EPA/635/R-09/010F www.epa.gov/iris TOXICOLOGICAL REVIEW OF CHLOROPRENE (CAS No. 126-99-8) In Support of Summary Information on the Integrated Risk Information System (IRIS) September 2010 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 TABLE OF CONTENTS LIST OF TABLES.................................................................................................................................... v LIST OF FIGURES ................................................................................................................................. ix LIST OF ABBREVIATIONS AND ACRONYMS ................................................................................ xi FOREWORD.........................................................................................................................................xiii AUTHORS, CONTRIBUTORS, AND REVIEWERS ......................................................................... xiv 1. INTRODUCTION ................................................................................................................................ 1 2. CHEMICAL AND PHYSICAL INFORMATION .............................................................................. 3 3. TOXICOKINETICS............................................................................................................................. 6 3.1. ABSORPTION............................................................................................................................... 6 3.2. DISTRIBUTION............................................................................................................................ 6 3.3. METABOLISM.............................................................................................................................. 7 3.4. ELIMINATION............................................................................................................................ 18 3.5. PHYSIOLOGICALLY BASED TOXICOKINETIC MODELS................................................. 18 4. HAZARD IDENTIFICATION........................................................................................................... 22 4.1. STUDIES IN HUMANS—EPIDEMIOLOGY, CASE REPORTS, CLINICAL CONTROLS .. 22 4.1.1. Chloroprene Exposure and Cancer Effects ............................................................................ 22 4.1.1.1. Overview...................................................................................................................... 22 4.1.1.2. Individual Occupational Studies....................................................................................22 4.1.1.3. Summary and Discussion of Relevant Methodological Issues......................................38 4.1.1.3.1. Lung Cancer Summary.............................................................................................. 40 4.1.1.3.2. Liver Cancer Summary. ............................................................................................ 41 4.1.2. Chloroprene Exposure and Noncancer Effects ...................................................................... 42 4.1.2.1. Acute-, Short-, and Subchronic-Duration Noncancer Effects .......................................42 4.1.2.2. Chronic Noncancer Effects............................................................................................44 4.2. SUBCHRONIC AND CHRONIC STUDIES AND CANCER BIOASSAYS IN ANIMALS— ORAL AND INHALATION............................................................................................................... 46 4.2.1. Oral Exposure ........................................................................................................................ 46 4.2.2. Inhalation Exposure ............................................................................................................... 48 4.3. REPRODUCTIVE/DEVELOPMENTAL STUDIES—ORAL AND INHALATION................ 73 4.4. OTHER DURATION- OR ENDPOINT-SPECIFIC STUDIES.................................................. 79 4.4.1. Acute and Subchronic Studies ............................................................................................... 79 4.4.2. Immunotoxicity...................................................................................................................... 81 4.5. MECHANISTIC DATA AND OTHER STUDIES IN SUPPORT OF MODE OF ACTION ... 82 4.5.1. Mode-of-Action Studies......................................................................................................... 82 4.5.2. Genotoxicity Studies.............................................................................................................. 85 4.5.2.1. Bacterial Mutagenicity Assays ......................................................................................87 4.5.2.2. Mammalian Cell Assays................................................................................................88 4.5.2.3. In Vivo Bioassays..........................................................................................................89 4.5.3. Structural Alerts ..................................................................................................................... 90 4.6. SYNTHESIS OF MAJOR NONCANCER EFFECTS ................................................................ 92 4.6.1. Human Studies ....................................................................................................................... 92 4.6.2. Animal Studies....................................................................................................................... 92 4.6.2.1. Oral Exposure ................................................................................................................92 4.6.2.2. Inhalation Exposure.......................................................................................................93 iii 4.7. EVALUATION OF CARCINOGENICITY................................................................................ 96 4.7.1. Synthesis of Human, Animal, and Other Supporting Evidence............................................. 97 4.7.1.1. Human............................................................................................................................97 4.7.1.1.1. Evidence for Causality. ........................................................................................... 100 4.7.1.2. Laboratory Animal.......................................................................................................102 4.7.2. Summary of Overall Weight of Evidence............................................................................ 103 4.7.3. Mode-of-Action Information ............................................................................................... 106 4.7.3.1. Hypothesized Mode of Action.....................................................................................106 4.7.3.2. Experimental Support for the Hypothesized Mode of Action.....................................106 4.7.3.3. Conclusions about the Hypothesized Mode of Action ................................................109 4.8. SUSCEPTIBLE POPULATIONS AND LIFE STAGES .......................................................... 111 4.8.1. Possible Childhood Susceptibility ....................................................................................... 111 4.8.2. Possible Sex Differences...................................................................................................... 112 5. DOSE-RESPONSE ASSESSMENTS.............................................................................................. 113 5.1. ORAL REFERENCE DOSE (RfD) ........................................................................................... 113 5.2. INHALATION REFERENCE CONCENTRATION (RfC)...................................................... 113 5.2.1. Choice of Principal Study and Critical Effect(s) ................................................................. 113 5.2.2. Methods of Analysis ............................................................................................................ 116 5.2.3. Exposure Duration and Dosimetric Adjustments................................................................. 118 5.2.4. RfC Derivation–Including Application of Uncertainty Factors........................................... 122 5.2.5. Previous RfC Assessment .................................................................................................... 123 5.2.6. RfC Comparison Information .............................................................................................. 123 5.3. UNCERTAINTIES IN THE INHALATION REFERENCE CONCENTRATION.................. 124 5.4. CANCER ASSESSMENT ......................................................................................................... 128 5.4.1. Choice of Study/Data–with Rationale and Justification ...................................................... 128 5.4.2. Dose-Response Data ............................................................................................................ 128 5.4.3. Dose Adjustments and Extrapolation Methods.................................................................... 130 5.4.4. Oral Slope Factor and Inhalation Unit Risk......................................................................... 132 5.4.5. Application