DRAFT - DO NOT CITE OR QUOTE EPA/635/R-09/003A www.epa.gov/iris TOXICOLOGICAL REVIEW OF TRICHLOROACETIC ACID (CAS No. 76-03-9) In Support of Summary Information on the Integrated Risk Information System (IRIS) September 2009 NOTICE This document is an External Review 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 draft for review purposes only. 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. 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 ii DRAFT - DO NOT CITE OR QUOTE CONTENTS—TOXICOLOGICAL REVIEW OF TRICHLOROACETIC ACID (CAS No. 76-03-9) LIST OF TABLES .......................................................................................................................... v LIST OF FIGURES ....................................................................................................................... vi LIST OF ABBREVIATIONS AND ACRONYMS ..................................................................... viii FOREWORD ................................................................................................................................. xi AUTHORS, CONTRIBUTORS, AND REVIEWERS ................................................................. xii 1. INTRODUCTION ..................................................................................................................... 1 2. CHEMICAL AND PHYSICAL INFORMATION .................................................................... 3 3. TOXICOKINETICS .................................................................................................................. 5 3.1. ABSORPTION ................................................................................................................. 5 3.2. DISTRIBUTION ............................................................................................................... 7 3.3. METABOLISM .............................................................................................................. 11 3.4. EXCRETION .................................................................................................................. 17 3.5. PHYSIOLOGICALLY BASED AND OTHER TOXICOKINETIC MODELS ............ 19 4. HAZARD IDENTIFICATION ................................................................................................ 20 4.1. STUDIES IN HUMANS ................................................................................................. 20 4.1.1. Oral Exposure ..................................................................................................... 20 4.1.2. Dermal Exposure ................................................................................................ 20 4.2. SUBCHRONIC AND CHRONIC STUDIES AND CANCER BIOASSAYS IN ANIMALS―ORAL AND INHALATION ................................................................... 22 4.2.1. Subchronic Studies ............................................................................................. 22 4.2.2. Chronic Studies and Cancer Assays ................................................................... 38 4.3. REPRODUCTIVE AND DEVELOPMENTAL STUDIES ........................................... 57 4.3.1. Reproductive Studies .......................................................................................... 57 4.3.2. Developmental Studies ....................................................................................... 57 4.4. OTHER ENDPOINT-SPECIFIC STUDIES .................................................................. 67 4.4.1. Immunological Studies ....................................................................................... 67 4.5. MECHANISTIC DATA AND OTHER STUDIES IN SUPPORT OF THE MODE OF ACTION ........................................................................................................................ 67 4.5.1. Mechanistic Studies ............................................................................................ 67 4.5.2. Genotoxicity Studies ........................................................................................... 81 4.6. SYNTHESIS OF MAJOR NONCANCER EFFECTS ................................................... 87 4.6.1. Oral ..................................................................................................................... 87 4.6.2. Inhalation ............................................................................................................ 89 4.6.3. Mode-of-Action Information .............................................................................. 90 4.7. EVALUATION OF CARCINOGENICITY ................................................................... 92 4.7.1. Summary of Overall Weight of Evidence ........................................................... 92 4.7.2. Synthesis of Human, Animal, and Other Supporting Evidence.......................... 92 4.7.3. Mode-of-Action Information .............................................................................. 93 4.8. SUSCEPTIBLE POPULATION AND LIFE STAGES ............................................... 115 4.8.1. Possible Childhood Susceptibility .................................................................... 115 4.8.2. Possible Gender Differences ............................................................................. 116 4.8.3. Other Factors Influencing Susceptibility .......................................................... 117 iii DRAFT - DO NOT CITE OR QUOTE 5. DOSE-RESPONSE ASSESSMENTS ................................................................................... 118 5.1. ORAL REFERENCE DOSE (RfD) .............................................................................. 118 5.1.1. Choice of Principal Study and Critical Effect—with Rationale and Justification ...................................................................................................... 118 5.1.2. Methods of Analysis ......................................................................................... 123 5.1.3. RfD Derivation—Including Application of Uncertainty Factors (UFs) ........... 131 5.1.4. RfD Comparison Information ........................................................................... 133 5.1.5. Previous RfD Assessment ................................................................................. 133 5.2. INHALATION REFERENCE CONCENTRATION (RfC) ......................................... 133 5.3. UNCERTAINTIES IN THE ORAL REFERENCE DOSE .......................................... 134 5.4. CANCER ASSESSMENT ............................................................................................ 135 5.4.1. Choice of Study/Data—with Rationale and Justification ................................. 137 5.4.2. Dose-Response Data ......................................................................................... 137 5.4.3. Dose Conversion ............................................................................................... 139 5.4.4. Extrapolation Methods ...................................................................................... 140 5.4.5. Oral Cancer Slope Factor and Inhalation Unit Risk ......................................... 142 5.4.6. Previous Cancer Assessment ............................................................................ 142 6. MAJOR CONCLUSIONS IN THE CHARACTERIZATION OF HAZARD AND DOSE RESPONSE ........................................................................................................................... 143 6.1. HUMAN HAZARD POTENTIAL ............................................................................... 143 6.2. DOSE RESPONSE ....................................................................................................... 146 6.2.1. Noncancer/Oral ................................................................................................. 146 6.2.2. Noncancer/Inhalation ........................................................................................ 147 6.2.3. Cancer/Oral and Inhalation ............................................................................... 147 7. REFERENCES ...................................................................................................................... 149 APPENDIX A. SUMMARY OF EXTERNAL PEER REVIEW AND PUBLIC COMMENTS AND DISPOSITION ............................................................................................................ A-1 APPENDIX B. BENCHMARK DOSE MODELING RESULTS FOR THE INCIDENCE OF HEPATOCELLULAR INFLAMMATION, HEPATOCELLULAR NECROSIS, AND TESTICULAR TUBULAR DEGENERATION IN MICE EXPOSED TO TCA IN DRINKING WATER FOR USE IN DERIVATION OF THE REFERENCE DOSE ......... B-1 APPENDIX C. INPUT AND OUTPUT DATA FOR BENCHMARK DOSE MODELING OF DEVELOPMENTAL DATA FROM SMITH ET AL. (1989) ............................................. C-1 APPENDIX D. MODELING OF LIVER TUMOR INCIDENCE DATA FOR