Interim 1:11/2006 INTERIM ACUTE EXPOSURE GUIDELINE LEVELS (AEGLs) DIMETHYL SULFATE (CAS Reg. No. 77-78-1) for NAS/COT-Subcommittee on AEGLs November, 2006 DIMETHYL SULFATE (CAS Reg. No. 77-78-1) CH3 O O S O H3C O INTERIM ACUTE EXPOSURE GUIDELINE LEVELS (AEGLs) Dimethyl Sulfate Interim 1: 11/2006 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. Three levels C AEGL-1, AEGL-2 and AEGL-3 C are developed for each of five exposure periods (10 and 30 minutes, 1 hour, 4 hours, and 8 hours) and are distinguished by varying degrees of severity of toxic effects. The three AEGLs are defined as follows: AEGL-1 is the airborne concentration (expressed as parts per million or milligrams per cubic meter [ppm or mg/m3]) 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/m3) 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/m3) 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 but transient and nondisabling odor, taste, and sensory irritation or certain asymptomatic, non-sensory effects. With increasing airborne concentrations above each AEGL, there is a progressive increase in the likelihood of occurrence and the severity of effects described for each corresponding AEGL. Although the AEGL values represent threshold levels for the general public, including susceptible subpopulations, such as infants, children, the elderly, persons with asthma, and those with other illnesses, it is recognized that individuals, subject to unique or idiosyncratic responses, could experience the effects described at concentrations below the corresponding AEGL. i Dimethyl Sulfate Interim 1: 11/2006 TABLE OF CONTENTS EXECUTIVE SUMMARY .....................................................v 1. INTRODUCTION .......................................................1 2. HUMAN TOXICITY DATA ...............................................3 2.1. Acute Lethality ......................................................3 2.1.1 Case Reports .................................................3 2.2. Nonlethal Toxicity ....................................................4 2.2.1. Case Reports .................................................4 2.2.2. Epidemiologic Studies .........................................8 2.3. Carcinogenicity ......................................................8 2.4. Summary ...........................................................8 3. ANIMAL TOXICITY DATA .............................................11 3.1. Acute Lethality .....................................................11 3.1.1. Non-human Primates ..........................................11 3.1.2. Dogs ......................................................11 3.1.3. Cats .......................................................11 3.1.4. Rats .......................................................12 3.1.5. Mice .......................................................13 3.1.6. Hamsters ...................................................14 3.1.7. Guinea Pigs .................................................15 3.1.8. Rabbits .....................................................16 3.2. Nonlethal Toxicity ...................................................20 3.2.1. Nonhuman Primates ..........................................20 3.2.2. Cats .......................................................20 3.2.3. Rats .......................................................20 3.2.4. Guinea Pigs .................................................22 3.2.5. Rabbits .....................................................22 3.3. Toxicity after Repeated Exposure .......................................24 3.4. Developmental/Reproductive Toxicity ...................................26 3.5. Sensitization .......................................................27 3.6. Methylating Properties and Mutagenicity .................................27 3.7. Carcinogenicity .....................................................29 3.8. Summary ..........................................................31 4. SPECIAL CONSIDERATIONS ...........................................33 4.1. Metabolism and Disposition ...........................................33 4.2. Mechanism of Toxicity ...............................................35 4.3. Other Relevant Information ............................................36 4.3.1. Species Variability ...........................................37 4.3.2. Susceptible Populations .......................................37 4.3.3. Concentration-Exposure Duration Relationship .....................38 ii Dimethyl Sulfate Interim 1: 11/2006 5. DATA ANALYSIS FOR AEGL-1 ..........................................39 5.1. Summary of Human Data Relevant to AEGL-1 ............................39 5.2. Summary of Animal Data Relevant to AEGL-1 ............................39 5.3. Derivation of AEGL-1 ................................................39 6. DATA ANALYSIS FOR AEGL-2 ..........................................41 6.1. Summary of Human Data Relevant to AEGL-2 ............................41 6.2. Summary of Animal Data Relevant to AEGL-2 ............................41 6.3. Derivation of AEGL-2 ................................................42 7. DATA ANALYSIS FOR AEGL-3 ..........................................44 7.1. Summary of Human Data Relevant to AEGL-3 ............................44 7.2. Summary of Animal Data Relevant to AEGL-3 ............................44 7.3. Derivation of AEGL-3 ................................................44 8. SUMMARY OF AEGLS .................................................46 8.1. AEGL Values and Toxicity Endpoints ...................................46 8.2. Comparison with Other Standards and Guidelines ..........................47 9. REFERENCES .........................................................51 APPENDIX A: Derivation of AEGL Values.......................................56 APPENDIX B: Carcinogenicity Assessment .......................................60 APPENDIX C: Derivation Summary for Acute Exposure Guideline Levels for Dimethyl Sulfate ............................................................................64 iii Dimethyl Sulfate Interim 1: 11/2006 LIST OF TABLES TABLE 1. Chemical and Physical Properties........................................1 TABLE 2. Criteria for Grading the Degree of Dimethyl Sulfate Intoxication by Wang et al. 1988 ...................................................................9 TABLE 3. Summary of Acute Lethal Inhalation Data in Laboratory Animals..............16 TABLE 4. Summary of Nonlethal Inhalation Data in Laboratory Animals................23 TABLE 5. Summary of Mutagenicity Test Results...................................29 TABLE 6. Tumor Incidences in Rats/Mice/Hamsters (Schlögel 1972) ...................30 TABLE 7. Characterization of Local and Systemic Effects of Dimethyl Sulfate............35 TABLE 8. AEGL-1 Values for Dimethyl Sulfate....................................40 TABLE 9. AEGL-2 Values for Dimethyl Sulfate....................................43 TABLE 10. AEGL-3 Values for Dimethyl Sulfate ...................................45 TABLE 11. Summary of AEGL Values ...........................................46 TABLE 12. Existent Standards and Guidelines for Dimethyl Sulfate ....................48 LIST OF FIGURES Figure 1: Main Pathways for the Methylation of Dimethyl Sulfate ......................34 Figure 2: Category Plot of Toxicity Data compared to AEGL Values....................47 iv Dimethyl Sulfate Interim 1: 11/2006 EXECUTIVE SUMMARY Dimethyl sulfate (DMSO4) is a colorless, oily liquid with a slight onion-like odor. A minimum odor threshold may not be derived. Dimethyl sulfate is miscible with organic solvents, and moderately soluble in water. It hydrolyzes readily in contact with water or moist surfaces to form monomethyl sulfate and methanol, and further to form sulfuric acid. Dimethyl sulfate is used as an alkylating agent in the dye, agricultural, pharmaceutical, surfactant, and perfumery industries and exposure results exclusively from industrial processes, mostly via inhalation pathway. Inhalation exposure to dimethyl sulfate results in irritation and other adverse effects of upper respiratory tract and eyes as primary effects, followed by lesions in bronchi and lung. Usually a latency period for local effects of 4 to 12 hours between exposure and onset of effects was reported from human case