EPA/635/R-09/003F www.epa.gov/iris TOXICOLOGICAL REVIEW OF TRICHLOROACETIC ACID (CAS No. 76-03-9) In Support of Summary Information on the Integrated Risk Information System (IRIS) September 2011 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 TRICHLOROACETIC ACID (CAS No. 76-03-9) LIST OF TABLES ........................................................................................................................ vii 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 ....................................................................3 3. TOXICOKINETICS ...................................................................................................................5 3.1. ABSORPTION ..................................................................................................................5 3.2. DISTRIBUTION................................................................................................................7 3.3. METABOLISM ...............................................................................................................11 3.4. EXCRETION ...................................................................................................................17 3.5. PHYSIOLOGICALLY BASED PHARMACOKINETIC MODELS .............................20 4. HAZARD IDENTIFICATION .................................................................................................21 4.1. STUDIES IN HUMANS..................................................................................................21 4.1.1. Oral Exposure ......................................................................................................21 4.1.2. Dermal Exposure .................................................................................................21 4.2. SUBCHRONIC AND CHRONIC STUDIES AND CANCER BIOASSAYS IN ANIMALS―ORAL AND INHALATION ....................................................................22 4.2.1. Short-term and Subchronic Studies .....................................................................22 4.2.1.1. Oral .......................................................................................................22 4.2.1.2. Subchronic Inhalation Studies ..............................................................38 4.2.2. Chronic Studies and Cancer Assays ....................................................................38 4.2.2.1. Oral Studies ...........................................................................................44 4.2.2.2. Inhalation Studies..................................................................................57 4.2.2.3. Studies Using Other Routes of Exposure..............................................57 4.3. REPRODUCTIVE/DEVELOPMENTAL STUDIES – ORAL AND INHALATION ...59 4.3.1. Reproductive Studies ...........................................................................................59 4.3.2. Developmental Studies ........................................................................................59 4.3.2.1. Oral Developmental Studies .................................................................59 4.3.2.2. Inhalation Developmental Studies ........................................................67 4.3.2.3. In Vitro Studies .....................................................................................67 4.4. OTHER DURATION- OR ENDPOINT-SPECIFIC STUDIES......................................68 4.4.1. Immunological Studies ........................................................................................68 4.5. MECHANISTIC DATA AND OTHER STUDIES IN SUPPORT OF THE MODE OF ACTION ...................................................................................................................69 4.5.1. Mechanistic Studies .............................................................................................69 4.5.1.1. Peroxisome Proliferation ......................................................................69 4.5.1.2. Oncogene Activation ............................................................................69 4.5.1.3. Cell Proliferation ...................................................................................71 4.5.1.4. DNA Hypomethylation .........................................................................73 4.5.1.5. Inhibition of Intercellular Communication ...........................................78 iii 4.5.1.6. Oxidative Stress ....................................................................................79 4.5.1.7. Histochemical Characteristics of TCA-Induced Tumors ......................81 4.5.2. Genotoxicity Studies ............................................................................................83 4.5.2.1. In Vitro Studies .....................................................................................83 4.5.2.2. In Vivo Studies .....................................................................................87 4.6. SYNTHESIS OF MAJOR NONCANCER EFFECTS ....................................................89 4.6.1. Oral ......................................................................................................................89 4.6.1.1. Metabolic Alterations............................................................................89 4.6.1.2. Liver Toxicity .......................................................................................90 4.6.1.3. Developmental Toxicity........................................................................91 4.6.2. Inhalation .............................................................................................................92 4.6.3. Mode-of-Action Information – Non-Cancer ........................................................92 4.6.3.1. Metabolic Alterations............................................................................92 4.6.3.2. Liver Toxicity .......................................................................................93 4.6.3.3. Developmental Toxicity........................................................................93 4.7. EVALUATION OF CARCINOGENICITY....................................................................94 4.7.1. Summary of Overall Weight of Evidence ............................................................94 4.7.2. Synthesis of Human, Animal, and Other Supporting Evidence...........................97 4.7.3. Mode-of-Action Information - Cancer.................................................................98 4.7.3.1. PPARα agonism. ...................................................................................99 4.7.3.2. Additional Proposed Hypotheses and Key Events with Limited Evidence or Inadequate Experimental Support ..................................117 4.7.3.3. Conclusions About the Hypothesized Mode of Action ......................121 4.8. SUSCEPTIBLE POPULATION AND LIFE STAGES ................................................122 4.8.1. Possible Childhood Susceptibility .....................................................................122 4.8.2. Possible Gender Differences ..............................................................................123 4.8.3. Other ..................................................................................................................123 5. DOSE-RESPONSE ASSESSMENTS ....................................................................................125 5.1. ORAL REFERENCE DOSE (RfD) ...............................................................................125 5.1.1. Choice of Principal Study and Critical Effect—Rationale and Justification .....125 5.1.2. Methods of Analysis—Including Models (e.g, PBPK and BMD) ....................130 5.1.2.1. BMD Modeling of Liver and Testicular Effects from DeAngelo et al. (2008) ............................................................................................130 5.1.2.2. BMD Modeling of Developmental Toxicity Data from Smith et al. (1989) .................................................................................................133 5.1.2.3. Selection of POD ................................................................................134 5.1.3. RfD Derivation—Including Application of Uncertainty Factors (UFs) ............134 5.1.4. RfD Comparison Information ............................................................................135 5.1.5. Previous RfD Assessment ..................................................................................136 5.2. INHALATION REFERENCE CONCENTRATION (RfC) .........................................136 5.3. UNCERTAINTIES IN THE RfD ..................................................................................137 5.4.