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Toxicological Review of Chlordecone (Kepone)

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Toxicological Review of Chlordecone (Kepone) DRAFT ­ DO NOT CITE OR QUOTE EPA/635/R­07/004 www.epa.gov/iris TOXICOLOGICAL REVIEW OF CHLORDECONE (KEPONE) (CAS No. 143­50­0) In Support of Summary Information on the Integrated Risk Information System (IRIS) July 2009 NOTICE This document is a final draft. This information is distributed solely for the purpose of pre­ dissemination peer review under applicable information quality guidelines. It has not been formally disseminated by EPA. It does not represent and should not be construed to represent any Agency determination or policy. It is being circulated for review of its technical accuracy and science policy implications. U.S. Environmental Protection Agency Washington, DC DISCLAIMER This document is a preliminary review draft for review purposes only. This information is distributed solely for the purpose of pre­dissemination peer review under applicable information quality guidelines. It has not been formally disseminated by EPA. It does not represent and should not be construed to represent any Agency determination or policy. Mention of trade names or commercial products does not constitute endorsement or recommendation for use. ii DRAFT ­ DO NOT CITE OR QUOTE CONTENTS —TOXICOLOGICAL REVIEW OF CHLORDECONE (CAS No. 143­50­0) LIST OF TABLES.......................................................................................................................... v LIST OF FIGURES ..................................................................................................................... viii LIST OF ABBREVIATIONS AND ACRONYMS ...................................................................... ix FOREWORD…. ............................................................................................................................ xi AUTHORS, CONTRIBUTORS, AND REVIEWERS ................................................................ xii 1. INTRODUCTION ..................................................................................................................... 1 2. CHEMICAL AND PHYSICAL INFORMATION RELEVANT TO ASSESSMENTS .......... 3 3. TOXICOKINETICS .................................................................................................................. 5 3.1. ABSORPTION ................................................................................................................. 5 3.2. DISTRIBUTION............................................................................................................... 7 3.3. METABOLISM .............................................................................................................. 10 3.4. ELIMINATION .............................................................................................................. 12 3.5. PHYSIOLOGICALLY BASED TOXICOKINETIC MODELS.................................... 15 4. HAZARD IDENTIFICATION................................................................................................ 17 4.1. STUDIES IN HUMANS―EPIDEMIOLOGY, CASE REPORTS, CLINICAL CONTROLS ........................................................................................................................... 17 4.2. SUBCHRONIC AND CHRONIC STUDIES AND CANCER BIOASSAYS IN ANIMALS―ORAL AND INHALATION............................................................................ 18 4.2.1. Subchronic Studies............................................................................................... 19 4.2.1.1. Oral Exposure Studies ........................................................................... 19 4.2.1.2. Inhalation Exposure Studies.................................................................. 19 4.2.2. Chronic Studies.................................................................................................... 20 4.2.2.1. Oral Exposure Studies ........................................................................... 20 4.3. REPRODUCTIVE/DEVELOPMENTAL STUDIES..................................................... 33 4.3.1. Reproductive Toxicity Studies............................................................................. 33 4.3.2. Developmental Toxicity Studies.......................................................................... 44 4.3.3. Screening Studies................................................................................................. 46 4.4. OTHER STUDIES.......................................................................................................... 47 4.4.1. Acute Toxicity Studies......................................................................................... 47 4.4.2. Potentiation of Halomethane Toxicity ................................................................. 47 4.4.3. Neurotoxicity Studies........................................................................................... 49 4.4.4. Endocrine Disruption Studies .............................................................................. 49 4.4.5. Immunological Studies ........................................................................................ 51 4.5. MECHANISTIC DATA AND OTHER STUDIES IN SUPPORT OF THE MODE OF ACTION ................................................................................................................................. 55 4.5.1. Genotoxicity......................................................................................................... 55 4.5.2. Tumor Promotion and Mechanistic Studies......................................................... 55 4.5.3. Structural Analog Data—Relationship to Mirex ................................................. 58 4.6. SYNTHESIS OF MAJOR NONCANCER EFFECTS................................................... 61 iii DRAFT ­ DO NOT CITE OR QUOTE 4.6.1. Oral Exposure ...................................................................................................... 64 4.6.2. Mode­of­Action Information—Glomerular Lesions ........................................... 67 4.7. EVALUATION OF CARCINOGENICITY................................................................... 68 4.7.1. Summary of Overall Weight of Evidence............................................................ 68 4.7.2. Synthesis of Human, Animal, and Other Supporting Evidence........................... 70 4.7.3. Mode­of­Action Information .......................................................................... 73 4.8. SUSCEPTIBLE POPULATIONS AND LIFE STAGES............................................... 74 4.8.1. Possible Childhood Susceptibility ....................................................................... 74 4.8.2. Possible Gender Differences................................................................................ 75 5. DOSE­RESPONSE ASSESSMENTS..................................................................................... 77 5.1. ORAL REFERENCE DOSE (RfD)................................................................................ 77 5.1.1. Choice of Principal Study and Critical Effect—with Rationale and Justification77 5.1.2. Methods of Analysis ............................................................................................ 83 5.1.3. RfD Derivation—Including Application of Uncertainty Factors (UFs).............. 85 5.1.4. RfV Comparison Information .............................................................................. 86 5.1.5. Previous RfD Assessment.................................................................................... 90 5.2. INHALATION REFERENCE CONCENTRATION (RfC) .......................................... 90 5.3. CANCER ASSESSMENT.............................................................................................. 91 5.3.1. Choice of Study/Data with Rationale and Justification ....................................... 91 5.3.2. Dose­Response Data ............................................................................................ 92 5.3.3. Dose Adjustments and Extrapolation Methods.................................................... 94 5.3.4. Derivation of the Oral Cancer Slope Factor ........................................................ 96 5.3.5. Uncertainties in Cancer Risk Values ................................................................... 97 6. MAJOR CONCLUSIONS IN THE CHARACTERIZATION OF ....................................... 102 HAZARD AND DOSE RESPONSE.......................................................................................... 102 6.1. HUMAN HAZARD POTENTIAL............................................................................... 102 6.2. DOSE RESPONSE ....................................................................................................... 104 6.2.1. Noncancer .......................................................................................................... 104 6.2.2. Cancer ................................................................................................................ 106 7. REFERENCES ...................................................................................................................... 108 APPENDIX A. SUMMARY OF EXTERNAL PEER REVIEW AND PUBLIC COMMENTS AND DISPOSITION .................................................................................................................. A­1 APPENDIX B. BENCHMARK DOSE CALCULATIONS FOR THE RfD............................ B­1 APPENDIX C. TIME­TO­TUMOR MODELING RESULTS FROM TOX_RISK BASED ON THE INCIDENCE OF HEPATOCELLULAR CARCINOMAS............................................... C­1 iv DRAFT ­ DO NOT CITE OR QUOTE LIST OF TABLES
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