses/litter; decreased total implants/litter, increased resorptions/litter |\n| 79 | Rat (Sprague-Dawley) 14 M, 14 F | 9 weeks (premating through GD 20) (GW) | 0, 0.1, 1.0, 10 | RX, DX | Develop | 1 |  | 10 | Decreased fetal body weight in males (34%) and females (33%); decreased body and tail length; delayed ossification |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Tang et al. 2016 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 80 | Rat (Sprague-Dawley) 6 M | 3 months (W) | 0, 0.28, 1.41, 7.07 | HP | Musc/skel | 1.41 | 7.07 |  | Decreased bone density and trabecular bone loss and damage in tibia (decreased trabecular volume and number, increased trabecular separation) |\n| Tian et al. 2017 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 81 | Rat (Sprague-Dawley) NS F | 6 weeks GD 0 to PND 21 (GW) | 0, 0.6, 3 | DX | Develop |  | 0.6 |  | Decreased serum progesterone and testosterone and in male offspring on PND 35 and 56, respectively; decreased relative testis weight on PND 21 |\n| Tucovic et al. 2018 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 82 | Rat (Dark Agouti) 4–6 M | 30 days (W) | 0, 0.7, 6.6 | BW, FI, WI, HE BC, UR, HP | Bd wt Hemato | 6.6 |  |  | Increased percent neutrophil leukocytes and eosinophil leukocytes |\n| 82 | Rat (Dark Agouti) 4–6 M | 30 days (W) | 0, 0.7, 6.6 | BW, FI, WI, HE BC, UR, HP | Hepatic Immuno | 6.6 0.7 | 6.6 |  | Increased IL-6 and TNF in skin |\n| Wan et al. 2022 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 83 | Rat (Sprague-Dawley) 3 M, 3 F | 4 weeks (G) | 0, 2, 4 | BW, WI, BC, UR, OW, HP | Bd wt Renal | 4 |  |  | Increased 24-hour urinary protein excretion, elevated urinary β 2M levels, increased serum BUN |\n| Wan et al. 2022 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 84 | Rat (Sprague-Dawley) 3 M, 3 F | 8 weeks (G) | 0, 2, 4 | BW, WI, BC, UR, OW, HP | Bd wt Renal | 4 |  |  | Increased 24-hour urinary protein excretion, elevated urinary β 2M levels, increased serum BUN |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Wang et al. 2014 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 85 | Rat (Sprague-Dawley) 8 M, 8 F | 28 days (GW) | 0, 1, 2.5, 5, 10, 20 | LE, CS, BW, FI, HE, BC, UR, GN, OW, HP | Bd wt | 5 | 10 |  | Decrease in terminal body weight in males (12%) and females (11%) |\n| 85 | Rat (Sprague-Dawley) 8 M, 8 F | 28 days (GW) | 0, 1, 2.5, 5, 10, 20 | LE, CS, BW, FI, HE, BC, UR, GN, OW, HP | Cardio | 20 |  |  | Decrease in terminal body weight in males (12%) and females (11%) |\n| 85 | Rat (Sprague-Dawley) 8 M, 8 F | 28 days (GW) | 0, 1, 2.5, 5, 10, 20 | LE, CS, BW, FI, HE, BC, UR, GN, OW, HP | Hemat | 10 F | 20 F |  | Increased platelets |\n| 85 | Rat (Sprague-Dawley) 8 M, 8 F | 28 days (GW) | 0, 1, 2.5, 5, 10, 20 | LE, CS, BW, FI, HE, BC, UR, GN, OW, HP | Hepatic | 2.5 M | 5 M |  | Increased platelets |\n| 85 | Rat (Sprague-Dawley) 8 M, 8 F | 28 days (GW) | 0, 1, 2.5, 5, 10, 20 | LE, CS, BW, FI, HE, BC, UR, GN, OW, HP | Renal | 10 F | 20 F |  | Increased serum ALT |\n| 85 | Rat (Sprague-Dawley) 8 M, 8 F | 28 days (GW) | 0, 1, 2.5, 5, 10, 20 | LE, CS, BW, FI, HE, BC, UR, GN, OW, HP | Endocr | 20 |  |  |  |\n| 85 | Rat (Sprague-Dawley) 8 M, 8 F | 28 days (GW) | 0, 1, 2.5, 5, 10, 20 | LE, CS, BW, FI, HE, BC, UR, GN, OW, HP | Immuno | 20 |  |  |  |\n| 85 | Rat (Sprague-Dawley) 8 M, 8 F | 28 days (GW) | 0, 1, 2.5, 5, 10, 20 | LE, CS, BW, FI, HE, BC, UR, GN, OW, HP | Neuro | 20 |  |  |  |\n| 85 | Rat (Sprague-Dawley) 8 M, 8 F | 28 days (GW) | 0, 1, 2.5, 5, 10, 20 | LE, CS, BW, FI, HE, BC, UR, GN, OW, HP | Repro | 5 | 10 |  | Decreased serum LH and testosterone in males; increased absolute and relative uterine weight |\n| 85 | Rat (Sprague-Dawley) 8 M, 8 F | 28 days (GW) | 0, 1, 2.5, 5, 10, 20 | LE, CS, BW, FI, HE, BC, UR, GN, OW, HP | Other | 1 F | 2.5 F |  | Decreased food intake |\n| 85 | Rat (Sprague-Dawley) 8 M, 8 F | 28 days (GW) | 0, 1, 2.5, 5, 10, 20 | LE, CS, BW, FI, HE, BC, UR, GN, OW, HP | noncancer |  |  |  |  |\n| Weng et al. 2014 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 86 | Rat (Wistar) 12 F | 8 weeks (G) | 0, 0.3, 1.2, 4.9 | BW, OW, HP | Bd wt | 4.9 |  |  |  |\n| 86 | Rat (Wistar) 12 F | 8 weeks (G) | 0, 0.3, 1.2, 4.9 | BW, OW, HP | Repro | 0.3 | 1.2 |  | Decreased absolute and relative ovary weight, increased atretic follicles, follicular cell apoptosis |\n| Xu et al. 2015 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 87 | Rat (Sprague-Dawley) 6 M | 90 days (GW) | 0, 0.7, 2.0, 6.0 | LE, CS, BW, HP | Bd wt | 6 |  |  |  |\n| 87 | Rat (Sprague-Dawley) 6 M | 90 days (GW) | 0, 0.7, 2.0, 6.0 | LE, CS, BW, HP | Neuro | 0.7 | 2 |  | Neuronal degeneration in cortex |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Yang et al. 2021a |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 88 | Rat (Sprague-Dawley) 9 NR | 8 weeks 5 days/week (GW) | 0, 0.15, 0.61, 2.5 | BC | Hepatic | 0.15 | 0.61 |  | Increased serum triglycerides, total cholesterol, and LDL cholesterol; decreased serum HDL cholesterol |\n|  |  |  |  |  | Renal | 0.61 | 2.5 |  | Increased serum urea nitrogen |\n| Yi et al. 2021b |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 89 | Rat (Sprague-Dawley) 6 M | 28 days (GO) | 0, 1, 3 | BW, BC, OW, HP, RX | Bd wt Repro | 3 | 1 |  | Decreased serum testosterone levels |\n| Zenick et al. 1982 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 90 | Rat (Long-Evans) 5 M | 70–80 days (W) | 0, 1.16, 2.32, 4.64 | BW, FI, WI, HP, RX, DX | Bd wt Repro Develop for fetal effects | 4.64 4.64 4.64 | 25 | 12 | LOAEL: 13% decrease in terminal body weight SLOAEL: 25% decrease in terminal body weight |\n| Males were mated with three untreated females; one litter evaluated for fetal effects and two litters evaluated for neurobehavior on PND 21 or 90 |  |  |  |  |  |  |  |  |  |\n| Zhang et al. 2022a |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 91 | Rat (Sprague-Dawley) 8 M | 12 weeks (G) | 0, 1.5, 3, 6.1, 12, 25 | LE, CS, BW, BC, OW, HP | Bd wt | 6.1 | 12 | 25 | LOAEL: 13% decrease in terminal body weight SLOAEL: 25% decrease in terminal body weight |\n|  |  |  |  |  | Hepatic | 1.5 | 3 | 12 | LOAEL: Hepatic fibrosis SLOAEL: Hepatic fibrous tissue proliferation |\n| Zhang et al. 2023a |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 92 | Rat (Sprague-Dawley) 6 M | 4 weeks (GW) | 0, 2.5, 5 | BC, HP, RX | Repro | 2.5 |  | 5 | Decreased serum testosterone, LH, and GnRH; decreased sperm count and motility; decreased seminiferous tubule diameter and seminiferous epithelial thickness |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Zhang et al. 2024a |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 93 | Rat (Sprague-Dawley) 10–30 M | 4 weeks (GW) | 0, 5 | BW, RX, DX | Bd wt Repro |  | 5 | 5 | 13% decrease in body weight Decreased fertility and percent live births, sperm quality, and levels of serum testosterone and gonad releasing hormone; decreased seminiferous tubule diameter and area, seminiferous epithelium thickness, and Johnsen score; decreased number of cells in interstitial region of testes and disordered cellular arrangement |\n| Males were mated with unexposed females. |  |  |  |  | Develop |  |  | 5 | 21% decrease in male fetal weight |\n| Blakley 1985 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 94 | Mouse (BDF1) 22 F | 3 weeks (W) | 0, 1.4, 2.8, 14 | CS, BW, GN, IX | Bd wt Immuno | 14 1.4 | 2.8 |  | Decreased humoral immune response |\n| Blakley 1988 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 95 | Mouse (BDF1) 14–16 F | 26 days (W) | 0, 2.5, 12.5 | BW, WI, IX | Immuno | 12.5 |  |  |  |\n| Aged mice (12-month-old) |  |  |  |  |  |  |  |  |  |\n| Chatterjee and Saxena 2015 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 96 | Mouse (C57BL/6) 10–15 M | 6 weeks (W) | 0, 7.6, 150 | HE, BC | Hemato Immuno | 150 | 7.6 |  | Decreased RBC count and hemoglobin |\n| Chou et al. 2023 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 97 | Mouse (C57BL/6) 11–18 M | 12 weeks (W) | 0, 11, 21 | BW, OF, HP | Bd wt Cardio | 21 |  | 11 | Cardiomyocyte apoptosis |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects | Cadmium chloride |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Exon et al. 1986 |  |  |  |  |  |  |  |  |  |  |\n| 98 | Mouse (Swiss-Webster) 20 M | 10 weeks (W) | 0, 0.57, 5.7, 57 | LE, BW, GN, HP, IX | Bd wt Immuno | 57 57 |  |  |  |  |\n| Exon et al. 1986 |  |  |  |  |  |  |  |  |  |  |\n| 99 | Mouse (Swiss-Webster) 20 M | 10 weeks (W) | 0, 0.57, 5.7, 57 | LE, BW, GN, HP, IX | Bd wt Immuno | 0.57 57 | 5.7 |  | Cadmium acetate | 14% decrease in body weight |\n| Exon et al. 1986 |  |  |  |  |  |  |  |  |  |  |\n| 100 | Mouse (Swiss-Webster) 20 M | 10 weeks (W) | 0, 0.57, 5.7, 57 | LE, BW, GN, HP, IX | Bd wt Immuno | 57 57 |  |  |  | Cadmium sulfate |\n| Gathwan and Albir 2020 |  |  |  |  |  |  |  |  |  |  |\n| 101 | Mouse (Swiss) 6 M | 30 days (G) | 0, 6.1, 12.3, 19.5 | BW, FI, WI, OW, HP | Bd wt | 6.1 | 12.3 | 19.5 | LOAEL: 13% decrease in terminal body weight SLOAEL: 23% decrease in terminal body weight | Cadmium oxide |\n| He et al. 2019a |  |  |  |  |  |  |  |  |  |  |\n| 102 | Mouse (C57BL/6) 10 M | 20 weeks (W) | 0, 1.475, 6.566 | LE, CS, WI, BC, BI, OW, HP | Bd wt Hepatic | Endocr | 6.566 | 1.475 | 6.566 | Cadmium chloride 22% decrease in body weight gain NAFLD; increased hepatic triglyceride levels |\n| He et al. 2019b |  |  |  |  |  |  |  |  |  |  |\n| 103 | Mouse (BALB/c) 12 F | 16 weeks (W) | 0, 2, 6.5 | BW, FI, BC, BI, HP | Bd wt Musc/skel | 6.5 | 2 |  |  | Cadmium chloride |\n\nTrabecular bone damage\n(decreased number, thickness;\nincreased separation, fat cells);\naltered bone turnover parameters\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| He et al. 2020 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 104 | Mouse (C57BL/6) 10 M | 20 weeks (W) | 0, 1.5, 7.6 | LE, CS, BW, HP | Bd wt Gastro | 7.6 1.5 | 7.6 |  | Decreased length of intestinal villus and thickness of intestinal wall |\n| Hudson et al. 2019 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 105 | Mouse (C57BL/6J) NS F | 8 weeks 5 weeks prior to mating until birth (W) | 0, 0.3, 13 | RX, DX | Repro Develop | 13 | 0.3 | 13 | LOAEL: Increased absolute and relative heart weight in female pups at birth; increased tail blood volume and tail blood flow in female offspring at 5.5 months of age SLOAEL: 12% decrease in birth weight in both sexes; increased absolute and relative heart weight in male pups at birth; increased systolic, diastolic, and mean arterial blood pressure in female offspring at 5.5 months of age |\n| C57BL/6J dams mated to unexposed CAST/EiJ males, to generate F1 hybrid mice |  |  |  |  |  |  |  |  |  |\n| Hudson et al. 2019 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 106 | Mouse (CAST/EiJ) NS F | 8 weeks 5 weeks prior to mating until birth (W) | 0, 0.3, 13 | RX, DX | Repro Develop | 13 | 0.3 | 13 | LOAEL: Decreased body weight at birth in males; increased absolute heart weight in females SLOAEL: 22% decrease in birth weight |\n| CAST/EiJ dams mated to unexposed C57BL/6J males, to generate F1 hybrid mice |  |  |  |  |  |  |  |  |  |\n| Krzystyniak et al. 1987 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 107 | Mouse (C57BL/6) 10 F | 12–16 weeks (W) | 0, 0.6, 17, 52 | IX | Immuno | 17 | 52 |  | Reduced humoral immune response |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Kurita et al. 2018 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 108 | Mouse (C57BL/6J) 3–10 F | 18 days GDs 1–18 (G) | 0, 5, 10 | DX | Develop | 5 |  | 10 | 34% decrease in fetal weight, decreased fetal length |\n| Li et al. 2022 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 109 | Mouse (ICR) 10 F | 70 days 4 weeks premating to PND 21 (W) | 0, 2.6, 19.7 | WI, DX | Develop |  | 2.6 | 19.7 | LOAEL: Decreased serum estradiol and increased primordial follicles and decreased secondary follicles at PND 21 in female offspring; increased prevalence of irregular estrous cycles SLOAEL: 40% decreased in PND 21 body weight in female offspring; delayed vaginal opening |\n| Liu et al. 2023 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 110 | Mouse F0: 9–12 F F1: 5-7 M, 5–7 F | ~220 days F0: 1 week premating through PND 21 F1: PND 21 to 6 months of age (W) | F0: 0, 0.1, 1.5 F1: 0, 0.2, 1.6 | BC, OW, HP, NX | Immuno Neuro | 1.6 | 0.2 |  | Increased locomotor activity, impaired spatial memory (Y-maze test) in adult F1 mice |\n| Mei et al. 2017 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 111 | Mouse (C57BL/6) 5 M | 8 weeks (W) | 0, 1.5, 4.5, 7.6 | IX | Immuno |  | 1.5 |  | Delayed wound healing |\n| Ohsawa et al. 1988 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 112 | Mouse (BALB/c) 9–10 M | 10 weeks (W) | 0, 0.75, 7.5, 75 | IX | Immuno | 7.5 | 75 |  | Induction of anti-nuclear autoantibodies |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Ohsawa et al. 1988 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 113 | Mouse (ICR) 5–12 M | 10 weeks (W) | 0, 0.75, 7.5, 75 | IX | Immuno |  | 0.75 |  | Induction of anti-nuclear autoantibodies; biphasic immune response (stimulation at low dose, suppression at high dose) |\n| Tan et al. 2023 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 114 | Mouse (C57BL/6) 20 M | 10 weeks (W) | 0, 1.5, 15 | DX | Develop | 1.5 | 15 |  | Impaired growth in both sexes (10% at terminal sacrifice on PND 125); impaired glucose metabolism in adult female offspring |\n| Males mated to untreated females after 10-week exposure |  |  |  |  |  |  |  |  |  |\n| Valois and Webster 1989 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 115 | Mouse (QS) 25 F | 22 weeks (W) | 0, 0.20, 1.4, 11 | CS, BW, WI, HP | Bd wt | 0.2 | 1.4 | 11 | LOAEL: 19% decrease in body weight SLOAEL: 28% decrease in body weight |\n|  |  |  |  |  | Neuro | 0.2 |  | 1.4 | Degenerative and necrotic cellular changes in choroid plexus |\n| Marked decreases in water consumption at 1.4 and 11 mg Cd/kg/day |  |  |  |  |  |  |  |  |  |\n| Wang et al. 2016a |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 116 | Mouse (CD-1) 10 F | 19 days GDs 0–18 (W) | 0, 1.3, 9.3, 26.9 | BW, WI, RX, DX | Bd wt Repro Develop | 26.9 26.9 9.3 |  | 26.9 | 17% decrease in fetal weight; decreased crown-rump length |\n| Xiong et al. 2022a |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 117 | Mouse (C57BL/6) F0: 6–7 M, 17 F F1: 4 M | 32 weeks F0: 2 weeks premating–PNW 3 F1: PNWs 3–27 (W) | 0, 0.1, 1.3 | BW, WI, OW, HP | Bd wt Repro | 1.3 M 0.1 M | 1.3 M |  | Decreased absolute testis weight, germ cell loss |\n| Endpoints reported for F1 males (evaluated at PNW 27) |  |  |  |  |  |  |  |  |  |\n\nEndpoints reported for F1 males (evaluated at PNW 27)\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects | Cadmium chloride |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Zhang et al. 2019a |  |  |  |  |  |  |  |  |  |  |\n| 118 | Mouse (C57BL/6J) F0: 10 M, 10 F F1: 6 M, 6 F | 17-18 weeks F0: 1 month premating to PNW 3 F1: PNWs 3–10 (W) | 0, 0.001089, 0.01003, 0.10012 | DX | Develop | 0.10012 |  |  |  |  |\n| F1 pups examined for developmental landmarks, neurobehavior (PNWs 8-9), endocrine, and reproductive endpoints at PNW 10 |  |  |  |  |  |  |  |  |  |  |\n| Zhang et al. 2019a |  |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 119 | Mouse (C57BL/6J) F0: 10 M, 10 F F1: 6 M, 6 F | 25-26 weeks F0: 3 months premating to PNW 3 F1: PNWs 3–10 (W) | 0, 0.001089, 0.01003, 0.10012 | DX | Develop | 0.10012 |  |  |  |  |\n| F1 pups examined for developmental landmarks, neurobehavior (PNWs 8-9), endocrine, and reproductive endpoints at PNW 10 |  |  |  |  |  |  |  |  |  | Cadmium chloride |\n| Zhang et al. 2019a |  |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 120 | Mouse (C57BL/6J) F0: 10 M, 10 F F1: 6 M, 6 F | 33–34 weeks F0: 5 months premating to PNW 3 F1: PNWs 3–10 (W) | 0, 0.001089, 0.01003, 0.10012 | DX | Develop | 0.01003 | 0.10012 |  | Increased anxiety-like behavior in open field; elevated corticosterone levels |  |\n| F1 pups examined for developmental landmarks, neurobehavior (PNWs 8-9), endocrine, and reproductive endpoints at PNW 10 |  |  |  |  |  |  |  |  |  | Cadmium chloride |\n| Zhang et al. 2024b |  |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 121 | Mouse (ICR) 9–11 M | 21 days PNDs 22–42 (W) | 0, 0.9, 1.5 | DX | Develop | 0.9 | 1.5 |  | Altered socioemotional behaviors during adolescence (immobility in forced swim and tail suspension, decreased social interaction/preference for novelty) |  |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Boscolo and Carmignani 1986 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 122 | Rabbit (New Zealand) 8 M | 9 months (W) | 0, 1.6 | CS, BW, HP, OF | Bd wt Cardio Renal | 1.6 | 1.6 |  | Increased aortic resistance, reduced contractility |\n| Stowe et al. 1972 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 123 | Rabbit (New Zealand) 5 M | 200 days (W) | 0, 14.9 | CS, BW, WI, HE | Bd wt Hemato |  | 14.9 | 14.9 | 20% decrease in body weight Decreased hematocrit and hemoglobin; elevated neutrophils and decreased lymphocytes |\n| Stowe et al. 1972 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 124 | Rabbit (Belgian Giant) 5 M | 200 days (W) | 0, 14.9 | CS, BW, WI, HE | Bd wt Hemato |  | 14.9 | 14.9 | 15% decrease in body weight Decreased hematocrit and hemoglobin; elevated neutrophils and decreased lymphocytes |\n| CHRONIC EXPOSURE |  |  |  |  |  |  |  |  |  |\n| Buchet et al. 1990; Shao et al. 2007; Suwazono et al. 2006; Uno et al. 2005; Wu et al. 2001; Zhang et al. 2016a |  |  |  |  |  |  |  |  | Cadmium |\n| 125 | Human 85–3,454 per dataset | 17 datasets (3 occupational and 8 general population cohorts) | UR | Renal |  |  |  | LMW proteinuria; 95% LCL weighted median of 17 UC10 values = 0.000760 mg Cd/kg/dayd |  |\n| Bernard et al. 1992 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 126 | Rat (Sprague-Dawley) 50 F | up to 18 months (W) | 0, 13 | BI, BC, UR, HP, OF | Renal |  |  | 13 | Loss of glomerular polyanion charge barrier, proteinuria |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Bomhard et al. 1984 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 127 | Rat (Wistar) 12 M, 12 F | 72 weeks (F) | M: 0, 0.7, 3.5, 17.5 F: 0, 0.8, 4.0, 20.0 | BC, UR | Renal | 4 F | 20 F |  | Increase in urinary LDH and GST levels Increase in urinary LDH and GST levels |\n| 127 | Rat (Wistar) 12 M, 12 F | 72 weeks (F) | M: 0, 0.7, 3.5, 17.5 F: 0, 0.8, 4.0, 20.0 | BC, UR | Renal | 3.5 M | 17.5 M |  | Increase in urinary LDH and GST levels Increase in urinary LDH and GST levels |\n| Brzóska 2012; Brzóska and Moniuszko-Jakoniuk 2004a, 2004b |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 128 | Rat (Wistar) 10 F | 24 months (W) | 0, 0.08 | BW, FI, WI, BC, BI, UR, HP, OF | Bd wt Musc/skel | 0.08 |  | 0.08 | Decreases in bone mineral content and density of lumbar spine, altered bone turnover parameters, increases in deformed and fractured vertebral bodies |\n| Decker et al. 1958 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 129 | Rat (Sprague-Dawley) 8–10 M, 8–10 F | 12 months (W) | M: 0, 0.008, 0.036, 0.197, 0.386, 0.696 F: 0, 0.012, 0.062, 0.315, 0.578, 1.052 | LE, BW, FI, WI, HE, HP | Bd wt Gastro | 1.052 F 0.696 M 1.052 F 0.696 M 1.052 F 0.696 M 1.052 F 0.696 M 1.052 F 0.696 M 1.052 F 0.696 M 0.696 M 0.696 M 0.696 M 0.696 M |  |  |  |\n| 129 | Rat (Sprague-Dawley) 8–10 M, 8–10 F | 12 months (W) | M: 0, 0.008, 0.036, 0.197, 0.386, 0.696 F: 0, 0.012, 0.062, 0.315, 0.578, 1.052 | LE, BW, FI, WI, HE, HP | Renal | 1.052 F 0.696 M 0.696 M |  |  |  |\n| 129 | Rat (Sprague-Dawley) 8–10 M, 8–10 F | 12 months (W) | M: 0, 0.008, 0.036, 0.197, 0.386, 0.696 F: 0, 0.012, 0.062, 0.315, 0.578, 1.052 | LE, BW, FI, WI, HE, HP | Endocrinoma | 1.052 F 0.696 M 0.696 M 0.696 M |  |  |  |\n| 129 | Rat (Sprague-Dawley) 8–10 M, 8–10 F | 12 months (W) | M: 0, 0.008, 0.036, 0.197, 0.386, 0.696 F: 0, 0.012, 0.062, 0.315, 0.578, 1.052 | LE, BW, FI, WI, HE, HP | Neuro | 1.052 F 0.696 M 0.696 M |  |  |  |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects | Cadmium chloride |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Fingerle et al. 1982 |  |  |  |  |  |  |  |  |  |  |\n| 130 | Rat (Sprague-Dawley) 10 M, 10 F | M: 92 weeks F: 84 weeks (W) | M: 0, 0.6, 1.51, 3.78 F: 0, 0.8, 1.64, 4.01 | HP, BW, OW, OF, FI, WI, CS, LE | Bd wt Cardio | 4.01 4.01 |  |  |  |  |\n| Mangler et al. 1988 |  |  |  |  |  |  |  |  |  |  |\n| 131 | Rat (Sprague-Dawley) 12 F | 18 months (W) | 0, 2.301 | LE, BW, HP | Bd wt Renal | 2.301 | 2.301 |  | Cloudy swelling of renal tubular cells | Cadmium chloride |\n| Mangler et al. 1988 |  |  |  |  |  |  |  |  |  |  |\n| 132 | Rat (Sprague-Dawley) 12 F | 12 months (W) | 0, 2.337 | LE, BW, HP | Bd wt Renal | 2.337 | 2.337 |  | Cloudy swelling of renal tubular cells | Cadmium chloride |\n| Sato et al. 1978 |  |  |  |  |  |  |  |  |  |  |\n| 133 | Rat (Wistar) 11 NS | 31 months (W) | 0, 2.7 | CS, BW, WI, HP | Bd wt Musc/skel Neuro | 2.7 |  | 2.7 2.7 | Muscle weakness and atrophy Peripheral neuropathy | Cadmium chloride |\n| Waalkes and Rehm 1992 |  |  |  |  |  |  |  |  |  |  |\n| 134 | Rat (Wistar) 24–28 M | 77 weeks (F) | 0, 1.1, 2.3, 5.28, 10.9 | LE, CS, BW, FI, GN, HP | Bd wt Cancer | 2.3 | 5.28 | 2.3 | 10% decrease in body weight CEL: Large granular lymphocyte leukemia | Cadmium chloride |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Hays and Margaretten 1985 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 135 | Mouse (CBA/H) 5–13 M; 5 F | 12 months (W) | 0, 40 | BW, FI, WI, HE, BC, HP | Bd wt Hematocrit | 40 |  | 40 | 21% decreased terminal body weight Decreased hematocrit and neutrophils; bone marrow hypoplasia |\n|  |  |  |  |  | Renal | 40 |  |  |  |\n\n<sup>a</sup>The number corresponds to entries in Figure 2-3; differences in levels of health effects between male and females are not indicated in Figure 2-3.  Where such \ndifferences exist, only the levels of effect for the most sensitive sex are presented.\n\n<sup>b</sup>Doses are expressed as mg Cd/kg/day.  If doses were reported by study authors in terms of the administered compound (e.g., cadmium chloride [CdCl2]), they were \nconverted to the equivalent dose in terms of the metal (i.e., cadmium [Cd])) for easy comparison across studies. Conversion was based on the ratio of the molecular \nweights using the following equation: Dose in terms of administered compound × (molecular weight Cd/molecular weight administered compound).\n\n<sup>c</sup>Used to derive an acute-duration oral MRL of 0.002 mg Cd/kg/day (2 μg Cd/kg/day).  The LOAEL of 2 mg Cd/kg/day divided by an uncertainty factor of 1,000 (10 for use \nof a LOAEL, 10 for animal to human, and 10 for human variability).\n\n<sup>d</sup>Used to derive a chronic-duration oral MRL of 0.0003 mg Cd/kg/day (0.3 μg Cd/kg/day).  The point of departure (POD) is based on the 95% lower confidence limit (LCL) \non the weighted median of the UC10 values from 17 datasets from 11 human studies; the weighted median and 95% LCL were 2.04 and 1.57 μg Cd/g Cr, respectively.  \nThese values were converted into oral dose equivalents of 9.88x10<sup>-4</sup> and 7.60x10<sup>-4</sup> mg Cd/kg/day, respectively, using PBPK modeling. The POD of 7.60x10<sup>-4</sup> mg \nCd/kg/day was divided by an uncertainty factor of 3 for human variability and a modifying factor of 3 for database deficiencies. See Appendix A for more detailed \ninformation regarding the MRL.\n\n## Principal studies for the MRLs\n\nACTH = adrenocorticotrophic hormone; ALT = alanine aminotransferase; β2M = β2-microglobulin; BC = serum (blood) chemistry; Bd wt or BW = body weight; \nBI = biochemical changes; BUN = blood urea nitrogen; Cardio = cardiovascular; Cd = cadmium; CEL = cancer effect level; Cr = creatinine; CS = clinical signs; Develop \n= developmental; DX = developmental toxicity; Endocr = endocrine; (F) = feed (dietary); F = female(s); FI = food intake; (G) = gavage; (GO) = gavage in oil; \n(GW) = gavage in water; Gastro = gastrointestinal; GD = gestation day; GN = gross necropsy; GnRH = gonadotropin releasing hormone; GST = glutathione \nS-transferase; HDL = high-density lipoprotein; HE = hematology; Hemato = hematological; HP = histopathology; IL-6 = interleukin-6; Immuno = immunological; \nIX = immune function; LD50 = lethal dose, 50% kill; LDH = lactate dehydrogenase; LDL = low-density lipoprotein; LE = lethality; LH = luteinizing hormone; LMW = low \nmolecular weight; LOAEL = lowest-observed-adverse-effect level; M = male(s); MCHC = mean corpuscular hemoglobin concentration; MCV = mean corpuscular volume; \nMRL = Minimal Risk Level; Musc/skel = musculoskeletal; NAFLD = non-alcoholic fatty liver disease; Neuro = neurological; NK = natural killer; NOAEL = no-observedadverse-effect level; NS = not specified; NX = neurological function; OF = organ function; OW = organ weight; PBPK = physiologically based pharmacokinetic; \nPND = postnatal day; PNW = postnatal week; RBC = red blood cell; Repro = reproductive; Resp = respiratory; RX = reproductive function; SLOAEL = serious lowestobserved-adverse-effect level; T3 = triiodothyronine; TNF = tumor necrosis factor; TSH = thyroid-stimulating hormone; UC10 = urinary cadmium level associated with \n10% extra risk; UR = urinalysis; (W) = drinking water; WBC = white blood cell; WI = water intake\n\n---\n\n**Figure 2-3.  Levels of Significant Exposure to Cadmium – Oral**\nAcute (≤14 days)\n\n**Figure 2-3. Levels of Significant Exposure to Cadmium – Oral Acute (≤14 days) - Death**\n\n| Category | Animal - LD50/LC50 (mg Cd/kg/day) | Animal - NOAEL (mg Cd/kg/day) | Animal - LOAEL (mg Cd/kg/day) | Animal - SLOAEL (mg Cd/kg/day) |\n| --- | --- | --- | --- | --- |\n| 3R |  |  |  | 100 |\n| 4R |  |  |  | 70 |\n| 6R |  |  |  | 30 |\n| 8R | 28 |  |  |  |\n| 9R | 140 |  |  |  |\n| 10R | 130 |  |  |  |\n| 11R | 100 |  |  |  |\n| 12R | 70 |  |  |  |\n| 15R | 230 |  |  |  |\n| 16R |  |  |  | 45 |\n| 17R |  |  |  | 65 |\n| 21R | 110 |  |  |  |\n| 22R | 340 |  |  |  |\n| 26M |  |  |  | 85 |\n| 28M | 95 |  |  |  |\n\n---\n\n**Figure 2-3.  Levels of Significant Exposure to Cadmium – Oral**\nAcute (≤14 days)\n\n**Figure 2-3. Levels of Significant Exposure to Cadmium – Oral Acute (≤14 days) - Body Weight**\n\n| Category | Animal - LD50/LC50 (mg Cd/kg/day) | Animal - LOAEL (mg Cd/kg/day) | Animal - NOAEL (mg Cd/kg/day) | Animal - SLOAEL (mg Cd/kg/day) |\n| --- | --- | --- | --- | --- |\n| 2R |  |  |  | 12 |\n| 2R |  |  | 2.0 |  |\n| 4R |  |  | 150 |  |\n| 5R |  | 8.0 |  |  |\n| 5R |  |  | 1.2 |  |\n| 5R |  |  |  | 11 |\n| 6R |  |  |  | 30 |\n| 6R |  |  |  | 15 |\n| 14R |  |  |  | 150 |\n| 14R |  |  | 100 |  |\n| 17R |  |  |  | 6.0 |\n| 17R |  |  | 1.8 |  |\n| 18R |  |  |  | 13 |\n| 18R |  |  | 3.3 |  |\n| 19R |  |  |  | 14 |\n| 20R |  |  |  | 18 |\n| 20R |  |  | 6.0 |  |\n| 23R |  |  | 0.20 |  |\n| 24R |  |  | 0.25 |  |\n| 25R |  |  | 4.0 |  |\n\n---\n\n**Figure 2-3.  Levels of Significant Exposure to Cadmium – Oral**\nAcute (≤14 days)\n\n| Category | Animal - NOAEL (mg Cd/kg/day) | Animal - LOAEL (mg Cd/kg/day) | Animal - SLOAEL (mg Cd/kg/day) |\n| --- | --- | --- | --- |\n| Respiratory | 14R: 160 |  |  |\n| Cardiovascular | 14R: 160 |  |  |\n| Gastrointestinal | 14R: 160 |  |  |\n|  |  | 17R: 65 |  |\n|  |  | 17R: 19 |  |\n|  |  | 26M: 30 |  |\n|  |  | 26M: 16 |  |\n|  |  | 26M: 85 |  |\n| Hematological | 1R: 15 |  |  |\n|  |  | 4R: 150 |  |\n|  |  | 5R: 14 |  |\n|  |  | 6R: 16 |  |\n|  |  | 14R: 160 |  |\n|  |  | 19R: 16 |  |\n| Hepatic | 4R: 150 |  |  |\n|  |  | 5R: 13 |  |\n|  |  | 6R: 16 |  |\n|  |  | 6R: 33 |  |\n|  |  | 14R: 160 |  |\n|  |  | 26M: 33 |  |\n|  |  | 26M: 16 |  |\n\n---\n\n**Figure 2-3.  Levels of Significant Exposure to Cadmium – Oral**\nAcute (≤14 days)\n\n**Figure 2-3. Levels of Significant Exposure to Cadmium – Oral Acute (≤14 days)**\n\n| Category | Animal - LD50/LC50 (mg Cd/kg/day) | Animal - LOAEL (mg Cd/kg/day) | Animal - NOAEL (mg Cd/kg/day) | Animal - SLOAEL (mg Cd/kg/day) | MRL for effect other than cancer (mg Cd/kg/day) |\n| --- | --- | --- | --- | --- | --- |\n| Renal |  |  | 4R: 150 |  |  |\n| Renal |  |  | 5R: 13 |  |  |\n| Renal |  |  | 6R: 70 | 6R: 70 |  |\n| Renal |  |  | 6R: 30 |  |  |\n| Renal |  |  | 14R: 160 |  |  |\n| Renal |  |  | 25R: 2.0 | 25R: 2.0 | 0.0022 |\n| Renal |  |  | 26M: 65 | 26M: 90 |  |\n| Dermal |  |  | 17R: 2.3 | 17R: 7.0 |  |\n| Endocrine |  |  | 14R: 150 |  |  |\n| Endocrine |  |  | 19R: 50 |  |  |\n| Immunological |  |  | 23R: 0.26 | 23R: 0.26 |  |\n| Immunological |  |  | 23R: 0.028 |  |  |\n| Immunological |  |  | 24R: 0.28 |  |  |\n| Neurolgical |  |  | 13R: 26 | 13R: 50 |  |\n| Neurolgical |  |  | 13R: 2.3 |  |  |\n\n---\n\n**Figure 2-3.  Levels of Significant Exposure to Cadmium – Oral**\nAcute (≤14 days)\n\n**Figure 2-3. Levels of Significant Exposure to Cadmium – Oral Acute (≤14 days)**\n\n| Category | Reproductive Animal - LD50/LC50 (mg Cd/kg/day) | Reproductive Animal - LOAEL (mg Cd/kg/day) | Reproductive Animal - NOAEL (mg Cd/kg/day) | Reproductive Animal - SLOAEL (mg Cd/kg/day) | Developmental Animal - LD50/LC50 (mg Cd/kg/day) | Developmental Animal - LOAEL (mg Cd/kg/day) | Developmental Animal - NOAEL (mg Cd/kg/day) | Developmental Animal - SLOAEL (mg Cd/kg/day) |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| 3R |  |  |  | 1', 'pages': None, 'truncated': True, 'extraction': 'firecrawl-public-document-markdown', 'request_id': '293c7827-ff96-4db1-b5ad-c97da5c1aeef', 'source_url': 'https://downloads.regulations.gov/ATSDR-2026-0133-0002/attachment_1.pdf', 'observed_at': '2026-10-04T00:38:44.750111+00:00', 'content_hash': '19390979349ee9f90ebdd60e3716b58502ea8d916d0b4add252a923c7eb753e3'}, 'title': 'Draft Toxicological Profile for Cadmium', 'check_failed': False}, {'url': 'https://downloads.regulations.gov/ATSDR-2026-0133-0002/content.pdf', 'body': {'text': '## Toxicological Profile for Cadmium\nDraft for Public Comment\nOctober 2026\n\nATSDR\nU.S. Department of Health and Human Services\nAgency for Toxic Substances and Disease Registry\n\nCS274127-A\n\n---\n\n## DISCLAIMER\n\nUse of trade names is for identification only and does not imply endorsement by the Agency for Toxic \nSubstances and Disease Registry, the Public Health Service, or the U.S. Department of Health and Human \nServices.\n\nThis information is distributed solely for the purpose of pre-dissemination for public comment under \napplicable information quality guidelines.  It has not been formally disseminated by the Agency for Toxic \nSubstances and Disease Registry.  It does not represent and should not be construed to represent any \nagency determination or policy.\n\n---\n\n## FOREWORD\n\nThis toxicological profile is prepared in accordance with guidelines developed by the Agency for Toxic \nSubstances and Disease Registry (ATSDR) and the Environmental Protection Agency (EPA).  The \noriginal guidelines were published in the *Federal Register* on April 17, 1987.  Each profile will be revised \nand republished as necessary.\n\nThe ATSDR toxicological profile succinctly characterizes the toxicologic and adverse health effects \ninformation for these toxic substances described therein.  Each peer-reviewed profile identifies and \nreviews the key literature that describes a substance\'s toxicologic properties.  Other pertinent literature is \nalso presented but is described in less detail than the key studies.  The profile is not intended to be an \nexhaustive document; however, more comprehensive sources of specialty information are referenced.\n\nThe focus of the profiles is on health and toxicologic information; therefore, each toxicological profile \nbegins with a relevance to public health discussion which would allow a public health professional to \nmake a real-time determination of whether the presence of a particular substance in the environment \nposes a potential threat to human health.  The adequacy of information to determine a substance\'s health \neffects is described in a health effects summary.  Data needs that are of significance to the protection of \npublic health are identified by ATSDR.\n\nEach profile includes the following:\n\n(A) The examination, summary, and interpretation of available toxicologic information and \nepidemiologic evaluations on a toxic substance to ascertain the levels of significant \nhuman exposure for the substance due to associated acute-, intermediate-, and chronicduration exposures;\n\n(B) A determination of whether adequate information on the health effects of each substance \nis available or in the process of development to determine the levels of exposure that \npresent a significant risk to human health due to acute-, intermediate-, and chronicduration exposures; and\n\n(C) Where appropriate, identification of toxicologic testing needed to identify the types or \nlevels of exposure that may present significant risk of adverse health effects in humans.\n\nThe principal audiences for the toxicological profiles are health professionals at the Federal, State, and \nlocal levels; interested private sector organizations and groups; and members of the public.  ATSDR plans \nto revise these documents in response to public comments and as additional data become available.  \nTherefore, we encourage comments that will make the toxicological profile series of the greatest use.\n\nElectronic comments may be submitted via: www.regulations.gov. Follow the on-line instructions for \nsubmitting comments.\n\nWritten comments may also be sent to:\n\nWritten comments may also be sent to:  Agency for Toxic Substances and Disease Registry\n\nOffice of Innovation and Analytics\n\nToxicology Section\n\n1600 Clifton Road, N.E.\n\nMail Stop S106-5\n\nAtlanta, Georgia 30329-4027\n\n---\n\nThe toxicological profiles are developed under the Comprehensive Environmental Response, \nCompensation, and Liability Act of 1980, as amended (CERCLA or Superfund).  CERCLA \nSection 104(i)(1) directs the Administrator of ATSDR to “…effectuate and implement the health-related \nauthorities” of the statute.  This includes the preparation of toxicological profiles for hazardous \nsubstances most commonly found at facilities on the CERCLA National Priorities List (NPL) and that \npose the most significant potential threat to human health, as determined by ATSDR and the EPA.  \nSection 104(i)(3) of CERCLA, as amended, directs the Administrator of ATSDR to prepare a \ntoxicological profile for each substance on the list.  In addition, ATSDR has the authority to prepare \ntoxicological profiles for substances not found at sites on the NPL, in an effort to “…establish and \nmaintain inventory of literature, research, and studies on the health effects of toxic substances” under \nCERCLA Section 104(i)(1)(B), to respond to requests for consultation under Section 104(i)(4), and as \notherwise necessary to support the site-specific response actions conducted by ATSDR.\n\nThis profile reflects ATSDR’s assessment of all relevant toxicologic testing and information that has been \npeer-reviewed.  Staffs of the Centers for Disease Control and Prevention and other Federal scientists have \nalso reviewed the profile.  In addition, this profile has been peer-reviewed by a nongovernmental panel \nand is being made available for public review.  Final responsibility for the contents and views expressed \nin this toxicological profile resides with ATSDR.\n\nChristopher M. Reh, Ph.D. \nAssociate Director,\nAgency for Toxic Substances and Disease Registry \nCenters for Disease Control and Prevention\n\n---\n\n**VERSION HISTORY**\n\n| Date | Description |\n| --- | --- |\n| October 2026 | Draft for public comment toxicological profile released |\n| September 2012 | Final toxicological profile released |\n| July 1999 | Final toxicological profile released |\n| April 1993 | Final toxicological profile released |\n| March 1989 | Final toxicological profile released |\n\n---\n\n# CONTRIBUTORS & REVIEWERS\n\n# CHEMICAL MANAGER TEAM\n\nBrittany Szafran, D.V.M, Ph.D., D.A.B.T. (lead)\nCustodio Muianga, M.P.H., Ph.D., C.H.M.M.\nMohammad Shoeb, Ph.D.\nBreanna Alman, M.P.H.\nFranco Scinicariello, M.D., M.P.H.\n\nKimberly Zaccaria, Ph.D., D.A.B.T.\nFrances Belmonte, Ph.D., D.A.B.T.\nHeather Carlson-Lynch, M.S., D.A.B.T.\nMario Citra, Ph.D.\nGary L. Diamond, Ph.D.\nZach Guerrette, Ph.D., D.A.B.T\nDeborah M. Herber, Ph.D.\nClaire Heit, Ph.D.\nLisa Ingerman, Ph.D., D.A.B.T.\nConnor McGuire, Ph.D.\nJennifer Rhoades, B.S.\n\nATSDR, Office of Innovation and Analytics, \nToxicology Section, Atlanta, GA\n\nSRC, Inc., North Syracuse, NY\n\n## REVIEWERS\n\n## Interagency Minimal Risk Level Workgroup:\n\nIncludes ATSDR; National Center for Environmental Health (NCEH); U.S. Environmental Protection \nAgency (EPA); National Toxicology Program (NTP).\n\n## Additional reviews for science and/or policy:\n\nATSDR, Office of Community Health Hazard Assessment; ATSDR, Office of Capacity Development \nand Applied Prevention Science; ATSDR, Office of Science; NCEH, Division of Laboratory Sciences; \nNCEH, Division of Environmental Health Science and Practice; National Institute for Occupational \nSafety and Health (NIOSH); EPA, Office of Research and Development; EPA, Office of Water.\n\n## PEER REVIEWERS\n\n1. Kristen Upson, Ph.D., M.P.H.; Associate Professor of Epidemiology and Biostatistics; Michigan \nState University; Department of Epidemiology and Biostatistics; 909 Wilson Road Room B601; \nEast Lansing, MI\n\n2. Zahir Shaikh, Ph.D.; Professor Emeritus and Former Founding Director of RI-INBRE; The \nUniversity of Rhode Island, College of Pharmacy; Kingston, RI\n\n3. Curtis D. Klaassen, M.S., Ph.D., FATS, FAASLD, FASPET; Director of the Mid-America \nToxicology Course; Previously University Distinguished Professor and Chair at The University \nof Kansas School of Medicine; Kansas City, KS (retired)\n\nThese experts collectively have knowledge of toxicology, chemistry, and/or health effects.  All reviewers \nwere selected in conformity with Section 104(I)(13) of the Comprehensive Environmental Response, \nCompensation, and Liability Act, as amended.\n\n---\n\nATSDR scientists review peer reviewers’ comments and determine whether changes will be made to the \nprofile based on comments.  The peer reviewers’ comments and responses to these comments are part of \nthe administrative record for this compound.\n\nThe listing of peer reviewers should not be understood to imply their approval of the profile\'s final \ncontent.  The responsibility for the content of this profile lies with ATSDR.\n\n---\n\n## CONTENTS\n\nDISCLAIMER .............................................................................................................................................. ii\nFOREWORD ............................................................................................................................................... iii\nVERSION HISTORY ................................................................................................................................... v\nCONTRIBUTORS & REVIEWERS ........................................................................................................... vi\nCONTENTS ............................................................................................................................................... viii\nLIST OF FIGURES ...................................................................................................................................... x\nLIST OF TABLES ....................................................................................................................................... xi\nCHAPTER 1. RELEVANCE TO PUBLIC HEALTH ................................................................................. 1\n1.1 OVERVIEW AND U.S. EXPOSURES ......................................................................................... 1\n1.2 SUMMARY OF HEALTH EFFECTS........................................................................................... 2\n1.3 MINIMAL RISK LEVELS (MRLs) .............................................................................................. 8\nCHAPTER 2. HEALTH EFFECTS ............................................................................................................ 12\n2.1 INTRODUCTION ........................................................................................................................ 12\n2.2 DEATH ........................................................................................................................................ 92\n2.3 BODY WEIGHT .......................................................................................................................... 99\n2.4 RESPIRATORY ........................................................................................................................ 104\n2.5 CARDIOVASCULAR ............................................................................................................... 113\n2.6 GASTROINTESTINAL ............................................................................................................. 124\n2.7 HEMATOLOGICAL ................................................................................................................. 125\n2.8 MUSCULOSKELETAL ............................................................................................................ 131\n2.9 HEPATIC ................................................................................................................................... 143\n2.10 RENAL ...................................................................................................................................... 151\n2.11 DERMAL ................................................................................................................................... 171\n2.12 OCULAR ................................................................................................................................... 172\n2.13 ENDOCRINE ............................................................................................................................. 172\n2.14 IMMUNOLOGICAL ................................................................................................................. 182\n2.15 NEUROLOGICAL..................................................................................................................... 189\n2.16 REPRODUCTIVE ..................................................................................................................... 196\n2.17 DEVELOPMENTAL ................................................................................................................. 213\n2.18 OTHER NONCANCER ............................................................................................................. 239\n2.19 CANCER .................................................................................................................................... 241\n2.20 GENOTOXICITY ...................................................................................................................... 256\n2.21 MECHANISMS OF ACTION ................................................................................................... 266\nCHAPTER 3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, \nCHEMICAL INTERACTIONS ......................................................................................... 269\n3.1 TOXICOKINETICS................................................................................................................... 269\n3.1.1 Absorption ........................................................................................................................... 269\n3.1.2 Distribution ......................................................................................................................... 274\n3.1.3 Metabolism .......................................................................................................................... 277\n3.1.4 Excretion ............................................................................................................................. 278\n3.1.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models ........... 278\n3.1.6 Animal-to-Human Extrapolations ....................................................................................... 285\n3.2 CHILDREN AND OTHER POPULATIONS THAT ARE UNUSUALLY \nSUSCEPTIBLE .......................................................................................................................... 286\n\n---\n\n3.3 BIOMARKERS OF EXPOSURE AND EFFECT ..................................................................... 290\n3.3.1 Biomarkers of Exposure ...................................................................................................... 291\n3.3.2 Biomarkers of Effect ........................................................................................................... 294\n3.4 INTERACTIONS WITH OTHER CHEMICALS ..................................................................... 297\nCHAPTER 4. CHEMICAL AND PHYSICAL INFORMATION ........................................................... 303\n4.1 CHEMICAL IDENTITY ........................................................................................................... 303\n4.2 PHYSICAL AND CHEMICAL PROPERTIES ........................................................................ 304\nCHAPTER 5. POTENTIAL FOR HUMAN EXPOSURE ....................................................................... 307\n5.1 OVERVIEW .............................................................................................................................. 307\n5.2 PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL ................................................ 310\n5.2.1 Production ........................................................................................................................... 310\n5.2.2 Import/Export ...................................................................................................................... 313\n5.2.3 Use ...................................................................................................................................... 314\n5.2.4 Disposal ............................................................................................................................... 314\n5.3 RELEASES TO THE ENVIRONMENT ................................................................................... 315\n5.3.1 Air ....................................................................................................................................... 315\n5.3.2 Water ................................................................................................................................... 319\n5.3.3 Soil ...................................................................................................................................... 320\n5.4 ENVIRONMENTAL FATE ...................................................................................................... 321\n5.4.1 Transport and Partitioning ................................................................................................... 321\n5.4.2 Transformation and Degradation ........................................................................................ 325\n5.5 LEVELS IN THE ENVIRONMENT ......................................................................................... 326\n5.5.1 Air ....................................................................................................................................... 327\n5.5.2 Water ................................................................................................................................... 328\n5.5.3 Sediment and Soil ............................................................................................................... 330\n5.5.4 Other Media ........................................................................................................................ 332\n5.6 GENERAL POPULATION EXPOSURE.................................................................................. 335\n5.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES .............................................. 362\nCHAPTER 6. ADEQUACY OF THE DATABASE ................................................................................ 363\n6.1 EXISTING INFORMATION ON HEALTH EFFECTS ........................................................... 363\n6.2 IDENTIFICATION OF DATA NEEDS .................................................................................... 365\n6.3 ONGOING STUDIES ................................................................................................................ 372\nCHAPTER 7. REGULATIONS AND GUIDELINES ............................................................................. 376\nCHAPTER 8. REFERENCES .................................................................................................................. 380\nAPPENDICES\nAPPENDIX A.  ATSDR MINIMAL RISK LEVEL WORKSHEETS .................................................... A-1 \nAPPENDIX B.  LITERATURE SEARCH FRAMEWORK FOR CADMIUM ...................................... B-1 \nAPPENDIX C.  FRAMEWORK FOR ATSDR’S SYSTEMATIC REVIEW OF HEALTH EFFECTS \nDATA FOR CADMIUM ................................................................................................ C-1 \nAPPENDIX D.  USER’S GUIDE ............................................................................................................. D-1 \nAPPENDIX E.  QUICK REFERENCE FOR HEALTH CARE PROVIDERS ....................................... E-1 \nAPPENDIX F.  GLOSSARY .................................................................................................................... F-1 \nAPPENDIX G.  ACRONYMS, ABBREVIATIONS, AND SYMBOLS................................................. G-1\n\n---\n\n## LIST OF FIGURES\n\n1-1.  Health Effects Found in Animals Following Inhalation Exposure to Cadmium .................................. 4\n1-2.  Health Effects Found in Animals Following Oral Exposure to Cadmium ........................................... 5\n1-3.  Summary of Sensitive Targets of Cadmium – Inhalation ..................................................................... 9\n1-4.  Summary of Sensitive Targets of Cadmium – Oral ............................................................................ 10\n2-1.  Overview of the Number of Studies Examining Cadmium Health Effects ........................................ 17\n2-2.  Levels of Significant Exposure to Cadmium – Inhalation .................................................................. 33\n2-3.  Levels of Significant Exposure to Cadmium – Oral ........................................................................... 72\n3-1.  Structure of Kjellström-Nordberg Cadmium Biokinetic Model ....................................................... 280\n3-2.  Structure of Diamond and Klotzbach Cadmium Biokinetics Model ................................................ 283\n5-1.  Number of NPL Sites with Cadmium Contamination ...................................................................... 307\n6-1.  Summary of Existing Health Effects Studies on Cadmium by Route and Endpoint ........................ 364\n\n---\n\n## LIST OF TABLES\n\n1-1.  Minimal Risk Levels (MRLs) for Cadmium ...................................................................................... 11\n2-1.  Levels of Significant Exposure to Cadmium – Inhalation .................................................................. 18\n2-2.  Levels of Significant Exposure to Cadmium – Oral ........................................................................... 41\n2-3.  Levels of Significant Exposure to Cadmium – Dermal ...................................................................... 90\n2-4.  Results of Meta-Analyses Evaluating Exposure to Cadmium and Mortality Endpoints .................... 93\n2-5.  Studies Included in Meta-Analyses Evaluating Exposure to Cadmium and Mortality \nEndpoints ............................................................................................................................................ 94\n2-6.  Results of General Population Studies Evaluating Urinary Cadmium Levels and All-Cause \nMortality ............................................................................................................................................. 94\n2-7.  Results of Meta-Analysis Evaluating Exposure to Cadmium and Respiratory Endpoints ............... 106\n2-8.  Results of Epidemiological Studies Evaluating Urinary Cadmium Levels and Respiratory \nEffects ............................................................................................................................................... 108\n2-9.  Results of Meta-Analyses Evaluating Exposure to Cadmium and Cardiovascular Endpoints ......... 113\n2-10.  Studies Included in Meta-Analyses Evaluating Exposure to Cadmium and Cardiovascular \nEndpoints ........................................................................................................................................ 116\n2-11.  Results of General Population Studies Evaluating Urinary Cadmium Levels and Blood \nPressure or Hypertension ................................................................................................................ 118\n2-12.  Results of General Population Studies Evaluating Urinary Cadmium Levels and \nCardiovascular Disease-Related Effects ......................................................................................... 122\n2-13.  Results of General Population Epidemiological Studies Evaluating Urinary Cadmium \nLevels and Hematological Effects .................................................................................................. 126\n2-14.  Results of Meta-Analyses Evaluating Exposure to Cadmium and Skeletal Endpoints .................. 132\n2-15.  Studies Included in Meta Analyses Evaluating Exposure to Cadmium and Skeletal \nEndpoints ........................................................................................................................................ 133\n2-16.  Results of General Population Epidemiological Studies Evaluating Urinary Cadmium \nLevels and Musculoskeletal Effects ............................................................................................... 136\n2-17.  Results of Meta-Analyses Evaluating Exposure to Cadmium and Serum Lipids .......................... 143\n2-18.  Studies Included in Meta-Analyses Evaluating Exposure to Cadmium and Serum Lipids ............ 144\n2-19.  Results of General Population Studies Evaluating Urinary Cadmium Levels and Blood \nLipid Levels .................................................................................................................................... 145\n\n---\n\n2-20.  Results of General Population Studies Evaluating Exposure to Urinary Cadmium Levels \nand Hepatic Disease and Clinical Chemistry ................................................................................. 147\n2-21.  Results of Occupational Studies Evaluating Urine Cadmium Levels and Renal Outcomes .......... 154\n2-22.  Results of Meta-Analyses Evaluating Exposure to Cadmium and Renal Endpoints ...................... 157\n2-23.  Studies Included in Meta-Analyses Evaluating Exposure to Cadmium and Renal Endpoints ....... 158\n2-24.  Results of Epidemiological Studies of General Populations Evaluating Urine Cadmium \nLevels and Renal Effects ................................................................................................................ 161\n2-25.  Results of Meta-Analysis Evaluating Exposure to Cadmium and Thyroid Endpoints ................... 173\n2-26.  Results of General Population Studies Evaluating Urinary Cadmium Levels and Thyroid \nEffects ............................................................................................................................................. 174\n2-27.  Results of Meta-Analyses Evaluating Exposure to Cadmium and Diabetes Endpoints ................. 175\n2-28.  Studies Included in Meta Analyses Evaluating Exposure to Cadmium and Diabetes \nEndpoints ........................................................................................................................................ 177\n2-29.  Results of Epidemiological Studies Evaluating Exposure to Cadmium and Diabetes-\nRelated Effects ................................................................................................................................ 179\n2-30.  Results of Epidemiological Studies Evaluating Urinary Cadmium Levels and \nImmunological Effects ................................................................................................................... 182\n2-31.  Results of Meta-Analyses Evaluating Exposure to Cadmium and Neurological Endpoints .......... 190\n2-32.  Studies Included in Meta-Analyses Evaluating Exposure to Cadmium and Neurological \nEndpoints ........................................................................................................................................ 191\n2-33.  Results of General Population Studies Evaluating Exposure to Urinary Cadmium and \nNeurological Effects ....................................................................................................................... 192\n2-34.  Results of Meta-Analyses Evaluating Exposure to Cadmium and Male Reproductive \nEndpoints ........................................................................................................................................ 196\n2-35.  Studies Included in Meta-Analyses Evaluating Exposure to Cadmium and Male \nReproductive Endpoints ................................................................................................................. 197\n2-36.  Results of General Population Studies Evaluating Urinary Cadmium Levels and \nReproductive Effects in Men .......................................................................................................... 199\n2-37.  Results of Meta-Analyses Evaluating Exposure to Cadmium and Female Reproductive \nEndpoints ........................................................................................................................................ 202\n2-38.  Studies Included in Meta-Analyses Evaluating Exposure to Cadmium and Female \nReproductive Endpoints ................................................................................................................. 203\n2-39.  Results of General Population Studies Evaluating Urinary Cadmium Levels and \nReproductive Effects in Women..................................................................................................... 204\n\n---\n\n2-40.  Results of Meta-Analyses Evaluating Exposure to Cadmium and Neurodevelopmental \nEndpoints ........................................................................................................................................ 213\n2-41.  Studies Included in Meta-Analyses Evaluating Exposure to Cadmium and \nNeurodevelopmental Endpoints ..................................................................................................... 214\n2-42.  Results of General Population Studies Evaluating Exposure to Cadmium and \nNeurodevelopmental Effects .......................................................................................................... 217\n2-43.  Results of General Population Studies Evaluating Urinary Cadmium Levels and Growth \nand Metabolism During Infancy, Childhood, and Adolescence ..................................................... 228\n2-44.  Results of General Population Studies Evaluating Urinary Cadmium Levels and \nReproductive Developmental Effects ............................................................................................. 233\n2-45.  Results of Meta-Analyses Evaluating Exposure to Cadmium and Metabolic Syndrome \nEndpoints ........................................................................................................................................ 240\n2-46.  Studies Included in Meta Analyses Evaluating Exposure to Cadmium and Metabolic \nSyndrome Endpoints ...................................................................................................................... 240\n2-47.  Results of Meta-Analyses Evaluating Exposure to Cadmium and Cancer ..................................... 242\n2-48.  Studies Included in Meta-Analyses Evaluating Exposure to Cadmium and Cancer ...................... 245\n2-49.  Results of Epidemiological Studies Evaluating Exposure to Cadmium and Cancer ...................... 250\n2-50.  Genotoxicity of Cadmium *In Vivo* .................................................................................................. 257\n2-51.  Genotoxicity of Cadmium *In Vitro* ................................................................................................. 259\n4-1.  Chemical Identity of Cadmium and Compounds ............................................................................. 303\n4-2.  Physical and Chemical Properties of Cadmium and Compounds .................................................... 304\n5-1.  Facilities that Produce, Process, or Use Cadmium ........................................................................... 310\n5-2.  Facilities that Produce, Process, or Use Cadmium Compounds ....................................................... 311\n5-3.  Releases to the Environment from Facilities that Produce, Process, or Use Cadmium .................... 316\n5-4.  Releases to the Environment from Facilities that Produce, Process, or Use Cadmium \nCompounds ....................................................................................................................................... 317\n5-5.  Lowest Limit of Detection Based on Standards ............................................................................... 326\n5-6.  Summary of Environmental Levels of Cadmium ............................................................................. 327\n5-7.  Range of Arithmetic Means for Cadmium from the AQS ................................................................ 327\n5-8.  Total Cadmium Levels in Groundwater and Surface Water in U.S. Samples Collected in \n2022–2024 ........................................................................................................................................ 329\n5-9.  Total Cadmium Levels in Ambient Sediment Collected in 2022–2024 ........................................... 331\n\n---\n\n5-10.  Mean Concentrations of Cadmium for FDA’s Total Diet Study Market Baskets 2006-1\nthrough 2008-4 ............................................................................................................................... 333\n5-11.  Geometric Mean and Selected Percentile Blood Concentrations (μg/L) of Cadmium in the\nU.S. Population, 1999–2018 ........................................................................................................... 336\n5-12.  Geometric Mean and Selected Percentile Urine Concentrations (Creatinine Corrected)\n(μg/g Creatinine) of Cadmium in the U.S. Population, 1999––2018 ............................................. 343\n5-13.  Geometric Mean and Selected Percentile Urine Concentrations (μg/L) of Cadmium in the\nU.S. Population, 1999–2018 ........................................................................................................... 350\n5-14.  Blood Cadmium Concentrations, Geometric Means, Adjusted Proportional Change in\nMeans, and 95<sup>th</sup> Percentiles in New York City Adults in Population \nSubgroups....................................................................................................................................... 357\n5-15.  Occupations with Potential Exposure to Cadmium and Cadmium Compounds ............................ 361\n6-1.  Ongoing Studies on Cadmium .......................................................................................................... 372\n7-1.  Regulations and Guidelines Applicable to Cadmium ....................................................................... 376\n\n---\n\n## CHAPTER 1. RELEVANCE TO PUBLIC HEALTH\n\n### 1.1 OVERVIEW AND U.S. EXPOSURES\n\nCadmium (Cd) occurs in the earth’s crust at a concentration of roughly 0.1–0.5 ppm and is commonly \nassociated with zinc, lead, and copper ores.  It is also a natural constituent of ocean water with average \nlevels between <5 and 110 ng/L, with higher levels reported near coastal areas and in marine phosphates \nand phosphorites (Morrow 2010).  The cadmium concentration of natural surface water and groundwater \nis usually <1 μg/L (Elinder 1985a, 1992).  Surface soil concentrations will depend on several factors such \nas its mobility, natural geochemistry, and magnitude of contamination from sources such as fertilizers and \natmospheric deposition.  Natural emissions of cadmium to the environment can result from volcanic \neruptions, forest fires, generation of sea salt aerosols, or other natural phenomena (EPA 1985; Morrow \n2010; Shevchenko et al. 2003).\n\n$$\n<1\\;\\mu g/L\n$$\n\nIn the environment, cadmium exists in only one oxidation state (Cd<sup>+2</sup>) and does not undergo oxidationreduction reactions.  In surface water and groundwater, cadmium can exist as the hydrated ion or as ionic \ncomplexes with other inorganic or organic substances.  Soluble forms of cadmium can migrate in water.  \nInsoluble forms of cadmium will settle and adsorb to sediments.  Cadmium’s fate in soil depends on \nseveral factors such as pH of the soil and availability of organic matter.  Generally, cadmium will bind \nstrongly to organic matter and this will, for the most part, immobilize it (Autier and White 2004).  \nHowever, cadmium’s behavior in soil will vary depending on the environmental conditions.  It is not \nlikely that cadmium will undergo significant transformation in the atmosphere (EPA 1980).  It will exist \nin particulate form and sometimes vapor form (emitted from high-temperature processes) where it will \nundergo atmospheric transport and eventually deposit onto soils and surface waters.\n\n$$\n\\left(\\mathrm{Cd^{+2}}\\right)\n$$\n\nNon-ferrous metal mining and refining, manufacture and application of phosphate fertilizers, fossil fuel \ncombustion, and waste incineration and disposal are the main anthropogenic sources of cadmium in the \nenvironment.  Except for those who live near cadmium-emitting industries, inhalation of cadmium in the \nambient air may occur but is not a major source of exposure.  Similarly, cadmium exposure through the \ndrinking water supply is of minor concern for the majority of the U.S. population.  However, water \nsources near cadmium-emitting industries, both with historic and current operations, have shown a \nmarked elevation of cadmium in water sediments and aquatic organisms (Angelo et al. 2007; Arnason and \nFletcher 2003; Brumbaugh et al. 2005; Mason et al. 2000; Paulson 1997).  Concentrations of cadmium in these polluted waters have ranged from <1.0 to 77 μg/L.  Cadmium from polluted soil and water can \naccumulate in plants and organisms, thus entering the food supply (Morrow 2010).\n\n$$\n7 7 \\mu \\mathrm {g} / \\mathrm {L}\n$$\n\nIn the United States, the largest source of cadmium exposure for nonsmoking adults and children is \nthrough dietary intake (NTP 2005).  The average daily intake of cadmium for children and adults \n(≥2 years of age) in the United States was estimated as 4.63 µg/day (Kim et al. 2019).  In general, leafy \nvegetables such as lettuce and spinach and staples such as potatoes and grains contain relatively high \nvalues of cadmium.  Peanuts, soybeans, and sunflower seeds have naturally high levels of cadmium \n(Morrow 2010).  Shellfish and organ meats (liver and kidney) also have relatively high concentrations of \ncadmium (Elinder 1985a).\n\nMean values of cadmium in the blood and urine of the U.S. population were reported in the National \nHealth and Nutrition Examination Survey (NHANES) 1999–2018 (CDC 2024).  Blood cadmium tends to \nreflect recent exposures, and urinary cadmium reflects cumulative cadmium exposure and body burden \n(particularly, kidney cadmium levels).  The geometric mean blood cadmium levels for the total population \n(≥1 year of age) have decreased nearly 50% from survey years 1999–2000 (0.412 µg/L) to survey years \n2017–2018 (0.241 µg/L).\n\n$$\n1999-2000\\left(0.412\\ \\mu g/L\\right)\n$$\n\n$$\n2017-2018\\left(0.241\\ \\mu g/L\\right)\n$$\n\nSmoking greatly increases exposure to cadmium, as tobacco leaves naturally accumulate high amounts of \ncadmium (Morrow 2010).  It has been estimated that tobacco smokers are exposed to 0.5–2.0 μg \ncadmium per cigarette, and about 10% is inhaled when smoked (Morrow 2010; Nordberg et al. 2015; \nNTP 2005).  A geometric mean blood cadmium level for a heavy smoker has been reported as high as \n1.58 μg/L (McKelvey et al. 2007), compared to the estimated national mean of 0.295 μg/L for all adults\n≥20 years of age, based on survey years 2017–2018 (CDC 2024).  Nonsmokers may also be exposed to \ncadmium in cigarettes via second-hand smoke.\n\n$$\n1. 5 8 \\mu \\mathrm {g} / \\mathrm {L}\n$$\n\n### 1.2 SUMMARY OF HEALTH EFFECTS\n\nSince the early 1950s, when the hazards of occupational cadmium exposure were recognized (Friberg \n1950), a large amount of information has been generated concerning the toxic effects of cadmium \nexposure in humans and laboratory animals.  Toxicological properties of cadmium are similar for the \nseveral different salts and oxides of cadmium that have been investigated, although differences in \nabsorption and distribution lead to different effect levels.  For inhalation exposure, particle size and \nsolubility in biological fluids (in contrast to solubility in water) appear to be the more important determinants of the toxicokinetics (Hirano et al. 1989a, 1989b; Oldiges and Glaser 1986; Rusch et al. \n1986).  For oral exposure, most experimental studies have used soluble cadmium, which exists as the Cd<sup>+2</sup>\nion regardless of the initial salt.  Absorption appears to be similar for cadmium ion and cadmium \ncomplexed with proteins in food, except for a few specific types of foods such as Bluff oysters and seal \nmeat.  Also, poorly soluble cadmium pigments may be absorbed to a lesser extent than soluble cadmium \nion (ILZRO 1977; Oldiges and Glaser 1986).\n\nThe database on the toxicity of cadmium in humans and animals following inhalation or oral exposure is \nextensive.  Target organs are similar among species and, in general, toxicokinetics following systemic \nabsorption from the gastrointestinal and respiratory tracts are similar.  Most of the human data involve \nevaluation of health effects associated with chronic-duration exposure in occupational studies, \ncommunity-based studies of populations living in cadmium-polluted areas, or epidemiological studies in \nthe general population.  When adequate exposure characterization is available, human studies generally \nreport exposure levels in terms of an internal biomarker of exposure (e.g., urinary cadmium).  Numerous \nstudies have conducted dose-response analyses between urinary cadmium levels and biomarkers of renal \ndysfunction (see Section 2.10); similar rigorous dose-response analyses are not available for other targets \nof toxicity in humans.  In animals, evaluation of available dose-response data by route and duration \nindicates that sensitive noncancer targets of cadmium toxicity are respiratory and neurodevelopmental \neffects following inhalation exposure (Figure 1-1) and renal, skeletal, and neurodevelopmental effects \nfollowing oral exposure (Figure 1-2).\n\nA systematic review of these sensitive noncancer endpoints resulted in the following hazard identification \nconclusions:\n\n• Respiratory effects are a known effect for humans following inhalation exposure.\n\n• Skeletal effects are a known effect for humans.\n\n• Renal effects are a known effect for humans.\n\n• Neurodevelopmental effects are a presumed effect for humans.\n\n---\n\n**Figure 1-1.  Health Effects Found in Animals Following Inhalation Exposure to** \n**Cadmium**\n\nConcentration (mg Cd/m<sup>3</sup>) Effects in Animals\n>8 Acute:  Mortality; clinical signs of neurotoxicity, female reproductive effects\n0.9-1.7 Acute:  Decreased body weight\nIntermediate:  Male and female reproductive effects\n0.19-0.4 Acute:  Developmental and immune effects\n0.05-0.1 Acute:  Respiratory effects\nIntermediate:  Death\n0.02-0.03 Intermediate:  Respiratory and neurodevelopmental effects\nChronic:  Cancer, mortality\n1x10<sup>-4</sup> mg Cd/m<sup>3</sup> Provisional Chronic MRL (based on human data and exposure levels predicted from biomarkers)\n\nCd = cadmium; MRL = minimal risk level\n\n---\n\n**Figure 1-2.  Health Effects Found in Animals Following Oral Exposure to** \n**Cadmium**\n\n## Dose (mg Cd/kg/day)\n\n## Effects in Animals\n\n**Acute:**  Death; hepatic, gastrointestinal, neurological, and male \nreproductive effects\n\n**5.28-15**\n\n**Intermediate:**  Death\n\n**Chronic:**  Hematological effects\n\n**Acute:**  Hematological effects; altered reproductive development\n\n**0.6-3.13**\n\n**Intermediate:**  Gastrointestinal effects\n\n**Chronic:**  Decreased body weight\n\n**Acute:**  Renal and developmental effects, decreased body weight\n\n**0.2-0.4**\n\n**Intermediate:**  Renal, hepatic, hematological, and male and female \nreproductive effects; increased blood pressure; decreased body weight\n\n**Chronic:**  Renal and neurological effects; cancer\n\n**0.04-0.08**\n\n**Intermediate:**  Skeletal, neurological, respiratory, and immunological \neffects; decreased birth weight and altered reproductive development\n\n## 0.002 mg Cd/kg/day 3x10<sup>-4</sup> mg Cd/kg/day\n\n3x10 -4 mg Cd/kg/day\n\n**Intermediate:**  Neurodevelopmental and endocrine effects\n\n**Chronic:**  Skeletal effects\n\n**Provisional Acute MRL**\n\n**Provisional Chronic MRL (based on human data and exposure levels predicted from biomarkers)**\n\nCd = cadmium; MRL = minimal risk level\n\n---\n\n**_Respiratory Effects._** A meta-analysis of 12 studies reported an association between chronic-duration \ninhalation exposure to cadmium and reduced forced expiratory volume in the first second to forced vital \ncapacity (FEV1/FVC), which is indicative of an increased risk of chronic obstructive pulmonary disease \n(Wang et al. 2024a).  A limited number of occupational studies not included in the meta-analysis also \nreported associations between impaired lung function and urinary cadmium levels in workers (Moitra et \nal. 2013, 2015; Zhou et al. 2022).  These findings are supported by occupational case reports of clinical \nsigns of respiratory distress and pulmonary damage after acute-duration exposure to fatal concentrations \n(Beton et al. 1966; Townshend 1982).  In animal acute- and intermediate-duration inhalation studies, the \nrespiratory tract is the most sensitive target of toxicity in animals (NTP 1995).  Available studies \nconsistently report histopathological and inflammatory reactions in the respiratory tract of multiple \nspecies; in studies that provide quantitative data, findings are clearly concentration-related \n(see Section 2.4).\n\n**_Skeletal Effects._** Cadmium-associated bone effects were first described in 1955 in the Jinzu River Basin, \na cadmium-contaminated area in Japan, following the development of a bone disease called Itai-Itai\n("ouch-ouch") disease, characterized by multiple fractures of the long bones, osteomalacia, and \nosteoporosis in combination with proteinuria (Järup et al. 1998; Nordberg et al. 1997; Shigematsu 1984).  \nFour meta-analyses evaluating 41 unique references confirm the association between cadmium exposure \nand adverse bone effects, including fractures, osteoporosis, and decreased bone mineral density (Cheng et \nal. 2016; Kunioka et al. 2022; Li et al. 2021; Qing et al. 2021), as do several studies published since the \nmeta-analyses (Lv et al. 2021; Wang et al. 2021a; Xie et al. 2023a, 2023b).  Occupational case studies \nindicate that calcium deficiency, osteoporosis, or osteomalacia can develop in some workers after longterm occupational exposure to high levels of cadmium (Adams et al. 1969; Blainey et al. 1980; Bonnell \n1955; Kazantzis 1979; Scott et al. 1980).  In rodents, decreases in bone mineralization, bone mineral \ndensity, and mechanical properties have been consistently observed following oral exposure to cadmium \nchloride (see Section 2.8).  While bone effects may be secondary to cadmium-associated renal damage \n(Bhattacharyya et al. 2023; Shevchenko et al. 2021; Zhang et al. 2020a), there is also evidence for a direct \neffect of cadmium on bone, and acceleration of bone resorption can occur in the absence of renal \ndysfunction (Reyes-Hinojosa et al. 2019; Shevchenko et al. 2021; Zhang et al. 2020a).\n\n**_Renal Effects._** The kidney is a well-established target of cadmium toxicity in humans following \noccupational or dietary exposure.  Available meta-analyses consistently reported associations between \none or more biomarkers of cadmium exposure and risk of proteinuria, urolithiasis, chronic kidney disease, \nhyperuricemia, renal cytotoxicity, and low glomerular filtration rate (GFR) (Chen et al. 2024; Doccioli et al. 2024; Gu et al. 2022; Jalili et al. 2021; Liu et al. 2016a; Woo et al. 2015; Zhu et al. 2024a).  These \nfindings are supported by several studies conducted since the meta-analyses were published (see \nSection 2.10).  In animals, there is no evidence for renal effects in acute- and intermediate-duration \ninhalation studies; however, exposure duration and concentration may not have been enough to reach the \ncritical kidney concentration to induce renal effects and chronic-duration inhalation studies evaluating \nrenal toxicity were not identified.  In oral studies, some studies reported adverse changes in sensitive \nbiomarkers of kidney damage, such as a β2-microglobulin (β2M) or N-acetyl-β-d-glucosaminidase \n(NAG) (Bernard et al. 1992; Liu et al. 2019; Wan et al. 2022).  However, other studies did not find this \neffect at similar or higher doses (Wang et al. 2014).  Similar inconsistencies were observed for serum \nclinical chemistry values and histopathological findings (see Section 2.10).\n\n**_Neurodevelopmental Effects._** While several general population studies are available, findings are mixed.  \nAvailable meta-analysis reported mixed conclusions regarding the potential association between cadmium \nexposure and autism spectrum disorder (ASD) (Ding et al. 2023; Dou et al. 2023; Ramazani et al. 2024; \nSaghazadeh and Rezaei 2017; Sulaiman et al. 2020) and did not find an association with attention deficit \nhyperactivity disorder (ADHD) (Dimitrov et al. 2023).  Some studies reported associations between \ncadmium exposure and decreased measures of cognitive development in children and adolescents (Gustin \net al. 2018; Kippler et al. 2016; Rodríguez-Barranco et al. 2014; Zhou et al. 2020); however, other studies \ndid not support this finding (Forns et al. 2014; Lucchini et al. 2019; Pan et al. 2018; Yang et al. 2020).  \nNo consistent findings were observed regarding potential associations between cadmium exposure and \nneurobehavioral or neurosensory evaluations during childhood or adolescence (see Section 2.17).  In \ncontrast, available animal studies collectively indicate that developmental cadmium exposure can cause \nalterations in sensorimotor function (including nerve conduction) and activity, socioemotional behavior, \nand learning and memory in rodents; however, the timing and duration of exposure and assessment \ninfluence findings (see Section 2.17).\n\n**_Cancer Effects._** The carcinogenicity of cadmium has been studied extensively in humans in studies \ninvolving workers and general populations and in animals after inhalation or oral exposures.  The \nInternational Agency for Research on Cancer (IARC) classified cadmium and cadmium compounds as \ncarcinogenic to humans (Group 1) based on sufficient evidence in humans for the carcinogenicity of \ncadmium and cadmium compounds, sufficient evidence in animals for the carcinogenicity of cadmium \ncompounds, and limited evidence in animals for the carcinogenicity of cadmium metal (IARC \n2012).  Similarly, the Department of Health and Human Services (HHS) classified cadmium and \ncadmium compounds as substances known to be human carcinogens based on sufficient evidence of carcinogenicity in humans, including epidemiological and mechanistic studies (NTP 2021).  In 1989, the \nU.S. Environmental Protection Agency (EPA) classified cadmium as a probable human carcinogen by \ninhalation (Group B1) based on limited evidence in humans and sufficient evidence in animals (IRIS \n1989).\n\n### 1.3 MINIMAL RISK LEVELS (MRLs)\n\nMRLs for inhalation and oral exposures to cadmium were derived.  As presented in Figure 1-3, the most \nsensitive effects following inhalation exposure to cadmium are respiratory and developmental \n(specifically neurodevelopmental effects) following acute- and intermediate-duration exposure and renal \nfollowing chronic-duration exposure.  A provisional chronic-duration inhalation MRL was derived based \non renal effects in humans; the inhalation database was considered inadequate for the derivation of acuteor intermediate-duration MRLs.  The lack of renal toxicity at shorter durations in animal inhalation\nstudies is attributed to inadequate exposure duration to meet the critical renal burden required to elicit \nadverse renal effects.  The relationship between renal and urinary cadmium appears to be nearly linear at \nchronic-duration intakes and kidney burdens that do not produce nephrotoxicity (i.e., elimination halftime is independent of dose).  However, at high kidney cadmium burdens, associated with renal damage \n(>50 μg Cd/g cortex), the elimination half-time increases with increasing severity of renal damage.  \nLinearity in the dose-urinary excretion relationship also does not appear to apply following an acuteduration, high exposure to cadmium.  Multicompartment, physiologically based pharmacokinetic (PBPK) \nmodels (described in detail in Section 3.1.5) can be used to estimate cadmium intakes (inhalation and oral \nexposure) associated with a given urinary cadmium level and/or kidney cadmium burden.  These models \nhave been extensively evaluated for predicting dose-kidney-urinary cadmium relationships within the \nlinear range of the dose-urinary cadmium relationship, and PBPK modeling was used in the derivation of \nthe provisional inhalation chronic-duration MRL.\n\nAs presented in Figure 1-4, the most sensitive effects following oral exposure are renal, developmental \n(specifically neurodevelopmental), and skeletal effects.  Provisional acute- and chronic-duration oral \nMRLs were derived based on renal effects in animals and humans, respectively; the oral database was \nconsidered inadequate for the derivation an intermediate-duration oral MRL.  As discussed for the provisional chronic-duration inhalation MRL, PBPK modeling was used in the derivation of the \nprovisional oral chronic-duration MRL.\n\nMRLs derived for both the inhalation and oral exposure routes for cadmium are summarized in Table 1-1\nand are discussed in greater detail in Appendix A.\n\n**Figure 1-3.  Summary of Sensitive Targets of Cadmium – Inhalation**\n\n**Available data indicate that the respiratory system and developing nervous system are the most \nsensitive targets following acute- and intermediate-duration exposure and the renal system is the \nmost sensitive target following chronic-duration exposure to cadmium via inhalation.**\n\nNumbers in circles are the lowest lowest-observed-adverse-effect levels (LOAELs) for all health effects in \nanimals and the number in the triangle is the point of departure (POD) for the chronic-duration inhalation \nMRL based on human data.*\n\n**Acute (mg Cd/m³ )**\n\n| Category | Acute (mg Cd/m³) | Intermediate (mg Cd/m³) | Chronic (mg Cd/m³) |\n| --- | --- | --- | --- |\n| Respiratory | 0.081 | 0.021 |  |\n| Immunological | 0.19 |  |  |\n| Developmental | 0.4 | 0.02 |  |\n| Hematological |  | 0.052 |  |\n| Body weight |  | 0.052 | 0.03 |\n| Renal |  |  | 0.00106 |\n| Death |  |  | 0.03 |\n\n*See Table 2-1 for animal studies identifying the LOAELs in circles.  The value of 0.00106 mg Cd/m<sup>3</sup> represented by \nthe triangle (human data) is the renal POD used for the provisional chronic-duration MRL; the value represents the \nlower 95% confidence limit on the weighted median of the urinary cadmium level associated with a 10% extra risk \nassociated with low-molecular weight proteinuria in 17 datasets from 11 human studies (see Appendix A for details).\n\n---\n\n## Figure 1-4. Summary of Sensitive Targets of Cadmium – Oral\n\n**Available data indicate that the renal, skeletal, and developing nervous system are the most \nsensitive targets of cadmium oral exposure.**\n\nNumbers in circles are the lowest lowest-observed-adverse-effect levels (LOAELs) for all health effects in \nanimals and the number in the triangle is the point of departure (POD) for the chronic-duration oral MRL \nbased on human data.*\n\n**Acute (mg Cd/kg/day)**\n\n| Category | LOAEL (mg Cd/kg/day) |\n| --- | --- |\n| Acute - Renal | 2 |\n| Acute - Body weight | 2 |\n| Acute - Developmental | 3.13 |\n| Intermediate - Developmental | 0.04 |\n| Intermediate - Endocrine | 0.053 |\n| Intermediate - Musculoskeletal | 0.2 |\n| Chronic - Renal (POD) | 0.00076 |\n| Chronic - Musculoskeletal | 0.08 |\n| Chronic - Renal | 2.301 |\n| Chronic - Cancer | 2.3 |\n\n*See Table 2-2 for animal studies identifying the LOAELs in circles.  The value of 7.60x10<sup>-4</sup> mg Cd/kg/day \nrepresented by a triangle (human data) is the renal POD used for the provisional chronic-duration MRL; the value \nrepresents the lower 95% confidence limit on the weighted median of the urinary cadmium level associated with a \n10% extra risk associated with low-molecular weight proteinuria in 17 datasets from 11 human studies \n(see Appendix A for details).\n\n$$\n7.60\\times10^{-4}\n$$\n\n---\n\n**Table 1-1.**\n\n**Minimal Risk Levels (MRLs) for Cadmium**\n\n| Exposure route | Exposure duration | Provisional MRL | Critical effect (species) | POD type | POD value | Uncertainty/modifying factor | Reference |\n| --- | --- | --- | --- | --- | --- | --- | --- |\n| Inhalation | Acute | None | - | - | - | - | - |\n| Inhalation | Intermediate | None | - | - | - | - | - |\n| Inhalation | Chronic | 1 × 10-4 mg CD/m3 | LMW proteinuria (humans) | 95% LCL of weighted median of UC10 from 17 datasets | 0.00106 mg Cd/m3 | UF: 3 MF: 3 | Weighted median from 17 datasetsb |\n| Oral | Acute | 0.002 mg Cd/kg/day | Total and LMW proteinuria; increased serum BUN (rats) | LOAEL | 2 mg Cd/kg/day | UF: 1,000 | Wan et al. 2022 |\n| Oral | Intermediate | None | - | - | - | - | - |\n| Oral | Chronic | 3 × 10-4 mg CD/kg/day | LMW proteinuria (humans) | 95% LCL of weighted median of UC10 from 17 datasets | 7.60 × 10-4 mg Cd/kg/day | UF: 3 | Weighted median from 17 datasetsb |\n\n<sup>a</sup>See Appendix A for additional information.\n\n<sup>b</sup>17 datasets from 3 occupational cohorts (Järup and Elinder 1994; Lei et al. 2007; Shao et al. 2007) and 8 general population cohorts (Buchet et al. 1990; Hong et \nal. 2004; Järup et al. 2000; Kobayashi et al. 2008; Suwazono et al. 2006; Uno et al. 2005; Wu et al. 2001; Zhang et al. 2016a).\n\nBUN = blood urea nitrogen; LCL = lower confidence limit; LMW = low molecular weight; LOAEL = lowest-observed-adverse-effect level; MF = modifying factor; \nPOD = point of departure; UC10 = urinary concentration associated with 10% extra risk; UF = uncertainty factor\n\n---\n\n## CHAPTER 2. HEALTH EFFECTS\n\n### 2.1 INTRODUCTION\n\nThe primary purpose of this chapter is to provide public health officials, physicians, toxicologists, and \nother interested individuals and groups with an overall perspective on the toxicology of cadmium.  It \ncontains descriptions and evaluations of toxicological studies and epidemiological investigations and \nprovides conclusions, where possible, on the relevance of toxicity and toxicokinetic data to public health.  \nWhen available, mechanisms of action specific to target organs are discussed along with the health effects \ndata, while general mechanisms of action are discussed in Section 2.21; toxicokinetic mechanistic data are \ndiscussed in Section 3.1.\n\nA glossary and list of acronyms, abbreviations, and symbols can be found at the end of this profile.\n\nTo help public health professionals and others address the needs of persons living or working near hazardous \nwaste sites, the information in this section is organized by health effect.  These data are discussed in terms of \nroute of exposure (inhalation, oral, and dermal) and three exposure periods:  acute (≤14 days), intermediate \n(15–364 days), and chronic (≥365 days).\n\nAs discussed in Appendix B, a literature search was conducted to identify relevant studies examining health \neffect endpoints.  Figure 2-1 provides an overview of the database of studies in humans or experimental \nanimals included in this chapter of the profile.  These studies evaluate the potential health effects associated \nwith inhalation, oral, or dermal exposure to cadmium, but may not be inclusive of the entire body of \nliterature.  As discussed in *Prioritization of Human Data* in Appendix B, the epidemiological database for \ncadmium is extensive, including thousands of primary studies and dozens of meta-analyses of available \nstudies.  To focus the profile review and discussion on the weight-of-evidence, recent evidence, and most \nrelevant data for hazard identification, ATSDR focused the discussion in Chapter 2 on meta-analyses \nconducted within the past 15 years.  To supplement discussion, any epidemiological study published since \nthe most recent meta-analysis for an endpoint was included if it provided: (1) reliable and reported estimates \nof cadmium exposure (measured levels in air or via urinary cadmium levels, as this is the most reliable \nbiomarker [see Section 3.3.1]); (2) analysis of potential confounders of the measures of association; and \n(3) appropriate statistical analysis.  For endpoints without a published meta-analysis, any study meeting these \ninclusion criteria were included, regardless of publication date.  Studies were excluded if they did not \nprovide quantitative evidence for associations, relied on semi-quantitative measures of exposure (e.g., food frequency questionnaires), or evaluated cadmium exposure from medical implants.  Exceptions to the above \ncriteria included studies reporting rare effects, inclusion of select older studies to provide historical context \n(e.g., Itai-Itai disease in the Jinzu River Basin region of Japan, early case reports and investigations of \nworkers exposed to cadmium that established targets of toxicity, etc.), and studies that fill data gaps (e.g., \nlower quality occupational studies in less-studied organ systems/tissues). The animal database for cadmium \nis also extensive.  As discussed in *Prioritization of Animal Data* in Appendix B, animal studies evaluating \nadverse effects were prioritized for efficient review.  Since cadmium is a well-established model of renal \ntoxicity, there are hundreds of studies describing administration of cadmium via oral or other routes (e.g., \nintraperitoneal) at known toxic doses to evaluate potential interventions to rescue (or prevent) renal toxicity \nor other cadmium-associated adverse effects at higher exposure levels.  Studies of this nature were excluded \nfrom the profile, as they do not inform dose-response effects at low, environmentally-relevant \ndoses. Similarly, acute- and intermediate-duration oral studies in rats or mice utilizing only one cadmium \ndose group were excluded due to lack of dose-response data; exceptions were made for acute-lethality \nstudies or studies addressing data-poor endpoints (e.g., lipid homeostasis studies).  All chronic-duration oral \nstudies and all inhalation and dermal studies of adequate quality were included in the profile.  A systematic \nreview of the scientific evidence of the most sensitive health effects associated with exposure to cadmium\nwas also conducted; the results of this review are presented in Appendix C.\n\nHuman and animal inhalation studies are presented together in Table 2-1 and Figure 2-2 and human and \nanimal oral studies are presented in Table 2-2 and Figure 2-3; limited dermal data were identified for \ncadmium and are presented in Table 2-3.\n\nLevels of significant exposure (LSEs) for each route and duration are presented in tables and illustrated in \nfigures.  The points in the figures showing no-observed-adverse-effect levels (NOAELs) or lowestobserved-adverse-effect levels (LOAELs) reflect the actual doses (levels of exposure) used in the studies.  \nEffects have been classified into “less serious LOAELs” or “serious LOAELs (SLOAELs).”  “Serious” \neffects are those that evoke failure in a biological system and can lead to morbidity or mortality (e.g., \nacute respiratory distress or death).  “Less serious” effects are those that are not expected to cause \nsignificant dysfunction or death, or those whose significance to the organism is not entirely clear.  \nATSDR acknowledges that a considerable amount of judgment may be required in establishing whether \nan endpoint should be classified as a NOAEL, “less serious” LOAEL, or “serious” LOAEL, and that in \nsome cases, there will be insufficient data to decide whether the effect is indicative of significant \ndysfunction.  However, the Agency has established guidelines and policies that are used to classify these \nendpoints.  ATSDR believes that there is sufficient merit in this approach to warrant an attempt at distinguishing between “less serious” and “serious” effects.  The distinction between “less serious” effects \nand “serious” effects is considered to be important because it helps the users of the profiles to identify \nlevels of exposure at which major health effects start to appear.  LOAELs or NOAELs should also help in \ndetermining whether or not the effects vary with dose and/or duration, and place into perspective the \npossible significance of these effects to human health.  Levels of exposure associated with cancer (Cancer \nEffect Levels, CELs) of cadmium are indicated in Tables 2-1 and 2-2 and Figures 2-2 and 2-3.\n\nA User\'s Guide has been provided at the end of this profile (see Appendix D).  This guide should aid in \nthe interpretation of the tables and figures for LSEs and MRLs.\n\nThis section provides information regarding potential adverse health effects of cadmium and cadmium \ncompounds.  To appropriately compare doses following exposures to various cadmium compounds, \ninhalation exposures are expressed throughout the profile as mg Cd/m<sup>3</sup> and oral exposures are expressed as \nmg Cd/kg/day, when possible.  This allows for evaluation of relative toxicities and determination of whether \ncertain chemical properties (e.g., solubility) impact toxicity.  When available, information pertaining to \nrelative toxicity of different cadmium compounds is discussed throughout Chapter 2.\n\nThe health effects of cadmium and cadmium compounds have been extensively evaluated in human and \nanimal studies.  As discussed above, due to the vast amount of available data, studies were prioritized for \ninclusion in Chapter 2 based on criteria defined in Appendix B.  A total of 69 meta-analyses of human \ndata were included.  An additional 219 human studies and 192 animal studies meeting inclusion criteria \nwere identified.  Most of the human data involve evaluation of health effects associated with chronicduration exposure in occupational studies, community-based studies of populations living in cadmiumpolluted areas, or epidemiological studies in the general population.  For workers, the predominant \nexposure route is inhalation; however, some gastrointestinal tract exposure may also occur when dust is \nremoved from the lungs by mucociliary clearance and subsequently swallowed, or by ingestion of dust on \nhands, cigarettes, or food (Adamsson et al. 1979).  For the nonsmoking general population, dietary \nexposure to cadmium is the most likely route of exposure (Kim et al. 2018; Nordberg et al. 2018; Zhu et \nal. 2024a).  However, since cadmium is present in tobacco leaves, tobacco smoking can contribute \nsignificantly to cadmium exposure in general populations (Diamond and Klotzbach 2025; Ellis et al. \n1979; Friis et al. 1998).  Therefore, both occupational and general population studies are classified as \nmulti-route exposure in Figure 2-1.  In animal studies, most of the health effects data in animals come \nfrom oral exposure studies (Figure 2-1).\n\n---\n\nHuman studies are available for nearly every organ system, with the predominant focus on renal, cancer, \ndevelopmental, musculoskeletal, and cardiovascular endpoints.  Animal studies predominantly focused on \nrespiratory endpoints following inhalation exposure and examined a comprehensive set of endpoints \nfollowing oral exposure.  For oral studies, the most well-studied effects include body weight, developmental, \nand reproductive endpoints.  Data from dermal exposure are very limited.\n\nAs outlined in Chapter 1, the most sensitive effects following exposure to cadmium appear to be respiratory, \nrenal, and neurodevelopmental following inhalation exposure and renal, skeletal, and neurodevelopmental \nfollowing oral exposure.  A systematic review was conducted on the available human and animal studies for \nthese endpoints.  The information in these studies indicates the following on the potential targets of cadmium\ntoxicity:\n\n• **Respiratory Endpoints.**  Respiratory effects are a known effect of cadmium toxicity following \ninhalation exposure based on a low level of evidence in human occupational studies, a high level \nof evidence in laboratory animal inhalation studies, and other relevant data including a metaanalysis, occupational case reports, and a plausible mechanism of action.  In humans, \noccupational exposure has been associated with respiratory irritation and impaired respiratory \nfunction.  In animals, inhalation exposure is consistently associated with inflammatory changes in \nthe lung and upper and lower respiratory tract lesions with increasing concentration and duration \nin multiple species.\n\n• **Skeletal Endpoints.**  Adverse effects on the skeletal system (e.g., decreased bone density, \nstrength, and mineralization) are a known effect of cadmium toxicity based on a moderate level of \nevidence from human epidemiological studies, a high level of evidence from laboratory animals, \nand other relevant data including several meta-analyses, older studies and case reports of high \ndietary or occupational exposure, and plausible mechanisms of action.  In humans, cadmium \nexposure is associated with adverse bone effects, including fractures, osteoporosis, and decreased \nbone mineral density.  Bone effects associated with cadmium exposure were first described in \ncadmium-contaminated communities in Japan with high dietary intake; the disease called Itai-Itai \n(“ouch-ouch”) disease was characterized by multiple fractures of the long bones, osteomalacia, \nand osteoporosis.  Bone effects have been confirmed in animal studies following oral exposure; \nthese endpoints have not been assessed following inhalation exposure in animals.\n\n• **Renal Endpoints.** Renal effects are a known effect of cadmium toxicity based on a high level of \nevidence from human epidemiological studies, a moderate level of evidence in laboratory animal \ninhalation studies, and other relevant data including several meta-analyses and a well-defined \nmechanism of action. The kidney has been a well-established target of cadmium toxicity in \nhumans following occupational and dietary exposure for decades.  Several studies have \ndeveloped dose-response analyses of sensitive biomarkers of cadmium exposure and renal \ntoxicity (e.g., urinary cadmium levels and low molecular weight [LMW] proteinuria).  Data in \nanimals following inhalation exposure are inadequate.  While findings in multi-dose oral studies \nin animals meeting inclusion criteria are mixed, several studies reported alterations in biomarkers \nof renal functions (e.g., LMW proteinuria, serum blood urea nitrogen [BUN]) and \nhistopathological changes.\n\n---\n\n## 2. HEALTH EFFECTS\n\n• **Neurodevelopmental Endpoints.** Neurodevelopmental effects are a presumed effect in humans \nbased on a low level of evidence in humans and a high level of evidence in animals.  Available \nepidemiological data from general population studies are mixed.  A limited number of inhalation \nstudies and numerous oral studies in animals indicate that developmental cadmium exposure can \ncause alterations in sensorimotor function (including nerve conduction) and activity, \nsocioemotional behavior, and learning and memory in rodents; however, the timing and duration \nof exposure and assessment influence findings.  Available data indicate that neurodevelopmental \neffects are the most sensitive indicator of developmental toxicity of cadmium (occur at lower \nexposures than those associated with standard developmental outcomes or specialized evaluations \nof other systems, such as reproductive development).\n\n---\n\n**Figure 2-1.  Overview of the Number of Studies Examining Cadmium Health Effects***\n\n## Most studies examined the potential body weight, renal, and developmental effects of cadmium\n\nNumerous studies are available in both **humans** and **animals** (counts represent studies examining endpoint)\n\n| Category | humans (count) | animals (count) |\n| --- | --- | --- |\n| Death | 11 | 42 |\n| Body weight |  | 98 |\n| Respiratory | 15 | 29 |\n| Cardiovascular | 28 | 13 |\n| Gastrointestinal | 6 | 9 |\n| Hematological | 5 | 31 |\n| Musculoskeletal | 30 | 16 |\n| Hepatic | 21 | 23 |\n| Renal | 54 | 34 |\n| Dermal | 2 | 1 |\n| Ocular | 2 | 2 |\n| Endocrine | 19 | 15 |\n| Immunological | 14 | 26 |\n| Neurolgical | 12 | 12 |\n| Reproductive | 30 | 39 |\n| Developmental | 33 | 45 |\n| Other Noncancer | 4 | 4 |\n| Cancer | 34 | 10 |\n\n**Exposure Route**\n\n| Category | Share of studies (%) |\n| --- | --- |\n| Multi-route | 56 |\n| Oral | 30 |\n| Dermal | 1 |\n| Inhalation | 13 |\n\n**Exposure Duration**\n\n| Category | Share of studies (%) |\n| --- | --- |\n| Chronic | 60 |\n| Intermediate | 25 |\n| Acute | 15 |\n\n*Includes studies discussed in Chapter 2.  A total of 69 meta-analyses and 411 studies meeting inclusion criteria (including those finding no effect) have examined \ntoxicity; most studies examined multiple endpoints. Note: Meta-analyses are counted as a single data-point in the figure above because only the overall results of \nthe meta-analysis, not the individual studies included in the meta-analyses, were included in Chapter 2.\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| ACUTE EXPOSURE |  |  |  |  |  |  |  |  |  |\n| Beton et al. 1966 |  |  |  |  |  |  |  |  | Cadmium oxide fume |\n| 1 | Human 5 M | 5 hours (occup) | 8.63 | LE, CS | Death Resp |  |  | 8.63 | 1/5 exposed workers died Severe dyspnea, wheezing, chest pain and precordial constriction, persistent cough (lasting up to 7 days post-exposure); severe pulmonary edema and alveolar cell metaplasia in the worker that died |\n| Barrett et al. 1947 |  |  |  |  |  |  |  |  | Cadmium oxide fume |\n| 2 | Rat (NS) 10–25 NS | 10–15 minutes (WB) | 8.8, 13, 18, 19, 22, 25, 31, 41, 79.2, 110 | LE | Death |  |  | 30 | LC50 at 7 days |\n| Buckley and Bassett 1987 |  |  |  |  |  |  |  |  | Cadmium oxide dust |\n| 3 | Rat (Wistar) 20 M | 3 hours (WB) | 0, 0.4, 4.6 | BW | Bd wt | 0.4 | 4.6 |  | 15% decrease in body weight 7 days post-exposure |\n| Bus et al. 1978 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 4 | Rat (Sprague-Dawley) 18 M | 1 hour (WB) | 0, 6.5 | LE, BW, BI, OW, OF | Bd wt |  | 6.5 |  | 11% decrease in body weight 11 days post-exposure |\n|  |  |  |  |  | Resp |  | 6.5 |  | Decreased tidal volume and increased respiratory frequency 1 and 5 days post-exposure |\n| Rats were examined at 1, 5, and 11 days post-exposure (6/group/timepoint) |  |  |  |  |  |  |  |  |  |\n| Grose et al. 1987 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 5 | Rat (Sprague-Dawley) 40 M | 2 hours (H) | 0, 0.25, 0.48, 4.50 | LE, CS, BW | Bd wt | 0.25 |  | 4.5 | 20% decrease in body weight 72 hours post-exposure |\n\nRats were examined immediately and 72 hours post-exposure (20/group/timepoint)\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects | Cadmium oxide dust |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Grose et al. 1987 |  |  |  |  |  |  |  |  |  |  |\n| 6 | Rat (Sprague-Dawley) 40 M | 2 hours (H) | 0, 0.25, 0.44, 4.45 | LE, CS, BW | Bd wt | 4.45 |  |  |  |  |\n| Rats were examined immediately and 72 hours post-exposure (20/group/timepoint) |  |  |  |  |  |  |  |  |  |  |\n| Hart 1986 |  |  |  |  |  |  |  |  |  |  |\n| 7 | Rat (Lewis) 3 M | 1 or 2 weeks 5 days/week 3 hours/day (N) | 0, 1.6 | BI, OW, HP | Resp |  | 1.6 |  |  | Cadmium acetate Increase in BALF cellularity (macrophages, PMNs, lymphocytes) and markers of cytotoxicity (LDH, ALP, AP, total protein) |\n| Jacobo-Estrada et al. 2016 |  |  |  |  |  |  |  |  |  |  |\n| 8 | Rat (Wistar) 6 F | 13 days GDs 8–20 2 hours/day (WB) | 0, 17.43 | BW, OW, DX | Bd wt Repro Develop | 17.43 | 17.43 | 17.43 |  | Cadmium chloride Decreased absolute placental weight Fetal kidney injury (decreased fetal plasma creatinine levels, increased total histopathological lesion score in fetal kidney); decreased fetal body weight (8%) |\n| NTP 1995 |  |  |  |  |  |  |  |  |  |  |\n| 9 | Rat (Fischer-344) 5 M, 5 F | 2 weeks 5 days/week 6.2 hours/day (WB) | 0, 0.081, 0.249, 0.844, 2.49, 8.60 | LE, CS, BW, OW, HP | Death Bd wt Resp | 2.49 | 0.081 | 8.6 |  | Cadmium oxide aerosol 100% mortality by day 6 |\n|  |  |  |  |  | Cardio | 2.49 |  |  |  | SLOAEL: Marked necrosis of alveolar ducts LOAEL: Minimal-to-mild alveolar histiocytic infiltrate and focal inflammation in alveolar septa |\n|  |  |  |  |  | Hepatic | 2.49 |  |  |  |  |\n|  |  |  |  |  | Renal | 2.49 |  |  |  |  |\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects | Cadmium chloride |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Palmer et al. 1986 |  |  |  |  |  |  |  |  |  |  |\n| 10 | Rat (Sprague-Dawley) 20–30 M | 2 hours (WB) | 0, 6.0 | BW, BC, BI, OW | Bd wt | 6 |  |  |  |  |\n| 10 | Rat (Sprague-Dawley) 20–30 M | 2 hours (WB) | 0, 6.0 | BW, BC, BI, OW | Resp |  | 6 |  |  | Increased BALF cellularity (primarily macrophages) 3 days post-exposure |\n| 10 | Rat (Sprague-Dawley) 20–30 M | 2 hours (WB) | 0, 6.0 | BW, BC, BI, OW | Endocr | 6 |  |  |  |  |\n| Rats were sacrificed |  | 1, 3, 7, or 10 days post-exposure (≥4/group/timepoint) |  |  |  |  |  |  |  |  |\n| Rusch et al. 1986 |  |  |  |  |  |  |  |  |  | Cadmium carbonate |\n| 11 | Rat (Sprague-Dawley) 26 M, 26 F | 2 hours (WB) | 0, 94 | LE, CS, GN | Resp |  |  | 94 |  | Rales persisting up to 4 hours post-exposure |\n| Rats were sacrificed immediately or 1, 3, 7, or 30 days post-exposure (10/group/timepoint); extra two rats were replacement animals |  |  |  |  |  |  |  |  |  |  |\n| Rusch et al. 1986 |  |  |  |  |  |  |  |  |  | Cadmium sulfide |\n| 12 | Rat (Sprague-Dawley) 26 M, 26 F | 2 hours (WB) | 0, 140 | LE, CS, BW | Bd wt | 140 |  |  |  |  |\n| Rats were sacrificed immediately or 1, 3, 7, or 30 days post-exposure (10/group/timepoint); extra two rats were replacement animals |  |  |  |  |  |  |  |  |  |  |\n| Rusch et al. 1986 |  |  |  |  |  |  |  |  |  | Cadmium selenide |\n| 13 | Rat (Sprague-Dawley) 26 M, 26 F | 2 hours (WB) | 0, 105 | LE, CS, BW | Bd wt | 105 |  |  |  |  |\n| Rats were sacrificed immediately or 1, 3, 7, or 30 days post-exposure (10/group/timepoint); extra two rats were replacement animals |  |  |  |  |  |  |  |  |  |  |\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Rusch et al. 1986 |  |  |  |  |  |  |  |  | Cadmium acetate |\n| 14 | Rat (Sprague-Dawley) 26 M, 26 F | 2 hours (WB) | 0, 83 | LE, CS | Death |  |  | 83 | 25/32 died between 1 and 7 days post-exposure |\n| 14 | Rat (Sprague-Dawley) 26 M, 26 F | 2 hours (WB) | 0, 83 | LE, CS | Resp |  |  | 83 | Labored breathing and rales persisting up to 4 hours post-exposure |\n| 14 | Rat (Sprague-Dawley) 26 M, 26 F | 2 hours (WB) | 0, 83 | LE, CS | Neuro |  | 83 |  | Reduced activity during exposure |\n| Rats were sacrificed immediately or 1, 3, 7, or 30 days post-exposure (10/group/timepoint); extra two rats were replacement animals |  |  |  |  |  |  |  |  |  |\n| Snider et al. 1973 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 15 | Rat (Sprague-Dawley) 18 M | 3 days 1 hour/day (WB) | 61 | LE, GN | Death |  |  | 61 | 17/18 died within 3 days |\n| 15 | Rat (Sprague-Dawley) 18 M | 3 days 1 hour/day (WB) | 61 | LE, GN | Resp |  |  | 61 | Pulmonary hemorrhage |\n| Barrett et al. 1947 |  |  |  |  |  |  |  |  | Cadmium oxide fume |\n| 16 | Mouse (NS) 10 NS | 15 minutes (WB) | 39, 61.3, 65.9 | LE | Death |  |  | 39 | 9/10 died within 7 days |\n| Graham et al. 1978 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 17 | Mouse (CD-1) 16–20 F | 2 hours (WB) | 0, 0.110, 0.190 | IX | Immuno | 0.11 | 0.19 |  | Decreased humoral immune response |\n| Krzystyniak et al. 1987 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 18 | Mouse (C57BL/6) 4–5 F | 60 minutes (N) | 0, 0.88 | IX | Immuno |  | 0.88 |  | Reduced humoral and cell-mediated immune responses |\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| NTP 1995 |  |  |  |  |  |  |  |  | Cadmium oxide aerosol |\n| 19 | Mouse (B6C3F1) 5 M, 5 F | 2 weeks 5 days/week 6.2 hours/day (WB) | 0, 0.081, 0.249, 0.844, 2.49, 8.60 | LE, CS, BW, OW, HP | Death Bd wt Resp | 2.49 | 0.081 | 8.6 | 100% mortality by day 7 |\n| 19 | Mouse (B6C3F1) 5 M, 5 F | 2 weeks 5 days/week 6.2 hours/day (WB) | 0, 0.081, 0.249, 0.844, 2.49, 8.60 | LE, CS, BW, OW, HP | Cardio Hepatic Renal | 2.49 2.49 2.49 | 0.081 | 0.844 | LOAEL: Minimal-to-mild alveolar histiocytic infiltrates SLOAEL: Fibrosis, inflammation, and mild necrosis of the alveolar ducts; degeneration of the nasal olfactory epithelium |\n| NTP 1995 |  |  |  |  |  |  |  |  | Cadmium oxide aerosol |\n| 20 | Mouse (Swiss) 33 F | 14 days GDs 4–17 6.27 hours/day (WB) | 0, 0.04, 0.4, 1.7 | LE, CS, BW, OW, DX | Bd wt Develop | 0.4 | 0.04 | 1.7 | 22% decrease in maternal body weight on GD 18 Increased total litter resorption; decreased fetal body weight (29–30%); reduced ossification of sternebrae Decreased male (9%) and female (8%) fetal body weight |\n| Friberg 1950 |  |  |  |  |  |  |  |  | Cadmium metal dust |\n| 21 | Rabbit (NS) 8 NS | 4 hours (H) | 11.5 - 48.4 | LE | Death |  |  | 28.4 | LC50 at 14 days |\n| Henderson et al. 1979 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 22 | Hamster (Golden Syrian) 30 B | 30 minutes (N) | 0, 1.1, 10.1 | LE, BI, HP | Resp |  | 1.1 | 10.1 | LOAEL: Increased BALF PMN and AP levels SLOAEL: Necrosis of bronchiolar epithelium 1 day post-exposure; severe pneumonitis 7 days post-exposure |\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| INTERMEDIATE EXPOSURE |  |  |  |  |  |  |  |  |  |\n| Baranski 1984 |  |  |  |  |  |  |  |  | Cadmium oxide aerosol |\n| 23 | Rat (Wistar) 7–15 F | 6-7 months (5 months premating, up to 3 weeks mating, GDs 1–20) 5 hours/day 5 days/week (WB) | 0, 0.02, 0.16 | RX, DX | Repro Develop | 0.16 | 0.02 | 0.16 | LOAEL: Age- and sex-dependent changes in offspring motor activity; impaired avoidance acquisition in 3- and 7-month-old females SLOAEL: 25% mortality by PND 4 (decreased viability index); 15% decrease in weanling body weight |\n| Baranski 1985 |  |  |  |  |  |  |  |  | Cadmium oxide dust |\n| 24 | Rat (Wistar) 5–16 F | 5–7 months (4–5 months premating, mating, GDs 1–20) 5 days/week 5 hours/day (WB) | 0, 0.02, 0.16, 1.0 | LE, BW, RX, DX | Death Bd wt Repro Develop | 1 1 | 0.02 | 1 | 55.1% mortality |\n| Baranski and Sitarek 1987 |  |  |  |  |  |  |  |  | LOAEL: Decreased motor activity in 3-month-old males and decreased conditioned reflexes in 5-month-old females SLOAEL: 23% decrease in pup viability index; unspecified decrease in pup weight during first 2 months |\n| 25 | Rat (Wistar) 13–14 F | 20 weeks 5 days/week 5 hours/day (WB) | 0, 0.02, 0.16, 1.0 | LE, CS, BW, RX | Death Bd wt Repro | 0.16 | 0.02 | 1 | Cadmium oxide dust 38% mortality by week 13; 100% mortality by week 20 30–50% decrease in body weight gain starting at week 4 Increased duration of estrous cycle |\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Glaser et al. 1986 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 26 | Rat (Wistar) 12 M | 30 days 7 days/week 22 hours/day (WB) | 0, 0.105 | LE, CS, BW, HE, BC, BI, UR | Bd wt Resp | 0.105 | 0.105 |  | Increase in BALF cellularity (PMNs, macrophages, leukocytes) and markers of cytotoxicity (LDH, total protein levels); macrophages, total protein and LDH remained elevated at 2-months post-exposure |\n| 26 | Rat (Wistar) 12 M | 30 days 7 days/week 22 hours/day (WB) | 0, 0.105 | LE, CS, BW, HE, BC, BI, UR | Hemato | 0.105 | 0.105 |  | Increased WBC counts at terminal sacrifice |\n| 26 | Rat (Wistar) 12 M | 30 days 7 days/week 22 hours/day (WB) | 0, 0.105 | LE, CS, BW, HE, BC, BI, UR | Renal | 0.105 |  |  |  |\n| Rats were sacrificed immediately following exposure (terminal sacrifice) or 2 months post-exposure (6/group/timepoint) |  |  |  |  |  |  |  |  |  |\n| Glaser et al. 1986 |  |  |  |  |  |  |  |  | Cadmium sulfide |\n| 27 | Rat (Wistar) 12 M | 30 days 7 days/week 22 hours/day (WB) | 0, 1.034 | LE, CS, BW, HE, BC, BI, OW | Bd wt Resp | 1.034 | 1.034 |  | Increase in BALF cellularity (PMNs, macrophages, leukocytes) and markers of cytotoxicity (LDH, total protein levels); macrophages, total protein and LDH remained elevated at 2-months post-exposure |\n| 27 | Rat (Wistar) 12 M | 30 days 7 days/week 22 hours/day (WB) | 0, 1.034 | LE, CS, BW, HE, BC, BI, OW | Hemato | 1.034 |  |  |  |\n| 27 | Rat (Wistar) 12 M | 30 days 7 days/week 22 hours/day (WB) | 0, 1.034 | LE, CS, BW, HE, BC, BI, OW | Renal | 1.034 |  |  |  |\n| Rats were sacrificed immediately following exposure (terminal sacrifice) or 2 months post-exposure (6/group/timepoint) |  |  |  |  |  |  |  |  |  |\n| Glaser et al. 1986 |  |  |  |  |  |  |  |  | Cadmium oxide dust |\n| 28 | Rat (Wistar) 12 M | 30 days 7 days/week 22 hours/day (WB) | 0, 0.098 | LE, CS, BW, HE, BC, BI, OW | Bd wt Resp | 0.098 | 0.098 |  | Increase in BALF cellularity (PMNs, macrophages, leukocytes) and markers of cytotoxicity (LDH, total protein levels); total protein remained elevated at 2-months post-exposure |\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n|  |  |  |  |  | Hemato |  | 0.098 |  | Increased WBC count at terminal sacrifice |\n|  |  |  |  |  | Renal | 0.098 |  |  |  |\n\n| Rats were sacrificed immediately following exposure (terminal sacrifice) or 2 months post-exposure (6/group/timepoint) |  |  |  |  |  |  |  |  |  |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Hart 1986 |  |  |  |  |  |  |  | Cadmium acetate |  |\n| 29 | Rat (Lewis) 3 M | 3–6 weeks 5 days/week 3 hours/day (N) | 0, 1.6 | BI, OW, HP | Resp |  | 1.6 |  | Transient increase in BALF cellularity (macrophages, PMNs, lymphocytes) and markers of cytotoxicity (LDH, ALP, AP, total protein); resolving weeks 4–6 |\n| Kutzman et al. 1986 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 30 | Rat (Fischer 344) 20 M | 62 days 5 days/week 6 hours/day (WB) | 0, 0.33, 1.06, 2.13 | LE, CS, BW, BI, OW, HP | Death |  |  | 2.13 | 100% mortality by day 45 |\n| 30 | Rat (Fischer 344) 20 M | 62 days 5 days/week 6 hours/day (WB) | 0, 0.33, 1.06, 2.13 | LE, CS, BW, BI, OW, HP | Bd wt | 0.33 |  | 1.06 | 27% decrease in body weight |\n| Kutzman et al. 1986 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 31 | Rat (Fischer 344) 8 M, 8 F | 62 days 5 days/week 6 hours/day (WB) | 0, 0.33, 1.06, 2.13 | LE, BW, RX | Death |  |  | 2.13 | 100% mortality by day 45 |\n| 31 | Rat (Fischer 344) 8 M, 8 F | 62 days 5 days/week 6 hours/day (WB) | 0, 0.33, 1.06, 2.13 | LE, BW, RX | Bd wt | 0.33 | 1.03 | 2.13 | LOAEL: 14% decreased in body weight SLOAEL: Body weight loss (decreased 40% compared to starting body weight) |\n| Repro |  |  |  |  |  | 1.06 M |  |  |  |\n| Exposed rats were mated with both exposed and unexposed rats 6 days post-exposure |  |  |  |  |  |  |  |  |  |\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| NTP 1995 |  |  |  |  |  |  |  |  | Cadmium oxide aerosol |\n| 32 | Rat (Fischer-344) 10 M, 10 F | 13 weeks 5 days/week 6.33 hours/day (WB) | 0, 0.021, 0.046, 0.088, 0.212, 0.902 | LE, CS, BW, HE, BC, UR, OW, HP, OF, RX | Bd wt Resp | 0.902 | 0.021 F | 0.902 M | Minimal epithelial degeneration in the larynx LOAEL: Minimal alveolar histiocytic infiltrate and epithelial hyperplasia; minimal epithelial degeneration in the larynx SLOAEL: Marked inflammation and moderate fibrosis in interstitium around alveolar ducts and terminal bronchioles |\n| 32 | Rat (Fischer-344) 10 M, 10 F | 13 weeks 5 days/week 6.33 hours/day (WB) | 0, 0.021, 0.046, 0.088, 0.212, 0.902 | LE, CS, BW, HE, BC, UR, OW, HP, OF, RX | Cardio Gastro Hemato Musc/skel Hepatic Renal Endocr Immuno Neuro Repro | 0.902 0.902 0.902 0.902 0.902 0.902 0.902 | 0.021 M | 0.046 M | Minimal epithelial degeneration in the larynx LOAEL: Minimal alveolar histiocytic infiltrate and epithelial hyperplasia; minimal epithelial degeneration in the larynx SLOAEL: Marked inflammation and moderate fibrosis in interstitium around alveolar ducts and terminal bronchioles |\n| NTP 1995 |  |  |  |  |  |  |  |  | Decreased spermatid counts in males, increased estrous cycle length in females |\n| 33 | Rat (Sprague-Dawley) 32 F | 16 days GDs 4–19 6.27 hours/day (WB) | 0, 0.04, 0.4, 1.7 | LE, CS, BW,OW, DX | Bd wt | 0.4 | 1.7 | Cadmium oxide aerosol | 14% decrease in maternal body weight on GD 20 Decreased male (16%) and female (17%) fetal body weight; reduced ossification of pelvis and sternebrae |\n| 33 | Rat (Sprague-Dawley) 32 F | 16 days GDs 4–19 6.27 hours/day (WB) | 0, 0.04, 0.4, 1.7 | LE, CS, BW,OW, DX | Develop | 0.4 |  | 1.7 | 14% decrease in maternal body weight on GD 20 Decreased male (16%) and female (17%) fetal body weight; reduced ossification of pelvis and sternebrae |\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects | Cadmium chloride |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Oberdörster et al. 1994 |  |  |  |  |  |  |  |  |  |  |\n| 34 | Rat (Fischer 344) 48 M | 4 weeks 5 days/week 6 hours/day (WB) | 0, 0.100 | BI | Resp |  | 0.1 |  | Increase in BALF PMNs (1 day post-exposure) |  |\n\n| Rats were sacrificed at 1, 7, or 28 days post-exposure (≥4/group/timepoint per endpoint) |  |  |  |  |  |  |  |\n| --- | --- | --- | --- | --- | --- | --- | --- |\n| Oldiges and Glaser 1986 |  |  |  |  |  |  | Cadmium oxide dust |\n| 35 | Rat (Wistar) 20 M, 20 F | 218–343 days 7 days/week 22 hours/day (WB) | M: 0, 0.030, 0.090 F: 0, 0.026, 0.081 | LE, GN, BW, Death FI, WI, HE, OW |  | 0.081 F 0.09 M | 6/20 died 6/20 died |\n| Oldiges and Glaser 1986 |  |  |  |  |  |  | Cadmium sulfide |\n| 36 | Rat (Wistar) 20–24 M, 20–24 F | 105–298 days 7 days/week 22 hours/day (WB) | M: 0, 0.843, 2.270 F: 0, 0.841, 2.247 | LE, GN, BW, Death FI, WI, HE, OW |  | 0.841 F 0.843 M | 7/20 died by day 298 6/20 died by day 208 |\n| Oldiges et al. 1989 |  |  |  |  |  |  | Cadmium chloride |\n| 37 | Rat (Wistar) 20 M, 18–20 F | 6 months 7 days/week 22 hours/day (WB) | 0, 0.090 | LE, GN, HP Death Cancer |  | 0.09 0.09 M | 25% mortality at 6 months CEL: Lung tumors (bronchioalveolar adenoma, adenocarcinoma, or squamous cell carcinoma) |\n| Scheduled sacrifice at 31 months; surviving Cd-exposed rats sacrificed at 29–30 months due to mortality ≥75% |  |  |  |  |  |  |  |\n| Oldiges et al. 1989 |  |  |  |  |  |  | Cadmium sulfide |\n| 38 | Rat (Wistar) 20 M, 20 F | 6 months 40 hours/week (WB) | 0, 0.270 | LE, GN, HP Death |  | 0.27 | 75% mortality at 27–29 months |\n| Scheduled sacrifice at 31 months; surviving Cd-exposed rats sacrificed at 27–29 months due to mortality ≥75% |  |  |  |  |  |  |  |\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Oldiges et al. 1989 |  |  |  |  |  |  |  |  | Cadmium sulfide |\n| 39 | Rat (Wistar) 16–20 M, 19–20 F | 3–10 months 7 days/week 22 hours/day (WB) | 0, 0.810, 2.430 | LE, GN, HP | Death Cancer |  |  | 0.81 | 25% mortality at 7–10 months CEL: Lung tumors (bronchioalveolar adenoma, adenocarcinoma, squamous cell carcinoma, or mixed tumor type) |\n\nScheduled sacrifice at 31 months; most surviving Cd-exposed rats sacrificed at 29-30 months due to mortality ≥75%\n\n| Oldiges et al. 1989 |  |  |  |  |  |  |  | Cadmium oxide dust |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| 40 | Rat (Wistar) 17–20 M, 16–20 F | 7–11 months 7 days/week 22 hours/day (WB) | 0, 0.090 | LE, GN, HP | Death Cancer | 0.09 | 0.09 | 25% mortality at 7–11 months CEL: Lung tumors (bronchioalveolar adenoma, adenocarcinoma, squamous cell carcinoma, or mixed tumor type) |\n\n| Scheduled sacrifice at 31 months |  |  |  |  |  |  |  |  |  |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Prigge 1978a |  |  |  |  |  |  |  | Cadmium oxide dust |  |\n| 41 | Rat (Wistar) 12 F | 90 days 24 hours/day (WB) | 0, 0.025, 0.052 | LE, BW, HE, BC, UR, OW, HP | Bd wt Resp | 0.025 | 0.025 | 0.052 | 23% decrease in body weight gain Proliferative lung lesions, histiocytic cell granulomas Increased hemoglobin and hematocrit |\n| 41 | Rat (Wistar) 12 F | 90 days 24 hours/day (WB) | 0, 0.025, 0.052 | LE, BW, HE, BC, UR, OW, HP | Hematoc | 0.025 | 0.052 | 0.052 | 23% decrease in body weight gain Proliferative lung lesions, histiocytic cell granulomas Increased hemoglobin and hematocrit |\n| 41 | Rat (Wistar) 12 F | 90 days 24 hours/day (WB) | 0, 0.025, 0.052 | LE, BW, HE, BC, UR, OW, HP | Hepatic Renal | 0.052 | 0.052 | 0.052 | 23% decrease in body weight gain Proliferative lung lesions, histiocytic cell granulomas Increased hemoglobin and hematocrit |\n\n| Prigge 1978a |  |  |  |  |  |  |  | Cadmium oxide dust |  |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| 42 | Rat (Wistar) 12 F | 63 days 24 hours/day (WB) | 0, 0.105 | LE, BW, HE, BC, UR | Death |  |  | 0.105 | 5/12 died |\n| 42 | Rat (Wistar) 12 F | 63 days 24 hours/day (WB) | 0, 0.105 | LE, BW, HE, BC, UR | Bd wt |  |  | 0.105 | 51% decrease in body weight gain |\n| 42 | Rat (Wistar) 12 F | 63 days 24 hours/day (WB) | 0, 0.105 | LE, BW, HE, BC, UR | Hematoc |  | 0.105 |  | Increased hemoglobin and hematocrit |\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Prigge 1978b |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 43 | Rat (Wistar) 12–13 F | 21 days 24 hours/day (WB) | 0, 0.204, 0.394, 0.581 | BW, HE, BC, UR, OW, HP | Bd wt Hemato | 0.581 | 0.204 |  | Increase in hemoglobin and hematocrit |\n|  |  |  |  |  | Renal | 0.581 |  |  |  |\n| Prigge 1978b |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 44 | Rat (Wistar) 12–13 F | 21 days GDs 1–21 24 hours/day (WB) | 0, 0.204, 0.394, 0.581 | BW, HE, BC, UR, OW, HP, DX | Bd wt |  | 0.204 | 0.394 | LOAEL: 12% decrease in maternal body weight gain SLOAEL: 35% decrease in maternal body weight gain Increased hemoglobin and hematocrit; elevated total (but not direct) bilirubin |\n|  |  |  |  |  | Hemato | 0.394 | 0.581 |  |  |\n|  |  |  |  |  | Renal | 0.581 |  |  |  |\n|  |  |  |  |  | Develop | 0.394 |  | 0.581 | 19% decrease in fetal body weight; decreased fetal hemoglobin |\n| NTP 1995 |  |  |  |  |  |  |  |  | Cadmium oxide aerosol |\n| 45 | Mouse (B6C3F1) 10 M, 10 F | 13 weeks 5 days/week 6.33 hours/day (WB) | 0, 0.021, 0.046, 0.088, 0.211, 0.910 | LE, CS, BW, OW, HP, RX | Bd wt Resp | 0.91 | 0.021 |  | Minimal alveolar histiocytic infiltrates and squamous metaplasia of the larynx |\n|  |  |  |  |  | Cardio | 0.91 |  |  |  |\n|  |  |  |  |  | Gastro | 0.91 |  |  |  |\n|  |  |  |  |  | Musc/skel | 0.91 |  |  |  |\n|  |  |  |  |  | Hepatic | 0.91 |  |  |  |\n|  |  |  |  |  | Renal | 0.91 |  |  |  |\n|  |  |  |  |  | Endocr | 0.91 |  |  |  |\n|  |  |  |  |  | Immuno | 0.91 |  |  |  |\n|  |  |  |  |  | Neuro | 0.91 |  |  |  |\n|  |  |  |  |  | Repro | 0.91 |  |  |  |\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Oberdörster et al. 1994 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 46 | Mouse (BALB/c) 72 M | 4 weeks 5 days/week 6 hours/day (WB) | 0, 0.100 | BI | Resp |  | 0.1 |  | Increase in BALF PMNs and LDH levels (1, 7, and 28 days post-exposure); increase cell proliferation in alveolar epithelium and macrophage infiltration (1 and 7 days post-exposure) |\n| Mice were sacrificed at 1, 7, or 28 days post-exposure (≥4/group/timepoint per endpoint) |  |  |  |  |  |  |  |  |  |\n| Johansson et al. 1984 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 47 | Rabbit (NS) 8 M | 4–6 weeks 5 days/week 6 hours/day (WB) | 0, 0.4 | BI, OW, HP | Resp |  | 0.4 |  | Lung interstitial inflammation, type 2 cell hyperplasia |\n| CHRONIC EXPOSURE |  |  |  |  |  |  |  |  |  |\n| Buchet et al. 1990; Hoo et al. 2004; Järup and Elinder 1994; Järup et al. 2000; Kobayashi et al. 2008; Lei et al. 2007; Shao et al. 2007; Suwazono et al. 2006; Uno et al. 2005; Wu et al. 2001; Zhang et al. 2016a |  |  |  |  |  |  |  |  | Cadmium |\n| 48 | Human 85–3,454 per dataset | 17 datasets (3 occupational and 8 general population cohorts) | UR | Renal |  |  |  | LMW proteinuria; 95% LCL weighted median of 17 UC10 values = 0.00106 mg Cd/m3 c |  |\n| Oldiges and Glaser 1986 |  |  |  |  |  |  |  |  | Cadmium sulfate |\n| 49 | Rat (Wistar) 20–40 M, 20 F | 413–455 days 7 days/week 22 hours/day (WB) | M: 0, 0.095 F: 0, 0.092 | LE, BW, FI, WI, HE, OW, GN | Death |  |  | 0.095 M | 6/20 died |\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Oldiges et al. 1989 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 50 | Rat (Wistar) 20 M, 18–20 F | 18 months 7 days/week 22 hours/day (WB) | 0, 0.030 | LE, GN, HP | Death Cancer |  |  | 0.03 M 0.03 | 75% mortality at 30 months CEL: Lung tumors (bronchioalveolar adenoma, adenocarcinoma, squamous cell carcinoma, or mixed tumor type) |\n| Scheduled sacrifice at 31 months; surviving Cd-exposed males sacrificed at 30 months due to mortality ≥75% |  |  |  |  |  |  |  |  |  |\n| Oldiges et al. 1989 |  |  |  |  |  |  |  |  | Cadmium sulfide |\n| 51 | Rat (Wistar) 19–20 M, 19–20 F | 16–18 months 7 days/week 22 hours/day (WB) | 0, 0.090, 0.270 | LE, GN, HP | Death Cancer |  |  | 0.09 0.270 | 75% mortality at 30 months in males 25% mortality at 16 months in females CEL: Lung tumors (bronchioalveolar adenoma, adenocarcinoma, squamous cell carcinoma, or mixed tumor type) |\n| Scheduled sacrifice at 31 months; surviving Cd-exposed rats sacrificed at 30 months due to mortality ≥75% |  |  |  |  |  |  |  |  |  |\n| Oldiges et al. 1989 |  |  |  |  |  |  |  |  | Cadmium oxide dust |\n| 52 | Rat (Wistar) 20 M, 20 F | 18 months 7 days/week 22 hours/day (WB) | 0, 0.030 | LE, GN, HP | Cancer |  |  | 0.03 | CEL: Lung tumors (bronchioalveolar adenoma, adenocarcinoma, squamous cell carcinoma, or mixed tumor type) |\n| Scheduled sacrifice at 31 months |  |  |  |  |  |  |  |  |  |\n| Oldiges et al. 1989 |  |  |  |  |  |  |  |  | Cadmium sulfate |\n| 53 | Rat (Wistar) 20 M, 20 F | 14–18 months 7 days/week 22 hours/day (WB) | 0, 0.09 | LE, GN, HP | Death Cancer |  |  | 0.09 | 25% mortality in males by 14 months; 75% mortality in females by 29 months CEL: Lung tumors (bronchioalveolar adenoma, adenocarcinoma, squamous cell carcinoma, or mixed tumor type) |\n\nScheduled sacrifice at 31 months; surviving Cd-exposed females sacrificed at 29 months due to mortality ≥75%\n\n---\n\n**Table 2-1.  Levels of Significant Exposure to Cadmium – Inhalation**\n(mg Cd/m<sup>3</sup>)\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Oldiges et al. 1989 |  |  |  |  |  |  |  |  | Cadmium oxide fume |\n| 54 | Rat (Wistar) 17–20 M | 18 months 7 days/week 22 hours/day (WB) | 0, 0.01, 0.03 | LE, GN, HP | Cancer |  |  | 0.03 | CEL: Lung tumors (bronchioalveolar adenoma, adenocarcinoma) |\n| Takenaka et al. 1983 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 55 | Rat (Wistar) 40–41 M | 18 months 7 days/week 23 hours/day (WB) | 0, 0.0134, 0.0257, 0.0508 | LE, BW, HP | Bd wt Cancer | 0.0508 |  | 0.0134 | CEL: Lung tumors (lung epidermoid carcinomas, or adenocarcinomas) |\n| Scheduled sacrifice at 31 months |  |  |  |  |  |  |  |  |  |\n\n<sup>a</sup>The number corresponds to entries in Figure 2-2; differences in levels of health effects between male and females are not indicated in Figure 2-2.  Where such \ndifferences exist, only the levels of effect for the most sensitive sex are presented.\n\n<sup>b</sup>Concentrations are expressed as mg Cd/m<sup>3</sup>. If concentrations were reported by the study authors in terms of the administered compound (e.g., cadmium chloride \n[CdCl2]), they were converted to the equivalent concentration in terms of the metal (i.e., cadmium [Cd])) for easy comparison across studies.  Conversion was based on \nthe ratio of the molecular weights using the following equation: Concentration in terms of administered compound x (molecular weight Cd/molecular weight administered \ncompound).\n\n<sup>c</sup>Used to derive a chronic-duration inhalation MRL of 0.0001 mg Cd/m<sup>3</sup> (0.1 μg Cd/m<sup>3</sup>).  The point of departure (POD) is based on the 95% lower confidence limit (LCL) \non the weighted median of the UC10 values from 17 datasets from 11 human studies; the weighted median and 95% LCL were 2.04 and 1.57 μg Cd/g Cr, respectively.  \nThese values were converted into inhalation concentration equivalents of 0.00141 and 0.00106 mg Cd/m<sup>3</sup>, respectively, using PBPK modeling.  The POD of 0.00106 mg \nCd/m<sup>3</sup> was divided by an uncertainty factor of 3 for human variability and a modifying factor of 3 for database deficiencies.  See Appendix A for more detailed information \nregarding the MRL.\n\n## Principal studies for the MRL\n\nALP = alkaline phosphatase; AP = acid phosphatase; BALF = bronchoalveolar lavage fluid; BC = serum (blood) chemistry; Bd wt or BW = body weight; BI = biochemical \nchanges; Cardio = cardiovascular; Cd = cadmium; CEL = cancer effect level; Cr = creatinine; CS = clinical signs; Develop = developmental; DX = developmental toxicity; \nEndocr = endocrine; F = female(s); FI = food intake; Gastro = gastrointestinal; GD = gestation day; GN = gross necropsy; (H) = head only; HE = hematology; \nHemato = hematological; HP = histopathology; Immuno = immunological; IX = immune function; LC50 = lethal concentration, 50% kill; LDH = lactate dehydrogenase; \nLE = lethality; LMW = low molecular weight; LOAEL = lowest-observed-adverse-effect level; M = male(s); MRL = Minimal Risk Level; Musc/skel = musculoskeletal; \n(N) = nose-only; Neuro = neurological; NOAEL = no-observed-adverse-effect level; NS = not specified; (occup) = occupational; OF = organ function; OW = organ weight; \nPMN = polymorphonuclear leukocyte; PND = postnatal day; Repro = reproductive; Resp = respiratory; RX = reproductive function; SLOAEL = serious lowest-observedadverse-effect level; UC10 = urinary cadmium level associated with 10% extra risk; UR = urinalysis; (WB) = whole body; WBC = white blood cell; WI = water intake\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Cadmium – Inhalation**\nAcute (≤14 days)\n\n**Figure 2-2. Levels of Significant Exposure to Cadmium – Inhalation, Acute (≤14 days) - Death**\n\n| Category | mg Cd/m3 |\n| --- | --- |\n| 1 | 9 |\n| 2R | 30 |\n| 9R | 9 |\n| 14R | 85 |\n| 15R | 65 |\n| 16M | 40 |\n| 19M | 9 |\n| 21H | 30 |\n\n**Figure 2-2. Levels of Significant Exposure to Cadmium – Inhalation, Acute (≤14 days) - Body Weight**\n\n| Category | Animal - NOAEL (mg Cd/m3) | Animal - LOAEL (mg Cd/m3) | Animal - SLOAEL (mg Cd/m3) |\n| --- | --- | --- | --- |\n| 3R | 0.4 | 4.5 |  |\n| 4R |  | 6.5 |  |\n| 5R | 0.23 | 4.5 |  |\n| 6R | 4.0 |  |  |\n| 8R | 17 |  |  |\n| 9R | 2.6 |  |  |\n| 10R | 6.0 |  |  |\n| 12R | 140 |  |  |\n| 13R | 110 |  |  |\n| 19M | 2.6 |  |  |\n| 20M | 0.4 |  | 1.7 |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Cadmium – Inhalation**\nAcute (≤14 days)\n\n| Category | Human - SLOAEL (mg Cd/m3) | Animal - NOAEL (mg Cd/m3) | Animal - LOAEL (mg Cd/m3) | Animal - SLOAEL (mg Cd/m3) |\n| --- | --- | --- | --- | --- |\n| 1 | 9 |  |  |  |\n| 4R |  | 6 |  |  |\n| 7R |  | 1.6 |  |  |\n| 9R |  | 0.08 |  | 9 |\n| 10R |  | 6 |  |  |\n| 11R |  |  |  | 100 |\n| 14R |  |  |  | 85 |\n| 15R |  |  |  | 65 |\n| 19M |  | 0.008 | 0.8 |  |\n| 22S |  | 1.1 |  | 10 |\n| 9R |  | 2.5 |  |  |\n| 19M |  | 2.7 |  |  |\n| 9R |  | 2.7 |  |  |\n| 19M |  | 2.7 |  |  |\n| 9R |  | 2.7 |  |  |\n| 19M |  | 2.7 |  |  |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Cadmium – Inhalation**\nAcute (≤14 days)\n\n**Figure 2-2. Levels of Significant Exposure to Cadmium – Inhalation (Acute ≤14 days)**\n\n| Category | Animal - NOAEL (mg Cd/m3) | Animal - LOAEL (mg Cd/m3) | Animal - SLOAEL (mg Cd/m3) |\n| --- | --- | --- | --- |\n| Endocrine | 6 |  |  |\n| Immunological | 0.11 | 0.19 |  |\n| Neuropsychological |  | 85 |  |\n| Reproductive |  | 16 |  |\n| Developmental | 0.043 | 0.35 | 1.7 |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Cadmium – Inhalation**\nIntermediate (15–364 days)\n\n**Figure 2-2. Levels of Significant Exposure to Cadmium – Inhalation Intermediate (15–364 days) - Death**\n\n| Category | mg Cd/m3 |\n| --- | --- |\n| 24R | 1.0 |\n| 25R | 1.0 |\n| 30R | 2.6 |\n| 31R | 2.6 |\n| 35R | 0.080 |\n| 36R | 0.80 |\n| 37R | 0.090 |\n| 38R | 0.33 |\n| 39R | 0.80 |\n| 40R | 0.090 |\n| 42R | 0.11 |\n\n**Figure 2-2. Levels of Significant Exposure to Cadmium – Inhalation Intermediate (15–364 days) - Body Weight**\n\n| Category | Animal - NOAEL (mg Cd/m3) | Animal - LOAEL (mg Cd/m3) | Animal - SLOAEL (mg Cd/m3) |\n| --- | --- | --- | --- |\n| 24R | 1.0 |  |  |\n| 25R | 0.17 | 1.0 |  |\n| 26R | 0.11 |  |  |\n| 27R | 1.1 |  |  |\n| 28R | 0.10 |  |  |\n| 30R | 0.40 | 1.1 |  |\n| 31R | 0.40 | 1.1 |  |\n| 31R |  |  | 2.6 |\n| 32R | 0.90 |  |  |\n| 33R | 0.50 | 1.8 |  |\n| 33R |  |  | 1.8 |\n| 41R | 0.030 | 0.055 |  |\n| 42R |  |  | 0.11 |\n| 43R | 0.60 |  |  |\n| 44R |  | 0.23 | 0.44 |\n| 45M | 0.90 |  |  |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Cadmium – Inhalation**\nIntermediate (15–364 days)\n\n**Figure 2-2. Levels of Significant Exposure to Cadmium – Inhalation Intermediate (15–364 days)**\n\n| Category | Respiratory Animal - NOAEL (mg Cd/m3) | Respiratory Animal - LOAEL (mg Cd/m3) | Respiratory Animal - SLOAEL (mg Cd/m3) | Respiratory Animal - Cancer Effect Level (mg Cd/m3) | Cardiovascular Animal - NOAEL (mg Cd/m3) | Cardiovascular Animal - LOAEL (mg Cd/m3) | Cardiovascular Animal - SLOAEL (mg Cd/m3) | Cardiovascular Animal - Cancer Effect Level (mg Cd/m3) | Gastrointestinal Animal - NOAEL (mg Cd/m3) | Gastrointestinal Animal - LOAEL (mg Cd/m3) | Gastrointestinal Animal - SLOAEL (mg Cd/m3) | Gastrointestinal Animal - Cancer Effect Level (mg Cd/m3) | Hematological Animal - NOAEL (mg Cd/m3) | Hematological Animal - LOAEL (mg Cd/m3) | Hematological Animal - SLOAEL (mg Cd/m3) | Hematological Animal - Cancer Effect Level (mg Cd/m3) |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| 26R | 0.11 |  |  |  |  |  |  |  |  |  |  |  | 0.11 |  |  |  |\n| 27R |  | 1.1 |  |  |  |  |  |  |  |  |  |  | 1.1 |  |  |  |\n| 28R |  | 0.10 |  |  |  |  |  |  |  |  |  |  |  | 0.10 |  |  |\n| 29R |  | 1.7 |  |  |  |  |  |  |  |  |  |  |  |  |  |  |\n| 32R |  | 0.023 | 0.90 |  | 0.90 |  |  |  | 0.90 |  |  |  | 0.90 |  |  |  |\n| 34R |  | 0.10 |  |  |  |  |  |  |  |  |  |  |  |  |  |  |\n| 41R |  | 0.026 |  |  |  |  |  |  |  |  |  |  | 0.026 | 0.053 |  |  |\n| 45M |  | 0.022 |  |  | 0.90 |  |  |  | 0.90 |  |  |  |  |  |  |  |\n| 46M |  | 0.10 |  |  |  |  |  |  |  |  |  |  |  |  |  |  |\n| 47H |  | 0.45 |  |  |  |  |  |  |  |  |  |  |  |  |  |  |\n| 42R |  |  |  |  |  |  |  |  |  |  |  |  |  | 0.11 |  |  |\n| 43R |  |  |  |  |  |  |  |  |  |  |  |  |  | 0.21 |  |  |\n| 44R |  |  |  |  |  |  |  |  |  |  |  |  | 0.45 |  | 0.60 |  |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Cadmium – Inhalation**\nIntermediate (15–364 days)\n\n**Figure 2-2. Levels of Significant Exposure to Cadmium – Inhalation Intermediate (15–364 days)**\n\n| Category | 32R (mg Cd/m3) | 45M (mg Cd/m3) | 41R (mg Cd/m3) | 26R (mg Cd/m3) | 27R (mg Cd/m3) | 28R (mg Cd/m3) | 32R (mg Cd/m3) | 43R (mg Cd/m3) | 44R (mg Cd/m3) | 45M (mg Cd/m3) | 32R (mg Cd/m3) | 45M (mg Cd/m3) | 32R (mg Cd/m3) | 45M (mg Cd/m3) |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Musculoskeletal | 0.9 | 0.9 |  |  |  |  |  |  |  |  |  |  |  |  |\n| Hepatic | 0.85 | 0.9 | 0.05 |  |  |  |  |  |  |  |  |  |  |  |\n| Renal |  |  |  | 0.11 | 1.1 | 0.1 | 0.9 | 0.55 | 0.55 | 0.85 |  |  |  |  |\n| Endocrine | 0.85 | 0.9 |  |  |  |  |  |  |  |  |  |  |  |  |\n| Immunological | 0.9 | 0.9 |  |  |  |  |  |  |  |  |  |  |  |  |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Cadmium – Inhalation**\nIntermediate (15–364 days)\n\n**Figure 2-2. Levels of Significant Exposure to Cadmium – Inhalation Intermediate (15–364 days)**\n\n| Category | Neurolgical mg Cd/m3 | Reproductive mg Cd/m3 | Developmental mg Cd/m3 | Cancer mg Cd/m3 |\n| --- | --- | --- | --- | --- |\n| 32R | 0.9 | 0.9 |  |  |\n| 45M | 0.9 | 0.9 |  |  |\n| 23R |  | 0.17 | 0.17 |  |\n| 24R |  | 1.0 | 0.17 |  |\n| 25R |  | 1.0 |  |  |\n| 25R |  | 0.18 |  |  |\n| 31R |  | 1.1 |  |  |\n| 32R |  | 0.24 |  |  |\n| 23R |  |  | 0.022 |  |\n| 24R |  |  | 0.022 |  |\n| 33R |  |  | 2.0 |  |\n| 33R |  |  | 0.53 |  |\n| 44R |  |  | 0.6 |  |\n| 44R |  |  | 0.5 |  |\n| 37R |  |  |  | 0.09 |\n| 39R |  |  |  | 0.75 |\n| 40R |  |  |  | 0.09 |\n\n---\n\n**Figure 2-2.  Levels of Significant Exposure to Cadmium – Inhalation**\nChronic (≥365 days)\n\n**Figure 2-2. Levels of Significant Exposure to Cadmium – Inhalation (Chronic ≥365 days)**\n\n| Category | Death mg Cd/m3 | Body Weight mg Cd/m3 |\n| --- | --- | --- |\n| 49R | 0.095 |  |\n| 50R | 0.033 |  |\n| 51R | 0.088 |  |\n| 53R | 0.088 |  |\n| 55R |  | 0.050 |\n\n**Figure 2-2. Levels of Significant Exposure to Cadmium – Inhalation (Chronic ≥365 days) - Renal**\n\n| Category | Human - Weighted median (mg Cd/m3) | Human - 95% lower confidence limit of weighted median (mg Cd/m3) |\n| --- | --- | --- |\n| 48 | 0.0014 | 0.00011 |\n\n**Figure 2-2. Levels of Significant Exposure to Cadmium – Inhalation (Chronic ≥365 days) - Cancer**\n\n| Category | Animal - Cancer Effect Level (mg Cd/m3) |\n| --- | --- |\n| 50R | 0.033 |\n| 51R | 0.092 |\n| 52R | 0.033 |\n| 53R | 0.092 |\n| 54R | 0.033 |\n| 55R | 0.013 |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| ACUTE EXPOSURE |  |  |  |  |  |  |  |  |  |\n| Andjelkovic et al. 2019 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 1 | Rat (Wistar) 6–8 M | Once (GW) | 0, 15, 30 | HE, BC, HP | Hemato |  | 15 |  | Decreased RBC count, hemoglobin, hematocrit, lymphocyte, and serum iron levels; increased MCHC |\n| Baranski 1985 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 2 | Rat (Wistar) 6–18 F | 10 days GDs 7–16 (GW) | 0, 2, 12, 40 | BW, OW, DX | Bd wt |  | 2 | 12 | LOAEL: 14% decrease in maternal body weight gain SLOAEL: 34% decrease in maternal body weight gain |\n| 2 | Rat (Wistar) 6–18 F | 10 days GDs 7–16 (GW) | 0, 2, 12, 40 | BW, OW, DX | Develop | 2 | 12 | 40 | LOAEL: 9% decrease in fetal weight SLOAEL: 23% decrease in fetal weight, decreased live fetuses/litter, increased resorptions/litter, fetal malformations (fused lower limbs, absent limbs) |\n| Bomhard et al. 1987 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 3 | Rat (Wistar) 25–35 M | Once (GW) | 0, 50, 100, 200 | LE, BW, CS, FI, WI, HP | Death Repro | 50 |  | 100 | 28/35 died within 3 days Testicular necrosis, focal proliferation of Leydig cells (6 months post-exposure); hyperemia and slight hemorrhages in testes and epididymides in rats that died |\n| Surviving rats sacrificed 6–30 months post-exposure |  |  |  |  |  |  |  |  |  |\n| Borzelleca et al. 1989 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 4 | Rat (Sprague-Dawley) 10 M, 10 F | Once (GW) | 0, 15, 31, 65.6, 138 | LE, CS, BW, HE, BC, GN, OW | Death |  |  | 138 F 65.6 M | 2/10 died within 24 hours 3/10 died within 24 hours |\n| 4 | Rat (Sprague-Dawley) 10 M, 10 F | Once (GW) | 0, 15, 31, 65.6, 138 | LE, CS, BW, HE, BC, GN, OW | Bd wt Hemato Hepatic Renal | 138 138 138 |  |  |  |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Borzelleca et al. 1989 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 5 | Rat (Sprague-Dawley) 10 M, 10 F | 10 days (W) | M: 0, 1.1, 7.85, 11.2 F: 0, 1.1, 8.16, 13.9 | LE, CS, BW, HE, BC, UR, GN, OW, HP | Bd wt | 13.9 F 1.1 M | 7.85 M | 11.2 M | LOAEL: 14% decrease in body weight SLOAEL: 25% decrease in body weight |\n| 5 | Rat (Sprague-Dawley) 10 M, 10 F | 10 days (W) | M: 0, 1.1, 7.85, 11.2 F: 0, 1.1, 8.16, 13.9 | LE, CS, BW, HE, BC, UR, GN, OW, HP | Hematocrit | 13.9 F 11.2 M 13.9 F 11.2 M 13.9 F 11.2 M |  |  |  |\n| 5 | Rat (Sprague-Dawley) 10 M, 10 F | 10 days (W) | M: 0, 1.1, 7.85, 11.2 F: 0, 1.1, 8.16, 13.9 | LE, CS, BW, HE, BC, UR, GN, OW, HP | Renal | 13.9 F 11.2 M 13.9 F 11.2 M |  |  |  |\n| 5 | Rat (Sprague-Dawley) 10 M, 10 F | 10 days (W) | M: 0, 1.1, 7.85, 11.2 F: 0, 1.1, 8.16, 13.9 | LE, CS, BW, HE, BC, UR, GN, OW, HP | Repro | 13.9 F 11.2 M |  |  |  |\n| Borzelleca et al. 1989 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 6 | Rat (Sprague-Dawley) 10 M, 10 F | 10 days (GW) | 0, 15, 31, 65.6, 138 | LE, CS, BW, HE, BC, UR, GN, OW, HP | Death | 31 F | 65.6 F 15 M | 31 M | 3/10 males and 4/10 females died within 7 days 18% decrease in terminal body weight LOAEL: 18% decrease in terminal body weight SLOAEL: 23% decrease in terminal body weight Increased WBC and platelet counts Increased RBC count Elevated serum ALT, decreased serum cholesterol Mild focal necrosis of hepatocytes or congestion Mild focal necrosis of tubular epithelium |\n| 6 | Rat (Sprague-Dawley) 10 M, 10 F | 10 days (GW) | 0, 15, 31, 65.6, 138 | LE, CS, BW, HE, BC, UR, GN, OW, HP | Bd wt | 31 F | 65.6 F 15 M 31 F |  |  |\n| 6 | Rat (Sprague-Dawley) 10 M, 10 F | 10 days (GW) | 0, 15, 31, 65.6, 138 | LE, CS, BW, HE, BC, UR, GN, OW, HP | Hematocrit | 15 F | 65.6 F 15 M 31 F |  |  |\n| 6 | Rat (Sprague-Dawley) 10 M, 10 F | 10 days (GW) | 0, 15, 31, 65.6, 138 | LE, CS, BW, HE, BC, UR, GN, OW, HP | Renal | 65.6 M | 138 M 65.6 F |  |  |\n\n***DRAFT FOR PUBLIC COMMENT***\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n|  |  |  |  |  | Repro | 65.6 M 138 F 31 M | 138 M |  | Mild focal necrosis of tubular epithelium |\n|  |  |  |  |  | Repro | 65.6 M 138 F 31 M | 138 M | 65.6 M | Necrotic changes in testes with atrophy and loss of spermatogenic elements |\n| Dixon et al. 1976 |  |  |  |  |  |  |  |  |  |\n| 7 | Rat (Sprague-Dawley) 10 M | Once (GW) | 0, 6.25, 12.5, 25 | RX | Repro | 25 |  |  | Cadmium chloride |\n| Males serially mated to untreated females for 70 days post-treatment |  |  |  |  |  |  |  |  |  |\n| Kostial et al. 1978 |  |  |  |  |  |  |  |  |  |\n| 8 | Rat (NS) 6 B | Once (G) | NS | LE | Death |  |  | 29 | Cadmium chloride LD50 calculated 8 days post-exposure |\n| Age at exposure: 2 weeks |  |  |  |  |  |  |  |  |  |\n| Kostial et al. 1978 |  |  |  |  |  |  |  |  |  |\n| 9 | Rat (NS) 6 B | Once (G) | NS | LE | Death |  |  | 147 | Cadmium chloride LD50 calculated 8 days post-exposure |\n| Age at exposure: 3 weeks |  |  |  |  |  |  |  |  |  |\n| Kostial et al. 1978 |  |  |  |  |  |  |  |  |  |\n| 10 | Rat (NS) 6 B | Once (G) | NS | LE | Death |  |  | 129 | Cadmium chloride LD50 calculated 8 days post-exposure |\n| Age at exposure: 6 weeks |  |  |  |  |  |  |  |  |  |\n| Kostial et al. 1978 |  |  |  |  |  |  |  |  |  |\n| 11 | Rat (NS) 6 B | Once (G) | NS | LE | Death |  |  | 104 | Cadmium chloride LD50 calculated 8 days post-exposure |\n| Age at exposure: 18 weeks |  |  |  |  |  |  |  |  |  |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Kostial et al. 1978 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 12 | Rat (NS) 6 B | Once (G) | NS | LE | Death |  |  | 66.8 | LD50 calculated 8 days post-exposure |\n| Age at exposure: 54 weeks |  |  |  |  |  |  |  |  |  |\n| Kotsonis and Klaassen 1977 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 13 | Rat (Sprague-Dawley) 6 M | Once (premating) (GW) | 0, 25, 50, 100, 150 | HP, RX, NX | Neuro Repro | 25 50 | 50 | 100 | Decreased motor activity Testicular necrosis; decreased spermatogenesis; decreased fertility (fewer females producing pups) |\n| Males mated to unexposed females |  |  |  |  |  |  |  |  |  |\n| Kotsonis and Klaassen 1977 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 14 | Rat (Sprague-Dawley) 6–12 M | Once (GW) | 0, 25, 50, 100, 150 | CS, BW, HE, BC, BI, UR, HP, OF | Bd wt Resp Cardio Gastro Hematoc Hepatic Renal Endocr | 100 150 150 150 150 150 |  | 150 | Initial body weight loss resulting in approximate 10% decrease in terminal body weight (2 weeks post-exposure) |\n| Kotsonis and Klaassen 1977 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 15 | Rat (Sprague-Dawley) 15–20 M | Once (GW) | NS | LE | Death |  |  | 225 | LD50 at 14 days |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Kotsonis and Klaassen 1978 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 16 | Rat (Sprague-Dawley) 9 M | 2 weeks (W) | 0, 42 | LE | Death |  |  | 42 | 7/9 died within 2 weeks |\n| Machemer and Lorke 1981 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 17 | Rat (Long-Evans) 22–28 F | 10 days GDs 6–15 (GW) | 0, 1.84, 6.13, 18.39, 61.32 | LE, CS, BW, DX | Death Bd wt | 1.84 |  | 61.32 6.13 | 15/25 dams died 27% decrease in maternal body weight gain during treatment period |\n| 17 | Rat (Long-Evans) 22–28 F | 10 days GDs 6–15 (GW) | 0, 1.84, 6.13, 18.39, 61.32 | LE, CS, BW, DX | Gastro | 18.39 |  | 61.32 | Intestinal necrosis, hemorrhage, ulcers, constipation/absence of defecation |\n| 17 | Rat (Long-Evans) 22–28 F | 10 days GDs 6–15 (GW) | 0, 1.84, 6.13, 18.39, 61.32 | LE, CS, BW, DX | Dermal Develop | 1.84 6.13 | 6.13 | 18.39 | Coarse fur Increased number of fetuses with malformations, increased number of runts (<3 g), 7% decrease in fetal body weight |\n| Machemer and Lorke 1981 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 18 | Rat (Long-Evans) 21–24 F | 10 days GDs 6–15 (F) | 0, 1.2, 3.5, 12.5 | LE, CS, BW, FI, DX | Bd wt | 3.5 | 12.5 |  | 19% decrease in maternal body weight gain during treatment period |\n| 18 | Rat (Long-Evans) 21–24 F | 10 days GDs 6–15 (F) | 0, 1.2, 3.5, 12.5 | LE, CS, BW, FI, DX | Develop | 12.5 |  |  |  |\n| Saedi et al. 2020a, 2020b |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 19 | Rat (Sprague-Dawley) 4 F | 13 days PNDs 21–33 (GW) | 0, 15, 31, 46 | BW, BC, HE, OW, HP, DX | Bd wt Hemato | Endocr Develop | 46 15 | 15 | 21% decrease in terminal body weight Decreased RBC and increased WBC levels |\n| 19 | Rat (Sprague-Dawley) 4 F | 13 days PNDs 21–33 (GW) | 0, 15, 31, 46 | BW, BC, HE, OW, HP, DX | Hemat | 15 | 46 15 | 15 | 21% decrease in terminal body weight Decreased RBC and increased WBC levels |\n| 19 | Rat (Sprague-Dawley) 4 F | 13 days PNDs 21–33 (GW) | 0, 15, 31, 46 | BW, BC, HE, OW, HP, DX | Develop | 46 15 | 31 | 15 | Increased atretic follicles and decreased secondary follicles in ovaries; decreased serum estradiol levels |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Samuel et al. 2011 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 20 | Rat (Wistar) 18 F | 13 days GDs 9–21 (W) | 0, 6, 18 | BW, FI, WI, DX | Bd wt | 6 | 18 |  | 11% decrease in maternal body weight on GD 21 |\n| 20 | Rat (Wistar) 18 F | 13 days GDs 9–21 (W) | 0, 6, 18 | BW, FI, WI, DX | Develop |  |  | 6 | Fetal effects: Increased resorption Postnatal effects (female offspring): Decreased postnatal weight on PND 10 (22%) and PND 21 (14%), ovarian follicular degeneration, decreased estradiol and testosterone, delayed vaginal opening, and altered estrous cycling |\n| 20 | Rat (Wistar) 18 F | 13 days GDs 9–21 (W) | 0, 6, 18 | BW, FI, WI, DX | Other noncancer | 6 | 18 |  | Decreased maternal food intake |\n| Three dams/group were sacrificed on GD 21; remaining offspring were sacrificed on PND 10, PND 21, or evaluated during puberty |  |  |  |  |  |  |  |  |  |\n| Shimizu and Morita 1990 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 21 | Rat (Sprague-Dawley) 10 M | Once (GW) | NS | LE | Death |  |  | 106.9 | LD50 at 24 hours (fasted rats) |\n| Shimizu and Morita 1990 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 22 | Rat (Sprague-Dawley) 10 M | Once (GW) | NS | LE | Death |  |  | 327.3 | LD50 at 24 hours (fed rats) |\n| Stacey et al. 1988 |  |  |  |  |  |  |  |  | Cadmium acetate |\n| 23 | Rat (Sprague-Dawley) 4 M | 6 weeks 5 days/week (G) | 0, 0.0025, 0.025, 0.250 | BW, OW, IX | Bd wt | 0.25 |  |  | Enhanced spleen cell proliferative responses |\n| 23 | Rat (Sprague-Dawley) 4 M | 6 weeks 5 days/week (G) | 0, 0.0025, 0.025, 0.250 | BW, OW, IX | Immuno | 0.025 | 0.25 |  | Enhanced spleen cell proliferative responses |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Stacey et al. 1988 |  |  |  |  |  |  |  |  | Cadmium acetate |\n| 24 | Rat (Sprague-Dawley) 4 M | 2 weeks 5 days/week (G) | 0, 0.0025, 0.025, 0.250 | BW, OW, IX | Bd wt Immuno | 0.25 0.25 |  |  |  |\n| Wan et al. 2022 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 25 | Rat (Sprague-Dawley) 3 M, 3 F | 2 weeks (G) | 0, 2, 4 | BW, WI, BC, UR, OW, HP | Bd wt Renal | 4 | 2c |  | Increased 24-hour urinary protein excretion, elevated urinary β 2M levels, increased serum BUN |\n| Andersen et al. 1988 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 26 | Mouse (CBA/Bom) 7–42 M | Once (GW) | 0, 0.6, 3.9, 7.9, 15.7, 30.3, 59.6, 88.8 | LE, HP | Death Gastro | 15.7 | 30.3 | 88.8 | 36/42 mice died within 10 days LOAEL: Gastritis and enteritis SLOAEL: Severe gastric necrosis Fatty infiltration of liver cells, occasional hepatocellular necrosis Proximal tubular necrosis with poor cell differentiation and irregular granulation of cells Testicular necrosis in most tubules and interstitial tissue |\n| 26 | Mouse (CBA/Bom) 7–42 M | Once (GW) | 0, 0.6, 3.9, 7.9, 15.7, 30.3, 59.6, 88.8 | LE, HP | Hepatic | 15.7 | 30.3 | 88.8 | 36/42 mice died within 10 days LOAEL: Gastritis and enteritis SLOAEL: Severe gastric necrosis Fatty infiltration of liver cells, occasional hepatocellular necrosis Proximal tubular necrosis with poor cell differentiation and irregular granulation of cells Testicular necrosis in most tubules and interstitial tissue |\n| 26 | Mouse (CBA/Bom) 7–42 M | Once (GW) | 0, 0.6, 3.9, 7.9, 15.7, 30.3, 59.6, 88.8 | LE, HP | Renal | 59.6 |  | 88.8 | 36/42 mice died within 10 days LOAEL: Gastritis and enteritis SLOAEL: Severe gastric necrosis Fatty infiltration of liver cells, occasional hepatocellular necrosis Proximal tubular necrosis with poor cell differentiation and irregular granulation of cells Testicular necrosis in most tubules and interstitial tissue |\n| 26 | Mouse (CBA/Bom) 7–42 M | Once (GW) | 0, 0.6, 3.9, 7.9, 15.7, 30.3, 59.6, 88.8 | LE, HP | Repro | 30.3 |  | 59.6 | 36/42 mice died within 10 days LOAEL: Gastritis and enteritis SLOAEL: Severe gastric necrosis Fatty infiltration of liver cells, occasional hepatocellular necrosis Proximal tubular necrosis with poor cell differentiation and irregular granulation of cells Testicular necrosis in most tubules and interstitial tissue |\n| Ara et al. 2016 |  |  |  |  |  |  |  |  | Form not specified |\n| 27 | Mouse (Swiss-Webster) 5 F | 7 days GDs 6–12 (GW) | 0, 3.13, 6.25, 12.5, 25.0 | RX, DX | Develop |  |  | 3.13 | 49% decrease in fetal body weight; decreased crown-rump length, head and eye circumference, and forelimb, hindlimb and tail length; anomalies in the brain, eyes, forelimbs, hindlimbs, and tail |\n| Baer and Benson 1987 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 28 | Mouse (Swiss-Webster) 10 M | Once (GW) | 100, 150 | LE | Death |  |  | 95.5 | LD50 at 96 hours |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Yi et al. 2021a |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 29 | Mouse (ICR) 13 F | 10 days GDs 8–17 (W) | 0, 8.1, 24 | DX | Develop |  | 8.1 |  | Impaired glucose tolerance in adult male offspring |\n| INTERMEDIATE EXPOSURE |  |  |  |  |  |  |  |  |  |\n| Chopra et al. 1984 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 30 | Monkey (Rhesus) 3–4 M | 6 months (F) | 0, 5 | CS, BW, IX | Bd wt Immuno | 5 5 |  |  |  |\n| Afolabi et al. 2012 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 31 | Rat (Wistar) 8 M | 7 weeks (W) | 0, 4.6, 9.1 | BW, BC, BI | Hepatic Immuno |  | 4.6 4.6 |  | Increased plasma lipid levels Increased plasma pro-inflammatory cytokines |\n| Ali et al. 1986 |  |  |  |  |  |  |  |  | Cadmium acetate |\n| 32 | Rat (Wistar) 10 F | 21 days GDs 1–21 (W) | 0, 0.706, 1.2 | BW, FI, WI, RX, DX | Bd wt Repro Develop | 1.2 1.2 | 0.706 | 1.2 | Decreased offspring body weight, persisting through PND 45 (~20%) Delayed development of sensory motor coordination reflexes; altered motor activity (increased PNDs 7–21; decreased PND 60) |\n| Aprioku et al. 2014 |  |  |  |  |  |  |  |  | Cadmium sulfate |\n| 33 | Rat (Wistar) 8 F | 21 days GDs 0–20 (W) | 0, 4, 8 | BW, OW, HP, RX, DX | Bd wt Repro Develop |  | 4 | 4 | 40% decrease in maternal body weight on GD 20 Increased abortions |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Baranski 1987 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 34 | Rat (Wistar) 12–16 F | 20 days GDs 1–20 (W) | 0, 4.6, 11.1 | LE, BW, FI, WI, HE, BC, DX | Bd wt Repro Develop | 11.1 |  | 4.6 | 37% decrease in maternal body weight gain |\n| 34 | Rat (Wistar) 12–16 F | 20 days GDs 1–20 (W) | 0, 4.6, 11.1 | LE, BW, FI, WI, HE, BC, DX | Bd wt Repro Develop | 11.1 |  | 4.6 | 12% decrease in fetal body weight and 7% decrease in fetal body length |\n| 34 | Rat (Wistar) 12–16 F | 20 days GDs 1–20 (W) | 0, 4.6, 11.1 | LE, BW, FI, WI, HE, BC, DX | Other noncancer |  | 4.6 |  | Decreased maternal food intake |\n| Baranski and Sitarek 1987 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 35 | Rat (Wistar) 11–13 F | 14 weeks 5 days/week (GW) | 0, 0.04, 0.4, 4, 40 | LE, CS, BW, RX | Death |  |  | 40 | 4/13 died by week 8; 7/13 by week 14 |\n| 35 | Rat (Wistar) 11–13 F | 14 weeks 5 days/week (GW) | 0, 0.04, 0.4, 4, 40 | LE, CS, BW, RX | Bd wt Repro | 0.4 |  | 4 | 40% decrease in body weight gain |\n| 35 | Rat (Wistar) 11–13 F | 14 weeks 5 days/week (GW) | 0, 0.04, 0.4, 4, 40 | LE, CS, BW, RX | Bd wt Repro | 4 |  | 40 | Increased duration of estrus cycle |\n| Baranski et al. 1983 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 36 | Rat (Wistar) NS F | 11 weeks (5 weeks premating, 3 weeks mating, 3 weeks gestation) 5 days/week (GW) | 0, 0.04, 0.4, 4 | RX, DX | Repro Develop | 4 |  |  | Decreased pup locomotor activity and impaired motor coordination at 2 months |\n| 36 | Rat (Wistar) NS F | 11 weeks (5 weeks premating, 3 weeks mating, 3 weeks gestation) 5 days/week (GW) | 0, 0.04, 0.4, 4 | RX, DX | Repro Develop | 4 | 0.04 |  | Decreased pup locomotor activity and impaired motor coordination at 2 months |\n| Half of dams were sacrificed on GD 21; half were allowed to deliver naturally and pups (8/sex/group) were assessed for 2 months after parturition |  |  |  |  |  |  |  |  |  |\n| Brzóska and Moniuszko-Jakoniuk 2005a, 2005b; 2010 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 37 | Rat (Wistar) 10 M | 12 months (W) | 0, 0.2, 0.5, 4 | BW, FI, WI, BC, BI, HP | Bd wt Musc/skel | 4 |  |  | Increased lumbar spine deformities, decreased in lumbar spine and femur mineralization, altered bone turnover parameters |\n| 37 | Rat (Wistar) 10 M | 12 months (W) | 0, 0.2, 0.5, 4 | BW, FI, WI, BC, BI, HP | Bd wt Musc/skel | 0.2 | 0.5 |  | Increased lumbar spine deformities, decreased in lumbar spine and femur mineralization, altered bone turnover parameters |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Brzóska and Moniuszko-Jakoniuk 2005c; Brzóska et al. 2005a, 2005c |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 38 | Rat (Wistar) 40 F | 12 months (W) | 0, 0.2, 0.5, 4 | BW, FI, WI, BC, BI, HP, OF | Bd wt Musc/skel | 4 | 0.2 |  | Decreased bone mineralization, mechanical properties of tibia and femur, and altered bone turnover parameters |\n| Brzóska et al. 2004, 2005b |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 39 | Rat (Wistar) 8–10 F | 12 months (W) | 0, 0.3, 0.7, 4, 8 | BW, FI, WI, BI, OF | Musc/skel |  | 0.3 |  | Alterations in bone mineral content and density and mechanical properties of lumbar vertebral and femoral bones |\n| Buha et al. 2013, 2019 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 40 | Rat (Wistar) 7 M | 28 days (G) | 0, 0.3, 0.6, 1.25, 2.5, 5, 10 | BW, BC, BI | Bd wt Musc/skel | 0.6 | 0.3 | 1.25 | 36% decrease in body weight gain Decreased bone mineral content in femur Increased serum creatinine and urea Decreased serum T3 levels |\n|  |  |  |  |  | Renal Endocr | 2.5 | 5 0.3 |  |  |\n| Caride et al. 2010 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 41 | Rat (Sprague-Dawley) 60 M | 30 days (W) | 0, 0.92, 1.8 | BC | Endocr |  | 0.92 |  | Altered daily secretory pattern of ACTH and growth hormone; increased median levels of ACTH and TSH |\n| Carmignani and Boscolo 1984 |  |  |  |  |  |  |  |  | Cadmium acetate |\n| 42 | Rat (Sprague-Dawley) 10 M | 190 days (W) | 0, 1.4, 2.8 | CS, BW, OF | Bd wt Cardio | 2.8 | 1.4 |  | Increased systolic and diastolic blood pressure |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Chen et al. 2013 |  |  |  |  |  |  |  |  | Form not specified |\n| 43 | Rat (Sprague-Dawley) 6 M | 12 weeks (W) | 0, 0.2, 1.1, 5.0 | BW, BC, BI, UR, HP | Bd wt Musc/skel | 5 | 0.2 |  | Trabecular bone damage in tibia (decreased number, thickness; increased separation, increased dissociated ends); altered bone turnover parameters |\n| Cifone et al. 1989 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 44 | Rat (Wistar) 4 F | 170 days (W) | 0, 29, 58 | CS, BW, FI, WI, OW, IX | Bd wt Immuno | 58 | 29 |  | Biphasic decrease (first 30–50 days) then increase in NK cell activity, splenic cellularity, and the number of large granular lymphocytes in the peripheral blood; increased total peripheral lymphocytes |\n| Desi et al. 1998 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 45 | Rat (Wistar) NS F | 94 days F0: GDs 5–15 + PNDs 2–28 F1: PNWs 5–12 5 days/week (GW) | 0, 3.5, 7.0, 14.0 | DX | Develop | 3.5 | 7 |  | Decreased peripheral nerve conduction velocity with increased refractory periods |\n| Locomotor and sensory function assessed in F1 males at 12 weeks of age |  |  |  |  |  |  |  |  |  |\n| Desi et al. 1998 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 46 | Rat (Wistar) NS F | 11 days GDs 5–15 (GW) | 0, 3.5, 7.0, 14.0 | DX | Develop | 14 |  |  |  |\n| Locomotor and sensory function assessed in F1 males at 12 weeks of age |  |  |  |  |  |  |  |  |  |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Desi et al. 1998 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 47 | Rat (Wistar) NS F | 38 days GDs 5–15 plus PNDs 2–28 (GW) | 0, 3.5, 7.0, 14.0 | DX | Develop | 3.5 | 7 |  | Decreased horizontal ambulation and rearing activity |\n| Locomotor and sensory function assessed in F1 males at 12 weeks of age |  |  |  |  |  |  |  |  |  |\n| Dixon et al. 1976 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 48 | Rat (Sprague-Dawley) 10 M | 30–90 days (W) | 0, 0.00014, 0.0014, 0.014 | BC, OW, RX | Repro | 0.014 |  |  |  |\n| Males mated to untreated females |  |  |  |  |  |  |  |  |  |\n| Feng et al. 2019 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 49 | Rat (Sprague-Dawley) NS F | 6 weeks GD 0 to PND 21 (W) | 0, 0.6, 3 | DX | Develop |  | 0.6 |  | Impaired learning and memory in F1 males at PNDs 35 and 56 |\n| Huang et al. 2020 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 50 | Rat (Sprague-Dawley) <10 F | 3 weeks GD 1 to birth (GW) | 0, 0.3, 1.2, 4.9 | DX | Develop |  | 0.3 |  | F1 males: Decreased serum testosterone and increased seminiferous tubule diameter at PND 21; decreased Johnsen score (decreased testicular maturity) on PND 56 |\n| Iqbal et al. 2021 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 51 | Rat (Sprague-Dawley) 6 M | 17 days (GW) | 0, 5, 10, 15 | BW, OW, HP | Bd wt | 10 |  | 15 | 12% body weight loss during exposure (compared to 12% body weight gain in control) |\n|  |  |  |  |  | Repro | 5 | 10 |  | Structural changes in the testis and epididymis |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\nstimulated plasma insulin levels\n\nAltered glucose tolerance at PND 21\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects | Cadmium chloride |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Jacquet et al. 2018 |  |  |  |  |  |  |  |  |  |  |\n| 52 | Rat (Wistar) 9 M, 9 F | 12 weeks (W) | M: 0, 0.0053, 0.0558, 0.515; F: 0, 0.0055, 0.053, 0.4959 | LE, BW, BC, UR, OW, OF | Bd wt | 0.4959 F 0.515 M 0.4959 F 0.515 M Endocr | 0.053 F |  |  |  |\n| Jacquet et al. 2019 |  |  |  |  |  |  |  |  |  |  |\n| 53 | Rat (Wistar) 15–17 F | 11 weeks 3 weeks prior to mating GD 0–PND 35 (W) | 0, 0, 0.05, 0.5 | UR, RX, DX | Renal Repro Develop | 0.5 0.5 | 0.05 |  |  | Cadmium chloride |\n| Dams were sacrificed on PND 35; pups were sacrificed on PND 21, 26, and 60 |  |  |  |  |  |  |  |  |  |  |\n| Kelman et al. 1978 |  |  |  |  |  |  |  |  |  |  |\n| 54 | Rat (Sprague-Dawley) 15 F | 22 days GDs 0–21 (W) | 0, 1.5, 3.8 | HE, BI, DX | Hemato Musc/skel Develop | 3.8 | 1.5 | 1.5 | Decreased hematocrit | Form not specified |\n| Kotsonis and Klaassen 1978 |  |  |  |  |  |  |  |  |  |  |\n| 55 | Rat (Sprague-Dawley) 6 M | 24 weeks (W) | 0, 1.1, 2.92, 8.49 | CS, BW, FI, WI, HE, BC, BI, OW, HP, OF, RX, NX | Bd wt Resp Cardio Gastro Hematocell Musc/skel Hepatic Renal Endocr | 8.49 8.49 8.49 8.49 | 8.49 8.49 8.49 | 8.49 8.49 | 8.49 | Cadmium chloride |\n\nProteinuria (starting at week 6)\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n|  |  |  |  |  | Immuno Neuro Repro | 8.49 1.1 8.49 | 2.92 |  | Decreased motor activity (starting at week 3) |\n| Males mated to unexposed females |  |  |  |  |  |  |  |  |  |\n| Kulas et al. 2019 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 56 | Rat (Dark Agouti) 8 M | 30 days (W) | 0, 0.35, 3.51 | OW, HP | Resp |  | 0.35 |  | Minimal to mild perivascular edema and respiratory epithelial desquamation in lungs |\n| Larregle et al. 2008 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 57 | Rat (Wistar) 8 M | 8 weeks daily (W) | 0, 18 | BC | Hepatic |  | 18 |  | Increased serum and liver triglyceride levels; increased serum cholesterol levels |\n| Li et al. 2018 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 58 | Rat (Sprague-Dawley) 10 F | 42 days GD 0-PND 21 (GW) | 0, 0.6, 3 | DX | Develop |  | 0.6 |  | F1 females: Decreased primordial follicles (PND 21) and increased serum estradiol (PND 21, PND 35) F2: females: Increased serum progesterone (PND 21) |\n| Liu et al. 2019 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 59 | Rat (Sprague-Dawley) 10 M | 60 days (G) | 0, 0.6, 1.5, 3 | CS, FI, WI, BW, BC, UR, OW, HP | Bd wt |  |  | 1.5 | 20% decrease in terminal body weights Decreased serum iron Increased BUN and serum creatinine |\n| Liu et al. 2020 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 60 | Rat (Sprague-Dawley) 5 F | 20 days GDs 1-21 (GW) | 0, 0.3, 1.2, 4.9 | DX | Develop |  | 0.3 |  | Decreased ovarian granulosa cell progesterone in F1 female offspring on PND 56 |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects | Cadmium chloride |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Loeser and Lorke 1977 |  |  |  |  |  |  |  |  |  |  |\n| 61 | Rat (Wistar) 20 M, 20 F | 3 months (F) | 0, 0.1, 0.3, 1, 3 | HP, BC, CS, UR, OW, OF, BW, FI | Bd wt Cardio Hematoc Hepatic Renal Endocr Immuno Repro | 3 3 3 3 3 3 | 0.439 | Decreased offspring body weights (by up to ~19% on PNW 9) | Cadmium chloride |  |\n| Luo et al. 2015 |  |  |  |  |  |  |  |  |  |  |\n| 62 | Rat (Sprague-Dawley) 10 F | 42 days GD 0-PND 21 (W) | 0, 0.089, 0.439, 0.955 | BW, RX, DX | Bd wt Repro Develop | 0.955 0.955 0.089 |  | 0.439 | Decreased offspring body weights (by up to ~19% on PNW 9) | Cadmium chloride |\n| McCalla et al. 2024 |  |  |  |  |  |  |  |  |  |  |\n| 63 | Rat (Sprague-Dawley) 10 M | 8 weeks 3 times/week (GW) | 0, 2.5, 5 | BW, HE, OF | Cardio Hematoc | 2.5 | 2.5 5 |  | Increased blood pressure Decreased mean cell volume and mean cell hemoglobin; increased red cell distribution width | Cadmium chloride |\n| Muller et al. 1988 |  |  |  |  |  |  |  |  |  |  |\n| 64 | Rat (Sprague-Dawley) 4 M | 6 weeks 5 days/week (GW) | 0, 0.0025, 0.025, 0.25 | BW, BC, BI, OW | Bd wt Hepatic | 0.25 0.25 |  |  |  | Cadmium acetate |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Nagymajtenyi et al. 1997 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 65 | Rat (Wistar) 5 M, 10 F | 3 generations ~16–18 weeks per generation (GW) | 0, 3.5, 7.0, 14.0 | CS, BW, RX, DX | Bd wt Repro Develop | 14 14 3.5 M | 7 M |  | Decreased tail nerve conduction velocity (all generations); prolonged latency and duration of somatosensory evoked potentials (F2, F3); increased frequency in auditory and visual evoked potentials (F3); 5% decrease in F3 body weight at PNW 12 |\n| Nasiadek et al. 2018 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 66 | Rat (Wistar) 20 F | 30 days (GW) | 0, 0.09, 1.8, 4.5 | CS, BW, BC, OW, HP | Bd wt Repro | 4.5 0.09 | 1.8 |  | Decreased plasma estradiol |\n| Nasiadek et al. 2019 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 67 | Rat (Wistar) 24 F | 90 days (GW) | 0, 0.09, 0.9, 1.8, 4.5 | LE, CS, BW, FI, WI, BC, OW, HP | Bd wt Repro | 4.5 0.09 | 0.9 |  | Decreased plasma estradiol |\n| Nation et al. 1984 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 68 | Rat (Sprague-Dawley) 9 M | 55 days (F) | 0, 1, 5 | CS, NX | Neuro | 1 | 5 |  | Increased anxiety-like behavior (passive avoidance) |\n| Ninkov et al. 2016 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 69 | Rat (Albino Oxford) 8–16 M | 30 days (W) | 0, 0.4, 4.1 | OW, HP, IX | Gastro Immuno | 4.1 | 0.4 |  | Increased intestinal lymphocyte counts, and mesenteric lymph node relative weight and cellularity; decreased spleen cell proliferative response |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Ogoshi et al. 1989 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 70 | Rat (NS) 19–22 F | 4 weeks (W) | 0, 1, 2.5 | BW, HE, BC, BI, OF | Bd wt Hemato | 2.5 | 1 |  | Decreased hematocrit, hemoglobin, MCHC, and MCV |\n|  |  |  |  |  | Musc/skel |  | 1 |  | Decreased bone strength |\n| Weanling rats (21-day-old) |  |  |  |  |  |  |  |  |  |\n| Ogoshi et al. 1989 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 71 | Rat (NS) 18–25 NS | 4 weeks (W) | 0, 1.6, 3.3, 6.6, 13, 26.2 | BW, HE, BC, BI, OF | Bd wt Hemato | 26.2 6.6 Musc/skel | 13 |  | Decreased hematocrit and MCV |\n| Adult rats (24-week-old) |  |  |  |  |  |  |  |  |  |\n| Ogoshi et al. 1989 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 72 | Rat (NS) 25–27 NS | 4 weeks (W) | 0, 11, 21.5 | BW, HE, BC, BI, OF | Bd wt Hemato | 11 21.5 | 11 21.5 |  | 10% decrease in body weight gain |\n|  |  |  |  |  | Musc/skel |  |  |  | Decreased hemoglobin and MCHC |\n| Aged rats (1.5-year-old) |  |  |  |  |  |  |  |  |  |\n| Oluranti et al. 2021 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 73 | Rat (Wistar) 5 M | 21 days (G) | 0, 3, 18 | BC, BI, OW | Endocr |  | 3 |  | Decreased plasma insulin and glucose levels |\n| Petering et al. 1979 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 74 | Rat (Sprague-Dawley) 5 F | 111 days (90 days prior mating through GD 21) (W) | 0, 0.56, 1.3, 2.61, 5.23 | HE, RX, DX | Repro Develop | 5.23 1.3 |  | 2.61 | 10% decrease in birth weight |\n| Prigge 1978a |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 75 | Rat (Wistar) 12 F | 90 days (W) | 0, 3.8, 7.6, 15.2 | LE, BW, HE, BC, BI, UR, OW | Bd wt Hemato | 3.8 3.8 Renal | 3.8 7.6 | 7.6 | 28% decrease in body weight gain |\n|  |  |  |  |  |  |  |  |  | Decreased serum iron |\n|  |  |  |  |  |  |  |  |  | Proteinuria |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Sarmiento-Ortega et al. 2017 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 76 | Rat (Wistar) 10 M | 3, 4, or 5 months (W) | 0, 2.94 | BC, OF | Hepatic |  | 2.94 |  | Increased serum and hepatic lipid concentrations |\n| 76 | Rat (Wistar) 10 M | 3, 4, or 5 months (W) | 0, 2.94 | BC, OF | Endocr |  | 2.94 |  | Increased serum glucose and insulin levels following administration of an oral glucose load |\n| 76 | Rat (Wistar) 10 M | 3, 4, or 5 months (W) | 0, 2.94 | BC, OF | Other noncancer |  | 2.94 |  | Increased abdominal circumference, body mass index, and percentage of body fat |\n| Sorell and Graziano 1990 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 77 | Rat (Sprague-Dawley) 42–66 F | 15 days GDs 6–20 (W) | 0, 0.629, 4.714, 8.171 | BW, WI, HE, DX | Bd wt | 0.629 | 4.714 | 8.171 | LOAEL: 13% decrease in maternal weight gain SLOAEL: 30% decrease in maternal body weight gain |\n| 77 | Rat (Sprague-Dawley) 42–66 F | 15 days GDs 6–20 (W) | 0, 0.629, 4.714, 8.171 | BW, WI, HE, DX | Hemato | 4.714 | 8.171 |  | Reduced maternal hemoglobin levels |\n| 77 | Rat (Sprague-Dawley) 42–66 F | 15 days GDs 6–20 (W) | 0, 0.629, 4.714, 8.171 | BW, WI, HE, DX | Develop | 0.629 | 4.714 |  | 8% decrease in fetal body weight |\n| Sun et al. 2023 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 78 | Rat (Sprague-Dawley) 10 M | 29 days (GW) | 0, 0.3, 1, 5 | DX | Develop | 0.3 | 1 |  | Decreased serum estradiol and progesterone in adult F1 females |\n| F0 males were mated to unexposed females; reproductive development was assessed in F1 and F2 female offspring |  |  |  |  |  |  |  |  |  |\n| Sutou et al. 1980 |  |  |  |  |  |  |  |  | Form not specified |\n| 79 | Rat (Sprague-Dawley) 14 M, 14 F | 9 weeks (premating through GD 20) (GW) | 0, 0.1, 1.0, 10 | RX, DX | Repro | 1 |  | 10 | Decreased number of copulating and pregnant females; 49% reduction in number of live fetuses/litter; decreased total implants/litter, increased resorptions/litter |\n| 79 | Rat (Sprague-Dawley) 14 M, 14 F | 9 weeks (premating through GD 20) (GW) | 0, 0.1, 1.0, 10 | RX, DX | Develop | 1 |  | 10 | Decreased fetal body weight in males (34%) and females (33%); decreased body and tail length; delayed ossification |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Tang et al. 2016 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 80 | Rat (Sprague-Dawley) 6 M | 3 months (W) | 0, 0.28, 1.41, 7.07 | HP | Musc/skel | 1.41 | 7.07 |  | Decreased bone density and trabecular bone loss and damage in tibia (decreased trabecular volume and number, increased trabecular separation) |\n| Tian et al. 2017 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 81 | Rat (Sprague-Dawley) NS F | 6 weeks GD 0 to PND 21 (GW) | 0, 0.6, 3 | DX | Develop |  | 0.6 |  | Decreased serum progesterone and testosterone and in male offspring on PND 35 and 56, respectively; decreased relative testis weight on PND 21 |\n| Tucovic et al. 2018 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 82 | Rat (Dark Agouti) 4–6 M | 30 days (W) | 0, 0.7, 6.6 | BW, FI, WI, HE BC, UR, HP | Bd wt Hemato | 6.6 |  |  | Increased percent neutrophil leukocytes and eosinophil leukocytes |\n| 82 | Rat (Dark Agouti) 4–6 M | 30 days (W) | 0, 0.7, 6.6 | BW, FI, WI, HE BC, UR, HP | Hepatic Immuno | 6.6 0.7 | 6.6 |  | Increased IL-6 and TNF in skin |\n| Wan et al. 2022 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 83 | Rat (Sprague-Dawley) 3 M, 3 F | 4 weeks (G) | 0, 2, 4 | BW, WI, BC, UR, OW, HP | Bd wt Renal | 4 | 2 |  | Increased 24-hour urinary protein excretion, elevated urinary β 2M levels, increased serum BUN |\n| Wan et al. 2022 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 84 | Rat (Sprague-Dawley) 3 M, 3 F | 8 weeks (G) | 0, 2, 4 | BW, WI, BC, UR, OW, HP | Bd wt Renal | 4 | 2 |  | Increased 24-hour urinary protein excretion, elevated urinary β 2M levels, increased serum BUN |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Wang et al. 2014 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 85 | Rat (Sprague-Dawley) 8 M, 8 F | 28 days (GW) | 0, 1, 2.5, 5, 10, 20 | LE, CS, BW, FI, HE, BC, UR, GN, OW, HP | Bd wt | 5 | 10 |  | Decrease in terminal body weight in males (12%) and females (11%) |\n| 85 | Rat (Sprague-Dawley) 8 M, 8 F | 28 days (GW) | 0, 1, 2.5, 5, 10, 20 | LE, CS, BW, FI, HE, BC, UR, GN, OW, HP | Cardio | 20 |  |  | Decrease in terminal body weight in males (12%) and females (11%) |\n| 85 | Rat (Sprague-Dawley) 8 M, 8 F | 28 days (GW) | 0, 1, 2.5, 5, 10, 20 | LE, CS, BW, FI, HE, BC, UR, GN, OW, HP | Hemat | 10 F | 20 F |  | Increased platelets |\n| 85 | Rat (Sprague-Dawley) 8 M, 8 F | 28 days (GW) | 0, 1, 2.5, 5, 10, 20 | LE, CS, BW, FI, HE, BC, UR, GN, OW, HP | Hepatic | 2.5 M | 5 M |  | Increased platelets |\n| 85 | Rat (Sprague-Dawley) 8 M, 8 F | 28 days (GW) | 0, 1, 2.5, 5, 10, 20 | LE, CS, BW, FI, HE, BC, UR, GN, OW, HP | Renal | 10 F | 20 F |  | Increased serum ALT |\n| 85 | Rat (Sprague-Dawley) 8 M, 8 F | 28 days (GW) | 0, 1, 2.5, 5, 10, 20 | LE, CS, BW, FI, HE, BC, UR, GN, OW, HP | Endocr | 20 |  |  |  |\n| 85 | Rat (Sprague-Dawley) 8 M, 8 F | 28 days (GW) | 0, 1, 2.5, 5, 10, 20 | LE, CS, BW, FI, HE, BC, UR, GN, OW, HP | Immuno | 20 |  |  |  |\n| 85 | Rat (Sprague-Dawley) 8 M, 8 F | 28 days (GW) | 0, 1, 2.5, 5, 10, 20 | LE, CS, BW, FI, HE, BC, UR, GN, OW, HP | Neuro | 20 |  |  |  |\n| 85 | Rat (Sprague-Dawley) 8 M, 8 F | 28 days (GW) | 0, 1, 2.5, 5, 10, 20 | LE, CS, BW, FI, HE, BC, UR, GN, OW, HP | Repro | 5 | 10 |  | Decreased serum LH and testosterone in males; increased absolute and relative uterine weight |\n| 85 | Rat (Sprague-Dawley) 8 M, 8 F | 28 days (GW) | 0, 1, 2.5, 5, 10, 20 | LE, CS, BW, FI, HE, BC, UR, GN, OW, HP | Other | 1 F | 2.5 F |  | Decreased food intake |\n| 85 | Rat (Sprague-Dawley) 8 M, 8 F | 28 days (GW) | 0, 1, 2.5, 5, 10, 20 | LE, CS, BW, FI, HE, BC, UR, GN, OW, HP | noncancer |  |  |  |  |\n| Weng et al. 2014 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 86 | Rat (Wistar) 12 F | 8 weeks (G) | 0, 0.3, 1.2, 4.9 | BW, OW, HP | Bd wt | 4.9 |  |  |  |\n| 86 | Rat (Wistar) 12 F | 8 weeks (G) | 0, 0.3, 1.2, 4.9 | BW, OW, HP | Repro | 0.3 | 1.2 |  | Decreased absolute and relative ovary weight, increased atretic follicles, follicular cell apoptosis |\n| Xu et al. 2015 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 87 | Rat (Sprague-Dawley) 6 M | 90 days (GW) | 0, 0.7, 2.0, 6.0 | LE, CS, BW, HP | Bd wt | 6 |  |  |  |\n| 87 | Rat (Sprague-Dawley) 6 M | 90 days (GW) | 0, 0.7, 2.0, 6.0 | LE, CS, BW, HP | Neuro | 0.7 | 2 |  | Neuronal degeneration in cortex |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Yang et al. 2021a |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 88 | Rat (Sprague-Dawley) 9 NR | 8 weeks 5 days/week (GW) | 0, 0.15, 0.61, 2.5 | BC | Hepatic | 0.15 | 0.61 |  | Increased serum triglycerides, total cholesterol, and LDL cholesterol; decreased serum HDL cholesterol |\n|  |  |  |  |  | Renal | 0.61 | 2.5 |  | Increased serum urea nitrogen |\n| Yi et al. 2021b |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 89 | Rat (Sprague-Dawley) 6 M | 28 days (GO) | 0, 1, 3 | BW, BC, OW, HP, RX | Bd wt Repro | 3 | 1 |  | Decreased serum testosterone levels |\n| Zenick et al. 1982 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 90 | Rat (Long-Evans) 5 M | 70–80 days (W) | 0, 1.16, 2.32, 4.64 | BW, FI, WI, HP, RX, DX | Bd wt Repro Develop for fetal effects | 4.64 4.64 4.64 | 25 | 12 | LOAEL: 13% decrease in terminal body weight SLOAEL: 25% decrease in terminal body weight |\n| Males were mated with three untreated females; one litter evaluated for fetal effects and two litters evaluated for neurobehavior on PND 21 or 90 |  |  |  |  |  |  |  |  |  |\n| Zhang et al. 2022a |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 91 | Rat (Sprague-Dawley) 8 M | 12 weeks (G) | 0, 1.5, 3, 6.1, 12, 25 | LE, CS, BW, BC, OW, HP | Bd wt | 6.1 | 12 | 25 | LOAEL: 13% decrease in terminal body weight SLOAEL: 25% decrease in terminal body weight |\n|  |  |  |  |  | Hepatic | 1.5 | 3 | 12 | LOAEL: Hepatic fibrosis SLOAEL: Hepatic fibrous tissue proliferation |\n| Zhang et al. 2023a |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 92 | Rat (Sprague-Dawley) 6 M | 4 weeks (GW) | 0, 2.5, 5 | BC, HP, RX | Repro | 2.5 |  | 5 | Decreased serum testosterone, LH, and GnRH; decreased sperm count and motility; decreased seminiferous tubule diameter and seminiferous epithelial thickness |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Zhang et al. 2024a |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 93 | Rat (Sprague-Dawley) 10–30 M | 4 weeks (GW) | 0, 5 | BW, RX, DX | Bd wt Repro |  | 5 | 5 | 13% decrease in body weight Decreased fertility and percent live births, sperm quality, and levels of serum testosterone and gonad releasing hormone; decreased seminiferous tubule diameter and area, seminiferous epithelium thickness, and Johnsen score; decreased number of cells in interstitial region of testes and disordered cellular arrangement |\n| Males were mated with unexposed females. |  |  |  |  | Develop |  |  | 5 | 21% decrease in male fetal weight |\n| Blakley 1985 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 94 | Mouse (BDF1) 22 F | 3 weeks (W) | 0, 1.4, 2.8, 14 | CS, BW, GN, IX | Bd wt Immuno | 14 1.4 | 2.8 |  | Decreased humoral immune response |\n| Blakley 1988 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 95 | Mouse (BDF1) 14–16 F | 26 days (W) | 0, 2.5, 12.5 | BW, WI, IX | Immuno | 12.5 |  |  |  |\n| Aged mice (12-month-old) |  |  |  |  |  |  |  |  |  |\n| Chatterjee and Saxena 2015 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 96 | Mouse (C57BL/6) 10–15 M | 6 weeks (W) | 0, 7.6, 150 | HE, BC | Hemato Immuno | 150 | 7.6 |  | Decreased RBC count and hemoglobin |\n| Chou et al. 2023 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 97 | Mouse (C57BL/6) 11–18 M | 12 weeks (W) | 0, 11, 21 | BW, OF, HP | Bd wt Cardio | 21 |  | 11 | Cardiomyocyte apoptosis |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects | Cadmium chloride |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Exon et al. 1986 |  |  |  |  |  |  |  |  |  |  |\n| 98 | Mouse (Swiss-Webster) 20 M | 10 weeks (W) | 0, 0.57, 5.7, 57 | LE, BW, GN, HP, IX | Bd wt Immuno | 57 57 |  |  |  |  |\n| Exon et al. 1986 |  |  |  |  |  |  |  |  |  |  |\n| 99 | Mouse (Swiss-Webster) 20 M | 10 weeks (W) | 0, 0.57, 5.7, 57 | LE, BW, GN, HP, IX | Bd wt Immuno | 0.57 57 | 5.7 |  | Cadmium acetate | 14% decrease in body weight |\n| Exon et al. 1986 |  |  |  |  |  |  |  |  |  |  |\n| 100 | Mouse (Swiss-Webster) 20 M | 10 weeks (W) | 0, 0.57, 5.7, 57 | LE, BW, GN, HP, IX | Bd wt Immuno | 57 57 |  |  |  | Cadmium sulfate |\n| Gathwan and Albir 2020 |  |  |  |  |  |  |  |  |  |  |\n| 101 | Mouse (Swiss) 6 M | 30 days (G) | 0, 6.1, 12.3, 19.5 | BW, FI, WI, OW, HP | Bd wt | 6.1 | 12.3 | 19.5 | LOAEL: 13% decrease in terminal body weight SLOAEL: 23% decrease in terminal body weight | Cadmium oxide |\n| He et al. 2019a |  |  |  |  |  |  |  |  |  |  |\n| 102 | Mouse (C57BL/6) 10 M | 20 weeks (W) | 0, 1.475, 6.566 | LE, CS, WI, BC, BI, OW, HP | Bd wt Hepatic | Endocr | 6.566 | 1.475 | 6.566 | Cadmium chloride 22% decrease in body weight gain NAFLD; increased hepatic triglyceride levels |\n| He et al. 2019b |  |  |  |  |  |  |  |  |  |  |\n| 103 | Mouse (BALB/c) 12 F | 16 weeks (W) | 0, 2, 6.5 | BW, FI, BC, BI, HP | Bd wt Musc/skel | 6.5 | 2 |  |  | Cadmium chloride |\n\nTrabecular bone damage\n(decreased number, thickness;\nincreased separation, fat cells);\naltered bone turnover parameters\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| He et al. 2020 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 104 | Mouse (C57BL/6) 10 M | 20 weeks (W) | 0, 1.5, 7.6 | LE, CS, BW, HP | Bd wt Gastro | 7.6 1.5 | 7.6 |  | Decreased length of intestinal villus and thickness of intestinal wall |\n| Hudson et al. 2019 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 105 | Mouse (C57BL/6J) NS F | 8 weeks 5 weeks prior to mating until birth (W) | 0, 0.3, 13 | RX, DX | Repro Develop | 13 | 0.3 | 13 | LOAEL: Increased absolute and relative heart weight in female pups at birth; increased tail blood volume and tail blood flow in female offspring at 5.5 months of age SLOAEL: 12% decrease in birth weight in both sexes; increased absolute and relative heart weight in male pups at birth; increased systolic, diastolic, and mean arterial blood pressure in female offspring at 5.5 months of age |\n| C57BL/6J dams mated to unexposed CAST/EiJ males, to generate F1 hybrid mice |  |  |  |  |  |  |  |  |  |\n| Hudson et al. 2019 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 106 | Mouse (CAST/EiJ) NS F | 8 weeks 5 weeks prior to mating until birth (W) | 0, 0.3, 13 | RX, DX | Repro Develop | 13 | 0.3 | 13 | LOAEL: Decreased body weight at birth in males; increased absolute heart weight in females SLOAEL: 22% decrease in birth weight |\n| CAST/EiJ dams mated to unexposed C57BL/6J males, to generate F1 hybrid mice |  |  |  |  |  |  |  |  |  |\n| Krzystyniak et al. 1987 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 107 | Mouse (C57BL/6) 10 F | 12–16 weeks (W) | 0, 0.6, 17, 52 | IX | Immuno | 17 | 52 |  | Reduced humoral immune response |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Kurita et al. 2018 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 108 | Mouse (C57BL/6J) 3–10 F | 18 days GDs 1–18 (G) | 0, 5, 10 | DX | Develop | 5 |  | 10 | 34% decrease in fetal weight, decreased fetal length |\n| Li et al. 2022 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 109 | Mouse (ICR) 10 F | 70 days 4 weeks premating to PND 21 (W) | 0, 2.6, 19.7 | WI, DX | Develop |  | 2.6 | 19.7 | LOAEL: Decreased serum estradiol and increased primordial follicles and decreased secondary follicles at PND 21 in female offspring; increased prevalence of irregular estrous cycles SLOAEL: 40% decreased in PND 21 body weight in female offspring; delayed vaginal opening |\n| Liu et al. 2023 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 110 | Mouse F0: 9–12 F F1: 5-7 M, 5–7 F | ~220 days F0: 1 week premating through PND 21 F1: PND 21 to 6 months of age (W) | F0: 0, 0.1, 1.5 F1: 0, 0.2, 1.6 | BC, OW, HP, NX | Immuno Neuro | 1.6 | 0.2 |  | Increased locomotor activity, impaired spatial memory (Y-maze test) in adult F1 mice |\n| Mei et al. 2017 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 111 | Mouse (C57BL/6) 5 M | 8 weeks (W) | 0, 1.5, 4.5, 7.6 | IX | Immuno |  | 1.5 |  | Delayed wound healing |\n| Ohsawa et al. 1988 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 112 | Mouse (BALB/c) 9–10 M | 10 weeks (W) | 0, 0.75, 7.5, 75 | IX | Immuno | 7.5 | 75 |  | Induction of anti-nuclear autoantibodies |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Ohsawa et al. 1988 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 113 | Mouse (ICR) 5–12 M | 10 weeks (W) | 0, 0.75, 7.5, 75 | IX | Immuno |  | 0.75 |  | Induction of anti-nuclear autoantibodies; biphasic immune response (stimulation at low dose, suppression at high dose) |\n| Tan et al. 2023 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 114 | Mouse (C57BL/6) 20 M | 10 weeks (W) | 0, 1.5, 15 | DX | Develop | 1.5 | 15 |  | Impaired growth in both sexes (10% at terminal sacrifice on PND 125); impaired glucose metabolism in adult female offspring |\n| Males mated to untreated females after 10-week exposure |  |  |  |  |  |  |  |  |  |\n| Valois and Webster 1989 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 115 | Mouse (QS) 25 F | 22 weeks (W) | 0, 0.20, 1.4, 11 | CS, BW, WI, HP | Bd wt | 0.2 | 1.4 | 11 | LOAEL: 19% decrease in body weight SLOAEL: 28% decrease in body weight |\n|  |  |  |  |  | Neuro | 0.2 |  | 1.4 | Degenerative and necrotic cellular changes in choroid plexus |\n| Marked decreases in water consumption at 1.4 and 11 mg Cd/kg/day |  |  |  |  |  |  |  |  |  |\n| Wang et al. 2016a |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 116 | Mouse (CD-1) 10 F | 19 days GDs 0–18 (W) | 0, 1.3, 9.3, 26.9 | BW, WI, RX, DX | Bd wt Repro Develop | 26.9 26.9 9.3 |  | 26.9 | 17% decrease in fetal weight; decreased crown-rump length |\n| Xiong et al. 2022a |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 117 | Mouse (C57BL/6) F0: 6–7 M, 17 F F1: 4 M | 32 weeks F0: 2 weeks premating–PNW 3 F1: PNWs 3–27 (W) | 0, 0.1, 1.3 | BW, WI, OW, HP | Bd wt Repro | 1.3 M 0.1 M | 1.3 M |  | Decreased absolute testis weight, germ cell loss |\n| Endpoints reported for F1 males (evaluated at PNW 27) |  |  |  |  |  |  |  |  |  |\n\nEndpoints reported for F1 males (evaluated at PNW 27)\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects | Cadmium chloride |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Zhang et al. 2019a |  |  |  |  |  |  |  |  |  |  |\n| 118 | Mouse (C57BL/6J) F0: 10 M, 10 F F1: 6 M, 6 F | 17-18 weeks F0: 1 month premating to PNW 3 F1: PNWs 3–10 (W) | 0, 0.001089, 0.01003, 0.10012 | DX | Develop | 0.10012 |  |  |  |  |\n| F1 pups examined for developmental landmarks, neurobehavior (PNWs 8-9), endocrine, and reproductive endpoints at PNW 10 |  |  |  |  |  |  |  |  |  |  |\n| Zhang et al. 2019a |  |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 119 | Mouse (C57BL/6J) F0: 10 M, 10 F F1: 6 M, 6 F | 25-26 weeks F0: 3 months premating to PNW 3 F1: PNWs 3–10 (W) | 0, 0.001089, 0.01003, 0.10012 | DX | Develop | 0.10012 |  |  |  |  |\n| F1 pups examined for developmental landmarks, neurobehavior (PNWs 8-9), endocrine, and reproductive endpoints at PNW 10 |  |  |  |  |  |  |  |  |  | Cadmium chloride |\n| Zhang et al. 2019a |  |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 120 | Mouse (C57BL/6J) F0: 10 M, 10 F F1: 6 M, 6 F | 33–34 weeks F0: 5 months premating to PNW 3 F1: PNWs 3–10 (W) | 0, 0.001089, 0.01003, 0.10012 | DX | Develop | 0.01003 | 0.10012 |  | Increased anxiety-like behavior in open field; elevated corticosterone levels |  |\n| F1 pups examined for developmental landmarks, neurobehavior (PNWs 8-9), endocrine, and reproductive endpoints at PNW 10 |  |  |  |  |  |  |  |  |  | Cadmium chloride |\n| Zhang et al. 2024b |  |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 121 | Mouse (ICR) 9–11 M | 21 days PNDs 22–42 (W) | 0, 0.9, 1.5 | DX | Develop | 0.9 | 1.5 |  | Altered socioemotional behaviors during adolescence (immobility in forced swim and tail suspension, decreased social interaction/preference for novelty) |  |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Boscolo and Carmignani 1986 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 122 | Rabbit (New Zealand) 8 M | 9 months (W) | 0, 1.6 | CS, BW, HP, OF | Bd wt Cardio Renal | 1.6 | 1.6 |  | Increased aortic resistance, reduced contractility |\n| Stowe et al. 1972 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 123 | Rabbit (New Zealand) 5 M | 200 days (W) | 0, 14.9 | CS, BW, WI, HE | Bd wt Hemato |  | 14.9 | 14.9 | 20% decrease in body weight Decreased hematocrit and hemoglobin; elevated neutrophils and decreased lymphocytes |\n| Stowe et al. 1972 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 124 | Rabbit (Belgian Giant) 5 M | 200 days (W) | 0, 14.9 | CS, BW, WI, HE | Bd wt Hemato |  | 14.9 | 14.9 | 15% decrease in body weight Decreased hematocrit and hemoglobin; elevated neutrophils and decreased lymphocytes |\n| CHRONIC EXPOSURE |  |  |  |  |  |  |  |  |  |\n| Buchet et al. 1990; Shao et al. 2007; Suwazono et al. 2006; Uno et al. 2005; Wu et al. 2001; Zhang et al. 2016a |  |  |  |  |  |  |  |  | Cadmium |\n| 125 | Human 85–3,454 per dataset | 17 datasets (3 occupational and 8 general population cohorts) | UR | Renal |  |  |  | LMW proteinuria; 95% LCL weighted median of 17 UC10 values = 0.000760 mg Cd/kg/dayd |  |\n| Bernard et al. 1992 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 126 | Rat (Sprague-Dawley) 50 F | up to 18 months (W) | 0, 13 | BI, BC, UR, HP, OF | Renal |  |  | 13 | Loss of glomerular polyanion charge barrier, proteinuria |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Bomhard et al. 1984 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 127 | Rat (Wistar) 12 M, 12 F | 72 weeks (F) | M: 0, 0.7, 3.5, 17.5 F: 0, 0.8, 4.0, 20.0 | BC, UR | Renal | 4 F | 20 F |  | Increase in urinary LDH and GST levels Increase in urinary LDH and GST levels |\n| 127 | Rat (Wistar) 12 M, 12 F | 72 weeks (F) | M: 0, 0.7, 3.5, 17.5 F: 0, 0.8, 4.0, 20.0 | BC, UR | Renal | 3.5 M | 17.5 M |  | Increase in urinary LDH and GST levels Increase in urinary LDH and GST levels |\n| Brzóska 2012; Brzóska and Moniuszko-Jakoniuk 2004a, 2004b |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 128 | Rat (Wistar) 10 F | 24 months (W) | 0, 0.08 | BW, FI, WI, BC, BI, UR, HP, OF | Bd wt Musc/skel | 0.08 |  | 0.08 | Decreases in bone mineral content and density of lumbar spine, altered bone turnover parameters, increases in deformed and fractured vertebral bodies |\n| Decker et al. 1958 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 129 | Rat (Sprague-Dawley) 8–10 M, 8–10 F | 12 months (W) | M: 0, 0.008, 0.036, 0.197, 0.386, 0.696 F: 0, 0.012, 0.062, 0.315, 0.578, 1.052 | LE, BW, FI, WI, HE, HP | Bd wt Gastro | 1.052 F 0.696 M 1.052 F 0.696 M 1.052 F 0.696 M 1.052 F 0.696 M 1.052 F 0.696 M 1.052 F 0.696 M 0.696 M 0.696 M 0.696 M 0.696 M |  |  |  |\n| 129 | Rat (Sprague-Dawley) 8–10 M, 8–10 F | 12 months (W) | M: 0, 0.008, 0.036, 0.197, 0.386, 0.696 F: 0, 0.012, 0.062, 0.315, 0.578, 1.052 | LE, BW, FI, WI, HE, HP | Renal | 1.052 F 0.696 M 0.696 M |  |  |  |\n| 129 | Rat (Sprague-Dawley) 8–10 M, 8–10 F | 12 months (W) | M: 0, 0.008, 0.036, 0.197, 0.386, 0.696 F: 0, 0.012, 0.062, 0.315, 0.578, 1.052 | LE, BW, FI, WI, HE, HP | Endocrinoma | 1.052 F 0.696 M 0.696 M 0.696 M |  |  |  |\n| 129 | Rat (Sprague-Dawley) 8–10 M, 8–10 F | 12 months (W) | M: 0, 0.008, 0.036, 0.197, 0.386, 0.696 F: 0, 0.012, 0.062, 0.315, 0.578, 1.052 | LE, BW, FI, WI, HE, HP | Neuro | 1.052 F 0.696 M 0.696 M |  |  |  |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects | Cadmium chloride |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Fingerle et al. 1982 |  |  |  |  |  |  |  |  |  |  |\n| 130 | Rat (Sprague-Dawley) 10 M, 10 F | M: 92 weeks F: 84 weeks (W) | M: 0, 0.6, 1.51, 3.78 F: 0, 0.8, 1.64, 4.01 | HP, BW, OW, OF, FI, WI, CS, LE | Bd wt Cardio | 4.01 4.01 |  |  |  |  |\n| Mangler et al. 1988 |  |  |  |  |  |  |  |  |  |  |\n| 131 | Rat (Sprague-Dawley) 12 F | 18 months (W) | 0, 2.301 | LE, BW, HP | Bd wt Renal | 2.301 | 2.301 |  | Cloudy swelling of renal tubular cells | Cadmium chloride |\n| Mangler et al. 1988 |  |  |  |  |  |  |  |  |  |  |\n| 132 | Rat (Sprague-Dawley) 12 F | 12 months (W) | 0, 2.337 | LE, BW, HP | Bd wt Renal | 2.337 | 2.337 |  | Cloudy swelling of renal tubular cells | Cadmium chloride |\n| Sato et al. 1978 |  |  |  |  |  |  |  |  |  |  |\n| 133 | Rat (Wistar) 11 NS | 31 months (W) | 0, 2.7 | CS, BW, WI, HP | Bd wt Musc/skel Neuro | 2.7 |  | 2.7 2.7 | Muscle weakness and atrophy Peripheral neuropathy | Cadmium chloride |\n| Waalkes and Rehm 1992 |  |  |  |  |  |  |  |  |  |  |\n| 134 | Rat (Wistar) 24–28 M | 77 weeks (F) | 0, 1.1, 2.3, 5.28, 10.9 | LE, CS, BW, FI, GN, HP | Bd wt Cancer | 2.3 | 5.28 | 2.3 | 10% decrease in body weight CEL: Large granular lymphocyte leukemia | Cadmium chloride |\n\n---\n\n**Table 2-2.  Levels of Significant Exposure to Cadmium – Oral\n(mg Cd/kg/day)**\n\n| Figure keya | Species (strain) No./group | Exposure parameters | Dosesb | Parameters monitored | Endpoint | NOAEL | Less serious LOAEL | Serious LOAEL | Effects |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Hays and Margaretten 1985 |  |  |  |  |  |  |  |  | Cadmium chloride |\n| 135 | Mouse (CBA/H) 5–13 M; 5 F | 12 months (W) | 0, 40 | BW, FI, WI, HE, BC, HP | Bd wt Hematoc | 40 | 40 | 21% decreased terminal body weight Decreased hematocrit and neutrophils; bone marrow hypoplasia |  |\n|  |  |  |  |  | Renal | 40 |  |  |  |\n\n<sup>a</sup>The number corresponds to entries in Figure 2-3; differences in levels of health effects between male and females are not indicated in Figure 2-3.  Where such \ndifferences exist, only the levels of effect for the most sensitive sex are presented.\n\n<sup>b</sup>Doses are expressed as mg Cd/kg/day.  If doses were reported by study authors in terms of the administered compound (e.g., cadmium chloride [CdCl2]), they were \nconverted to the equivalent dose in terms of the metal (i.e., cadmium [Cd])) for easy comparison across studies. Conversion was based on the ratio of the molecular \nweights using the following equation: Dose in terms of administered compound × (molecular weight Cd/molecular weight administered compound).\n\n<sup>c</sup>Used to derive an acute-duration oral MRL of 0.002 mg Cd/kg/day (2 μg Cd/kg/day).  The LOAEL of 2 mg Cd/kg/day divided by an uncertainty factor of 1,000 (10 for use \nof a LOAEL, 10 for animal to human, and 10 for human variability).\n\n<sup>d</sup>Used to derive a chronic-duration oral MRL of 0.0003 mg Cd/kg/day (0.3 μg Cd/kg/day).  The point of departure (POD) is based on the 95% lower confidence limit (LCL) \non the weighted median of the UC10 values from 17 datasets from 11 human studies; the weighted median and 95% LCL were 2.04 and 1.57 μg Cd/g Cr, respectively.  \nThese values were converted into oral dose equivalents of 9.88x10<sup>-4</sup> and 7.60x10<sup>-4</sup> mg Cd/kg/day, respectively, using PBPK modeling. The POD of 7.60x10<sup>-4</sup> mg \nCd/kg/day was divided by an uncertainty factor of 3 for human variability and a modifying factor of 3 for database deficiencies. See Appendix A for more detailed \ninformation regarding the MRL.\n\n## Principal studies for the MRLs\n\nACTH = adrenocorticotrophic hormone; ALT = alanine aminotransferase; β2M = β2-microglobulin; BC = serum (blood) chemistry; Bd wt or BW = body weight; \nBI = biochemical changes; BUN = blood urea nitrogen; Cardio = cardiovascular; Cd = cadmium; CEL = cancer effect level; Cr = creatinine; CS = clinical signs; Develop \n= developmental; DX = developmental toxicity; Endocr = endocrine; (F) = feed (dietary); F = female(s); FI = food intake; (G) = gavage; (GO) = gavage in oil; \n(GW) = gavage in water; Gastro = gastrointestinal; GD = gestation day; GN = gross necropsy; GnRH = gonadotropin releasing hormone; GST = glutathione \nS-transferase; HDL = high-density lipoprotein; HE = hematology; Hemato = hematological; HP = histopathology; IL-6 = interleukin-6; Immuno = immunological; \nIX = immune function; LD50 = lethal dose, 50% kill; LDH = lactate dehydrogenase; LDL = low-density lipoprotein; LE = lethality; LH = luteinizing hormone; LMW = low \nmolecular weight; LOAEL = lowest-observed-adverse-effect level; M = male(s); MCHC = mean corpuscular hemoglobin concentration; MCV = mean corpuscular volume; \nMRL = Minimal Risk Level; Musc/skel = musculoskeletal; NAFLD = non-alcoholic fatty liver disease; Neuro = neurological; NK = natural killer; NOAEL = no-observedadverse-effect level; NS = not specified; NX = neurological function; OF = organ function; OW = organ weight; PBPK = physiologically based pharmacokinetic; \nPND = postnatal day; PNW = postnatal week; RBC = red blood cell; Repro = reproductive; Resp = respiratory; RX = reproductive function; SLOAEL = serious lowestobserved-adverse-effect level; T3 = triiodothyronine; TNF = tumor necrosis factor; TSH = thyroid-stimulating hormone; UC10 = urinary cadmium level associated with \n10% extra risk; UR = urinalysis; (W) = drinking water; WBC = white blood cell; WI = water intake\n\n---\n\n**Figure 2-3.  Levels of Significant Exposure to Cadmium – Oral**\nAcute (≤14 days)\n\n**Figure 2-3. Levels of Significant Exposure to Cadmium – Oral Acute (≤14 days) - Death**\n\n| Category | Animal - LD50/LC50 (mg Cd/kg/day) | Animal - NOAEL (mg Cd/kg/day) | Animal - LOAEL (mg Cd/kg/day) | Animal - SLOAEL (mg Cd/kg/day) |\n| --- | --- | --- | --- | --- |\n| 3R |  |  |  | 100 |\n| 4R |  |  |  | 70 |\n| 6R |  |  |  | 30 |\n| 8R | 30 |  |  |  |\n| 9R | 140 |  |  |  |\n| 10R | 130 |  |  |  |\n| 11R | 100 |  |  |  |\n| 12R | 70 |  |  |  |\n| 15R | 230 |  |  |  |\n| 16R |  |  |  | 45 |\n| 17R |  |  |  | 65 |\n| 21R | 110 |  |  |  |\n| 22R | 340 |  |  |  |\n| 26M |  |  |  | 85 |\n| 28M | 95 |  |  |  |\n\n---\n\n**Figure 2-3.  Levels of Significant Exposure to Cadmium – Oral**\nAcute (≤14 days)\n\n**Figure 2-3. Levels of Significant Exposure to Cadmium – Oral Acute (≤14 days) - Body Weight**\n\n| Category | Animal - LD50/LC50 (mg Cd/kg/day) | Animal - LOAEL (mg Cd/kg/day) | Animal - NOAEL (mg Cd/kg/day) | Animal - SLOAEL (mg Cd/kg/day) |\n| --- | --- | --- | --- | --- |\n| 2R |  |  |  | 12 |\n| 2R |  |  | 2.0 |  |\n| 4R |  |  | 150 |  |\n| 5R |  | 8.0 |  |  |\n| 5R |  |  | 1.2 |  |\n| 5R |  |  |  | 11 |\n| 6R |  |  |  | 30 |\n| 6R |  |  |  | 15 |\n| 6R |  |  | 14 |  |\n| 14R |  |  |  | 150 |\n| 14R |  |  | 100 |  |\n| 17R |  |  |  | 6.0 |\n| 17R |  |  | 1.8 |  |\n| 18R |  |  |  | 12 |\n| 18R |  |  | 3.3 |  |\n| 19R |  |  |  | 13 |\n| 20R |  |  |  | 18 |\n| 20R |  |  | 6.0 |  |\n| 23R |  |  | 0.20 |  |\n| 24R |  |  | 0.25 |  |\n| 25R |  |  | 4.0 |  |\n\n---\n\n**Figure 2-3.  Levels of Significant Exposure to Cadmium – Oral**\nAcute (≤14 days)\n\n| Category | Animal - NOAEL (mg Cd/kg/day) | Animal - LOAEL (mg Cd/kg/day) | Animal - SLOAEL (mg Cd/kg/day) |\n| --- | --- | --- | --- |\n| Respiratory | 14R: 160 |  |  |\n| Cardiovascular | 14R: 160 |  |  |\n| Gastrointestinal | 14R: 160 |  |  |\n|  |  | 17R: 65 |  |\n|  |  | 17R: 19 |  |\n|  |  | 26M: 30 |  |\n|  |  | 26M: 16 |  |\n|  |  | 26M: 85 |  |\n| Hematological | 1R: 15 |  |  |\n|  |  | 4R: 150 |  |\n|  |  | 5R: 14 |  |\n|  |  | 6R: 16 |  |\n|  |  | 14R: 160 |  |\n|  |  | 19R: 16 |  |\n| Hepatic | 4R: 150 |  |  |\n|  |  | 5R: 13 |  |\n|  |  | 6R: 16 |  |\n|  |  | 6R: 33 |  |\n|  |  | 14R: 160 |  |\n|  |  | 26M: 33 |  |\n|  |  | 26M: 16 |  |\n\n---\n\n**Figure 2-3.  Levels of Significant Exposure to Cadmium – Oral**\nAcute (≤14 days)\n\n**Figure 2-3. Levels of Significant Exposure to Cadmium – Oral Acute (≤14 days)**\n\n| Category | Animal - LD50/LC50 (mg Cd/kg/day) | Animal - LOAEL (mg Cd/kg/day) | Animal - NOAEL (mg Cd/kg/day) | Animal - SLOAEL (mg Cd/kg/day) | MRL for effect other than cancer (mg Cd/kg/day) |\n| --- | --- | --- | --- | --- | --- |\n| Renal |  |  | 160 |  |  |\n|  |  |  | 13 |  |  |\n|  |  |  | 65 |  |  |\n|  |  |  | 30 |  |  |\n|  |  |  | 160 |  |  |\n|  |  |  | 2.0 |  |  |\n|  |  |  | 90 |  |  |\n|  |  |  | 60 |  |  |\n|  |  |  | 1.8 |  |  |\n| Dermal |  |  | 6.5 |  |  |\n|  |  |  | 2.0 |  |  |\n| Endocrine |  |  | 160 |  |  |\n|  |  |  | 55 |  |  |\n| Immunological |  |  | 0.26 |  |  |\n|  |  |  | 0.030 |  |  |\n| Neurolgical |  |  | 50 |  |  |\n|  |  |  | 24 |  |  |\n\n---\n\n**Figure 2-3.  Levels of Significant Exposure to Cadmium – Oral**\nAcute (≤14 days)\n\n**Figure 2-3. Levels of Significant Exposure to Cadmium – Oral Acute (≤14 days)**\n\n| Category | Reproductive Animal - LD50/LC50 (mg Cd/kg/day) | Reproductive Animal - LOAEL (mg Cd/kg/day) | Reproductive Animal - NOAEL (mg Cd/kg/day) | Reproductive Animal - SLOAEL (mg Cd/kg/day) | Developmental Animal - LD50/LC50 (mg Cd/kg/day) | Developmental Animal - LOAEL (mg Cd/kg/day) | Developmental Animal - NOAEL (mg Cd/kg/day) | Developmental Animal - SLOAEL (mg Cd/kg/day) |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| 3R |  |  | 55 | 100 |  |  |  |  |\n| 5R |  |  | 13 |  |  |  |  |  |\n| 6R |  | 30 |  | 70 |  |  |  |  |\n| 7R |  |  | 26 |  |  |  |  |  |\n| 13R |  |  | 55 | 100 |  |  |  |  |\n| 26M |  | 34 |  | 65 |  |  |  |  |\n| 2R |  |  |  |  |  | 1.7 |  | 40 |\n| 17R |  |  |  |  ', 'pages': None, 'truncated': True, 'extraction': 'firecrawl-public-document-markdown', 'request_id': '6dbf2162-3841-4eb2-a566-2e2a25ac24a4', 'source_url': 'https://downloads.regulations.gov/ATSDR-2026-0133-0002/content.pdf', 'observed_at': '2026-10-04T00:39:30.279437+00:00', 'content_hash': '48479c728d0b8f13ff13edfd55d511d6e1fa5337c3b6b487129b37d5698c38f2'}, 'title': 'pdf', 'check_failed': False}]}

Oct. 4, 2026, 12:20 a.m.: effective_date, abstract, document_body, attachments changed since Oct. 3, 2026, 8:03 p.m..

{'abstract': None, 'attachments': None, 'document_body': None, 'effective_date': None}

{'abstract': '', 'attachments': [{'url': 'https://downloads.regulations.gov/ATSDR-2026-0133-0002/attachment_1.pdf', 'title': 'Draft Toxicological Profile for Cadmium'}, {'url': 'https://downloads.regulations.gov/ATSDR-2026-0133-0002/content.pdf', 'title': 'pdf'}], 'document_body': '', 'effective_date': ''}

Collection history starts with our observations; it is not complete legislative amendment history.

Detail checked 2026-10-12T09:21:44.661162+00:00.

• 2026-10-01: Introduced in House
• 2026-10-01: Referred to the House Committee on Foreign Affairs.

• 2026-10-07 Introduced: Official bill text

Observed 2026-10-12T09:21:57.936992+00:00. Text limited; read the complete official file.

I
119TH CONGRESS
2D SESSION H. R. 10675
To strengthen critical mineral, energy, manufacturing and technology supply
chains, advance innovation and allied cooperation, enhance United States
technological leadership and competitiveness, and for other purposes.
IN THE HOUSE OF REPRESENTATIVES
OCTOBER 1, 2026
Mr. HUIZENGA (for himself and Mrs. K IM) introduced the following bill; which
was referred to the Committee on Foreign Affairs
A BILL
To strengthen critical mineral, energy, manufacturing and
technology supply chains, advance innovation and allied
cooperation, enhance United States technological leader-
ship and competitiveness, and for other purposes.
Be it enacted by the Senate and House of Representa-1
tives of the United States of America in Congress assembled, 2
SECTION 1. SHORT TITLE; TABLE OF CONTENTS. 3
(a) S HORT TITLE.—This Act may be cited as the 4
‘‘Building United States Industrial Leadership and Devel-5
opment with Allies Act of 2026’’ or the ‘‘BUILD with Al-6
lies Act of 2026’’. 7
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•HR 10675 IH
(b) TABLE OF CONTENTS.—The table of contents for 1
this Act is as follows: 2
Sec. 1. Short title; table of contents.
Sec. 2. Sense of Congress.
Sec. 3. Purposes.
Sec. 4. Definitions.
TITLE I—CRITICAL MINERAL INNOVATION PARTNERSHIP
PROGRAM
Sec. 101. Sense of Congress.
Sec. 102. Establishment.
Sec. 103. Eligibility.
Sec. 104. Notification and briefing.
Sec. 105. Elements.
Sec. 106. Responsibilities of Director.
Sec. 107. Staff.
Sec. 108. International Centers of Excellence for Innovative Critical Minerals
Supply Chain Technologies.
Sec. 109. Digital platform.
Sec. 110. Facilities and infrastructure support.
Sec. 111. Assistance for science and technology cooperation; limitations.
Sec. 112. Termination of authority.
Sec. 113. Definitions.
TITLE II—EXCHANGE PROGRAM TO STRENGTHEN
MANUFACTURING WORKFORCE EDUCATION
Sec. 201. Manufacturing revitalization exchange program.
Sec. 202. Implementation coordination assistance.
Sec. 203. Authority to engage in independent consultation.
Sec. 204. Study for future expansion.
Sec. 205. Sunset.
Sec. 206. Definitions.
TITLE III—LIST OF ENTITIES CARRYING OUT MINING INVOLVING
FORCED LABOR OR CAUSING ENVIRONMENTAL HARM
Sec. 301. Annual list of PRC entities carrying out mining involving forced
labor, forced child labor, or environmental harm in certain Af-
rican countries.
Sec. 302. Definitions.
TITLE IV—FOREIGN PARTNER PROCUREMENT OF UNITED
STATES-ORIGIN CYBER AND DIGITAL TECHNOLOGIES
Sec. 401. Sense of Congress.
Sec. 402. United States Technology Procurement Program.
Sec. 403. Office of United States Technology Procurement.
Sec. 404. Expanding necessary technology and related expertise at United
States overseas missions.
Sec. 405. Extending authorization of appropriations for the Regional Tech-
nology Officer Program.
Sec. 406. Preserving market-based competition for cyber and digital tech-
nologies.
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•HR 10675 IH
Sec. 407. Government Accountability Office report.
Sec. 408. Definitions.
TITLE V—UNITED STATES TRADE AND DEVELOPMENT AGENCY
MODERNIZATION
Sec. 501. Sense of Congress.
Sec. 502. Expansion of country eligibility.
Sec. 503. Personnel authorities.
TITLE VI—COMBATING CHINA’S UNFAIR AND NON-MARKET-ORI-
ENTED TRADE PRACTICES RELATED TO THE SHIPBUILDING
INDUSTRY
Sec. 601. Statement of policy to counter shipbuilding practices of the People’s
Republic of China.
Sec. 602. Strategic ports; United States International Development Finance
Corporation.
Sec. 603. Briefing and report on China Ocean Shipping Company Shipping
Heavy Industry and China State Shipbuilding Corporation.
Sec. 604. Assistant Secretary for Water, Environment, and Space Affairs.
Sec. 605. Exchange program for shipbuilding industry experts.
Sec. 606. Maritime investigators.
Sec. 607. Allied maritime framework.
Sec. 608. Maritime group of nations.
Sec. 609. International Maritime Organization.
Sec. 610. Definitions.
SEC. 2. SENSE OF CONGRESS. 1
It is the sense of Congress that— 2
(1) secure, resilient, and trusted supply chains 3
for critical minerals, energy systems, advanced man-4
ufacturing, and digital infrastructure are essential to 5
United States national security, economic competi-6
tiveness, and technological leadership; 7
(2) these supply chains are increasingly inter-8
connected, spanning critical mineral extraction, proc-9
essing, refining, advanced manufacturing, compute 10
infrastructure, and digital systems; 11
(3) deeper coordination between the United 12
States and allied and partner countries in invest-13
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•HR 10675 IH
ment, industrial capacity, and supply chains develop-1
ment can improve access to critical inputs and infra-2
structure and reduce to exposure to concentrated, 3
coercive, or unreliable supply relationships; expanded 4
collaboration in critical minerals extraction, proc-5
essing, refining, recycling, and substitution tech-6
nologies can improve supply resilience while improv-7
ing resource efficiency and environmental perform-8
ance; 9
(4) joint research, workforce training, and the 10
sharing of infrastructure, data, and expertise among 11
the United States and allied and partner countries 12
can accelerate the development of next-generation 13
materials, semiconductors, mineral processing, and 14
advanced manufacturing technologies across critical 15
supply chains; 16
(5) public-private collaboration involving gov-17
ernments, industry, academic institutions, and re-18
search organizations is essential to commercializing 19
innovation and scaling trusted supply ecosystems; 20
(6) coordination among allied and partner na-21
tions in investment, industrial capacity, and supply 22
chain development can enhance resilience and reduce 23
vulnerabilities associated with concentrated or adver-24
sarial supply dependencies; 25
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•HR 10675 IH
(7) strengthening secure digital infrastructure, 1
telecommunications systems, and data-driven tech-2
nologies alongside physical supply chains is critical 3
to supporting the full technology ecosystem under-4
lying artificial intelligence and advanced computing; 5
(8) ensuring trusted technology ecosystems re-6
quires strong supply chain integrity measures, in-7
cluding transparency, traceability, and responsible 8
sourcing standards, and addressing the use of forced 9
labor, child labor, and other exploitative labor prac-10
tices in global critical mineral and related supply 11
chains that undermine market integrity, human 12
rights, and the security of trusted trade relation-13
ships; 14
(9) workforce development, technical education, 15
and international exchanges are essential to building 16
long-term capacity across critical minerals, advanced 17
manufacturing, and emerging technology sectors; 18
and 19
(10) strengthening secure and trusted tech-20
nology ecosystems across critical minerals, semi-21
conductors, shipbuilding, and digital infrastructure 22
enhances the commercial competitiveness of the 23
United States by supporting the export of American 24
technologies and standards to allied and partner 25
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•HR 10675 IH
markets and expanding global demand for United 1
States-origin innovation. 2
SEC. 3. PURPOSES. 3
The purposes of this Act are to— 4
(1)…