EPA/635/R-11/006F www.epa.gov/iris TOXICOLOGICAL REVIEW OF TETRAHYDROFURAN (CAS No. 109-99-9) In Support of Summary Information on the Integrated Risk Information System (IRIS) February 2012 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 TETRAHYDROFURAN (CAS No. 109-99-9) LIST OF TABLES ......................................................................................................................... vi LIST OF FIGURES ..................................................................................................................... viii ABBREVIATIONS AND ACRONYMS ...................................................................................... ix FOREWORD ................................................................................................................................. xi AUTHORS, CONTRIBUTORS, AND REVIEWERS ................................................................ xii 1. INTRODUCTION .................................................................................................................. 1-1 2. CHEMICAL AND PHYSICAL INFORMATION ................................................................ 2-1 3. TOXICOKINETICS ............................................................................................................... 3-1 3.1. ABSORPTION .............................................................................................................. 3-1 3.1.1. Gastrointestinal Absorption ................................................................................ 3-1 3.1.2. Respiratory Tract Absorption ............................................................................. 3-4 3.1.3. Dermal Absorption ............................................................................................. 3-5 3.2. DISTRIBUTION ........................................................................................................... 3-5 3.3. METABOLISM ........................................................................................................... 3-10 3.4. ELIMINATION ........................................................................................................... 3-13 3.5. BIOACCUMULATION .............................................................................................. 3-15 3.6. PHYSIOLOGICALLY BASED PHARMACOKINETIC MODELS ......................... 3-16 3.7. SUMMARY ................................................................................................................. 3-17 4. HAZARD IDENTIFICATION ............................................................................................... 4-1 4.1. STUDIES IN HUMANS—EPIDEMIOLOGY, CASE REPORTS, CLINICAL CONTROLS .................................................................................................................. 4-1 4.2. SUBCHRONIC AND CHRONIC STUDIES AND CANCER BIOASSAYS IN ANIMALS—ORAL AND INHALATION ................................................................... 4-3 4.2.1. Subchronic Studies ............................................................................................. 4-3 4.2.1.1. Oral ...................................................................................................... 4-3 4.2.1.2. Inhalation ............................................................................................. 4-3 4.2.2. Chronic Studies and Cancer Bioassays ............................................................ 4-10 4.2.2.1. Oral .................................................................................................... 4-10 4.2.2.2. Inhalation ........................................................................................... 4-10 4.3. REPRODUCTIVE/DEVELOPMENTAL TOXICITY STUDIES—ORAL AND INHALATION ............................................................................................................ 4-13 4.3.1. Oral ................................................................................................................... 4-13 4.3.2. Inhalation .......................................................................................................... 4-23 4.4. OTHER DURATION- OR ENDPOINT-SPECIFIC STUDIES ................................. 4-25 4.5. MECHANISTIC DATA AND OTHER STUDIES ..................................................... 4-26 4.6. SYNTHESIS AND EVALUATION OF MAJOR NONCANCER EFFECTS ........... 4-26 4.6.1. Oral ................................................................................................................... 4-26 4.6.2. Inhalation .......................................................................................................... 4-29 iii 4.7. EVALUATION OF CARCINOGENICITY ................................................................ 4-38 4.7.1. Summary of Overall Weight of Evidence ........................................................ 4-38 4.7.2. Synthesis of Human, Animal, and Other Supporting Evidence ....................... 4-39 4.7.3. Mode of Action Information ............................................................................ 4-40 4.7.3.1. Kidney Tumors .................................................................................. 4-40 4.7.3.2. Liver Tumors ..................................................................................... 4-46 4.8. SUSCEPTIBLE POPULATIONS AND LIFE STAGES ............................................ 4-50 4.8.1. Possible Childhood Susceptibility .................................................................... 4-50 4.8.2. Possible Gender Differences ............................................................................ 4-51 4.8.3. Other ................................................................................................................. 4-52 5. DOSE-RESPONSE ASSESSMENTS .................................................................................... 5-1 5.1. ORAL REFERENCE DOSE (RfD) ............................................................................... 5-1 5.1.1. Choice of Principal Study and Candidate Critical Effects—with Rationale and Justification ........................................................................................................ 5-1 5.1.2. Methods of Analysis ........................................................................................... 5-3 5.1.3. RfD Derivation—Including Application of Uncertainty Factors (UFs) ............. 5-5 5.1.4. Previous RfD Assessment .................................................................................. 5-7 5.2. INHALATION REFERENCE CONCENTRATION (RfC) ......................................... 5-7 5.2.1. Choice of Principal Study and Critical Effect—with Rationale and Justification ........................................................................................................ 5-7 5.2.2. Methods of Analysis ......................................................................................... 5-11 5.2.2.1. Calculation of HECs .......................................................................... 5-11 5.2.2.2. Dose-Response Modeling .................................................................. 5-12 5.2.3. RfC Derivation—Including Application of Uncertainty Factors (UFs) ........... 5-14 5.2.4. Previous RfC Assessment ................................................................................. 5-16 5.3. CANCER ASSESSMENT ........................................................................................... 5-16 5.3.1. Evaluation of Inhalation Cancer Data .............................................................. 5-16 5.3.2. Previous Cancer Assessment ............................................................................ 5-18 6. MAJOR CONCLUSIONS IN THE CHARACTERIZATION OF HAZARD AND DOSE RESPONSE............................................................................................................................ 6-1 6.1. HUMAN HAZARD POTENTIAL ................................................................................ 6-1 6.1.1. Oral Noncancer ................................................................................................... 6-1 6.1.2. Inhalation Noncancer .......................................................................................... 6-2 6.1.3. Cancer ................................................................................................................. 6-4 7. REFERENCES ....................................................................................................................... R-1 APPENDIX A. SUMMARY OF EXTERNAL PEER REVIEW AND PUBLIC COMMENTS AND DISPOSITION ............................................................................................................ A-1 APPENDIX B. DOSE-RESPONSE MODELING .....................................................................B-1 B.1. NONCANCER ENDPOINTS ...................................................................................... B-1 B.1.1. Methods ............................................................................................................. B-1 B.1.2. Modeling Results for Noncancer Effects Resulting from Oral Exposure .........B-4 B.1.3. Modeling Results for Noncancer Effects Resulting from Inhalation Exposure ..........................................................................................................B-18