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TOXICOLOGICAL REVIEW of METHANOL (Noncancer)( CAS NO EPA/635/R-11/001Fa www.epa.gov/iris TOXICOLOGICAL REVIEW OF METHANOL (NONCANCER) (CAS No. 67-56-1) In Support of Summary Information on the Integrated Risk Information System (IRIS) September 2013 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 METHANOL (Noncancer)( CAS NO. 67- 56- 1) CONTENTS TOXICOLOGICAL REVIEW OF METHANOL (Noncancer)(CAS NO. 67-56-1) ................................. iii LIST OF TABLES ........................................................................................................................................................... v LIST OF FIGURES ......................................................................................................................................................... vii LIST OF ABBREVIATIONS AND ACRONYMS ........................................................................................................ viii AUTHORS, CONTRIBUTORS, AND REVIEWERS.................................................................................................... xvii EXECUTIVE SUMMARY ............................................................................................................................................. xxi INTRODUCTION ....................................................................................................................................................... xxi CHEMICAL AND PHYSICAL INFORMATION ...................................................................................................... xxii TOXICOKINETICS .................................................................................................................................................... xxii HAZARD IDENTIFICATION .................................................................................................................................... xxiv DOSE-RESPONSE ASSESSMENT AND CHARACTERIZATION ......................................................................... xxvi RELATIONSHIP OF THE RFC AND RFD TO BACKGROUND METHANOL BLOOD LEVELS AND MONKEY BLOOD LEVELS ASSOCIATED WITH EFFECTS OF UNCERTAIN ADVERSITY ............... xxviii 1. .. INTRODUCTION ..................................................................................................................................................... 1-1 2. .. CHEMICAL AND PHYSICAL INFORMATION .................................................................................................... 2-1 3. .. TOXICOKINETICS .................................................................................................................................................. 3-1 3.1. OVERVIEW ......................................................................................................................................................... 3-1 3.2. KEY STUDIES ..................................................................................................................................................... 3-11 3.3. HUMAN VARIABILITY IN METHANOL METABOLISM ............................................................................. 3-18 3.4. PHYSIOLOGICALLY BASED PHARMACOKINETIC MODELS .................................................................. 3-20 3.4.1. Model Requirements for EPA Purposes ........................................................................................................ 3-20 3.4.2. Methanol PBPK Models ................................................................................................................................ 3-26 3.4.3. Selected Modeling Approach......................................................................................................................... 3-27 3.4.4. Monkey PK Data and Analysis ...................................................................................................................... 3-32 3.4.5. Summary and Conclusions ............................................................................................................................ 3-33 4. .. HAZARD IDENTIFICATION .................................................................................................................................. 4-1 4.1. STUDIES IN HUMANS – CASE REPORTS, OCCUPATIONAL AND CONTROLLED STUDIES ............... 4-1 4.1.1. Case Reports .................................................................................................................................................. 4-1 4.1.2. Occupational Studies ..................................................................................................................................... 4-3 4.1.3. Controlled Human Studies ............................................................................................................................. 4-5 4.2. ACUTE, SUBCHRONIC AND CHRONIC STUDIES IN ANIMALS – ORAL AND INHALATION ................................................................................................................................................. 4-7 4.2.1. Oral Studies ................................................................................................................................................... 4-7 4.2.2. Inhalation Studies .......................................................................................................................................... 4-11 4.3. REPRODUCTIVE AND DEVELOPMENTAL STUDIES – ORAL AND INHALATION ............................... 4-20 4.3.1. Oral Reproductive and Developmental Studies ............................................................................................. 4-20 4.3.2. Inhalation Reproductive and Developmental Studies .................................................................................... 4-23 4.3.3. Other Reproductive and Developmental Studies ........................................................................................... 4-40 4.4. NEUROTOXICITY .............................................................................................................................................. 4-47 4.4.1. Oral Neurotoxicity Studies ............................................................................................................................ 4-47 4.4.2. Inhalation Neurotoxicity Studies ................................................................................................................... 4-50 iii 4.4.3. Neurotoxicity Studies Employing i.p. and in vitro Methanol Exposures ....................................................... 4-58 4.5. IMMUNOTOXICITY .......................................................................................................................................... 4-63 4.6. SYNTHESIS OF MAJOR NONCANCER EFFECTS ......................................................................................... 4-68 4.6.1. Summary of Key Studies in Methanol Toxicity ............................................................................................ 4-68 4.7. NONCANCER MOA INFORMATION .............................................................................................................. 4-77 4.7.1. Role of Methanol and Metabolites in the Developmental Toxicity of Methanol .......................................... 4-78 4.7.2. Role of Folate Deficiency in the Developmental Toxicity of Methanol ........................................................ 4-83 4.7.3. Methanol-Induced Formation of Free Radicals, Lipid Peroxidation, and Protein Modifications .................. 4-84 4.7.4. Exogenous Formate Dehydrogenase as a Means of Detoxifying the Formic Acid that Results from Methanol Exposure .............................................................................................................................. 4-88 4.7.5. Summary and Conclusions Regarding MOA for Developmental Toxicity ................................................... 4-89 4.8. EVALUATION OF CARCINOGENICITY ......................................................................................................... 4-90 4.9. SUSCEPTIBLE POPULATIONS AND LIFE STAGES ..................................................................................... 4-90 4.9.1. Possible Childhood Susceptibility ................................................................................................................. 4-90 4.9.2. Possible Gender Differences .......................................................................................................................... 4-91 4.9.3. Genetic Susceptibility .................................................................................................................................... 4-92 5. .. DOSE-RESPONSE ASSESSMENTS ....................................................................................................................... 5-1 5.1. INHALATION REFERENCE CONCENTRATION (RFC) ................................................................................ 5-1 5.1.1. Choice of Principal Study and Critical Effect(s) ........................................................................................... 5-1 5.1.2. Methods of Analysis for Identifying the POD—Application of PBPK and BMD Models ........................... 5-7 5.1.3. RfC Derivation – Including Application of Uncertainty Factors ..................................................................
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