EPA/635/R-16/079a Public Comment Draft www.epa.gov/iris Toxicological Review of tert-Butyl Alcohol (tert-Butanol) (CAS No. 75-65-0) April 2016 NOTICE This document is a Public Comment Draft. This information is distributed solely for the purpose of pre-dissemination peer review under applicable information quality guidelines. It has not been formally disseminated by EPA. It does not represent and should not be construed to represent any Agency determination or policy. It is being circulated for review of its technical accuracy and science policy implications. National Center for Environmental Assessment Office of Research and Development U.S. Environmental Protection Agency Washington, DC Toxicological Review of tert-Butyl Alcohol DISCLAIMER This document is a preliminary draft for review purposes only. This information is distributed solely for the purpose of pre-dissemination peer review under applicable information quality guidelines. It has not been formally disseminated by EPA. It does not represent and should not be construed to represent any Agency determination or policy. Mention of trade names or commercial products does not constitute endorsement or recommendation for use. This document is a draft for review purposes only and does not constitute Agency policy. ii DRAFT—DO NOT CITE OR QUOTE Toxicological Review of tert-Butyl Alcohol CONTENTS AUTHORS | CONTRIBUTORS | REVIEWERS ................................................................................................. viii PREFACE ........................................................................................................................................................ x PREAMBLE TO IRIS TOXICOLOGICAL REVIEWS............................................................................................ xiv EXECUTIVE SUMMARY ............................................................................................................................. ES-1 LITERATURE SEARCH STRATEGY | STUDY SELECTION AND EVALUATION ............................................... LS-1 1. HAZARD IDENTIFICATION .................................................................................................................... 1-1 1.1. Overview of Chemical Properties and Toxicokinetics ................................................................... 1-1 1.1.1. Chemical Properties .......................................................................................................... 1-1 1.1.2. Toxicokinetics .................................................................................................................... 1-2 1.1.3. Description of Toxicokinetic Models ................................................................................. 1-3 1.1.4. Chemicals Extensively Metabolized to tert-Butanol ......................................................... 1-4 1.2. PRESENTATION AND SYNTHESIS OF EVIDENCE BY ORGAN/SYSTEM ............................................ 1-4 1.2.1. Kidney Effects .................................................................................................................... 1-4 1.2.2. Thyroid Effects ................................................................................................................. 1-38 1.2.3. Developmental Effects .................................................................................................... 1-46 1.2.4. Neurodevelopmental Effects........................................................................................... 1-53 1.2.5. Reproductive Effects ....................................................................................................... 1-56 1.2.6. Other Toxicological Effects .............................................................................................. 1-61 1.3. INTEGRATION AND EVALUATION ............................................................................................... 1-61 1.3.1. Effects Other Than Cancer ............................................................................................... 1-61 1.3.2. Carcinogenicity ................................................................................................................ 1-63 1.3.3. Susceptible Populations and Lifestages for Cancer and Noncancer Outcomes .............. 1-65 2. DOSE-RESPONSE ANALYSIS ................................................................................................................. 2-1 2.1. ORAL REFERENCE DOSE FOR EFFECTS OTHER THAN CANCER ...................................................... 2-1 2.1.1. Identification of Studies and Effects for Dose-Response Analysis .................................... 2-1 2.1.2. Methods of Analysis .......................................................................................................... 2-2 2.1.3. Derivation of Candidate Values ......................................................................................... 2-4 2.1.4. Derivation of Organ/System-Specific Reference Doses .................................................... 2-8 2.1.5. Selection of the Overall Reference Dose ........................................................................... 2-8 This document is a draft for review purposes only and does not constitute Agency policy. iii DRAFT—DO NOT CITE OR QUOTE Toxicological Review of tert-Butyl Alcohol 2.1.6. Confidence Statement ....................................................................................................... 2-9 2.1.7. Previous IRIS Assessment .................................................................................................. 2-9 2.2. INHALATION REFERENCE CONCENTRATION FOR EFFECTS OTHER THAN CANCER ....................... 2-9 2.2.1. Identification of Studies and Effects for Dose-Response Analysis .................................... 2-9 2.2.2. Methods of Analysis ........................................................................................................ 2-10 2.2.3. Derivation of Candidate Values ....................................................................................... 2-13 2.2.4. Derivation of Organ/System-Specific Reference Concentrations ................................... 2-16 2.2.5. Selection of the Overall Reference Concentration .......................................................... 2-16 2.2.6. Confidence Statement ..................................................................................................... 2-17 2.2.7. Previous IRIS Assessment ................................................................................................ 2-17 2.2.8. Uncertainties in the Derivation of the Reference Dose and Reference Concentration .................................................................................................................. 2-17 2.3. ORAL SLOPE FACTOR FOR CANCER ............................................................................................. 2-18 2.3.1. Analysis of Carcinogenicity Data ..................................................................................... 2-18 2.3.2. Dose-Response Analysis—Adjustments and Extrapolations Methods ........................... 2-19 2.3.3. Derivation of the Oral Slope Factor ................................................................................. 2-20 2.3.4. Uncertainties in the Derivation of the Oral Slope Factor ................................................ 2-21 2.3.5. Previous IRIS Assessment: Oral Slope Factor .................................................................. 2-23 2.4. INHALATION UNIT RISK FOR CANCER ......................................................................................... 2-23 2.4.1. Previous IRIS Assessment: Inhalation Unit Risk ............................................................... 2-24 2.5. APPLICATION OF AGE-DEPENDENT ADJUSTMENT FACTORS ...................................................... 2-24 REFERENCES ............................................................................................................................................... R-1 This document is a draft for review purposes only and does not constitute Agency policy. iv DRAFT—DO NOT CITE OR QUOTE Toxicological Review of tert-Butyl Alcohol TABLES Table ES-1. Organ/system-specific RfDs and overall RfD for tert-butanol .............................................. ES-2 Table ES-2. Organ/system-specific RfCs and overall RfC for tert-butanol ............................................... ES-3 Table LS-1. Details of the search strategy employed for tert-butanol ..................................................... LS-4 Table LS-2. Summary of additional search strategies for tert-butanol .................................................... LS-4 Table LS-3. Inclusion-exclusion criteria .................................................................................................... LS-5 Table LS-4. Considerations for evaluation of experimental animal studies ............................................ LS-8 Table LS-5. Summary of experimental animal database ......................................................................... LS-8 Table 1-1. Physicochemical properties and chemical identity of tert-butanol .......................................... 1-1 Table 1-2. Changes in kidney histopathology in animals following exposure to tert-butanol ................ 1-12 Table 1-3. Changes in kidney tumors in animals following exposure to tert-butanol ............................. 1-15 Table 1-4. Summary of data on the α2u-globulin process in male rats exposed to tert-butanol ...........