1 INTERIM 1: 1/2003 2 INTERIM 2: 2/2005 3 INTERIM ACUTE EXPOSURE GUIDELINE LEVELS 4 (AEGLs) 5 METHANOL 6 (CAS Reg. No. 67-56-1) 7 For 8 NAS/COT Subcommittee for AEGLs 9 February 2005 METHANOL Interim 2: 2/2005 10 PREFACE 11 Under the authority of the Federal Advisory Committee Act (FACA) P. L. 92-463 of 1972, the 12 National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances 13 (NAC/AEGL Committee) has been established to identify, review and interpret relevant toxicologic and 14 other scientific data and develop AEGLs for high priority, acutely toxic chemicals. 15 AEGLs represent threshold exposure limits for the general public and are applicable to emergency 16 exposure periods ranging from 10 minutes to 8 hours. AEGL-2 and AEGL-3 levels, and AEGL-1 levels as 17 appropriate, will be developed for each of five exposure periods (10 and 30 minutes, 1 hour, 4 hours, and 18 8 hours) and will be distinguished by varying degrees of severity of toxic effects. It is believed that the 19 recommended exposure levels are applicable to the general population including infants and children, and 20 other individuals who may be sensitive or susceptible. The three AEGLs have been defined as follows: 21 AEGL-1 is the airborne concentration (expressed as ppm or mg/m³) of a substance above which it 22 is predicted that the general population, including susceptible individuals, could experience notable 23 discomfort, irritation, or certain asymptomatic, non-sensory effects. However, the effects are not disabling 24 and are transient and reversible upon cessation of exposure. 25 AEGL-2 is the airborne concentration (expressed as ppm or mg/m³) of a substance above which it 26 is predicted that the general population, including susceptible individuals, could experience irreversible or 27 other serious, long-lasting adverse health effects, or an impaired ability to escape. 28 AEGL-3 is the airborne concentration (expressed as ppm or mg/m³) of a substance above which it 29 is predicted that the general population, including susceptible individuals, could experience 30 life-threatening health effects or death. 31 Airborne concentrations below the AEGL-1 represent exposure levels that could produce mild and 32 progressively increasing odor, taste, and sensory irritation, or certain asymptomatic, non-sensory effects. 33 With increasing airborne concentrations above each AEGL level, there is a progressive increase in the 34 likelihood of occurrence and the severity of effects described for each corresponding AEGL level. 35 Although the AEGL values represent threshold levels for the general public, including sensitive 36 subpopulations, it is recognized that certain individuals, subject to unique or idiosyncratic responses, could 37 experience the effects described at concentrations below the corresponding AEGL level. ii METHANOL Interim 2: 2/2005 38 TABLE OF CONTENTS 39 PREFACE ......................................................................... ii 40 TABLE OF CONTENTS ............................................................ iii 41 EXECUTIVE SUMMARY ..........................................................viii 42 1. INTRODUCTION ........................................................... 1 43 2. HUMAN TOXICITY DATA ................................................... 2 44 2.1. Acute Lethality ........................................................ 2 45 2.2. Nonlethal Toxicity ...................................................... 6 46 2.2.1. Experimental Studies ............................................. 7 47 2.2.2. Occupational Exposure ............................................ 9 48 2.2.3. Case Studies ................................................... 11 49 2.3. Developmental/Reproductive Toxicity ...................................... 12 50 2.4. Genotoxicity ......................................................... 13 51 2.5. Carcinogenicity ....................................................... 13 52 2.6. Summary ............................................................ 13 53 3. ANIMAL TOXICITY DATA ................................................. 14 54 3.1. Acute Lethality ....................................................... 14 55 3.1.1. Non-human Primates ............................................ 14 56 3.1.2. Cats ......................................................... 15 57 3.1.3. Rats ......................................................... 15 58 3.1.4. Mice ......................................................... 15 59 3.2. Nonlethal Toxicity ..................................................... 17 60 3.2.1 Non-human Primates ............................................ 17 61 3.2.2. Dogs ......................................................... 19 62 3.2.3. Cats ......................................................... 19 63 3.2.4. Rats ......................................................... 19 64 3.2.5. Mice ......................................................... 20 65 3.3. Developmental/Reproductive Toxicity ...................................... 21 66 3.3.1. Nonhuman Primates ............................................. 22 67 3.3.2. Rats ......................................................... 23 68 3.3.3. Mice ......................................................... 24 69 3.4. Genotoxicity ......................................................... 25 iii METHANOL Interim 2: 2/2005 70 3.5. Carcinogenicity ....................................................... 26 71 3.6. Summary ............................................................ 26 72 4. SPECIAL CONSIDERATIONS ............................................... 27 73 4.1. Metabolism and Disposition ............................................. 27 74 4.1.1. Absorption, Distribution and Elimination ............................. 27 75 4.1.2. Metabolism .................................................... 28 76 4.1.3. Pharmacokinetic Models .......................................... 30 77 4.2. Mechanism of Toxicity ................................................. 35 78 4.3. Pharmacokinetics and Toxic Effects in Normal and Folate-Deficient Animals ........ 37 79 4.4. Structure-Activity Relationships .......................................... 39 80 4.5. Other Relevant Information .............................................. 40 81 4.5.1. Species Variability .............................................. 40 82 4.5.2. Intraspecies Variability ........................................... 40 83 4.5.3. Combination Effects ............................................. 40 84 4.5.4. Role of Folate in Human Birth Defects ............................... 40 85 5. RATIONALE AND PROPOSED AEGL-1 ...................................... 41 86 5.1. Human Data Relevant to AEGL-1 ......................................... 41 87 5.2. Animal Data Relevant to AEGL-1 ......................................... 42 88 5.3. Derivation of AEGL-1 .................................................. 42 89 6. RATIONALE AND PROPOSED AEGL-2 ...................................... 43 90 6.1. Human Data Relevant to AEGL-2 ......................................... 43 91 6.2. Animal Data Relevant to AEGL-2 ......................................... 44 92 6.3. Derivation of AEGL-2 .................................................. 45 93 7. RATIONALE AND PROPOSED AEGL-3 ...................................... 47 94 7.1. Human Data Relevant to AEGL-3 ......................................... 47 95 7.2. Animal Data Relevant to AEGL-3 ........................................ 49 96 7.3. Derivation of AEGL-3 .................................................. 50 97 8. SUMMARY OF PROPOSED AEGLS .......................................... 52 98 8.1. AEGL Values and Toxicity Endpoints ...................................... 52 99 8.2. Comparison with Other Standards and Criteria ............................... 54 100 8.3. Data Adequacy and Research Needs ....................................... 57 101 9. REFERENCES ............................................................. 58 iv METHANOL Interim 2: 2/2005 102 APPENDIX A Time Scaling Calculations for AEGLs ...................................... 69 103 AEGL-1 ................................................................... 70 104 AEGL-2 ................................................................... 71 105 AEGL-3 ................................................................... 72 106 APPENDIX B Pharmacokinetic Calculations ............................................ 73 107 Calculation of Exposure Concentrations for Humans ................................. 74 108 Comparison of the Perkins et al. (1995a) and Bouchard et al. (2001) models ............... 76 109 APPENDIX C Level of Distinct Odor Awareness ......................................... 78 110 APPENDIX D Derivation Summary for Methanol AEGLs .................................. 80 111 AEGL-1 VALUES ........................................................... 81 112 AEGL-2 VALUES ........................................................... 84 113 AEGL-3 VALUES ........................................................... 88 v METHANOL Interim 2: 2/2005 114 LIST OF TABLES 115 TABLE 1: CHEMICAL AND PHYSICAL DATA .......................................... 1 116 TABLE 2: ACUTE ORAL METHANOL INTOXICATIONS IN HUMANS ...................... 5 117 TABLE 3: SUMMARY OF EFFECTS ON HUMANS AFTER INHALATION OF METHANOL ..... 12 118 TABLE 4: SUMMARY OF ACUTE LETHAL INHALATION DATA IN LABORATORY ANIMALS 119 .........................................................................