EPA/635/R-08/005F www.epa.gov/iris TOXICOLOGICAL REVIEW OF CARBON TETRACHLORIDE (CAS No. 56-23-5) In Support of Summary Information on the Integrated Risk Information System (IRIS) March 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 CONTENTS —TOXICOLOGICAL REVIEW OF CARBON TETRACHLORIDE (CAS No. 56-23-5) LIST OF TABLES ........................................................................................................................ vii LIST OF FIGURES ........................................................................................................................ x LIST OF ABBREVIATIONS AND ACRONYMS ..................................................................... xii FOREWARD ................................................................................................................................ xv AUTHORS, CONTRIBUTORS, AND REVIEWERS ............................................................... xvi 1. INTRODUCTION ..................................................................................................................... 1 2. CHEMICAL AND PHYSICAL INFORMATION ................................................................... 3 3. TOXICOKINETICS .................................................................................................................. 6 3.1. ABSORPTION ................................................................................................................ 6 3.1.1. Oral Exposure ....................................................................................................... 6 3.1.2. Inhalation Exposure .............................................................................................. 7 3.1.3. Dermal Exposure .................................................................................................. 7 3.2. DISTRIBUTION ............................................................................................................. 8 3.2.1. Oral Exposure ....................................................................................................... 8 3.2.2. Inhalation Exposure .............................................................................................. 8 3.2.3. Dermal Exposure ................................................................................................ 10 3.2.4. Lactational Transfer ........................................................................................... 11 3.3. METABOLISM ............................................................................................................. 11 3.4. ELIMINATION ............................................................................................................. 15 3.5. PHYSIOLOGICALLY BASED PHARMACOKINETIC MODELS ........................... 17 4. HAZARD IDENTIFICATION ................................................................................................ 28 4.1. STUDIES IN HUMANS—EPIDEMIOLOGY, CASE REPORTS, CLINICAL CONTROLS ................................................................................................................... 28 4.1.1. Oral Exposure ..................................................................................................... 28 4.1.1.1. Human Poisoning Incidents ...................................................................... 28 4.1.1.2. Epidemiology Studies ............................................................................... 28 4.1.2. Inhalation Exposure ............................................................................................ 30 4.1.2.1. Acute Exposure Incidents ......................................................................... 30 4.1.2.2. Epidemiology Studies ............................................................................... 31 4.1.3. Dermal Exposure ................................................................................................ 38 4.2. SUBCHRONIC AND CHRONIC STUDIES AND CANCER BIOASSAYS IN ANIMALS—ORAL AND INHALATION ................................................................... 38 4.2.1. Oral Exposure ..................................................................................................... 39 4.2.1.1. Subchronic Toxicity ................................................................................. 39 4.2.1.2. Chronic Toxicity and Carcinogenicity ..................................................... 44 4.2.2. Inhalation Exposure ............................................................................................ 47 4.2.2.1. Subchronic Toxicity ................................................................................. 47 4.2.2.2. Chronic Toxicity and Carcinogenicity ..................................................... 52 iii 4.3. REPRODUCTIVE/DEVELOPMENTAL STUDIES—ORAL AND INHALATION ............................................................................................................... 63 4.3.1. Oral Exposure ..................................................................................................... 63 4.3.2. Inhalation Exposure ............................................................................................ 66 4.4. OTHER DURATION- OR ENDPOINT-SPECIFIC STUDIES ................................... 68 4.4.1. Acute and Short-term Toxicity Data .................................................................. 68 4.4.1.1. Oral Exposure ........................................................................................... 68 4.4.1.2. Inhalation Exposure .................................................................................. 70 4.4.1.3. Acute Studies Comparing Oral and Inhalation Exposures ....................... 71 4.4.2. Genotoxicity Studies .......................................................................................... 72 4.4.2.1. Genotoxicity Studies: Prokaryotic Organisms ........................................ 91 4.4.2.2. Genotoxicity Studies: Nonmammalian Eukaryotic Organisms ............... 93 4.4.2.3. Genotoxicity Studies: Mammalian Cells In Vitro ................................... 95 4.4.2.4. Genotoxicity Studies: Mammalian Cells In Vivo ................................... 98 4.4.2.5. Genotoxicity Studies: Summary of the Evidence for Genotoxic and Mutagenic Effects .................................................................................. 110 4.4.3. Initiation-promotion Studies ............................................................................ 112 4.4.4. Neurotoxicity Studies ....................................................................................... 113 4.4.5. Immunotoxicity Studies ................................................................................... 114 4.5. MECHANISTIC DATA AND OTHER STUDIES IN SUPPORT OF THE MODE OF ACTION .................................................................................................... 118 4.5.1. Metabolism is Required for Toxicity ............................................................... 118 4.5.2. Role of Free Radicals ....................................................................................... 119 4.5.3. Lipid Peroxidation ............................................................................................ 120 4.5.4. Depletion of Glutathione .................................................................................. 125 4.5.5. Disruption of Calcium Homeostasis ................................................................ 127 4.5.6. Immunological and Inflammatory Effects ....................................................... 130 4.5.7. Changes in Gene Expression ............................................................................ 132 4.5.8. Mechanisms of Kidney Toxicity ...................................................................... 133 4.6. SYNTHESIS OF MAJOR NONCANCER EFFECTS................................................ 134 4.6.1. Oral ................................................................................................................... 134 4.6.2. Inhalation .......................................................................................................... 140 4.6.3. Mode of Action Information ............................................................................ 144 4.7. EVALUATION OF CARCINOGENICITY ............................................................... 147 4.7.1. Summary of Overall Weight-of-Evidence ....................................................... 147 4.7.2. Synthesis of Human, Animal, and Other Supporting Evidence ....................... 148 4.7.3. Mode of Action Information for Liver Tumors ............................................... 151 4.7.3.1. Hypothesized Mode of Action and Identification of Key Events .......... 151 4.7.3.2. Experimental Support for the Hypothesized Mode of Action ................ 155 4.7.3.3. Other Possible Modes of Action ............................................................ 164 4.7.3.4. Conclusions About the Hypothesized Mode of Action .......................... 166 4.7.3.5. Relevance of the Hypothesized Modes of Action to Humans ................ 167 4.7.4. Mode-of-Action Information for Pheochromocytomas ................................... 167 4.8. SUSCEPTIBLE POPULATIONS AND LIFE STAGES ...........................................