EPA/635/R-07/002F www.epa.gov/iris TOXICOLOGICAL REVIEW OF BROMOBENZENE (CAS No. 108-86-1) In Support of Summary Information on the Integrated Risk Information System (IRIS) September 2009 U.S. Environmental Protection Agency Washington, DC DISCLAIMER This document has been reviewed in accordance with U.S. Environmental Protection Agency policy and approved for publication. Mention of trade names or commercial products does not constitute endorsement or recommendation for use. ii CONTENTS−TOXICOLOGICAL REVIEW OF BROMOBENZENE (CAS No. 108-86-1) LIST OF TABLES......................................................................................................................... vi LIST OF FIGURES ....................................................................................................................... ix LIST OF ABBREVIATIONS AND ACRONYMS ....................................................................... x FOREWORD ................................................................................................................................. xi AUTHORS, CONTRIBUTORS, AND REVIEWERS ................................................................ xii 1. INTRODUCTION ..................................................................................................................... 1 2. CHEMICAL AND PHYSICAL INFORMATION RELEVANT TO ASSESSMENTS .......... 3 3. TOXICOKINETICS .................................................................................................................. 6 3.1. ABSORPTION ................................................................................................................. 6 3.2. DISTRIBUTION............................................................................................................... 6 3.3. METABOLISM ................................................................................................................7 3.4. ELIMINATION .............................................................................................................. 12 3.5. PHYSIOLOGICALLY BASED TOXICOKINETIC MODELS.................................... 13 4. HAZARD IDENTIFICATION................................................................................................ 14 4.1. STUDIES IN HUMANS—EPIDEMIOLOGY, CASE REPORTS, CLINICAL CONTROLS .................................................................................................................. 14 4.2. SUBCHRONIC AND CHRONIC STUDIES AND CANCER BIOASSAYS IN ANIMALS—ORAL AND INHALATION................................................................... 14 4.2.1. Oral Exposure ..................................................................................................... 14 4.2.1.1. Subchronic Toxicity............................................................................. 14 4.2.1.2. Chronic Toxicity .................................................................................. 25 4.2.2. Inhalation Exposure ............................................................................................ 25 4.2.2.1. Subchronic Toxicity............................................................................. 25 4.2.2.2. Chronic Toxicity .................................................................................. 32 4.3. REPRODUCTIVE/DEVELOPMENTAL STUDIES—ORAL AND INHALATION .. 32 4.3.1. Reproductive Toxicity Studies............................................................................ 32 4.3.2. Developmental Toxicity Studies......................................................................... 32 4.4. OTHER DURATION- OR ENDPOINT-SPECIFIC STUDIES..................................... 32 4.4.1. Acute Toxicity Studies........................................................................................ 32 4.4.2. Genotoxicity Studies........................................................................................... 33 4.4.3. Tumor Promotion Studies................................................................................... 36 4.5. MECHANISTIC STUDIES............................................................................................ 36 4.5.1. Mechanistic Studies of Liver Effects.................................................................. 36 4.5.2. Mechanistic Studies of Kidney Effects............................................................... 41 4.5.3. Genomic/Proteomic Responses of the Liver to Bromobenzene ......................... 42 4.5.4. Similarities Between Bromobenzene and Chlorobenzene.................................. 43 4.6. SYNTHESIS AND EVALUATION OF MAJOR NONCANCER EFFECTS .............. 46 4.6.1. Oral ..................................................................................................................... 46 4.6.2. Inhalation ............................................................................................................ 47 4.6.3. Mode of Action Information............................................................................... 48 4.7. EVALUATION OF CARCINOGENICITY................................................................... 50 iii 4.8. SUSCEPTIBLE POPULATIONS .................................................................................. 50 4.8.1. Possible Childhood Susceptibility ...................................................................... 50 4.8.2. Possible Gender Differences............................................................................... 50 4.8.3. Other ...................................................................................................................51 5. DOSE-RESPONSE ASSESSMENTS..................................................................................... 52 5.1. ORAL REFERENCE DOSE .......................................................................................... 52 5.1.1. Subchronic Oral RfD .......................................................................................... 52 5.1.1.1. Choice of Principal Study and Critical Effect—with Rationale and Justification......................................................................................... 52 5.1.1.2. Methods of Analysis—Including Models (PBPK, BMD, etc.) ........... 55 5.1.1.3. Subchronic RfD Derivation—Including Application of Uncertainty Factors (UFs) ...................................................................................... 57 5.1.2. Chronic Oral RfD................................................................................................ 58 5.1.2.1. Choice of Principal Study and Critical Effect—with Rationale and Justification......................................................................................... 58 5.1.2.2. Methods of Analysis—Including Models (PBPK, BMD, etc.) ........... 59 5.1.2.3. RfD Derivation—Including Application of Uncertainty Factors (UFs) ...................................................................................... 59 5.1.3. Previous Oral Assessment................................................................................... 60 5.2. INHALATION REFERENCE CONCENTRATION (RfC) .......................................... 61 5.2.1. Subchronic Inhalation RfC ................................................................................. 61 5.2.1.1. Choice of Principal Study and Critical Effect—with Rationale and Justification......................................................................................... 61 5.2.1.2. Methods of Analysis—Including Models (PBPK, BMD, etc.) ........... 62 5.2.1.3. Subchronic RfC Derivation—Including Application of Uncertainty Factors (UFs) ...................................................................................... 64 5.2.2. Chronic Inhalation RfC....................................................................................... 65 5.2.2.1. Choice of Principal Study and Critical Effect—with Rationale and Justification......................................................................................... 65 5.2.2.2. Methods of Analysis—Including Models (PBPK, BMD, etc.) ........... 65 5.2.2.3. RfC Derivation—Including Application of Uncertainty Factors (UFs) ...................................................................................... 65 5.2.3. Previous RfC Assessment................................................................................... 67 5.3. CANCER ASSESSMENT.............................................................................................. 67 6. MAJOR CONCLUSIONS IN THE CHARACTERIZATION OF HAZARD AND DOSE RESPONSE ................................................................................................................. 68 6.1. HUMAN HAZARD POTENTIAL................................................................................. 68 6.2. DOSE RESPONSE ......................................................................................................... 69 6.2.1. Noncancer/Oral................................................................................................... 69 6.2.2. Noncancer/Inhalation.......................................................................................... 70 6.2.3. Cancer/Oral or Inhalation ................................................................................... 71 7. REFERENCES ........................................................................................................................ 72 APPENDIX A. SUMMARY OF EXTERNAL PEER REVIEW AND PUBLIC COMMENTS AND DISPOSITION................................................................ A-1 iv APPENDIX B.