6

Methyl Chloride
1

Acute Exposure Guideline Levels

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 (min) to 8 hours (h). Three levels—AEGL-1, AEGL-2, and AEGL-3—are developed for each of five exposure periods (10 and 30 min and 1, 4, and 8 h) 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, nonsensory

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1 This document was prepared by the AEGL Development Team composed of Sylvia Talmage (Summitec Corporation), Julie M. Klotzbach (Syracuse Research Corporation), Chemical Manager George Rodgers (National Advisory Committee [NAC] on Acute Exposure Guideline Levels for Hazardous Substances), and Ernest V. Falke (U.S. Environmental Protection Agency). The NAC reviewed and revised the document and AEGLs as deemed necessary. Both the document and the AEGL values were then reviewed by the National Research Council (NRC) Committee on Acute Exposure Guideline Levels. The NRC committee has concluded that the AEGLs developed in this document are scientifically valid conclusions based on the data reviewed by the NRC and are consistent with the NRC guidelines reports (NRC 1993, 2001).



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6 Methyl Chloride1 Acute Exposure Guideline Levels PREFACE Under the authority of the Federal Advisory Committee Act (FACA) P.L. 92-463 of 1972, the National Advisory Committee for Acute Exposure Guide- line Levels for Hazardous Substances (NAC/AEGL Committee) has been estab- lished 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 (min) to 8 hours (h). Three levels—AEGL-1, AEGL-2, and AEGL-3—are developed for each of five exposure periods (10 and 30 min and 1, 4, and 8 h) and are distin- guished 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, nonsensory 1 This document was prepared by the AEGL Development Team composed of Sylvia Talmage (Summitec Corporation), Julie M. Klotzbach (Syracuse Research Corporation), Chemical Manager George Rodgers (National Advisory Committee [NAC] on Acute Exposure Guideline Levels for Hazardous Substances), and Ernest V. Falke (U.S. Envi- ronmental Protection Agency). The NAC reviewed and revised the document and AEGLs as deemed necessary. Both the document and the AEGL values were then reviewed by the National Research Council (NRC) Committee on Acute Exposure Guideline Levels. The NRC committee has concluded that the AEGLs developed in this document are sci- entifically valid conclusions based on the data reviewed by the NRC and are consistent with the NRC guidelines reports (NRC 1993, 2001). 233

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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. 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 sus- ceptible 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 sus- ceptible individuals, could experience life-threatening health effects or death. Airborne concentrations below the AEGL-1 represent exposure concentra- tions that could produce mild and progressively increasing but transient and nondisabling odor, taste, and sensory irritation or certain asymptomatic, nonsen- sory 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 concentrations for the general public, including susceptible subpopula- tions, such as infants, children, the elderly, persons with asthma, and those with other illnesses, it is recognized that individuals, subject to idiosyncratic re- sponses, could experience the effects described at concentrations below the cor- responding AEGL. SUMMARY Methyl chloride is a substantially odorless, colorless gas with moderate flammability and explosiveness. Most methyl chloride produced today is used as a chemical intermediate in the production of silicones, agricultural chemicals, methyl cellulose, quaternary amines, butyl rubber, and tetraethyl lead. Previous use in refrigeration systems led to accidental exposures and, in some cases, deaths. In the late 1880s, methyl chloride had limited use as a general and local anesthetic. Data on toxicity to humans were available from accidental exposures, occupational exposures, and clinical studies. Animal studies, primarily with the rat and mouse, generally used a repeat-exposure scenario. Data were available on lethal and sublethal concentrations, neurotoxicity, developmental and repro- ductive effects, genotoxicity, and carcinogenicity. Metabolism is rapid. The hu- man and animal studies document the central nervous system as the target of acute and chronic exposures. In animal studies, other organs such as the kidneys and testes have been affected by repeat exposures. Clinical studies show that single exposures of healthy adults to methyl chloride at 200 ppm for 3 or 3.5 h (Putz-Anderson et al. 1981a,b) and a two-day repeat exposure of exercising adults exposed at 150 ppm for 7.5 h/day (Stewart et al. 1980) are without adverse neurotoxic effects. The subjects included both “fast” and “slow” metabolizers of methyl chloride. These exposures failed to elicit physiologic, neurologic, behavioral, or clinical symptoms. Furthermore, in

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235 Methyl Chloride the absence of a clearly defined odor at these concentrations, the subjects were unable to differentiate between control and exposure days. None of the expo- sures produced mild, transient effects that define the AEGL-1 values. Because methyl chloride has no clearly defined odor or warning properties at concentra- tions that might be neurotoxic, an AEGL-1 is not recommended. The AEGL-2 values were based on several studies with rats; a monitoring study was used as support. The basis for the AEGL-2 values was the absence of clinical signs in rats exposed at 1,500 ppm for 6 h/day for 1 day (Dodd et al. 1982) or 90 days (Mitchell et al. 1979). Because of the greater blood uptake of chemicals by rodents than humans (Landry et al. 1981, 1983; Nolan et al. 1985), an interspecies uncertainty factor of 1 was applied. Although humans differ in the rate at which they metabolize methyl chloride, the difference does not appear to be toxicologically significant (Nolan et al. 1985). Because of differences in uptake and metabolism among the human population, an intraspecies uncertainty factor of 3 was considered sufficient. Time scaling was performed using the equation Cn × t = k, using the default values of n = 3 for shorter durations and n = 1 for longer durations. Because of the long exposure duration of the key study, the 10-min value was set equal to the 30-min value. In a monitoring study, accidental exposures at 1,000-2,000 ppm and repeated exposure at 2,000- 4,000 ppm resulted in transient symptoms of blurred vision, dizziness, headache, and nausea in workers (MacDonald 1964). Exposure durations were not re- ported, but appeared to be throughout the workday. Application of an intraspe- cies uncertainty factor of 3 to 1,500 ppm, the mean concentration of methyl chloride in the occupational monitoring studies, results in 500 ppm, a value similar to the 4- and 8-h AEGL-2 values. The only lethality data were 50% lethality (LC50) values for the mouse, a particularly sensitive species. Two studies reported no deaths in rats during the first 4 days of exposures to methyl chloride at 5,000 ppm for 6 h/day (Morgan et al. 1982; Chellman et al. 1986a). A single 6-h exposure at 5,000 ppm was se- lected as the point-of-departure for the threshold for lethality. Interspecies and intraspecies uncertainty factors of 1 and 3, respectively, were applied as was done in the calculation for AEGL-2 values. Time scaling was performed using the equation Cn × t = k, using n = 3 for shorter durations and n = 1 for longer durations. Because of the long exposure duration of the key study, the 10-min AEGL-3 was set equal to the 30-min value. The AEGL values for methyl chloride are presented in the Table 6-1. 1. INTRODUCTION Methyl chloride is a substantially odorless, colorless gas with moderate flammability and explosiveness. Additional chemical and physical properties are listed in Table 6-2. At “high concentrations” it has a mild ethereal odor and sweet taste. Methyl chloride is ubiquitous in the environment because it is pro- duced by wood burning and is released by natural organic processes, such as

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236 Acute Exposure Guideline Levels microbial fermentation. Most industrially-produced methyl chloride is used as a chemical intermediate. The primary use is in the manufacture of silicones (72%); other products in which it is used as an intermediate include agricultural chemicals, methyl cellulose, quaternary amines, butyl rubber, and tetraethyl lead. Previously, it was used as a refrigerant and as an agricultural pesticide or fumigant (ATSDR 1998; O’Neil et al. 2001; Reid 2001). It had limited use as a general and local anesthetic in the late 1800s. It comprised 16% of the anesthetic “Somnoform” (Henderson 1930). Skin contact with the liquid may cause frost- bite (DOT 1985). Major production methods of methyl chloride involve the reaction of methanol and hydrogen chloride or the chlorination of methane (Holbrook 1992). Production in the United States was 920 million pounds in 1994 (CMR 1995). Methyl chloride (99.5-99.9% purity) is marketed as a liquefied gas under pressure (WHO 2000). 2. HUMAN TOXICITY DATA The most important route of exposure to methyl chloride in humans is via the respiratory tract. Reported human exposures have primarily been the result of its use as a refrigerant gas and as a blowing agent for plastic foams. Early published reports of acute intoxications involved leaks in domestic refrigerators and overexposures of industrial workers. Uses as a refrigeration gas and as a blowing agent for plastic foams have been discontinued. TABLE 6-1 Summary of AEGL Values for Methyl Chloride End Point Classification 10 min 30 min 1h 4h 8h (Reference) NRa NRa NRa NRa NRa AEGL-1 (nondisabling) AEGL-2 1,100 ppm 1,100 ppm 910 ppm 570 ppm 380 ppm NOAEL for (disabling) (2,277 (2,277 (1,884 (1,180 (787 clinical signs, mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) tissue lesions in rats (Mitchell et al. 1979; Dodd et al. 1982) AEGL-3 3,800 ppm 3,800 ppm 3,000 ppm 1,900 ppm 1,300 ppm Threshold (lethal) (7,866 (7,866 (6,210 (3,933 (2,691 for lethality mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) in rats (Morgan et al. 1982; Chellman et al. 1986a) a AEGL-1 values are not recommended because methyl chloride has no odor or warning properties at concentrations that may be neurotoxic. Abbreviations: NR, not recommended; NOAEL, no-observed-adverse-effect level.

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237 Methyl Chloride The central nervous system (CNS) is the primary target of methyl chlo- ride, with behavioral symptoms and neurologic effects resulting from both acute and chronic exposures. Overexposures can result in loss of equilibrium, dizzi- ness, semiconsciousness, and delayed death. Case histories show that acute ex- posures at high concentrations and chronic exposures to moderately high con- centrations result in degeneration of portions of the CNS. Symptoms include headache, confusion, ataxia, muscle weakness, and tremor. Gastrointestinal dis- turbances may also occur, but there is no effect on pulmonary function. Recov- ery may be protracted. Renal, hepatic, cardiovascular, gastrointestinal, and other complications also have been documented (Repko and Lasley 1979). Data on the toxicity of methyl chloride have been reviewed by the Agency for Toxic Sub- stances and Disease Registry (ATSDR 1998), the International Agency for the Research on Cancer (IARC 1999), the World Health Organization (WHO 2000), and the Hazardous Substances Databank (HSDB 2005). Although mortalities have been reported as a result of accidental overex- posure to methyl chloride, no information was available on measured concentra- tions. 2.2. Nonlethal Toxicity Methyl chloride is considered nonirritating to the eyes, nose, and throat; however, the liquid can cause frostbite (DOT 1985). TABLE 6-2 Chemical and Physical Properties of Methyl Chloride Parameter Value Reference Synonyms Chloromethane, monochloromethane O’Neil et al. 2001 CAS registry no. 74-87-3 O’Neil et al. 2001 Chemical formula CH3Cl O’Neil et al. 2001 Molecular weight 50.49 O’Neil et al. 2001 Physical state Colorless gas O’Neil et al. 2001 Melting point -97.7°C O’Neil et al. 2001 Boiling point -23.7°C O’Neil et al. 2001 Density Holbrook 1992 Vapor 2.3 g/L at 0°C, 1 atm (air = 1) Liquid 0.9 g/mL at 20/4°C (water = 1) Solubility in water 4.8 g/L at 25°C O’Neil et al. 2001 Vapor pressure 3670 mm Hg at 20°C Holbrook 1992 Flammability limits Flammable; 8.1-17.2% DOT 1985 3 Conversion factors 1 ppm = 2.07 mg/m ACGIH 2003 1 mg/m3 = 0.483 ppm

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238 Acute Exposure Guideline Levels 2.1. Acute Lethality 2.2.1. Odor Threshold and Awareness Data on the odor and irritation thresholds of methyl chloride are conflict- ing. The odor threshold has been reported at 10 ppm (Billings and Jonas 1981; Ruth 1986), and an irritation threshold was reported in a literature review as approximately 500 ppm (Ruth 1986). However, the specific source of the odor and irritation thresholds was not reported. In well-conducted clinical studies with male and female subjects, odor was not clearly perceived at concentrations of 150 ppm (Stewart et al. 1980) or 200 ppm (Putz-Anderson et al. 1981a). Sev- eral reviews, including one by Repko and Lasley (1979), state that methyl chlo- ride is undetectable at concentrations that are dangerous to breathe. The odor is described as ethereal or sweet (Reid 2001). 2.2.2. Case Reports Numerous case reports of exposure to methyl chloride as a result of refrig- eration losses or industrial leaks have been reported. A few examples are cited here. Symptoms of fatigue, drowsiness, staggered walk, headache, blurred vi- sion, mental confusion, vertigo, muscular cramping and rigidity, and tremor may be preceded by a latent period of 1-4 h. Depending on the severity of the expo- sure, symptoms may persist for several months, and personality changes, such as depression, may develop (ATSDR 1998). MacDonald (1964) described nine case reports of employees at a syn- thetic-rubber plant where he was the medical supervisor. Where concentrations were noted in the work area, measurements were taken by gas chromatography or, in one case, by a Riken indicator, which gives immediate indication of the presence of methyl chloride at concentrations up to 10,000 ppm. In some cases exposures continued for several days before employees reported to the medical department. The cases were reported in short paragraphs, and no further details on exposure durations were reported. In the first case, an employee experienced vision disturbance, headache, dizziness, nausea, and staggering for several days prior to reporting to the medical department. Concentrations of methyl chloride in his work area was <25-1,600 ppm. Symptoms disappeared slowly, and he returned to work after 36 days. Two other employees working in the same area had similar symptoms, but medical examinations were normal. Apprehension and depression occurred for some time following the exposures. A fourth employee neglected to wear a mask in an area where concentra- tions of methyl chloride were known to be 1,000-2,000 ppm. He experienced dizziness, blurred vision, headache, nausea, and vomiting. The exposure dura- tion could not be quantified. The symptoms cleared quickly and he returned to work the next day. A second exposure one year later, although considered more moderate, resulted in more persistent symptoms. After a methyl chloride spill, a

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239 Methyl Chloride fifth employee reported symptoms similar to those described above, and he ap- peared to be euphoric. He completed his work shift, but reported to the medical department the next day with persistent symptoms. He returned to work 2 weeks later. Over the next 10 years he experienced occasional periods of dizziness and headaches, which he attributed to mild overexposures. Concentrations in his work area rarely exceeded 100 ppm. Following another accidental spill, an employee repeatedly entered and left an area that had methyl chloride in excess of 10,000 ppm (Riken indicator). Although he experienced symptoms of blurred vision, dizziness, and sight head- ache, he did not report to the medical department. At another time, he worked in an area with a leak that was not controlled for 13 days. Monitoring data showed concentrations of methyl chloride at 2,000-4,000 ppm. During the first week, the employee slept for long periods; the following week he experienced the typical symptoms described above. Although the symptoms lessened with time, the employee became irritable and depressed. This continued until his reassignment into another area of the plant. Another employee exposed at the same time, but not to the same degree, experienced milder symptoms. An eighth employee was found unconscious lying in a cloud of escaping methyl chloride gas by other workmen. He was admitted to the hospital where he remained unconscious for several hours. Weakness and headaches were still present when he was discharged 10 days later. Follow-up examinations over the next 5 years revealed persistent symptoms, personality changes, and neurologic damage. In 1963, 17 male crew members on an Icelandic fishing trawler were ex- posed for 2 days to methyl chloride from a leaking refrigerator located under their sleeping quarters (Gudmundsson 1977). No estimates of exposure concen- trations were made. Fifteen of the crew members had signs of intoxication and abnormal neurologic symptoms. One survivor died within 24 h of exposure, two committed suicide 11 and 18 months later, and one died 10 years later. Six of 10 survivors (one survivor could not be located) still had neurologic deficits 20 months later. All survivors suffered from mild to permanent neurologic or psy- chiatric sequelae 13 years after the exposure occurred. Lanham (1982) reported a case of a husband and wife who stored Styro- foamTM insulating boards in the basement of their new home prior to installation. The home was of tight, energy-efficient construction. Several days later they developed symptoms of blurred vision, fatigue, vertigo, tremor, and abnormal gait. Concentrations of methyl chloride measured by three different devices were above 200 ppm. Battigelli and Perini (1955) described two workers exposed to methyl chloride while repairing a refrigeration system. On the basis of the room size and the amount of gas in the system, the exposure was estimated at >29,000 ppm (duration was not provided). The workers developed vertigo, tremors, dulled senses, nausea, vomiting, and abdominal pain 3-4 h after exposure. Symptoms disappeared 1 day after the exposure.

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240 Acute Exposure Guideline Levels Four refrigeration-repair workers were exposed to methyl chloride at ap- proximately 39,000, 50,000, 440,000, and 600,000 ppm (Jones 1942). Common symptoms were ataxia, staggering, headache, drowsiness, anorexia, blurred and double vision, convulsions, nausea, and vomiting. The exposure duration was not reported. 2.2.3. Occupational Exposures Scharnweber et al. (1974) described six cases of prolonged worker expo- sure to “relatively low levels” of methyl chloride. Exposures were for 2-3 weeks, sometimes with 12- to 16-h workdays, before onset of symptoms. The analysis method was not reported. Two workers exposed at up to 300 ppm (8-h time-weighted average [TWA]) for several weeks were hospitalized with symp- toms of confusion, blurry vision, difficulty in eating and swallowing, headache, and combativeness. Some symptoms, such as poor memory and headache, per- sisted for several months. Four workers exposed at 265 ppm (8-h TWA) for 2-3 weeks, with 12- to 16-h workdays, developed similar symptoms, including im- paired memory, gait, and speech and slight elevation in blood pressure. Scharn- weber et al. (1974) concluded that 8-h of exposure to methyl chloride at concen- trations greater than 200 ppm is necessary for development of chronic methyl- chloride intoxication. Continuous monitoring studies (for up to 4 months) during manufacturing operations at nine plants were conducted by the Dow Chemical Co. (personal communication, 1970, as cited in ACGIH 2003). Time-weighted average expo- sure concentrations were determined for 54 job classifications. The average TWA was 30 ppm with a range of 5-78 ppm; peaks as high as 400 ppm were recorded. Routine, periodic medical examinations did not identify any evidence of overexposure. Methyl chloride concentrations in relation to reported illnesses in StyrofoamTM-manufacturing plants were summarized. On the basis of 100 sample points at 9 plants, illness was reported in plants where average concen- trations of methyl chloride were 2-1,500 ppm; the range of average exposures was 195-475 ppm. Symptoms of illness included weakness, drowsiness, stag- gered gait, thickness of the tongue, and lapses of memory. At 141 plants (1,784 sample points) without reported illnesses, average concentrations at sample points were 2-500 ppm, and the range of average exposures was 15-195 ppm. Repko et al. (1976) compared neurologic functions in a group of 122 healthy male and female workers exposed to methyl chloride in the manufacture of foam products with 49 workers also engaged in the manufacture of foam products but not exposed to methyl chloride. Average daily air concentrations were determined for each worker individually. Air concentrations were moni- tored by different methods in different plants and involved continuous and sin- gle-sampling techniques. For continuous monitoring with gas or infrared analyz- ers (five plants), the amount of time each employee spent in an area was used to

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241 Methyl Chloride calculate TWA exposures. On testing days, carbon tubes were used to collect area samples. Results correlated “reasonably” with concentrations determined from conductivity and infrared analyzers. In the sixth plant, continuous monitor- ing was conducted with an automated gas chromatograph. Carbon tubes also were used during the battery of tests. The study was not blind; volunteers were paid and were told the objectives of the tests. Functional capacity was evaluated with a series of comprehensive neurologic, electroencephalogram (EEG), and behavioral test batteries. Ambient concentrations of methyl chloride were 7.4-70 ppm, with an overall average of 33.6 ppm. There were no significant differences in results of neurologic tests or EEGs. Although the exposed group outperformed the control group on a few tasks, significant performance deficits were observed for most tasks. The concentration of methyl chloride was related to the decrease in per- formance deficits, primarily cognitive time sharing, and increased finger tremor. Methyl chloride concentration also was correlated with breath concentration, as well as urine pH and hematocrit. The authors concluded that daily exposure to methyl chloride below 100 ppm can cause significant, transitory changes in functional capacity. Because exposures before the study were higher and be- cause questionable statistical methods were used, the study is of limited value (Torkelson and Rowe 1981). The National Institute of Occupational Safety and Health (Cohen et al. 1980) conducted a survey of four U.S. chemical plants. Three of the plants pro- duced methyl chloride and the fourth used methyl chloride as a blowing agent in the production of polystyrene foam. The personal 8-h TWA concentrations at the first three plants were 8.9-12.4 ppm, <0.2-7.5 ppm, and <0.1-12.7 ppm; per- sonal exposures in the fourth plant were 3.0-21.4 ppm. In a Dutch methyl chlo- ride plant, individual 8-h TWA area samples (which correlated closely with per- sonal samples) were 30- 90 ppm during one working week (van Doorn et al. 1980). Symptoms, if present, were not reported in these studies. 2.2.4. Clinical Studies Clinical studies of methyl chloride are summarized in Table 6-3. As part of a pharmacokinetic study of methyl chloride, six male volunteers were ex- posed at 10-50 ppm on separate days for 6 h (Nolan et al. 1985). Exposures took place in a 70-m3 chamber. Atmospheres were measured continuously with an infrared spectrometer and at 15-min intervals with a gas chromatograph equipped with a flame ionization detector. There was no recognizable odor or irritation. No adverse effects were reported by the subjects or by the physicians conducting the post-exposure examinations. Additional clinical studies are discussed below in the section on neurotox- icity (Stewart et al. 1980; Putz-Anderson et al. 1981a,b) or on metabolism (Lof et al. 2000).

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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. Lof et al. 2000 10, 50 6h No recognizable odor or irritation. Nolan et al. 1985 0, 20, 1, 3, or No eye, nose, or throat irritation; no Stewart et al. 1980 100, 150 7.5 h, 2-5 d effect on physiologic, neurologic, behavioral, or clinical parameters; exercise incorporated into the protocol for male subjects. 0, 100, 200 3h No odor perception; little to no Putz-Anderson effect on tests of alertness. et al. 1981a 0, 200 3.5 h No odor perception; no effect on Putz-Anderson tests of alertness. et al. 1981b 2.3. Neurotoxicity In a study using a controlled atmospheric chamber, nine male subjects (ages 19-34) were exposed to methyl chloride at 0, 20, 100, or 150 ppm for 1, 3, or 7.5 h, and nine female subjects were exposed at 0 or 100 ppm for identical periods of time (Hake et al. 1977; Stewart et al. 1980). Male subjects were ex- posed at 150 ppm on 2 consecutive days and male and female subjects were exposed at 100 ppm on 5 consecutive days. An additional exposure of male sub- jects involved fluctuating concentrations of 50, 100, and 150 ppm (TWA of 100 ppm) for 1, 3, or 7.5 h/day for 5 days. Groups were composed of 2-4 subjects. Groups were defined by exposure duration; for example, the four male subjects exposed for 7.5 h were exposed to methyl chloride at 0, 20, 100, fluctuating 50- 150, and 150 ppm on different weeks. The entire testing period was 5 weeks. The male subjects were sedentary except for 11 min of exercise on a bicycle ergometer (6 min at 350 kpm and 5 min at 750 kpm) between the fifth and sev- enth hour h of exposure on the fourth day at all concentrations (day 2 for the male group exposed at 150 ppm). Concentrations were verified by gas chroma- tography and infrared analysis. Clinical symptoms and physiologic (EEG and visual evoked response patterns), clinical chemistry and hematology, neurologic, and behavioral effects were monitored; blood and alveolar breath samples were monitored for methyl chloride. Subjective responses were recorded immediately after entering the chamber, at the half hour, and hourly thereafter. The report form contained the descriptors headache; nausea; dizziness; abdominal pain; eye, nose, throat irritation; odor; and other, with modifiers of mild, moderate, and strong (only abnormalities reported). Neurologic studies consisted of a modified Romberg test, equilibrium test, spontaneous EEG, and visual evoked response. Cognitive testing, consisting of time estimation, eye-hand coordina- tion, arithmetic, and number recognition, was performed after 2 and 3 h during

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243 Methyl Chloride the 3- and 7.5-h exposures, respectively. The physiologic, neurologic, behav- ioral, clinical, and medical responses revealed no deleterious effects from methyl chloride (blood and breath analysis for methyl chloride are summarized in Section 4.1). The notation of a mild odor was reported as frequently for con- trol exposure (0 ppm) as for test exposures. Putz-Anderson et al. (1981a) assessed the behavioral effects of inhaled methyl chloride in groups of 8 or 12 healthy male and female subjects. Ages ranged from 18 to 32 years. Methyl chloride was administered at concentrations of 0, 100, or 200 ppm for 3 h. Three performance tests (visual vigilance, dual task, and time discrimination), designed to test attention or alertness, were ad- ministered before and during the treatment period. The net impairment resulting from exposure at 200 ppm was marginally significant (4.5%). The authors con- cluded that exposure at 200 ppm produced little or no behavioral impairment. In a second study (Putz-Anderson et al. 1981b), conducted in the same manner and using the same tests, groups of 12 healthy male and female subjects were ex- posed at 200 ppm for 3.5 h. The subjects did not experience any significant im- pairment on the tests. The authors note that the subjects were no more successful than chance in assessing whether they had been exposed to the control or chemi- cal atmosphere. 2.4. Developmental/Reproductive Toxicity No studies were found regarding reproductive or developmental effects in humans after inhalation of methyl chloride. 2.5. Genotoxicity No studies were found regarding genotoxic effects in humans after inhala- tion exposure to methyl chloride. In an in vitro test, methyl chloride at 0.3-5% induced an increase in the frequency of sister chromatid exchanges in human lymphoblasts, but did not induce DNA damage (Fostel et al. 1985). Unscheduled DNA synthesis was induced in primary cultures of human hepatocytes of three individuals exposed at 1%, but not at 0.1-0.3% (Butterworth et al. 1989). 2.6. Carcinogenicity Holmes et al. (1986) conducted a retrospective study of 852 workers ex- posed to methyl chloride in a butyl rubber manufacturing plant. Mortality from all causes was lower than expected compared with the U.S. male population. There was no statistical evidence that the death rate from cancer at any site was increased. No concentrations of methyl chloride were specified in this study. Rafnsson and Gudmundsson (1997) conducted a long-term follow-up study of the survivors of the acute exposure described by Gudmundsson (1977)

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277 Methyl Chloride ronmental Protection Agency, Washington, DC. EPA Document No. 87820010220, Microfiche No. OTS0206129. McKenna, M.J., J.D. Burek, J.W. Henck, D.L. Wackerle, and R.C. Childs. 1981b. Methyl Chloride: A 90-Day Inhalation Toxicity Study in Rats, Mice and Beagle Dogs. Five Reports Dealing with Studies of Methyl Chloride Pharmacokinetics and Inha- lation Toxicity Studies, with Cover Letter Dated July11, 1981. Submitted by Toxi- cology Research Laboratory, Dow Chemical USA, Midland, MI, to U.S. Environ- mental Protection Agency, Washington, DC. EPA Document No. No. 40-8120723. Microfiche No. OTS0511317. Mitchell, R.I., K. Pavkov, R.M. Everett, and D.A. Holzworth. 1979. A Ninety Day Inha- lation Toxicology Study in F-344 Albino Rats and B6C3F1 Mice Exposed to At- mospheric Methyl Chloride Gas. Battelle Columbus Laboratories for the Chemical Industry Institute of Toxicology, Research Triangle Park, NC. Microfishe No. OTS0205952. Morgan, A., A. Black, and D.R. Belcher. 1970. The excretion in breath of some aliphatic halogenated hydrocarbons following administration by inhalation. Ann. Occup. Hyg. 13(4):219-233. Morgan, K.T., J.A. Swenberg, T.E. Hamm, Jr., R. Wolkowski-Tyl, and M. Phelps. 1982. Histopathology of acute toxic response in rats and mice exposed to methyl chloride by inhalation. Fundam. Appl. Toxicol. 2(6):293-299. MSZW (Ministerie van Sociale Zaken en Werkgelegenheid). 2004. Nationale MAC-lijst 2004: Methylchloride. Den Haag: SDU Uitgevers [online]. Available: http://www. lasrook.net/lasrookNL/maclijst2004.htm [accessed Feb. 3, 2012]. Nelson, H.H., J.K. Wiencke, D.C. Christiani, T.J. Chang, Z.F. Zuo, B.S. Schwartz, B.K. Lee, M.R. Spitz, M. Wang, X. Xu, and K.T. Kelsey. 1995. Ethnic differences in the prevalence of the homozygous deleted genotype of glutathione S-transferase theta. Carcinogenesis 16(5):1243-1245. NIOSH (National Institute for Occupational Safety and Health). 1984. Monoha- lomethanes: Methyl Chloride CH3Cl, Methyl Bromide CH3Br, Methyl Iodide CH3I. Current Intelligence Bulletin 43, September 27, 1984 [online]. Available: http://www.cdc.gov/niosh/84117_43.html [accessed Feb. 3, 2012]. NIOSH (National Institute for Occupational Safety and Health). 1994. Documentation for Immediately Dangerous to Life or Health Concentrations (IDLHs): Methyl chloride. U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, Cincinnati, OH [online]. Available: http://www.cdc.gov/niosh/idlh/74873.html [accessed Feb. 3, 2012]. NIOSH (National Institute for Occupational Safety and Health). 2010. NIOSH Pocket Guide to Chemical Hazards: Methyl chloride. U.S. Department of Health and Hu- man Services, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, Cincinnati, OH [online]. Available: http://www. cdc.gov/niosh/npg/npgd0403.html [accessed Feb. 03, 2012]. Nolan, R.J., D.L. Rick, T.D. Landry, L.P. McCarty, G.L. Agin, and J.H. Saunders. 1985. Pharmacokinetics of inhaled methyl chloride (CH3Cl) in male volunteers. Fundam. Appl. Toxicol. 5(2):361-369. NRC (National Research Council). 1993. Guidelines for Developing Community Emer- gency Exposure Levels for Hazardous Substances. Washington, DC: National Academy Press.

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278 Acute Exposure Guideline Levels NRC (National Research Council). 2001. Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals. Washington, DC: Na- tional Academy Press. O’Neil, M.J., A. Smith, and P.E. Heckelman, eds. 2001. The Merck Index: An Encyclo- pedia of Chemicals, Drugs, and Biologicals, 13th Ed. Whitehouse Station, NJ: Merck. Ott, M.G., G.L. Carlo, S. Steinberg, and G.G. Bond. 1985. Mortality among employees engaged in chemical manufacturing and related activities. Am. J. Epidemiol. 122(2):311-322. Pavkov, K.L., W.D. Kerns, R.I. Mitchell, M.M. Connell, R.L. Persing, C.E. Chrisp, and H.H. Harroff. 1981. Final Report on a Chronic Inhalation Toxicology Study in Rats and Mice Exposed to Methyl Chloride. Dow Chemical Company/Battelle Co- lumbus Laboratories for Chemical Industry Institute of Toxicology. Microfiche No. OTS0535223. Peter, H., S. Deutschmann, C. Reichel, and E. Hallier. 1989. Metabolism of methyl chlo- ride by human erythrocytes. Arch. Toxicol. 63(5):351-355. Putz-Anderson, V., J.V. Setzer, J.S. Croxton, and F.C. Phipps. 1981a. Methyl chloride and diazepam effects on performance. Scand. J. Work Environ. Health 7(1):8-13. Putz-Anderson, V., J.V. Setzer, and J.S. Croxton. 1981b. Effects of alcohol, caffeine and methyl chloride on man. Psychol. Rep. 48(3):715-725. Rafnsson, V., and G. Gudmundsson. 1997. Long-term follow-up after methyl chloride intoxication. Arch. Environ. Health 52(5):355-359. Redford-Ellis, M., and A.H. Gowenlock. 1971. Studies on the reaction of chloromethane with human blood. Acta Pharmacol. Toxicol. 30(1):36-48. Reid, J.B. 2001. Saturated methyl halogenated aliphatic hydrocarbons: Methyl chloride. Pp. 2-12 in Patty’s Toxicology, 5th Ed., Vol. 5. New York: John Wiley & Sons. Reitz, R.H., A.L. Mendrala, and F.P. Guengerich. 1989. In vitro metabolism of methyl- ene chloride in human and animal tissues: Use in physiologically based pharma- cokinetic models. Toxicol. Appl. Pharmacol. 97(2):230-246. Repko, J.D., and S.M. Lasley. 1979. Behavioral neurological and toxic effects of methyl chloride: A review of the literature. CRC Crit. Rev. Toxicol. 6(4):283-302. Repko, J.D., P.D. Jones, L.S. Garcia, E.J. Schneider, E. Roseman, and C.R. Corum. 1976. Behavioral and Neurological Effects of Methyl Chloride. NIOSH (DHEW) Publi- cation No. 77-125, PB-274-770. U.S. Department of Health, Education, and Wel- fare, Public Health Service, Center for Disease Control, National Institute for Oc- cupational Safety and Health, Cincinnatti, OH. Ristau, C., H.M. Bolt, and R.R. Vangala. 1989. Detection of DNA-protein crosslinks in the kidney of male B6C3F1 mice after exposure to methyl chloride. Arch. Toxicol. Suppl. 13:243-245. Ruth, J.H. 1986. Odor thresholds and irritation levels of several chemical substances: A review. Am. Ind. Hyg. Assoc. J. 47(3):A142-A151. Scharnweber, H.C., G.N. Spears, and S.R. Cowles. 1974. Chronic methyl chloride intoxi- cation in six industrial workers. J. Occup. Med. 16(2):112-113. Sikov, M.R., W.C. Cannon, D.B. Carr, R.A. Miller, L.F. Montgomery, and D.W. Phelps. 1981. Teratologic Assessment of Butylene Oxide, Styrene Oxide and Methyl Bro- mide. DHHS Publication (NIOSH) 81-124. PB 81-168-510. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control, National Institute for Occupational Safety and Health, Cincinnati, OH.

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279 Methyl Chloride Smith, W.W., and W.F. von Oettingen. 1947a. The acute and chronic toxicity of methyl chloride. I. Mortality resulting from exposure to methyl chloride in concentrations of 4000 to 300 parts per million. J. Ind. Hyg. Toxicol. 29(1):47-52. Smith, W.W., and W.F. von Oettingen. 1947b. The acute and chronic toxicity of methyl chloride. II. Symptomatology of animals poisoned by methyl chloride. J. Ind. Hyg. Toxicol. 29(2):123-128. Stewart, R.D., C.L. Hake, A. Wu, S.A. Graff, H.V. Forster, W.H. Keeler, A.J. Lebrun, P.E. Newton, and R.J. Soto. 1980. Methyl Chloride: Development of a Biologic Standard for the Industrial Worker by Breath Analysis. PB 81167 686. Medical College of Wisconsin, Milwaukee, WI. Thier, R., F.A. Wiebel, A. Hinkel, A. Burger, T. Bruning, K. Morgenroth, T. Senge, M. Wilhelm, T.G. Schulz. 1998. Species differences in the glutathione transferase GSTT1-1 activity towards the model substrates methyl chloride and dichloro- methane in liver and kidney. Arch. Toxicol. 72(10):622-629. Torkelson, T.R., and V.K. Rowe. 1981. Halogenated aliphatic hydrocarbons containing chlorine, bromine, and iodine. Pp. 3433-3601 in Patty’s Industrial Hygiene and Toxicology, Vol. IIB. Toxicology, 3rd Ed., G.D. Clayton, and F.E. Clayton, eds. New York: John Wiley & Sons. van Doorn, R., P.J. Borm, C.M. Leijdekkers, P.T. Henderson, J. Reuvers, and T.J. van Bergen. 1980. Detection and identification of S-methylcysteine in urine of workers exposed to methyl chloride. Int. Arch. Occup. Environ. Health 46(2):99-109. von Oettingen, W.F., C.C. Powell, N.E. Sharpless, W.C. Alford, and L.J. Pecora. 1949. Relation Between the Toxic Action of Chlorinated Methanes and their Chemical and Physicochemical Properties. National Institutes of Health Bulletin No. 191. Washington, DC: U.S. Government Printing Office. von Oettingen, W.F., C.C. Powell, N.E. Sharpless, W.C. Alford, and L.J. Pecora. 1950. Comparative studies of the toxicity and pharmacodynamic action of chlorinated methanes with special reverence to their physical and chemical properties. Arch. Int. Pharmacodyn. Ther. 81(1):17-34. Warholm, M., A.K. Alexandrie, J. Hogberg, K. Sigvardsson, and K. Rannug. 1994. Po- lymorphic distribution of glutathione transferase activity with methyl chloride in human blood. Pharmacogenetics 4(6):307-311. White, R.D., R. Norton, and J.S. Bus. 1982. Evidence for S-methyl glutathione metabo- lism in mediating the acute toxicity of methyl chloride (MeCl). Pharmacologist 24(3):172 [Abstract 429]. WHO (World Health Organization). 2000. Concise International Chemical Assessment Document 28: Methyl Chloride. World Health Organization: Geneva, Switzerland. Wolkowski-Tyl, R., M. Phelps, and J.K. Davis. 1983a. Structural teratogenicity evalua- tion of methyl chloride in rats and mice after inhalation exposure. Teratology 27(2):181-195. Wolkowski-Tyl, R., A.D. Lawton, M. Phelps, and T.E. Hamm, Jr. 1983b. Evaluation of heart malformations in B6C3F1 mouse fetuses induced by in utero exposure to methyl chloride. Teratology 27(2):197-206. Working, P.K., and J.S. Bus. 1986. Failure of fertilization as a cause of preimplantation loss induced by methyl chloride in Fischer 344 rats. Toxicol. Appl. Pharmacol. 86(1):124-130. Working, P.K., and G.J. Chellman. 1989. The use of multiple endpoints to define the mechanism of action of reproductive toxicants and germ cell mutagens. Prog. Clin. Biol. Res. 302:211-227.

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280 Acute Exposure Guideline Levels Working, P.K., J.S. Bus, and T.E. Hamm, Jr. 1985a. Reproductive effects of inhaled methyl chloride in the male Fischer 344 rat. I. Mating performance and dominant lethal assay. Toxicol. Appl. Pharmacol. 77(1):133-143. Working, P.K., J.S. Bus, and T.E. Hamm, Jr. 1985b. Reproductive effects of inhaled methyl chloride in the male Fischer 344 rat. II. Spermatogonial toxicity and sperm quality. Toxicol. Appl. Pharmacol. 77(1):144-157.

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281 Methyl Chloride 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. Pavkov, R.M. Everett, and D.A. Holzworth. 1979. A Ninety Day Inhalation Toxicology Study in F-344 Albino Rats and B6C3F1 Mice Exposed to Atmospheric Methyl Chloride Gas. Battelle Columbus Laboratories for the Chemical Industry Institute of Toxicology, Research Triangle Park, NC. Microfiche No. OTS0205952. Dodd, D.E., J.S. Bus, and C.S. Barrow. 1982. Nonprotein sulfhydryl alterations in F-344 rats following acute methyl chloride inhalation. Toxicol. Appl. Pharmacol. 62(2):228-236. Toxicity end point: No clinical signs in rats exposed at 1,500 ppm for 6 h. No clinical signs in rats exposed at 1,500 ppm for 6 h/day, 5 days/week for 90 days. Cn × t = k, default values of n = 3 for shorter Time scaling: exposure durations and n = 1 for longer exposure durations. (1,500 ppm/3)3 × 360 min = 4.5 × 1010 ppm3-min (1,500 ppm/3) × 360 = 1.8 × 105 ppm-min Uncertainty factors: 1 for interspecies differences; uptake is greater in rats than in humans. 3 for intraspecies variability; differences in metabolism were not considered toxicologically significant. Modifying factor: Not applicable

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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. C = (4.5 ×x 1010 ppm3-min ÷ 30min)1/3 30-min AEGL-2: C = 1,100 ppm C = (4.5 × 1010 ppm3-min ÷ 60 min)1/3 1-h AEGL-2: C = 910 ppm C = (4.5 × 1010 ppm3-min ÷ 240 min)1/3 4-h AEGL-2: C = 570 ppm C = (1.8 × 105 ppm-min) ÷ 480 min 8-h AEGL-2: C = 380 ppm Derivation of AEGL-3 Values Key studies: Morgan, K.T., J.A. Swenberg, T.E. Hamm, Jr., R. Wolkowski-Tyl, and M. Phelps. 1982. Histopathology of acute toxic response in rats and mice exposed to methyl chloride by inhalation. Fundam. Appl. Toxicol. 2(6):293-299. Chellman, G.J., K.T. Morgan, J.S. Bus, and P.K. Working. 1986a. Inhibition of methyl chloride toxicity in male F-344 rats by the anti- inflammatory agent BW755C. Toxicol. Appl. Pharmacol. 85(3):367-379. Toxicity end point: 5,000 ppm for 6 h/day for 12 days was nonlethal to rat for 5 days, one death following the fifth day of exposure. 5,000 ppm for 6 h/day for 5 days was nonlethal to rats. Cn × t = k; default values of n = 3 for shorter Time scaling: exposure durations and n = 1 for longer exposure durations. (5,000 ppm ÷ 3)3 × 360 min = 1.67 × 1012 ppm3-min (5,000 ppm ÷ 3) × 360 = 6.0 × 105 ppm-min

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283 Methyl Chloride 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. C = (1.67 × 1012 ppm3-min ÷ 30 min)1/3 30-min AEGL-3: C = 3,800 C = (4.5 × 1012 ppm3-min ÷ 60 min)1/3 1-h AEGL-3: C = 3,000 ppm C = (1.67 × 1012 ppm3-min ÷ 240 min)1/3 4-h AEGL-3: C = 1,900 ppm C = (6.0 × 105 ppm3-min) ÷ 480 min 8-h AEGL-3: C = 1,300 ppm

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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 Animal - No Effect AEGL-3 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. The two lethal concentrations are for the mouse, a particularly sensitive species.

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285 Methyl Chloride 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) Dodd, D.E., J.S. Bus, and C.S. Barrow. 1982. Nonprotein sulfhydryl alterations in F-344 rats following acute methyl chloride inhalation. Toxicol. Appl. Pharmacol. 62(2):228-236. (2) Mitchell, R.I., K. Pavkov, R.M. Everett, and D.A. Holzworth. 1979. A Ninety Day Inhalation Toxicology Study in F-344 Albino Rats and B6C3F1 Mice Exposed to Atmospheric Methyl Chloride Gas. Battelle Columbus Laboratories. Microfiche No. OTS0205952. Test species/Strain/Number: (1) groups of 20 male F344 rats; (2) 10 male and 10 female F344 rats/group Exposure route/Concentrations/Durations: Inhalation, (1) 0, 100, 500, or 1,500 ppm for 6 h; (2) 0, 375, 750, or 1,500 ppm, 6 h/day, 5 days/week for 90 days. Effects: (1) no clinical signs; (2) no clinical signs, no tissue lesions, increased liver weight at 1,500 ppm. End point/Concentration/Rationale: NOAEL for clinical signs and tissue lesions. Uncertainty factors/Rationale: Total uncertainty factor: 3 Interspecies: 1, uptake is greater in rodents than in humans as measured by blood concentrations. Intraspecies: 3, differences in uptake (by a factor of 2-3) and metabolism among humans are not considered toxicologically significant. Modifying factor: Not applicable Animal-to-human dosimetric adjustment: Not applied Time scaling: Cn × t = k; default values of n = 3 for durations shorter than 6 h and n = 1 for durations longer than 6 h. Because of the long exposure durations of the key studies, the 10-min value was set equal to the 30-min value. (Continued)

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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. Animal tissues were examined microscopically after the 90-day exposure. The AEGL values are supported by a monitoring study in which accidental, repeat exposures to methyl chloride at 1,000-4,000 ppm (duration not known) resulted in transient neurotoxic symptoms (MacDonald 1964). The values are also supported by clinical studies in which no effects were observed after a 3.5-h exposure at 200 ppm (Putz-Anderson et al. 1981b) or after a 7.5-h exposure (with exercise) at 150 ppm (Stewart et al. 1980). AEGL-3 VALUES 10 min 30 min 1h 4h 8h 3,800 ppm 3,800 ppm 3,000 ppm 1,900 ppm 1,300 ppm Key references: (1) Morgan, K.T., J.A. Swenberg, T.E. Hamm, Jr., R. Wolkowski-Tyl, and M. Phelps. 1982. Histopathology of acute toxic response in rats and mice exposed to methyl chloride by inhalation. Fundam. Appl. Toxicol. 2(6):293-299. (2) Chellman, G.J., K.T. Morgan, J.S. Bus, and P.K. Working. 1986a. Inhibition of methyl chloride toxicity in male F-344 rats by the anti-inflammatory agent BW755C. Toxicol. Appl. Pharmacol. 85(3):367-379. Test species/Strain/Number: (1) Groups of 10 male and 10 female F344 rats; (2) groups of 5 male F344 rats Exposure route/Concentrations/Durations: Inhalation, (1) 5,000 ppm for 6 h/day, 12 days; (2) 5,000 ppm for 6 h/day, 5 days. Effects: (1) moribund state in 11/20 rats on day 5, tissue and organ lesions; (2) death of 1/5 on day 5. End point/Concentration/Rationale: Threshold for lethality on day 1 at exposure concentration of 5,000 ppm. Uncertainty factors/Rationale: Total uncertainty factor: 3 Interspecies: 1, uptake is greater in rodents than in humans as measured by blood concentrations. Intraspecies: 3, differences in uptake (by a factor of 2-3) and metabolism among humans are not considered toxicologically significant. Modifying factor: Not applicable Animal-to-human dosimetric adjustment: Not applied Time scaling: Cn × t = k; default values of n = 3 for durations shorter than 6 h and n = 1 for durations longer than 6 h. Because of the long exposure durations of the key studies, the 10-min value was set equal to the 30-min value. (Continued)

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287 Methyl Chloride 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 1,000- 4,000 (durations not known) resulted in transient neurotoxic symptoms (MacDonald 1964).