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Methanol Interim AEGL Document INTERIM 1: 1/2003 INTERIM 2: 2/2005 INTERIM ACUTE EXPOSURE GUIDELINE LEVELS (AEGLs) METHANOL (CAS Reg. No. 67-56-1) For NAS/COT Subcommittee for AEGLs February 2005 METHANOL Interim 2: 2/2005 PREFACE Under the authority of the Federal Advisory Committee Act (FACA) P. L. 92-463 of 1972, the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances (NAC/AEGL Committee) has been established to identify, review and interpret relevant toxicologic and other scientific data and develop AEGLs for high priority, acutely toxic chemicals. AEGLs represent threshold exposure limits for the general public and are applicable to emergency exposure periods ranging from 10 minutes to 8 hours. AEGL-2 and AEGL-3 levels, and AEGL-1 levels as appropriate, will be developed for each of five exposure periods (10 and 30 minutes, 1 hour, 4 hours, and 8 hours) and will be distinguished by varying degrees of severity of toxic effects. It is believed that the recommended exposure levels are applicable to the general population including infants and children, and other individuals who may be sensitive or susceptible. The three AEGLs have been defined as follows: AEGL-1 is the airborne concentration (expressed as ppm or mg/m;) of a substance above which it is predicted that the general population, including susceptible individuals, could experience notable discomfort, irritation, or certain asymptomatic, non-sensory effects. However, the effects are not disabling and are transient and reversible upon cessation of exposure. AEGL-2 is the airborne concentration (expressed as ppm or mg/m;) of a substance above which it is predicted that the general population, including susceptible individuals, could experience irreversible or other serious, long-lasting adverse health effects, or an impaired ability to escape. AEGL-3 is the airborne concentration (expressed as ppm or mg/m;) of a substance above which it is predicted that the general population, including susceptible individuals, could experience life-threatening health effects or death. Airborne concentrations below the AEGL-1 represent exposure levels that could produce mild and progressively increasing odor, taste, and sensory irritation, or certain asymptomatic, non-sensory effects. With increasing airborne concentrations above each AEGL level, there is a progressive increase in the likelihood of occurrence and the severity of effects described for each corresponding AEGL level. Although the AEGL values represent threshold levels for the general public, including sensitive subpopulations, it is recognized that certain individuals, subject to unique or idiosyncratic responses, could experience the effects described at concentrations below the corresponding AEGL level. ii METHANOL Interim 2: 2/2005 TABLE OF CONTENTS PREFACE ..................................................................................................................................... ii TABLE OF CONTENTS................................................................................................................iii EXECUTIVE SUMMARY ............................................................................................................viii 1. INTRODUCTION............................................................................................................... 1 2. HUMAN TOXICITY DATA ................................................................................................ 2 2.1. Acute Lethality....................................................................................................... 2 2.2. Nonlethal Toxicity.................................................................................................. 6 2.2.1. Experimental Studies................................................................................. 7 2.2.2. Occupational Exposure..............................................................................9 2.2.3. Case Studies........................................................................................... 11 2.3. Developmental/Reproductive Toxicity................................................................. 12 2.4. Genotoxicity......................................................................................................... 13 2.5. Carcinogenicity.................................................................................................... 13 2.6. Summary ............................................................................................................. 13 3. ANIMAL TOXICITY DATA.............................................................................................. 14 3.1. Acute Lethality..................................................................................................... 14 3.1.1. Non-human Primates............................................................................... 14 3.1.2. Cats ......................................................................................................... 15 3.1.3. Rats ......................................................................................................... 15 3.1.4. Mice ......................................................................................................... 15 3.2. Nonlethal Toxicity................................................................................................ 17 3.2.1 Non-human Primates............................................................................... 17 3.2.2. Dogs ........................................................................................................ 19 3.2.3. Cats ......................................................................................................... 19 3.2.4. Rats ......................................................................................................... 19 3.2.5. Mice ......................................................................................................... 20 3.3. Developmental/Reproductive Toxicity................................................................. 21 3.3.1. Nonhuman Primates................................................................................ 22 3.3.2. Rats ......................................................................................................... 23 3.3.3. Mice ......................................................................................................... 24 3.4. Genotoxicity......................................................................................................... 25 iii METHANOL Interim 2: 2/2005 3.5. Carcinogenicity.................................................................................................... 26 3.6. Summary ............................................................................................................. 26 4. SPECIAL CONSIDERATIONS ....................................................................................... 27 4.1. Metabolism and Disposition ............................................................................... 27 4.1.1. Absorption, Distribution and Elimination.................................................. 27 4.1.2. Metabolism .............................................................................................. 28 4.1.3. Pharmacokinetic Models..........................................................................30 4.2. Mechanism of Toxicity......................................................................................... 35 4.3. Pharmacokinetics and Toxic Effects in Normal and Folate-Deficient Animals .... 37 4.4. Structure-Activity Relationships........................................................................... 39 4.5. Other Relevant Information ................................................................................. 40 4.5.1. Species Variability................................................................................... 40 4.5.2. Intraspecies Variability............................................................................. 40 4.5.3. Combination Effects.................................................................................40 4.5.4. Role of Folate in Human Birth Defects .................................................... 40 5. RATIONALE AND PROPOSED AEGL-1 ...................................................................... 41 5.1. Human Data Relevant to AEGL-1 ....................................................................... 41 5.2. Animal Data Relevant to AEGL-1........................................................................ 42 5.3. Derivation of AEGL-1........................................................................................... 42 6. RATIONALE AND PROPOSED AEGL-2 ...................................................................... 43 6.1. Human Data Relevant to AEGL-2 ....................................................................... 43 6.2. Animal Data Relevant to AEGL-2........................................................................ 44 6.3. Derivation of AEGL-2........................................................................................... 45 7. RATIONALE AND PROPOSED AEGL-3 ...................................................................... 47 7.1. Human Data Relevant to AEGL-3 ....................................................................... 47 7.2. Animal Data Relevant to AEGL-3 ....................................................................... 49 7.3. Derivation of AEGL-3..........................................................................................
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