EPA/635/R-03/013 www.epa.gov/iris TOXICOLOGICAL REVIEW OF 1,1,1-TRICHLOROETHANE (CAS No. 71-55-6) In Support of Summary Information on the Integrated Risk Information System (IRIS) August 2007 U.S. Environmental Protection Agency Washington, DC DISCLAIMER This document has been reviewed in accordance with U.S. Environmental Protection Agency (EPA) policy and approved for publication. Mention of trade names or commercial products does not constitute endorsement or recommendation for use. i CONTENTS—TOXICOLOGICAL REVIEW OF 1,1,1-TRICHLOROETHANE (CAS No. 71-55-6) LIST OF TABLES.......................................................................................................................... v LIST OF FIGURES ....................................................................................................................... vi LIST OF ACRONYMS AND ABBREVIATIONS...................................................................... vii FOREWORD ................................................................................................................................. ix AUTHORS, CONTRIBUTORS, AND REVIEWERS................................................................... x 1. INTRODUCTION ..................................................................................................................... 1 2. CHEMICAL AND PHYSICAL INFORMATION.................................................................... 3 3. TOXICOKINETICS .................................................................................................................. 6 3.1. ABSORPTION.................................................................................................................. 6 3.2. DISTRIBUTION............................................................................................................. 10 3.3. METABOLISM .............................................................................................................. 14 3.4. ELIMINATION .............................................................................................................. 19 3.5. PHYSIOLOGICALLY BASED PHARMACOKINETIC MODELS ............................ 20 3.5.1. Summary of Available Models............................................................................ 20 3.5.2. Model Selection................................................................................................... 28 4. HAZARD IDENTIFICATION................................................................................................ 30 4.1. STUDIES IN HUMANS—EPIDEMIOLOGY, CASE REPORTS, CLINICAL CONTROLS ................................................................................................................... 30 4.1.1. Oral Exposure ...................................................................................................... 30 4.1.2. Inhalation Exposure ............................................................................................. 31 4.1.2.1. Experimental Human Exposure Studies ................................................ 32 4.1.2.2. Epidemiological Studies ........................................................................ 40 4.2. LESS-THAN-LIFETIME AND CHRONIC STUDIES AND CANCER BIOASSAYS IN ANIMALS—ORAL AND INHALATION........................................ 48 4.2.1. Oral Exposure ...................................................................................................... 48 4.2.1.1. Acute Studies ......................................................................................... 48 4.2.1.2. Short-term Studies ................................................................................. 49 4.2.1.3. Subchronic Studies ................................................................................ 51 4.2.1.4. Chronic Studies...................................................................................... 55 4.2.2. Inhalation Exposure ............................................................................................. 56 4.2.2.1. Acute Studies ......................................................................................... 56 4.2.2.2. Short-term Studies ................................................................................. 61 4.2.2.3. Subchronic Studies ................................................................................ 62 4.2.2.4. Chronic Studies...................................................................................... 66 4.3. REPRODUCTIVE/DEVELOPMENTAL STUDIES—ORAL AND INHALATION... 68 4.3.1. Oral Exposure ...................................................................................................... 68 4.3.2. Inhalation Exposure ............................................................................................. 72 ii 4.4. OTHER ENDPOINT-SPECIFIC STUDIES................................................................... 77 4.4.1. Neurological Effects ............................................................................................ 77 4.4.1.1. Oral Exposure ........................................................................................ 77 4.4.1.2. Inhalation Exposure ............................................................................... 77 4.4.2. Immunological Effects......................................................................................... 85 4.4.3. Effects by Dermal Exposure................................................................................ 85 4.4.4. Effects by Parenteral Exposure............................................................................ 86 4.5. MECHANISTIC DATA AND OTHER STUDIES IN SUPPORT OF THE MODE OF ACTION....................................................................................................... 87 4.5.1. Mechanistic Data from In Vitro Studies.............................................................. 87 4.5.2. Genotoxicity ........................................................................................................ 88 4.6. SYNTHESIS OF MAJOR NONCANCER EFFECTS................................................... 91 4.6.1. Oral ...................................................................................................................... 91 4.6.2. Inhalation ............................................................................................................. 99 4.6.3. Mode-of-Action Information ............................................................................. 112 4.7. EVALUATION OF CARCINOGENICITY................................................................. 115 4.7.1. Summary of Overall Weight of Evidence.......................................................... 115 4.7.2. Synthesis of Human, Animal, and Other Supporting Evidence ........................ 115 4.8. SUSCEPTIBLE POPULATIONS AND LIFE STAGES ............................................. 118 4.8.1. Possible Childhood Susceptibility ..................................................................... 118 4.8.2. Possible Gender Differences.............................................................................. 118 4.8.3. Other Potentially Susceptible Populations......................................................... 118 5. DOSE-RESPONSE ASSESSMENTS ................................................................................... 120 5.1. ORAL REFERENCE DOSE (RfD).............................................................................. 120 5.1.1. Acute Oral RfD.................................................................................................. 120 5.1.2. Short-term Oral RfD .......................................................................................... 120 5.1.3. Subchronic Oral RfD ......................................................................................... 121 5.1.3.1. Choice of Principal Study and Critical Effect—with Rationale and Justification .................................................................. 121 5.1.3.2. Methods of Analysis ............................................................................ 123 5.1.3.3. Subchronic RfD Derivation—Including Application of Uncertainty Factors (UFs) ................................................................... 125 5.1.4. Chronic Oral RfD............................................................................................... 126 5.1.4.1. Choice of Principal Study and Critical Effect—with Rationale and Justification .................................................................. 126 5.1.4.2. Methods of Analysis ............................................................................ 127 5.1.4.3. RfD Derivation—Including Application of Uncertainty Factors (UFs) ....................................................................................... 127 5.1.4.4. Previous Oral Assessment ................................................................... 129 5.1.5. RfD Derivation Using Route-to-Route Extrapolation ....................................... 129 5.1.5.1. Acute and Short-term Durations.......................................................... 129 5.1.5.2. Subchronic and Chronic Durations...................................................... 130 5.2. INHALATION REFERENCE CONCENTRATION (RfC)......................................... 130 5.2.1. Acute Inhalation RfC......................................................................................... 130 5.2.1.1. Choice of Principal Study and Critical Effect—with Rationale and Justification..................................................................................