EPA/635/R-11/005F www.epa.gov/iris TOXICOLOGICAL REVIEW OF BIPHENYL (CAS No. 92-52-4) In Support of Summary Information on the Integrated Risk Information System (IRIS) August 2013 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 BIPHENYL (CAS No. 92-52-4) LIST OF TABLES ......................................................................................................................... vi LIST OF FIGURES ....................................................................................................................... ix LIST OF ABBREVIATIONS AND ACRONYMS ........................................................................x FOREWORD ................................................................................................................................ xii AUTHORS, CONTRIBUTORS, AND REVIEWERS ............................................................... xiii 1. INTRODUCTION ......................................................................................................................1 2. CHEMICAL AND PHYSICAL INFORMATION ....................................................................4 3. TOXICOKINETICS ...................................................................................................................6 3.1. ABSORPTION ................................................................................................................. 6 3.2. DISTRIBUTION............................................................................................................... 8 3.3. METABOLISM ................................................................................................................ 8 3.3.1. Identification of Metabolites ..................................................................................8 3.3.1.1. Results from In Vivo Animal Studies ..................................................... 8 3.3.1.2. Results from In Vitro Studies with Animal and Human Cells or Tissues...................................................................................................... 9 3.3.2. Metabolic Pathways .............................................................................................11 3.3.2.1. Description of Metabolic Scheme and Enzymes Involved ................... 11 3.3.3. Regulation of Metabolism and Sites of Metabolism ............................................13 3.3.3.1. Evidence for Induction of Phase I and II Enzymes ............................... 13 3.3.3.2. Demonstrated Tissue Sites of Metabolism ............................................ 15 3.4. ELIMINATION .............................................................................................................. 15 3.5. PHYSIOLOGICALLY BASED PHARMACOKINETIC (PBPK) MODELS .............. 16 4. HAZARD IDENTIFICATION .................................................................................................17 4.1. STUDIES IN HUMANS................................................................................................. 17 4.2. SUBCHRONIC AND CHRONIC STUDIES AND CANCER BIOASSAYS IN ANIMALS—ORAL AND INHALATION .................................................................... 21 4.2.1. Oral Exposure ......................................................................................................22 4.2.1.1. Subchronic Toxicity .............................................................................. 22 4.2.1.2. Chronic Toxicity and Carcinogenicity .................................................. 24 4.2.2. Inhalation Studies .................................................................................................38 4.3. REPRODUCTIVE/DEVELOPMENTAL STUDIES—ORAL AND INHALATION ................................................................................................................ 40 4.3.1. Oral Exposure ......................................................................................................40 4.3.2. Inhalation Exposure .............................................................................................43 4.4. OTHER DURATION- OR ENDPOINT-SPECIFIC STUDIES..................................... 43 4.4.1. Acute and Short-term Toxicity Data ....................................................................43 4.4.2. Kidney/Urinary Tract Endpoint Studies ..............................................................44 4.4.3. Biphenyl as a Tumor Promoter ............................................................................48 4.5. MECHANISTIC DATA AND OTHER STUDIES IN SUPPORT OF THE MODE OF ACTION .................................................................................................................... 50 4.5.1. Effects on the Urinary Bladder of Rats ................................................................50 4.5.2. Genotoxicity .........................................................................................................50 iii 4.6. SYNTHESIS OF MAJOR NONCANCER EFFECTS ................................................... 51 4.6.1. Oral ......................................................................................................................57 4.6.2. Inhalation .............................................................................................................60 4.6.3. Mode-of-Action Information ...............................................................................60 4.7. EVALUATION OF CARCINOGENICITY................................................................... 61 4.7.1. Summary of Overall Weight of Evidence ............................................................61 4.7.2. Synthesis of Human, Animal, and Other Supporting Evidence ...........................63 4.7.3. Mode-of-Action Information ...............................................................................65 4.7.3.1. Mode-of-Action Information for Bladder Tumors in Male Rats .......... 65 4.7.3.2. Mode-of-Action Information for Liver Tumors in Female Mice .......... 71 4.8. SUSCEPTIBLE POPULATIONS AND LIFE STAGES ............................................... 73 4.8.1. Possible Childhood Susceptibility .......................................................................73 4.8.2. Possible Gender Differences ................................................................................74 5. DOSE-RESPONSE ASSESSMENTS ......................................................................................75 5.1. ORAL REFERENCE DOSE (RfD) ................................................................................ 75 5.1.1. Choice of Candidate Principal Studies and Candidate Critical Effects— with Rationale and Justification ...........................................................................75 5.1.2. Methods of Analysis—Including Models (e.g., PBPK, BMD) ...........................78 5.1.3. RfD Derivation—Including Application of Uncertainty Factors (UFs) ..............85 5.1.4. Previous RfD Assessment ....................................................................................86 5.2. INHALATION REFERENCE CONCENTRATION (RfC) .......................................... 87 5.2.1. Choice of Principal Study and Critical Effect—with Rationale and Justification ..........................................................................................................87 5.2.2. Previous RfC Assessment ....................................................................................88 5.3. UNCERTAINTIES IN THE RfD AND RfC .................................................................. 88 5.4. CANCER ASSESSMENT .............................................................................................. 89 5.4.1. Choice of Study/Data—with Rationale and Justification ....................................90 5.4.2. Dose-Response Data ............................................................................................90 5.4.3. Dose Adjustments and Extrapolation Method(s) .................................................91 5.4.3.1. Liver Tumors in Female Mice ............................................................... 91 5.4.3.2. Bladder Tumors in Male Rats ............................................................... 94 5.4.4. Oral Slope Factor and Inhalation Unit Risk .........................................................94 5.4.5. Uncertainties in Cancer Risk Values ...................................................................95 5.4.5.1. Oral Slope Factor ................................................................................... 95 5.4.5.2. Inhalation Unit Risk .............................................................................. 97 5.4.6. Previous Cancer Assessment ...............................................................................97 6. MAJOR CONCLUSIONS IN THE CHARACTERIZATION OF HAZARD AND DOSE RESPONSE ..................................................................................................................98 6.1. HUMAN HAZARD POTENTIAL ................................................................................. 98 6.1.1. Noncancer ............................................................................................................98 6.1.2. Cancer ..................................................................................................................99