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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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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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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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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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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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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.
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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).
