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5
Methyl Bromide1
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).
171
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172 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 bromide is a colorless, nonflammable gas, with no taste or odor
properties at low concentrations. Methyl bromide is currently used as a fumigant
for buildings and soil and as a methylation agent in industry. Methyl bromide is
an effective herbicide, rodenticide, nematicide, insecticide, bactericide, and fun-
gicide. In the past, it was used as a refrigerant and fire extinguisher. Worldwide
consumption of methyl bromide in 1996 was approximately 68 thousand metric
tons. It is available as a liquefied gas in steel cylinders or cans.
Although numerous reports of accidental exposure of humans to methyl
bromide that resulted in neurotoxicity or deaths are available in the literature,
reliable information on exposure concentrations was not available. Acute, re-
peat-exposure, subchronic, and chronic studies, primarily with rats and mice,
were available. Human case reports and controlled animal studies document that
the central nervous system (CNS) is the primary target of methyl bromide. Neu-
rotoxic symptoms can be delayed for several hours. Extremely high concentra-
tions also produce lung edema. The mechanism-of-action of monohalomethanes
is not completely understood, but could involve metabolism via the glutathione-
S-transferase (GST) pathway to products that alkylate or inactivate cellular pro-
teins. Species with higher cellular concentrations of GST appear to be more sen-
sitive to the effects of methyl bromide than those with lower concentrations. The
same is true for humans because of genetic polymorphisms of GST in the human
population.
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173
Methyl Bromide
Data from animal studies were available on lethal and sublethal concentra-
tions, neurotoxicity, developmental and reproductive effects, genotoxicity, and
potential carcinogenicity. Although genotoxicity studies show that alkylation of
DNA and proteins occurs, carcinogenicity has not been established in chronic
studies with rats and mice. The dose-response curve for lethality is steep and the
margin of safety between no-effect and lethal values is small. Data from rat and
mouse studies show that the concentration-response curve for 50% lethality
(LC50 values) over exposure durations of 3.5-480 min can be determined with
the equation C1.2 × t = k.
Methyl bromide has no odor or irritation properties at concentrations be-
low those that define the AEGL-2 values. Therefore, AEGL-1 values were not
established.
The AEGL-2 values are based on the no-observed-adverse-effect level
(NOAEL) for neurotoxicity, as evidenced by a lack of clinical signs in studies
with rats and dogs. The weight-of-evidence from those studies indicates that 200
ppm of methyl bromide for 4 h is the threshold concentration for neurotoxicity
(Hurtt et al. 1988; Hastings 1990; Japanese Ministry of Labour 1992; Newton
1994a). Reversible impairment of olfactory function (lesions of the olfactory
epithelium) was observed in the rat (Hurtt et al. 1988; Hastings 1990; Japanese
Ministry of Labour 1992). These lesions are specific to the nasal olfactory epi-
thelium of the rat, based on nasal air flow patterns (Bush et al. 1998; Frederick
et al. 1998), so it is unlikely that such lesions would occur in primates at the
same exposure concentration and duration. Because uptake of methyl bromide is
greater in rodents than in humans (based on comparative respiratory rates and
comparisons with methyl chloride) and because GST concentrations in rodents
are greater than in humans (resulting in more rapid production of toxic metabo-
lites), an interspecies uncertainty factor of 1 was applied. Humans differ in their
capacity to metabolize the related chemical methyl chloride; but, toxicologi-
cally, the difference is thought to be less than 3-fold (Nolan et al. 1985). There-
fore, an intraspecies uncertainty factor of 3 was applied. The resulting 4-h value
of 67 ppm was time scaled to the other exposure durations using the equation Cn
× t = k, with n = 1.2. The value of n was based on lethality studies in rats. The
mechanism for delayed neurotoxic effects (AEGL-2) and death (AEGL-3) are
assumed to be the same. Because the time-scaled 8-h AEGL-2 value of 37 ppm
is close to the chronic NOAEL of 33 ppm for mice (NTP 1992), is less than the
4-day NOAEL of 55 ppm for clinical signs and tissue lesions in dogs (Newton
1994a), and less than the 36-week NOAEL of 55 ppm for neurobehavioral pa-
rameters and nerve conduction velocity in rats (Anger et al. 1981), the 8-h value
was set equal to the 4-h AEGL-2 value of 67 ppm.
Because of differences in methyl-halide metabolism between mice and
other rodents and the greater sensitivity of mice to the structurally-similar
chemical methyl chloride (metabolism is also by the glutathione [GHS] path-
way), the mouse was not considered an appropriate model from which to derive
AEGL values for methyl bromide. The AEGL-3 values were based on the
BMCL05 (benchmark concentration, 95% lower confidence limit with 5% re-
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174 Acute Exposure Guideline Levels
sponse) of 701 ppm in a 4-h exposure study of rats (Kato et al. 1986). The
BMCL05 was also the highest nonlethal value in the study. An interspecies un-
certainty factor of 1 and an intraspecies uncertainty factor of 3 were applied, as
was done in the calculation of AEGL-2 values. For time scaling (Cn × t = k), n
was set equal to 1.2, based on lethality data in the rat. Because uptake of methyl
bromide is greater in rodents than in humans (based on comparative respiratory
rates and comparisons with methyl chloride) and because GST concentrations in
rodents are higher than in humans (resulting in more rapid production of toxic
metabolites), an interspecies uncertainty factor of 1 was considered sufficient.
Humans differ in their capacity to metabolize methyl bromide, but toxicologi-
cally the difference is not thought to be greater than 3-fold (Nolan et al. 1985).
An intraspecies uncertainty factor of 3 is supported by the steep dose-response
curve for lethality by methyl bromide, which indicates that there might be little
intraspecies variation. Furthermore, a larger uncertainty factor would result in
values that would be near the AEGL-2 values. Therefore, an intraspecies uncer-
tainty factor of 3 was considered sufficient. The 8-h AEGL-3 value of 130 ppm
is supported by a repeat-dose study in which dogs exposed to methyl bromide at
156 ppm for 7 h/day did not exhibit severe clinical signs until the third day of
exposure (Newton 1994a). There were no remarkable histopathologic lesions at
autopsy.
The AEGL values for methyl bromide are presented in Table 5-1.
TABLE 5-1 Summary of AEGL Values for Methyl Bromide
End Point
Classification 10 min 30 min 1h 4h 8h (Reference)
NRa NRa NRa NRa NRa
AEGL-1
(nondisabling)
AEGL-2 940 ppm 380 ppm 210 ppm 67 ppm 67 ppm NOAEL for
(disabling) (3,657 (1,478 (817 (261 (261 clinical signs
mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) in rats and
dogs (Hurtt
et al. 1988;
Hastings
1990;
Japanese
Ministry of
Labour 1992;
Newton
1994a)
AEGL-3 3,300 ppm 1,300 ppm 740 ppm 230 ppm 130 ppm BMCL05 in
(lethal) (12,837 (5,057 (2,879 (895 (506 rats (Kato et
mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) al. 1986)
a
Numerical values are not recommended because the data indicate that toxic effects might
occur below the odor threshold for methyl bromide. Absence of an AEGL-1 value does
not imply that exposure below the AEGL-2 value is without adverse effects.
Abbreviations: BMCL05, benchmark concentration, 95% lower confidence limit with 5%
response; NOAEL, no-observed-adverse-effect level; NR, not recommended.
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175
Methyl Bromide
1. INTRODUCTION
Methyl bromide is a colorless, highly volatile gas that exists as a liquid be-
low 3.6°C. It is heavier than air. Methyl bromide is nonflammable over a wide
range of concentrations in air, and poses practically no fire hazard. These physi-
cal properties result in excellent penetration properties and make it a good fumi-
gant. Additional chemical and physical properties are listed in Table 5-2.
Methyl bromide is ubiquitous in the environment, because it is generated
naturally by oceans, biomass burning, and plants. For industrial purposes, methyl
bromide is produced by direct bromination of methane and by the hydrobromina-
tion of methanol (Davis et al. 1977; O’Neil et al. 2001; Ioffe and Kampf 2002).
Sulfur or hydrogen sulfide may be added as reducing agents to the methanol and
sodium bromide. Anthropogenic methyl bromide is used mainly as a fumigant. It
is an effective herbicide, rodenticide, nematicide, insecticide, bactericide, and fun-
gicide, and has been used commercially in the United States for most of the twen-
tieth century for the fumigation of soil, structures (such as warehouses), and food
commodities, as well as for quarantine purposes (Duafala and Gillis 1999). Ap-
proximately 77% is used in preplanting fumigation of soil (IPCS 1995). In 1995,
between 25,000 and 27,000 tons of methyl bromide were applied as a fumigant in
the United States. Methyl bromide is also used as an intermediate for the manufac-
ture of pharmaceuticals, in ionization chambers, for degreasing wool, and for ex-
tracting oils from nuts, seeds, and flowers (O’Neil et al. 2001; Ioffe and Kampf
2002). In the past, methyl bromide was used in fire extinguishers, as a refrigerant,
and even as an anesthetic agent in dentistry (Alexeeff and Kilgore 1983).
In 1996, world consumption of methyl bromide was 68.4 thousand metric
tons (Ioffe and Kampf 2002). The U.S. Environmental Protection Agency (EPA
2011) lists the production range of methyl bromide as 16.4 million pounds in
2003 and 1.8 in 2010. Production has decreased because of environmental con-
cerns about depletion of the ozone layer by such chemicals.
Methyl bromide is easily liquefied, and is commercially available as a liq-
uefied gas contained in steel cylinders or cans, usually under its own pressure of
about two atmospheres (Braker and Mossman 1980; IPCS 1995; Duafala and
Gillis 1999). Nitrogen or carbon dioxide may be added before shipment to per-
mit rapid ejection at low temperatures. Formulations for soil fumigation contain
chloropicrin (2%) or amyl acetate (0.3%) as warning agents.
2. HUMAN TOXICITY DATA
2.1. Odor Threshold
Methyl bromide has almost no odor or irritating effect, even at physiologi-
cally hazardous concentrations (Reid 2001). Reported odor thresholds vary from
20 to 1,000 ppm (Van den Oever et al. 1982; Sittig 1985; Ruth 1986). The odor
of methyl bromide has been described as sweetish and similar to chloroform
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176 Acute Exposure Guideline Levels
(O’Neil et al. 2001), musty or fruity at concentrations above 1,000 ppm (Mar-
raccini et al. 1983; ATSDR 1992), or faintly acrid at around 500 ppm (Hustinx
et al. 1993). Methyl bromide has a burning taste, and contact with the skin may
cause frostbite (O’Neil et al. 2001). When methyl bromide is used as a structural
fumigant, it may react with sulfur-containing materials in buildings to produce a
persistent odor (Anger et al. 1986).
The addition of 2% chloropicrin as a warning agent (a potent lacrimator
sensed at 1.3 ppm) to some preparations of methyl bromide intended for fumiga-
tion (IPCS 1995; Reid 2001) is of limited safety efficacy, because chloropicrin
vapor typically disappears before the methyl bromide vapor dissipates.
2.2. Toxicity and Neurotoxicity
The toxicity of methyl bromide has been reviewed by EPA (1980, 1992),
Alexeeff and Kilgore (1983), ATSDR (1992), IPCS (1995), Yang et al. (1995),
Reid (2001), OECD SIDS (2002), and HSDB (2010). A review of the literature
published in 1983 documented 115 fatalities, 523 systemic illnesses, and 242
skin and eye injuries on a worldwide basis (Alexeeff and Kilgore 1983).
TABLE 5-2 Chemical and Physical Properties of Methyl Bromide
Parameter Value Reference
Synonyms Bromomethane, monobromomethane, O’Neil et al. 2001
methyl fume, isobrome
CAS registry no. 74-83-9 O’Neil et al. 2001
Chemical formula CH3Br O’Neil et al. 2001
Molecular weight 94.95 O’Neil et al. 2001
Physical state Colorless gas (above 4°C) O’Neil et al. 2001
Melting point -93.7°C Reid 2001
Boiling point 3.56°C Reid 2001
Density O’Neil et al. 2001
Vapor 3.97 g/L at 20°C (air = 1)
Liquid 1.73 g/mL at 4°C (water = 1)
Solubility 1.75 g/100 g in water at 20°C, 748 mm Hg O’Neil et al. 2001
Vapor pressure 1,420 mm Hg at 20°C O’Neil et al. 2001
Flammability limits Practically nonflammable; flame Reid 2001
propagation range is 13.5-14.5% by
volume in air; ignition temperature is
537°C; burns in O2
1 ppm = 3.89 mg/m3 at 25°C
Conversion factors Reid 2001
1 mg/m3 = 0.257 ppm
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177
Methyl Bromide
Most cases of accidental exposures have involved manufacturing or pack-
aging operations, use of fire extinguishers containing methyl bromide, or fumi-
gation activities. Exposures at high concentrations may occur during fumigation
activities, especially when methyl bromide is first released to the environment
after fumigation ends, or when fumigated areas are not properly ventilated.
When methyl bromide is used as a storage fumigant, its concentrations usually
range from 4,112 to 25,700 ppm for 2-3 days; higher concentrations are required
to kill eggs and pupae. Accidental inhalation exposure incidents have occurred
during atmospheric inversions, which prevent methyl bromide gas from rising
and dispersing into the troposphere, or when children, adults, or animals enter
sealed, fumigated structures. Most human exposure data on methyl bromide are
from its use as an agricultural fumigant. It is applied to soil under plastic sheets
or used in space fumigation under tarpaulins. It is also applied to a variety of
agricultural commodities in specially designed fumigation chambers. Worker
exposure may result from leaks in the plastic sheets or tarpaulin or from failure
to allow adequate time for the methyl bromide to dissipate following fumigation
(NIOSH 1984). The data from these accidental exposures are generally old, and
concentration measurements were either not made or conducted using outdated
analytic techniques. Regardless, estimates of concentrations leading to human
deaths range from 1,600 to 60,000 ppm, depending on duration of exposure
(ATSDR 1992).
The primary target of toxicity in humans accidentally or occupationally
exposed to methyl bromide is the CNS (Alexeeff and Kilgore 1983; O’Neil et al.
2001). Symptoms of overexposure by inhalation to methyl bromide are head-
ache, visual disturbance, vertigo, nausea, vomiting, anorexia, irritation of the
respiratory system, abdominal pain, malaise, muscle weakness, incoordination,
slurring of speech, staggering gait, hand tremor, convulsions, mental confusion,
dyspnea, pulmonary edema, coma, and death from respiratory or circulatory
collapse (O’Neil et al. 2001). Severe exposures may result in bronchial or pul-
monary inflammation and pulmonary edema, which may not appear for 24 h or
more after exposure. Death may occur from respiratory or cardiovascular failure.
Exposure to methyl bromide has been known to adversely affect the kidneys,
eyes, liver, and skin. Methyl bromide is an insidiously-acting chemical because
of its lack of odor or immediate irritating properties at low concentrations (Reid
2001), and because signs of exposure are often delayed. In severe cases of poi-
soning, recovery can be protracted, with persisting neurologic problems.
Inhalation is the most significant route of exposure to methyl bromide, al-
though skin absorption does occur. Standard protective clothing did not protect
fumigators wearing respirators from developing skin lesions during two 20-min
exposures at concentrations estimated to be about 9,000 ppm (Zwaveling et al.
1987; Hezemans-Boer et al. 1988). Absorption of methyl bromide was indicated
by bromide concentrations in the blood.
Numerous case reports of methyl bromide exposure are described in the
literature. In these reports, concentrations are either unknown or were measured
or calculated after the incident. Analytic methods used in older studies, such as
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178 Acute Exposure Guideline Levels
colorimetry, have limited sensitivity. For example, Watrous (1942) describes
both mild symptoms and more severe symptoms of nausea, vomiting, headache,
and skin lesions in workers exposed for up to 2 weeks. Measurements of methyl
bromide were generally less than 35 ppm, but exposures were based on a color
detection method (methanol torch) with a lower detection limit of 35 ppm. Ana-
lytic methods for detecting higher concentrations involved flame colorimetry, an
imprecise method. The exposures were complicated by accidents and routine
dermal contact with the cooled liquid. In a factory where fire extinguishers were
filled with methyl bromide, one death occurred (accompanied by convulsions)
and another employee suffered less severe effects (Tourangeau and Plamondon
1945). Measurements taken at 30 min and 1 h had methyl bromide at concentra-
tions of 297-390 ppm in front of the hood, where filling took place. Three addi-
tional nonfatal cases are described as examples below. Two of these cases also
measured or estimated concentrations after the event. These cases are followed
by a description of study of neurologic changes in methyl bromide applicators.
Because over 50 cases of methyl-bromide poisoning were reported in date
processing and packaging plants in Southern California, Ingram (1951) and
Johnstone (1945) conducted a series of surveys in 40 plants. Fumigation took
place in a chamber that opened directly into the employee’s workroom. Appro-
priate amounts of methyl bromide were released from 50-pound drums or by
using 2-pound or 1-pound cans. Exhaust systems were generally inadequate to
dissipate the fumes following fumigation. Tests in these plants showed methyl
bromide at concentrations up to 100 ppm in the general workroom air, up to 500
ppm near the walls of ineffectively sealed chambers, and over 1,000 ppm at the
breathing zone of workers entering the fumigation chamber. Semiquantitative
measurements were made with a halide torch, and average concentrations over
time were measured colorimetrically with a halogenated-hydrocarbon apparatus.
Hustinx et al. (1993) described an accidental exposure during greenhouse
fumigation. Nine individuals were inadvertently exposed while working in an
enclosed area adjacent to the area being fumigated. The areas were separated by
a poorly sealed partition. Three weeks earlier, the portion of the greenhouse in
which the accident occurred had been fumigated with methyl bromide at 200
g/m2 (five times greater than the legally allowable concentration of 40 g/m2). At
that time, two of the five workers in the nonfumigated section experienced nau-
sea, vomiting, and dizziness. During fumigation, the highest methyl bromide
concentration (25 ppm) was measured near the partition in the nonfumigated
portion of the greenhouse. Measurements were made with Drager gas detectors
(lower detection limit of 3-5 ppm). On the day before the accident (3 weeks after
fumigation of the first greenhouse section), all nine workers were in the nonfu-
migated portion of the greenhouse for an average of 6 h (range of 4-8 h). Most
workers experienced nausea and headache that day, and two of them stayed
home the following day. The next day, fumigation was carried out in the previ-
ously nonfumigated section of the greenhouse, while the laborers worked in the
section that had been fumigated 3 weeks earlier. After spending 2 h at work, all
but one of the remaining seven workers experienced sudden and almost simulta-
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179
Methyl Bromide
neous nausea, dizziness, and vomiting (the one exception experienced only a
slight burning sensation in the throat). All seven workers left the greenhouse and
went home. Within 2 h, two workers developed twitching of all limbs followed
by generalized and continuous seizure activity, necessitating the induction of a
sodium thiopental coma to stop the seizures. Methyl bromide concentrations
ranged from 200 ppm near the partition to 150 ppm at the far end of the nonfu-
migated section 5 h after the accident, suggesting that the actual exposure was
≥200 ppm. Three days after admission to the hospital, chest x-rays revealed uni-
lateral infiltration and pleural effusion, which subsided over the next 10-14 days.
The thiopental coma was withdrawn after 3 weeks from the two severely af-
fected patients, who then manifested persistent signs of axonal neuropathy.
These signs improved only slightly over 6 months. Both workers had exhibited
similar rises in serum alanine aminotransferase, aspartate aminotransferase, and
lactic acid dehydrogenase activities, which peaked on the sixth day after admis-
sion and returned to normal before the thiopental treatment was discontinued,
suggesting the increased activities reflected a methyl-bromide-related hepatic
effect. The other seven patients experienced remarkably uniform signs, which
included headache, nausea, and a “floating” sensation. Within 19 days after the
accident, all residual complaints had disappeared in these seven patients. An
unused, dry set of drainage pipes that crossed the entire length of both green-
house sections was identified as the most likely major cause of the spread of
methyl bromide to the nonfumigated section.
In the third case report, two fumigation workers entered a fumigated build-
ing in which the measured concentration (gas chromatography) was 4,370 ppm
(Deschamps and Turpin 1996; Garnier et al. 1996). The workers wore cartridge
respirators, which are saturable within a few minutes at that concentration
(autonomous air flow masks are obligatory under these circumstances). The
workers failed to wait until the concentration had decreased to the recommended
level of 5 ppm. Both workers opened windows and doors in the nine-floor build-
ing over a period of 45 min to 1 h. During the 100-mile journey home, both
workers experienced dizziness, fatigue, nausea, vomiting, chest pain, and short-
ness of breath. They were admitted to a hospital where the condition of the one
improved rapidly. The other patient experienced convulsions, ataxia, and kidney
failure. His tremors and ataxia were still present 5 months later (he experienced
permanent neurologic damage). Bromide concentrations in the blood measured
40-48 h after admittance to the hospital were 47 and 156 mg/L in the first and
second patient, respectively. Inspection of the charcoal cartridges of the respira-
tors showed a concentration bromide greater than 10 mg/g; the highest concen-
tration was found in the cartridge of the most injured worker.
Verberk et al. (1979) described bromine in the blood, electroencephalo-
graphic (EEG) disturbances, liver function (serum transaminases), serum pro-
teins, and neurologic changes in 33 men engaged in soil disinfection inside
greenhouses. Duration of employment ranged from a few months to 11 years.
The amount of methyl bromide applied within the past year ranged from 1,500
to 6,000 kg. The relationship between different factors was based on a product-
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180 Acute Exposure Guideline Levels
moment correlation coefficient or Student’s t-test. No relationship was found
between bromine concentration in blood and subjective symptoms, general neu-
rologic deficits, or serum proteins. Slight EEG changes and a small increase in
serum transaminases were related to blood concentrations of bromine. The au-
thors considered the effects marginal.
2.3. Developmental and Reproductive Toxicity
No studies were found on reproductive or developmental effects in hu-
mans after inhalation of methyl bromide.
2.4. Genotoxicity
Liquid methyl bromide tested positive for sister chromatid exchanges
(SCE) in in vitro tests with human lymphocytes (Tucker et al. 1986; Garry et al.
1990). When people who are GSH conjugators and nonconjugators were tested,
methyl bromide tested positive for SCE in lymphocytes from GSH nonconjuga-
tors but not in lymphocytes from GSH conjugators (Hallier et al. 1990). See
Section 4.4.2 for an explanation of human variability in GSH conjugation.
2.5. Carcinogenicity
EPA has classified methyl bromide as a Group D carcinogen, “not classi-
fiable as to human carcinogenicity” (EPA 1992). On the basis of animal studies,
the National Institute for Occupational Safety and Health characterizes methyl
bromide as a “potential occupational carcinogen” (NIOSH 2010). The Interna-
tional Agency for Research on Cancer (IARC 1999) has determined that there is
limited evidence for carcinogenicity in animals and inadequate evidence in hu-
mans. The overall evaluation states that methyl bromide “is not classifiable as to
its carcinogenicity to humans” (Group 3). The American Conference of Gov-
ernmental Industrial Hygienists (ACGIH 2004) classifies methyl bromide as A4,
“not classifiable as a human carcinogen.”
Alavanja et al. (2003) investigated the link between exposure to 45 com-
mon agricultural pesticides and the eventual development of prostate cancer in a
cohort of 55,332 initially healthy male pesticide applicators in Iowa and North
Carolina. The data were collected by self-administered questionnaires that were
completed at enrollment (1993-1997). The incidence of cancer in the general
population was determined through cancer registries between the time of en-
rollment through the end of 1999, and a prostate cancer standardized incidence
ratio was computed for the cohort. Odds ratios were determined for individual
pesticides and for pesticide use patterns identified by the use of factor analysis.
Over a period of 4 years, 566 of the men developed prostate cancer, a number
greater than the total number of expected prostate cancer cases (494.5; odds ra-
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181
Methyl Bromide
tio of 1.14), based on state age-adjusted incidence rates. Among the 45 pesti-
cides studied, only methyl bromide use showed a statistically significant expo-
sure-response trend. The data suggested that if methyl bromide is responsible for
the increased incidence of prostate cancer, this effect occurs only in those indi-
viduals with relatively frequent exposure. Limitations of this study acknowl-
edged by the authors include the fact that the method of data collection was sub-
ject to significant recall bias, particularly in participants who had been exposed
to the pesticides many years prior to the study. In addition, no direct measure-
ments of pesticide exposure were obtained for the study. The follow-up period
for the study was relatively short (an average of 4.3 years), precluding the
evaluation of time-dependent exposures and risk. Finally, the authors acknowl-
edged that the finding of increased risk of prostate cancer from the combined
effect of exposure to several pesticides and a family history of prostate cancer
was somewhat unexpected, and that the study must be replicated before any rec-
ommendations can be made.
2.6. Summary
Methyl bromide has been responsible for many occupational poisoning in-
cidents, reflecting its wide use as a fumigant. Although many occupational and
accidental exposures to methyl bromide have occurred, few cases have accu-
rately documented exposure concentrations or durations. Methyl bromide is
practically odorless, even at lethal concentrations. Descriptive symptoms indi-
cate methyl bromide acts on the CNS (e.g., headache, visual disturbance, mental
disturbance, nausea, vomiting) and directly on the lungs (lung edema). Case
reports indicate that daily exposure to methyl bromide at 35 ppm (with possible
dermal contact) and acute exposures to several hundred ppm can cause mild to
severe symptoms.
3. ANIMAL TOXICITY DATA
3.1. Acute Lethality
Early studies with several species of mammals were carried out by Irish et
al. (1940) and Sayers et al. (1929). These reports lack details, used obsolete ana-
lytic methods, and used visual inspection rather than standard neurotoxicity tests
to assess behavioral deficits. The studies are described here for completeness,
but were not considered in the determination of AEGL values. Rats and rabbits
were given single exposures to methyl bromide at a series of concentrations
which resulted in either 100% mortality or 100% survival (Irish et al. 1940). The
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100% when exposures at the respective concentrations were 3, 6, and 25 min
OCR for page 222
222 Acute Exposure Guideline Levels
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225
Methyl Bromide
APPENDIX A
TIME-SCALING CALCULATION FOR METHYL BROMIDE
Best Fit Concentration x Time Curve
4.5
4
Log Concentration (ppm)
3.5
3
2.5
2
0.5 1 1.5 2 2.5 3
Log Time (minutes)
FIGURE A-1 Regression line of LC50 data in rats. Source: Data from Bakhishev 1973;
Honma et al. 1985; Kato et al. 1986; Zwart 1988).
Data:
Time (min) Concentration (ppm) Log time Log concentration
3.5 19,460 0.5441 4.2891
30 2,830 1.4771 3.4518
60 1,880 1.7782 3.2742
240 780 2.3802 2.8921
480 302 2.6812 2.4800
480 334 2.6812 2.5237
Regression Output:
Intercept 4.7129
Slope -0.8115
R Squared 0.9914
Correlation -0.9957
Degrees of Freedom 4
Observations 6
n = 1.23
k = 642,119
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226 Acute Exposure Guideline Levels
APPENDIX B
DERIVATION OF AEGL VALUES FOR METHYL BROMIDE
Derivation of AEGL-1 Values
AEGL-1 values are not recommended because toxic effects might occur
below the odor threshold for methyl bromide. Absence of AEGL-1 values does
not imply that exposures below the AEGL-2 values are without adverse effects.
Derivation of AEGL-2 Values
Key studies: Hurtt, M.E., D.A. Thomas, P.K. Working,
T.M. Monticello, and K.T. Morgan. 1988.
Degeneration and regeneration of the olfactory
epithelium following inhalation exposure to
methyl bromide: pathology, cell kinetics, and
olfactory function. Toxicol. Appl. Pharmacol.
94(2):311-328.
Hastings, L. 1990. Sensory neurotoxicology:
Use of the olfactory system in the assessment of
toxicity. Neurotoxicol. Teratol. 12(5):455-459.
Japanese Ministry of Labour. 1992. Toxicology
and Carcinogenesis Studies of Methyl Bromide
in F344 Rat and BDF Mice (Inhalation Studies).
Industrial Safety and Health Association,
Japanese Bioassay Laboratory, Tokyo (as cited
in IPCS 1995).
Newton, P.E. 1994a. An Up-and-Down Acute
Inhalation Toxicity Study of Methyl Bromide in
the Dog. Study No. 93-6067. Pharmaco LSR,
East Millstone, NJ.
Toxicity end points: Clinical signs of neurotoxicity, NOAEL is 200
ppm for 4 h
C1.2 × t = k, based on rat lethality data
Time scaling:
k = (200 ppm ÷ 3)1.2 × 240 min
k = 37,059.7 ppm-min
Uncertainty factors: 1 for interspecies differences
3 for intraspecies differences
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227
Methyl Bromide
Modifying factor: Not applied
Calculations:
C1.2 = 37,059.7 ppm-min ÷ 10 min
10-min AEGL-2:
C = 940 ppm
C1.2 = 37,059.7 ppm-min ÷ 30 min
30-min AEGL-2:
C = 380 ppm
C1.2 = 37,059.7 ppm-min ÷ 60 min
1-h AEGL-2:
C = 210 ppm
C1.2 = 37,059.7 ppm-min ÷ 240 min
4-h AEGL-2:
C = 67 ppm
8-h AEGL-2: Set equal to the 4-h AEGL-2 of 67 ppm
(If based on a chronic NOAEL of 33 ppm for
mice (NTP 1992), a 4-day NOAEL of 55 ppm
for clinical signs and tissue lesions in dogs
(Newton 1994a), and the 36-week NOAEL of
55 ppm for neurobehavioral parameters and
nerve conduction velocity in rats (Anger et al.
1981), the time-scaled value would be 37 ppm.)
Derivation of AEGL-3 Values
Key study: Kato, N., S. Morinobu, and S. Ishizu. 1986.
Subacute inhalation experiment for methyl
bromide in rats. Ind. Health 24(2):87-103.
Toxicity end point: BMCL05 of 701 ppm in the rat
C1.2 × t = k, based on rat lethality data.
Time scaling:
k = (701 ppm ÷ 3)1.2 × 240 min
k = 166,927.3 ppm-min
Uncertainty factors: 1 for interspecies differences
3 for intraspecies variability
Modifying factor: Not applied
Calculations:
C1.2 = 166,927.3 ppm-min ÷ 10 min
10-min AEGL-3:
C = 3,300 ppm
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228 Acute Exposure Guideline Levels
30-min AEGL-3: C = 166,927.3 ppm-min ÷ 30 min
C = 1,300 ppm
1-h AEGL-3 C = 166,927.3 ppm-min ÷ 60 min
C = 740 ppm
4-h AEGL-3: C = 166,927.3 ppm-min ÷ 240 min
C = 230 ppm
8-h AEGL-3: C = 166,927.3 ppm-min ÷ 480 min
C = 130 ppm
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229
Methyl Bromide
APPENDIX C
CATEGORY GRAPH OF TOXICITY DATA AND
AEGL VALUES FOR METHYL BROMIDE
100000
10000
No Effect
Discomfort
ppm
1000
Disabling
AEGL-3
Some Lethality
100
AEGL-2 Lethal
10
0 60 120 180 240 300 360 420 480
Minutes
FIGURE C-1 Category graph of toxicity data on methyl bromide compared with AEGL
values. All of the toxicity data pertain to laboratory animals; no clinical data were avail-
able.
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230 Acute Exposure Guideline Levels
APPENDIX D
ACUTE EXPOSURE GUIDELINE LEVELS FOR METHYL BROMIDE
Derivation Summary for Methyl Bromide
AEGL-1 VALUES
AEGL-1 values are not recommended because toxic effects might occur
below the odor threshold for methyl bromide. Absence of AEGL-1 values does
not imply that exposures below the AEGL-2 values are without adverse effects.
AEGL-2 VALUES
10 min 30 min 1h 4h 8h
940 ppm 380 ppm 210 ppm 67 ppm 67 pm
Key references:
(1) Hurtt, M.E., D.A. Thomas, P.K. Working, T.M. Monticello, and K.T. Morgan.
1988. Degeneration and regeneration of the olfactory epithelium following
inhalation exposure to methyl bromide: Pathology, cell kinetics, and olfactory
function. Toxicol. Appl. Pharmacol. 94(2):311-328.
(2) Hastings, L. 1990. Sensory neurotoxicology: Use of the olfactory system in
the assessment of toxicity. Neurotoxicol. Teratol. 12(5):455-459.
(3) Japanese Ministry of Labour. 1992. Toxicology and Carcinogenesis Studies
of Methyl Bromide in F344 Rat and BDF Mice (Inhalation Studies). Industrial
Safety and Health Association, Japanese Bioassay Laboratory, Tokyo (as cited
in IPCS 1995).
(4) Newton, P.E. 1994a. An Up-and-Down Acute Inhalation Toxicity Study of
Methyl Bromide in the Dog. Study No. 93-6067. Pharmaco LSR, East Millstone, NJ.
Test species/Strain/Number: (1) dog/beagle/1 (with support from higher and lower
exposures; (2) rat/not specified/30; (3) rat/F-344/10 male and 10 female; and (4)
rat/male F-344/15
Exposure route/Concentrations/Durations: Inhalation, (1) 233 ppm for 5 h; (2) 200
ppm for 4 h; (3) 225 ppm for 4 h; and (4) 200 ppm for 6 h
Effects:
(1) No toxic signs or brain lesions; (2) no clinical signs; (3) reversible metaplasia of
the olfactory epithelium; and (4) no clinical signs, reversible olfactory epithelium
degeneration.
End point/Concentration/Rationale: Threshold for neurotoxic signs is 200 ppm for 4
h. Neurotoxicity (e.g., ataxia) would inhibit the ability to escape. Olfactory lesions
were considered specific to the rat.
(Continued)
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231
Methyl Bromide
AEGL-2 VALUES Continued
10 min 30 min 1h 4h 8h
940 ppm 380 ppm 210 ppm 67 ppm 67 pm
Uncertainty factors/Rationale:
Total uncertainty factor: 3
Interspecies: 1, based on studies with methyl chloride, uptake is greater in rodents
than in humans; GST concentrations are greater in rodents than humans, resulting in
faster production of toxic metabolites.
Intraspecies: 3, differences in metabolism among humans are no greater than 3-fold
(Nolan et al. 1985).
Modifying factor: Not applied
Animal-to-human dosimetric adjustment: Not applied
Time scaling: C1.2 × t = k, based on lethality studies with the rat.
Data adequacy: Although there are no controlled clinical studies, the database of
experimental animal studies is robust. Studies of dogs exposed to methyl bromide at
156 ppm (no clinical signs for first 2 days) or 268 ppm (severe signs during first day)
indicate that 200 ppm for 4 h would be near the threshold for neurotoxicity in dogs
(Newton 1994a).
AEGL-3 VALUES
10 min 30 min 1h 4h 8h
3,300 ppm 1,300 ppm 740 ppm 230 ppm 130 ppm
Key Reference: Kato, N., S. Morinobu, and S. Ishizu. 1986. Subacute inhalation
experiment for methyl bromide in rats. Ind. Health 24(2):87-103.
Test species/Strain/Number: Male rat/Sprague-Dawley/5 or 10
Exposure route/Concentrations/Durations: Inhalation at 502, 622, 667, 701, 767,
808, 832, or 896 ppm for 4 h
Effects: clinical signs were not described
502 ppm no morality
622 ppm no mortality
667 ppm no mortality
701 ppm no mortality
767 ppm 30% mortality
799 ppm 60% mortality
808 ppm 70% mortality
817 ppm 80% mortality
832 ppm 100% mortality
896 ppm 100% mortality
LC50 = 780 ppm (95% confidence limits of 760-810 ppm)
LC01 = 701 ppm
BMCL05 = 701 ppm
(Continued)
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232 Acute Exposure Guideline Levels
AEGL-3 VALUES Continued
10 min 30 min 1h 4h 8h
3,300 ppm 1,300 ppm 740 ppm 230 ppm 130 ppm
End point/Concentration/Rationale: BMCL05, 701 ppm, threshold for lethality
Uncertainty factors/Rationale:
Total uncertainty factor: 3
Interspecies: 1, based on studies with methyl chloride, uptake is greater in rodents
than in humans; GST concentrations are greater in rodents than humans, resulting in
faster production of toxic metabolites.
Intraspecies: 3, differences in metabolism among humans are no greater than 3-fold
(Nolan et al. 1985). Use of an intraspecies uncertainty factor of 3 is supported by the
steep dose-response curve for lethality which indicates that there might be little
intraspecies variation (see Chapter 6). Furthermore, larger reduction of the AEGL-3
values would result in values near the AEGL-2 values.
Modifying factor: Not applied
Animal-to-human dosimetric adjustment: Not applied
Time scaling: C1.2 × t = k, based on several lethality studies with the rat
Data adequacy: Although reliable human data are lacking, the database of animal
studies is robust, consisting of acute, repeat-exposure, subchronic, chronic,
neurotoxicity, genotoxicity, and carcinogenicity studies.
