Acute Exposure Guideline Levels for Selected Airborne Chemicals Volume 12 (2012) / Chapter Skim
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6 Methyl Chloride1 Acute Exposure Guideline Levels PREFACE Under the authority of the Federal Advisory Committee Act (FACA)
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234 Acute Exposure Guideline Levels effects. However, the effects are not disabling and are transient and reversible upon cessation of exposure.
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Methyl Chloride 235 the absence of a clearly defined odor at these concentrations, the subjects were unable to differentiate between control and exposure days. None of the exposures produced mild, transient effects that define the AEGL-1 values.
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236 Acute Exposure Guideline Levels microbial fermentation. Most industrially-produced methyl chloride is used as a chemical intermediate.
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Methyl Chloride 237 The central nervous system (CNS) is the primary target of methyl chloride, with behavioral symptoms and neurologic effects resulting from both acute and chronic exposures.
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238 Acute Exposure Guideline Levels 2.1. Acute Lethality 2.2.1.
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Methyl Chloride 239 fifth employee reported symptoms similar to those described above, and he appeared to be euphoric. He completed his work shift, but reported to the medical department the next day with persistent symptoms.
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240 Acute Exposure Guideline Levels Four refrigeration-repair workers were exposed to methyl chloride at approximately 39,000, 50,000, 440,000, and 600,000 ppm (Jones 1942)
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Methyl Chloride 241 calculate TWA exposures. On testing days, carbon tubes were used to collect area samples.
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242 Acute Exposure Guideline Levels TABLE 6-3 Summary of Clinical Studies of Methyl Chloride Concentration Exposure (ppm) Duration Effect Reference 10 2h No irritation or CNS effects.
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Methyl Chloride 243 the 3- and 7.5-h exposures, respectively. The physiologic, neurologic, behavioral, clinical, and medical responses revealed no deleterious effects from methyl chloride (blood and breath analysis for methyl chloride are summarized in Section 4.1)
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244 Acute Exposure Guideline Levels in Section 2.2.2. The 24 crew members, which included individuals that had not been heavily exposed, were compared with a matched referent group.
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Methyl Chloride 245 cally significant neurobehavioral symptoms during separate 3- and 3.5-h exposures (Putz-Anderson et al.
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246 Acute Exposure Guideline Levels timated by the amount of chemical volatilized over the 7-h period and by a titration method. Mice exhibited increased activity soon after exposure began; this was followed by quiescence at 2 h.
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TABLE 6-4 Summary of Acute, Repeat-Exposure, and Subchronic Inhalation Studies of Methyl Chloride in Laboratory Animals Species Concentration (ppm) Exposure Duration Effecta Reference Dog 0, 200, 500 23.5 h/d, 3 d No clinical signs or microscopic lesions at McKenna et al.
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248 TABLE 6-4 Continued Species Concentration (ppm) Exposure Duration Effecta Reference Rat 0, 375, 750, 1,500 6 h/d, 5 d/wk, 90 d No clinical signs or tissue lesions; increased Mitchell et al.
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Methyl Chloride 249 3.1.2. Mice The 6-h LC50 values for methyl chloride in male and female B6C3F1 mice were 2,250 and 8,500 ppm, respectively (White et al.
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250 Acute Exposure Guideline Levels 1981a)
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Methyl Chloride 251 sure-related histopathologic lesions of the brain and spinal cord and no effect on brain weight. In a similar 90-day study, the no-effect concentration for methyl chloride in Sprague-Dawley rats was 400 ppm (McKenna et al.
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252 Acute Exposure Guideline Levels formance were observed at 800 and 1,600 ppm after 4 days, but not after 8 or 11 days. Cerebellar damage was observed at 400 ppm.
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Methyl Chloride 253 The reproductive toxicity of methyl chloride in the male rat has been well characterized in studies performed at the Chemical Industry Institute of Toxicology (Burek et al. 1981; Morgan et al.
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254 Acute Exposure Guideline Levels TABLE 6-6 Developmental Effects of Methyl Chloride in Animal Models Concentration Exposure (ppm) Duration Effects Reference Rat 0, 150, 475, 1,500 6 h/d, 5 d/wk premating; No significant differences in Hamm et 6 h/d, 7 d/wk from mating litter size, sex ratio, pup al.
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Methyl Chloride 255 moribund and killed. In a subsequent study, the same malformations were observed in fetuses when mouse dams were exposed at 500 or 750 ppm.
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256 Acute Exposure Guideline Levels among males. Neurofunctional impairment was observed in mice exposed at 1,000 ppm beginning with the 18-month interim sacrifice.
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Methyl Chloride 257 tion of DNA appears to be minimal. Mutagenicity is considered weak to moderate.
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258 Acute Exposure Guideline Levels ferences in measurement methods (Nolan et al.
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Methyl Chloride 259 rapidly during the 15-min post-exposure period, and methyl chloride concentration in expired air dropped so rapidly as to be of little or no value in quantifying exposure. In four low-responder females exposed at 100 ppm for 7.5 h, the average pre-exit blood concentration was 6 ppm.
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260 Acute Exposure Guideline Levels both species. Apparent steady-state blood values after exposure to methyl chloride at 50 or 1,000 ppm were 160 and 3,690 ng/g (dogs)
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Methyl Chloride 261 Inhibition of GSH conjugation decreases the toxicity of methyl chloride (White et al. 1982; Chellman et al.
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262 Acute Exposure Guideline Levels after an 8-h exposure. These crosslinks were attributed to the action of formaldehyde and were rapidly repaired.
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Methyl Chloride 263 activity was similar in the kidneys of male and female mice. Formaldehyde dehydrogenase (FDH)
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264 Acute Exposure Guideline Levels istics in the nasal turbinates. In rodents, an inhaled vapor traverses a few millimeters of resistant respiratory epithelium before reaching sensitive olfactory tissue; whereas, in humans, an inhaled vapor has to traverse several centimeters and a much larger surface area of respiratory epithelium to reach the olfactory tissue.
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Methyl Chloride 265 Among Caucasians, the majority of individuals possess at least one copy of the GST gene; 10-25% are non-conjugators (Warholm et al. 1994; Nelson et al.
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266 Acute Exposure Guideline Levels 10 or 50 ppm for 6 h (Nolan et al.
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Methyl Chloride 267 6.
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268 Acute Exposure Guideline Levels appropriate for intraspecies differences. In the absence of time-scaling information, the AEGL values were scaled using the equation Cn × t= k, with default values of n = 3 for shorter durations and n = 1 for longer durations (NRC 2001)
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Methyl Chloride 269 7.3. Derivation of AEGL-3 Values Data on lethality are limited to LC50 values for the mouse, a particularly sensitive species.
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270 Acute Exposure Guideline Levels particularly on the single and repeat exposures to methyl chloride at 1,500 ppm. The ERPG-3 was based on LC50 values for the mouse and rat which were apparently reduced by a factor of 2.
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Methyl Chloride 271 TABLE 6-10 Extant Standards and Guidelines for Methyl Chloride Exposure Duration Guideline 10 min 30 min 1h 4h 8h AEGL-1 NRa NRa NRa NRa NRa AEGL-2 1,100 ppm 1,100 ppm 910 ppm 570 ppm 380 ppm AEGL-3 3,800 ppm 3,800 ppm 3,000 ppm 1,900 ppm 1,300 ppm ERPG-1 (AIHA)
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272 Acute Exposure Guideline Levels The ERPG-2 is the maximum airborne concentration below which it is believed nearly all individuals could be exposed for up to 1 h without experiencing or developing irreversible or other serious health effects or symptoms that could impair an individual's ability to take protective action. The ERPG-3 is the maximum airborne concentration below which it is believed nearly all individuals could be exposed for up to 1 h without experiencing or developing lifethreatening health effects.
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Methyl Chloride 273 such studies for assess single exposures provides a margin of safety for AEGL-2 and AEGL-3 values. Although the neurotoxic mechanism of action of methyl chloride is not completely understood, metabolism is similar in various species and rate of metabolism appears related to body size and respiratory rate.
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274 Acute Exposure Guideline Levels Butterworth, B.E., T Smith-Oliver, L
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Methyl Chloride 275 interspecies dosimetry extrapolation of acidic vapors in the upper airways.
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276 Acute Exposure Guideline Levels Jager, R., H Peter, W
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Methyl Chloride 277 ronmental Protection Agency, Washington, DC. EPA Document No.
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278 Acute Exposure Guideline Levels NRC (National Research Council)
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Methyl Chloride 279 Smith, W.W., and W.F. von Oettingen.
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280 Acute Exposure Guideline Levels Working, P.K., J.S.
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Methyl Chloride 281 APPENDIX A DERIVATION OF AEGL VALUES FOR METHYL CHLORIDE Derivation of AEGL-1 Values AEGL-1 values are not recommended because methyl chloride has no odor or warning properties at concentrations that might be neurotoxic. Derivation of AEGL-2 Values Key studies: Mitchell, R.I., K
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282 Acute Exposure Guideline Levels Calculations: 10-min AEGL-2: Set equal to the 30-min value because of the long exposure durations of the key studies.
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Methyl Chloride 283 Uncertainty factors: 1 for interspecies difference; uptake is greater in rats than in humans 3 for intraspecies variability; differences in metabolism were not considered toxicologically significant. Modifying factor: Not applicable Calculations: 10-min AEGL-3: Set equal to the 30-min value because of the long exposure durations of the key studies.
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284 Acute Exposure Guideline Levels APPENDIX B CATEGORY GRAPH OF HUMAN AND ANIMAL TOXICITY DATA AND AEGL VALUES FOR METHYL CHLORIDE 100000 Human - No Effect Human - Discomfort 10000 Human - Disabling AEGL-3 Animal - No Effect ppm 1000 Animal - Discomfort AEGL-2 Animal - Disabling 100 Animal - Some Lethality Animal - Lethal 10 AEGL 0 60 120 180 240 300 360 420 480 Minutes FIGURE B-1 Category graph of human and animal toxicity data in relation to AEGL values for methyl chloride. Some of the data points represent repeat exposures.
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Methyl Chloride 285 APPENDIX C ACUTE EXPOSURE GUIDELINE LEVELS FOR METHYL CHLORIDE Derivation Summary for Methyl Chloride AEGL-1 VALUES AEGL-1 values are not recommended because methyl chloride has no odor or warning properties at concentrations that might be neurotoxic. AEGL-2 VALUES 10 min 30 min 1h 4h 8h 1,100 ppm 1,100 ppm 910 ppm 570 ppm 380 ppm Key references: (1)
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286 Acute Exposure Guideline Levels AEGL-2 VALUES Continued 10 min 30 min 1h 4h 8h 1,100 ppm 1,100 ppm 910 ppm 570 ppm 380 ppm Data adequacy: The animal studies were well conducted. The 90-day exposure duration of one of the key studies ensures a true NOAEL after a single 6-h exposure.
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Methyl Chloride 287 AEGL-3 VALUES Continued 10 min 30 min 1h 4h 8h 3,800 ppm 3,800 ppm 3,000 ppm 1,900 ppm 1,300 ppm Data adequacy: Lethality data are sparse and, with the exception of the mouse, usually occurred after repeat exposures. The AEGL values are supported by a monitoring study in which accidental, repeat exposures to methyl chloride at 1,0004,000 (durations not known)
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