DRAFT - DO NOT CITE OR QUOTE EPA/635/R-07/002 www.epa.gov/iris TOXICOLOGICAL REVIEW OF BROMOBENZENE (CAS No. 108-86-1) In Support of Summary Information on the Integrated Risk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) June 2007 NOTICE This document is an interagency review draft. It has not been formally released by the U.S. Environmental Protection Agency and should not at this stage be construed to represent Agency position on this chemical. 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 and does not constitute U.S. Environmental Protection Agency policy. Mention of trade names or commercial products does not constitute endorsement or recommendation for use. 6/7/07 ii DRAFT – DO NOT CITE OR QUOTE CONTENTSCTOXICOLOGICAL REVIEW OF BROMOBENZENE (CAS No. 108-86-1) LIST OF FIGURES ....................................................................................................................... vi LIST OF TABLES........................................................................................................................ vii 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 RELEVANT TO ASSESSMENTS.........................................................6 3.1. ABSORPTION .................................................................................................................6 3.2. DISTRIBUTION...............................................................................................................6 3.3. METABOLISM................................................................................................................7 3.4. ELIMINATION..............................................................................................................11 3.5. PHYSIOLOGICALLY BASED TOXICOKINETIC MODELS (PBTK)......................12 4. HAZARD IDENTIFICATION................................................................................................13 4.1. STUDIES IN HUMANS—EPIDEMIOLOGY, CASE REPORTS, CLINICAL CONTROLS ...................................................................................................................13 4.2. LESS-THAN-LIFETIME AND CHRONIC STUDIES AND CANCER BIOASSAYS IN ANIMALS—ORAL AND INHALATION .......................................13 4.2.1. Oral Exposure ......................................................................................................13 4.2.1.1. Subchronic Toxicity..............................................................................13 4.2.1.2. Chronic Toxicity....................................................................................23 4.2.2. Inhalation Exposure .............................................................................................24 4.2.2.1. Subchronic Toxicity..............................................................................24 4.2.2.2. Chronic Toxicity...................................................................................31 4.3. REPRODUCTIVE/DEVELOPMENTAL STUDIES—ORAL AND INHALATION................................................................................................................31 4.3.1. Reproductive Toxicity Studies.............................................................................31 4.3.2. Developmental Toxicity Studies..........................................................................31 4.4. OTHER STUDIES..........................................................................................................31 4.4.1. Acute Toxicity Studies.........................................................................................31 4.4.2. Genotoxicity Studies............................................................................................32 4.4.3. Tumor Promotion Studies....................................................................................35 4.5. MECHANISTIC STUDIES............................................................................................35 4.5.1. Mechanistic Studies of Liver Effects...................................................................35 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 ..............48 4.6.1. Oral ......................................................................................................................48 4.6.2. Inhalation .............................................................................................................48 6/7/07 iii DRAFT – DO NOT CITE OR QUOTE 4.6.3. Mode of Action Information................................................................................49 4.7. EVALUATION OF CARCINOGENICITY...................................................................51 4.8. SUSCEPTIBLE POPULATIONS..................................................................................51 4.8.1. Possible Childhood Susceptibility .......................................................................51 4.8.2. Possible Gender Differences................................................................................51 4.8.3. Other ....................................................................................................................52 5. DOSE-RESPONSE ASSESSMENTS.....................................................................................53 5.1. ORAL REFERENCE DOSE..........................................................................................53 5.1.1. Subchronic Oral RfD ...........................................................................................53 5.1.1.1. Choice of Principal Study and Critical Effect - with Rationale and Justification ...........................................................................................53 5.1.1.2. Methods of Analysis - Including Models (PBPK, BMD, etc.)..............54 5.1.1.3. Subchronic RfD Derivation - Including Application of Uncertainty Factors (UFs).....................................................................59 5.1.2. Chronic Oral RfD.................................................................................................60 5.1.2.1. Choice of Principal Study and Critical Effect - with Rationale and Justification ...........................................................................................60 5.1.2.2. Methods of Analysis - Including Models (PBPK, BMD, etc.)..............60 5.1.2.3. Chronic RfD Derivation - Including Application of Uncertainty Factors (UFs).........................................................................................60 5.1.3. Previous Oral Assessment....................................................................................62 5.2. INHALATION REFERENCE CONCENTRATION (RfC) ..........................................62 5.2.1. Subchronic Inhalation RfC ..................................................................................62 5.2.1.1. Choice of Principal Study and Critical Effect - with Rationale and Justification.....................................................................................62 5.2.1.2. Methods of Analysis - Including Model (PBPK, BMD, etc.) ...............64 5.2.1.3. Subchronic RfC Derivation - Including Application of Uncertainty Factors (UFs).....................................................................68 5.2.2. Chronic Inhalation RfC........................................................................................69 5.2.2.1. Choice of Principal Study and Critical Effect - with Rationale and Justification.....................................................................................69 5.2.2.2. Methods of Analysis - Including Model (PBPK, BMD, etc.) ...............70 5.2.2.3. Chronic RfC Derivation - Including Application of Uncertainty Factors (UFs).........................................................................................70 5.3. CANCER ASSESSMENT..............................................................................................71 6. MAJOR CONCLUSIONS IN THE CHARACTERIZATION OF HAZARD AND DOSE RESPONSE..................................................................................................................72 6.1. HUMAN HAZARD POTENTIAL.................................................................................72 6.2. DOSE RESPONSE.........................................................................................................73 6.2.1. Noncancer/Oral....................................................................................................73 6.2.2. Noncancer/Inhalation...........................................................................................73 6.2.3. Cancer/Oral..........................................................................................................74