TECHNICAL REPORT DATA
(Please rttd Instructions on the re vene be fort compleringj
1. REPORT NO.
EPA/600/8-88/022
2.
3. REC
4. TITLE AND SUBTITLE
Health Effects Assessment for Broniornethane
5. REPORT DATE
6. PERFORMING ORGANIZATION CODE
7. AUTMOR
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EPA/600/8-88/022
June. 1987
HEALTH EFFECTS ASSESSMENT
FOR BROHOMETHANE
ENVIRONMENTAL CRITERIA AND ASSESSMENT OFFICE
OFFICE OF HEALTH AND ENVIRONMENTAL ASSESSMENT
OFFICE OF RESEARCH AND DEVELOPMENT
U.S. ENVIRONMENTAL PROTECTION AGENCY
CINCINNATI, OH 45268
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DISCLAIMER
This document has been reviewed In accordance with the U.S.
Environmental Protection Agency's peer and administrative review policies
and approved for publication. Mention of trade names or commercial products
does not constitute endorsement or recommendation for use.
11
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PREFACE
This report summarizes and evaluates Information relevant to a prelimi-
nary Interim assessment of adverse health effects associated with bromo-
methane. All estimates of acceptable Intakes and carcinogenic potency
presented In this document should be considered as preliminary and reflect
limited resources allocated to this project. Pertinent toxlcologlc and
environmental data were located through on-line literature searches of the
TOXLINE and the CHEMFATE/DATALOG data bases. The basic literature searched
supporting this document Is current up to June, 1986. Secondary sources of
Information have also been relied upon In the preparation of this report and
represent large-scale health assessment efforts that entail extensive peer
and Agency review. The following Office of Health and Environmental Assess-
ment (OHEA) sources have been extensively utilized:
U.S. EPA. 1980a. Ambient Water Quality Criteria Document for
Halomethanes. Prepared by the Office of Health and Environmental
Assessment, Environmental Criteria and Assessment Office, Cincin-
nati, OH for the Office of Water Regulations and Standards, Wash-
ington, DC. EPA 440/5-80-051. NTIS PB81-117624.
U.S. EPA. 1982. Errata for Ambient Water Quality Criteria
Document for Halomethanes. Prepared by the Office of Health and
Environmental Assessment, Environmental Criteria and Assessment
Office, Cincinnati, OH for the Office of Water Regulations and
Standards, Washington, DC.
U.S. EPA. 1986a. Health and Environmental Effects Profile for
Methyl Bromide. Prepared by the Office of Health and Environmental
Assessment, Environmental Criteria and Assessment Office, Cincin-
nati, OH for the Office of Solid Waste and Emergency Response,
Washington, DC.
U.S. EPA. 1986b. Integrated Risk Information System (IRIS).
Reference dose (RfD) for oral exposure for bromomethane. Online.
(Verification date 09/29/86). Office of Health and Environmental
Assessment, Environmental Criteria and Assessment Office,
Cincinnati, OH.
The Intent In these assessments Is to suggest acceptable exposure levels
for noncardnogens and risk cancer potency estimates for carcinogens
whenever sufficient data were available. Values were not derived or larger
uncertainty factors were employed when the variable data were limited In
scope tending to generate conservative (I.e., protective) estimates.
Nevertheless, the Interim values presented reflect the relative degree of
hazard or risk associated with exposure to the chemlcal(s) addressed.
Whenever possible, two categories of values have been estimated for
systemic toxicants (toxicants for which cancer Is not the endpolnt of
concern). The first, RfLt, (formerly AIS) or subchronlc reference dose, 1s
an estimate of an exposure level that would not be expected to cause adverse
effects when exposure occurs during a limited time Interval (I.e., for an
Interval that does not constitute a significant portion of the Hfespan).
111
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This type of exposure estimate has not been extensively used, or rigorously
defined, as previous risk assessment efforts have been primarily directed
towards exposures from toxicants In ambient air or water where lifetime
exposure Is assumed. Animal data used for RFD$ estimates generally
Include exposures with durations of 30-90 days. Subchronlc human data are
rarely available. Reported exposures are usually from chronic occupational
exposure situations or from reports of acute accidental exposure. These
values are developed for both Inhalation (RfD$j) and oral (RfD$g)
exposures.
The RfO (formerly AIC) Is similar In concept and addresses chronic
exposure. It Is an estimate of an exposure level that would not be expected
to cause adverse effects when exposure occurs for a significant portion of
the Hfespan [see U.S. EPA (1980b) for a discussion of this concept]. The
RfD 1s route-specific and estimates acceptable exposure for either oral
(RfDn.) or Inhalation (RfDi) with the Implicit assumption that exposure
by other rou-tes 1s Insignificant.
Composite scores (CSs) for noncarclnogens have also been calculated
where data permitted. These values are used for Identifying reportable
quantities and the methodology for their development 1s explained In U.S.
EPA (1984).
For compounds for which there 1s sufficient evidence of cardnogenldty
RfD$ and RfD values are not derived. For a discussion of risk assessment
methodology for carcinogens refer to U.S. EPA (1980b). Since cancer 1s a
process that 1s not characterized by a threshold, any exposure contributes
an Increment of risk. For carcinogens, q-|*s have been computed, 1f appro-
priate, based on oral and Inhalation data 1f available.
1v
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ABSTRACT
In order to place the risk assessment evaluation In proper context,
refer to the preface of this document. The preface outlines limitations
applicable to all documents of this series as well as the appropriate
Interpretation and use of the quantitative estimates presented.
RfD$o (1 nig/day) and RfDg (0.1 mg/day) values for bromomethane were
based on a NOEL of 2 mg/kg 5 days/weeks 1n a 13-week gavage study using rats
(Danse et al., 1984). Hyperplasla of the forestomach, anemia and
atalectosls of the lung occurred at higher levels. The RfDg Is consistent
with an RfD derived In another recent U.S. EPA (1986a) analysis.
RfD$i (5 mg/day) and RfDj (0.5 mg/day) values were based on a NOEL
of 7.6 mg/kg/day associated with exposure to 65 mg/m3 In rabbits (Irish et
al., 1940). Rabbits appeared to be the most sensitive of several species
te-sted. A CS of 27.9 was based on paralysis 1n rabbits at 130 mg/m3 In
the same study (Irish et al., 1940; U.S. EPA, 1986a).
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ACKNOWLEDGEMENTS
The Initial draft of this report was prepared by Syracuse Research
Corporation under Contract No. 68-03-3112 for EPA's Environmental Criteria
and Assessment Office, Cincinnati, OH. Dr. Christopher DeRosa and Karen
Blackburn were the Technical Project Monitors and John Helms (Office of
Toxic Substances) was the Project Officer. The final documents 1n this
series were prepared for the Office of Emergency and Remedial Response,
Washington, DC.
Scientists from the following U.S. EPA offices provided review comments
for this document series:
Environmental Criteria and Assessment Office, Cincinnati, OH
Carcinogen Assessment Group
Office of Air Quality Planning and Standards
Office of Solid Waste
Office of Toxic Substances
Office of Drinking Water
Editorial review for the document series was provided by the following:
Judith Olsen and Erma Durden
Environmental Criteria and Assessment Office
Cincinnati, OH
Technical support services for the document series was provided by the
following:
Bette Zwayer, Jacky Bohanon and K1m Davidson
Environmental Criteria and Assessment Office
Cincinnati, OH
vl
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TABLE OF CONTENTS
Page
1. ENVIRONMENTAL CHEMISTRY AND FATE
2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS
2.1. ORAL
2.2. INHALATION
3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
3.1.1. Oral
3.1.2. Inhalation
3.2. CHRONIC
3.2.1. Oral
3.2.2. Inhalation
1
3
3
3
4
4
4
5
7
7
7
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS.
4.
5.
3.4.
3.3.1. Oral. . .
3.3.2. Inhalation
TOXICANT INTERACTIONS
CARCINOGENICITY ,
4.1.
4.2.
4.3.
4.4.
HUMAN DATA
4.1.1. Oral
4.1.2. Inhalation
BIOASSAYS ,
4.2.1. Oral
4.2.2. Inhalation
OTHER RELEVANT DATA
WEIGHT OF EVIDENCE
REGULATORY STANDARDS AND CRITERIA
8
8
9
. 10
10
10
10
10
10
10
11
11
12
V11
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TABLE OF CONTENTS (cont.)
Page
6. RISK ASSESSMENT 13
6.1. SUBCHRONIC REFERENCE DOSE (RfDs) 13
6.1.1. Oral (RfDso) 13
6.1.2. Inhalation (RfDSI) 13
6.2. REFERENCE DOSE (RfD) 13
6.2.1. Oral (RfD0) 13
6.2.2. Inhalation (RfD]} 14
6.3. CARCINOGENIC POTENCY (q-|*) 14
6.3.1. Oral 14
6.3.2. Inhalation. 16
7. REFERENCES 17
APPENDIX: Summary Table for Bromomethane 25
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LIST OF ABBREVIATIONS
ADI Acceptable dally Intake
CAS Chemical Abstract Service
CS Composite score
DNA Deoxyrlbonuclelc add
PEL Frank-effect level
MED Minimum effective dose
NOAEL No-observed-adverse-effect level
NOEL No-observed-effect level
ppm Parts per million
RfD Reference dose
RfDj Inhalation reference dose
RfDg Oral reference dose
RfD$ Subchronlc reference dose
RfD$j Subchronlc Inhalation reference dose
RfD$o Subchronlc oral reference dose
RQ Reportable quantity
RVd Dose-rating value
RVe Effect-rating value
STEL Short-term-effect level
TLV Threshold limit value
TWA Time-weighted average
1x
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1. ENVIRONMENTAL CHEMISTRY AND FATE
The relevant physical and chemical properties and environmental fate of
bromomethane are presented In Table 1-1. Synonyms for bromomethane are
methyl bromide, monobromomethane, Terabol* and Embafume*.
In the troposphere, the main route of bromomethane degradation 1s
reaction with hydroxyl radicals (Robblns, 1976), and the estimated residence
time of bromomethane as a result of this reaction Is -1 year (Howard and
Evenson, 1976). Based on the tropospheMc lifetime of bromomethane, -354 of
this compound can be expected to reach the stratosphere where It can undergo
direct photolysis (Dllllng, 1982; Robblns, 1976).
Volatilization of bromomethane from water Is likely to be the dominant
removal mechanism from aquatic systems. The average half-life for the loss
of bromomethane from a surface drainage ditch (0.8 m deep) under environ-
mental conditions at 11°C was 6.6 hours Wegman et al. (1981). Other vola-
tilization half-lives listed In Table 1-1 were estimated using a calculated
re-aeration rate ratio and typical oxyten re-aeration rates from typical
water bodies. Hydrolysis may be a significant removal process In water at
pH 7 since the hydrolytlc half-life at 20-25°C Is -20-38 days (Ehrenberg et
al., 1974; Mabey and Mill, 1978).
Brown and Rolston (1980) used soil column tests with a variety of soils
to conclude that most bromomethane used In soil fumigation enters the atmo-
sphere, although a small amount of bromomethane Is chemically transformed
Into bromine Ions. The half-life of bromomethane In soil listed In Table
1-1 Is based on Its volatilization half-life derived from a soil chemical
screening model. There Is a potential for leaching of th1<: chemical Into
groundwater, as Indicated by significant leaching In fumigated greenhouse
soils (Wegman et al., 1981; Vanachter et al., 1981).
0090h -1- 12/17/86
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TABLE 1-1
Selected Physical and Chemical Properties and
Environmental Fate of Bromomethane
Property
Value
Reference
CAS number
Chemical class:
Molecular weight:
74-83-9
bromlnated aliphatic hydrocarbon
94.95
Chemical structure:
H-C-Br
Melting point:
Boiling point:
Vapor pressure:
Water solubility:
Log octanol/water
partition coefficient:
or
Bloconcentratlon factor:
Soil adsorption
coefficient:
Half-lives:
A1r
Hater
Soil
-93.7°C
3.56°C
1420 mm Hg
17,500 mg/8, at 20°C
1.19
3-5 (calculated)
1.0 loamy sandy
10.0 loam
9.5 peaty clay soil
0.5-1.0 year
(estimated)
6.6. hours (0.8 m deep)
1 day (river), estimated
3.9 days (lake,) estimated
5 days (pond), estimated
0.2 days (when applied
1 cm deep), estimated
0.5 days (when applied
10 cm deep), estimated
Stenger, 1978
Stenger, 1978
Stenger, 1978
Stenger, 1978
Hansch and Leo,
1985
Lyman et al., 1982
Daelmans and
SlebeMng, 1977
Davis et al.. 1976
Maklde and Rowland,
1981; Singh et al.,
1981
Hegman et al., 1981
Mabey et al., 1981
Mabey et al., 1981
Mabey et al., 1981
Jury et al., 1984
Jury et al., 1984
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2. ABSORPTION
2.1. ORAL
Approximately 97% of a single oral dose of 250 ymol/kg of 14C-bromo-
methane administered 1n corn oil was absorbed from the gastrointestinal
tract of rats (Medlnsky et al., 1984). By 72 hours after a single oral
dose, <3% of the administered 14C-bromomethane had been recovered from the
feces. Rapid absorption Is Implied by the excretion of -67% of the adminis-
tered radioactivity (-29% In the expired air and -38% 1n the urine) within
the first 20 hours after dosing.
2.2. INHALATION
Medlnsky et al. (1985) exposed rats for 6 hours to atmospheric concen-
trations of 14C-bromomethane of 50, 300, 5700 or 10,400 nmol/i (4.7, 28,
541 or 987 mg/m3) 1n a head-only exposure chamber. Respiratory volumes
were measured and, when combined with measured concentrations, permitted
accurate estimation of the quantity of 14C-bromomethane Inhaled. The rats
were killed Immediately following exposure and the amount of radioactivity
retained 1n the carcass was measured. From the data, the authors determined
that the percentages of Inhaled 14C-bromomethane absorbed at 50, 300, 5700
and 10,400 nmol/8. were 48, 48, 38 and 27%, respectively. The authors
estimated a first-order rate constant for Inhalation absorption for bromo-
methane of 1.6 kg/hour for concentrations up to 6000 nmol/l. They
suggested that saturation of a metabolic pathway for the elimination of
bromomethane may have been responsible for the apparent reduction In absorp-
tion (exposed as percent of Inhaled "dose") at the highest concentration 1n
this experiment. Expressed as vrool/kg body weight equivalent amounts of
14C-bromomethane were absorbed at 5700 and 10,400 nmol/l.
0090h -3- 12/15/86
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3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
3.1.1. Oral. Treatment of groups of 10 male and 10 female Wlstar rats by
gavage with 0, 0.4, 2, 10 or 50 mg/kg of bromomethane 5 days/week for 13
weeks resulted In severe hyperplasla of the stratified squamous epithelium
In the forestomachs of high-dose male and female rats and slight epithelial
hyperplasla 1n the forestomachs of male and female rats treated with 10
mg/kg (Danse et al., 1984). Although Danse et al. (1984) reported that 6/10
females and 7/10 males treated with 50 mg/kg/day had carcinoma of the
forestomach, the NTP scientists who reevaluated the hlstologlcal slides from
this study concluded that there were Inflammatory and hyperplastlc lesions,
but no neoplastlc lesions. In addition to the forestomach hlstopathology,
decreased food consumption and body weight gain and anemia were observed In
the male rats and slight pulmonary atelectasls was observed In both male and
female rats treated with 50 mg/kg/day. No neurotoxlc effects or liver
hlstopathologlcal alterations were observed at any dose level tested. Renal
hlstopathology was not evaluated. Adverse effects were not observed In rats
treated with 0.4 or 2.0 mg/kg/day.
Groups of four beagle dogs (sex unspecified) were fed bromomethane fumi-
gated food for 1 year that provided Intakes of 41.6, 89.1 or 178.2 mg/kg/day
of bromomethane, assuming all the bromide Identified 1n the diet was present
as methyl bromide (Rosenblum et ai., 1960). Three dogs/sex served as
controls. At the highest dose, the dogs became lethargic, occasionally had
diarrhea and excessive salivation, and had significantly Increased body
weights. The gain 1n body weight was the result of frank obesity that the
authors attributed to compound-Induced polyphagln. Although no effects were
observed on hematologlcal values, urlnalysls, blood chemistry or mortality
0090h -4- 12/17/86
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rates after 1 year of treatment, mild hepatic and renal Inflamatlon were
reported In dogs exposed to the highest dietary level of bromomethane.
3.1.2. Inhalation. As summarized In Table 3-1, groups of rats, guinea
pigs, rabbits and monkeys were exposed to bromomethane at 0, 65, 130, 250,
420 or 850 mg/m3, 7.5 hours/day, 5 days/week for up to 6 months (Irish et
a!., 1940).
The exposure level of 850 mg/m3 was acutely toxic to both rats and
guinea pigs. Rats and the one monkey exposed to 420 mg/m3 had convul-
sions. Although no convulsions were reported In the guinea pigs, 4/11
guinea pigs exposed to 420 mg/m3 died during treatment.
The exposure level of 250 mg/m3 had no effect 1n rats and guinea pigs.
In contrast, almost all (38/42) of the rabbits and half (3/6) of the monkeys
showed signs of paralysis when exposed to 250 mg/m3. Although no adverse
effects were seen In monkeys exposed to 130 mg/m3, this concentration
caused paralysis In all the rabbits that survived long enough for the effect
to develop. Fifteen of the 58 rabbits exposed to 130 mg/m3 died suddenly
from a severe lung Infection, perhaps exacerbated by methyl bromide
Inhalation. Adverse changes 1n lung histology were reported In the rabbits
that were paralyzed. An exposure level of 65 mg/m3 Is a NOAEL for rats,
guinea pigs, rabbits and monkeys and the highest NOAEL tested for rabbits.
These data suggest a steep dose-response curve, and not a great difference
1n the concentration associated with a NOAEL and a PEL.
More recently, Russo et al. (1984) exposed six adult male New Zealand
White rabbits to 27 ppm (105 mg/m3) of bromomethane by Inhalation, 7.5
hours/day, 4 days/week during an 8-month period for a total duration of 900
hours. Two rabbits served as controls. No effects on the mean latency
rates of the sciatic and ulnar nerves or on eyebllnk amplitudes were
0090h -5- 12/15/86
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TABLE 3-1
Summary of Experimental Design 1n the Study of Irish et al. (1940)
Exposure
(mg/l)
0
0.065
0.13
0.25
0.42
0.85
Level
(mg/m3)
0
65
130
250
420
850
Rats
15
0
8 males;
8 females
10 males;
12 females
30
20
Number of
Guinea pigs
6 males;
6 females
0
5 males;
6 females
14 males;
10 females
11
16
Animals
Rabbits
6
6
58
42
0
0
Monkeys
2
0
4
6
1 female
0
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observed. Exposed rabbits gained less weight than controls, but this
difference was reported to be unrelated to treatment. Comparing their
results with the results of Irish et al. (1940) who reported paralysis 1n
rabbits exposed to (130 mg/m3), Russo et al. (1984) conjectured that thler
failure to find neurobehavlor Impaired 1n rabbits exposed to concentrations
of 27 ppm (105 mg/m3) may have been due to the differences 1n the strain
of the rabbits, to the possibility that the range of 27-33 ppm of methyl
bromide defines the threshold level for the Incidence of neurobehavloral
Impairment or, more likely, to Imprecise monitoring procedures that resulted
In variations of concentrations, which Influenced the effects of exposure,
since Irish et al. (1940) did not report the details of their analytical
procedures.
NTP (1986) Indicates that a subchronlc Inhalation study In rats and mice
1s currently In progress 1n preparation for a chronic toxlclty-cardno-
genlcHy experiment.
3.2. CHRONIC
3.2.1. Oral. Pertinent data regarding the systemic toxlclty of bromo-
methane after chronic oral exposure could not be located In the available
literature.
3.2.2. Inhalation. As Indicated 1n Section 4.2.2., there are two chronic
Inhalation bloassays currently In progress, one on mice (NTP, 1986) and one
on rats (U.S. EPA, 1985a; Danse et al., 1984).
Because bromomethane 1s a gas at 4°C and atmospheric pressure, most
human exposure has occurred by Inhalation. Although there are studies on
the effects of occupational exposure to bromomethane (Wong et al., 1984;
Verberk et al., 1979), they are not useful 1n quantitative risk assessment
because the level of bromomethane exposure was not reported. The primary
0090h -7- 12/15/86
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targets of bromomethane exposure 1n humans are the respiratory, nervous and
gastrointestinal systems. The dose-response curve Is quite steep, but the
onset of symptoms may be delayed several hours after an acute exposure.
Workers exposed to 35 ppm (140 mg/m3) for 2 weeks developed mild systemic
poisoning accompanied by nausea, vomiting, headache and skin lesions
(Watrous, 1942).
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS
3.3.1. Oral. Pertinent data on the oral teratogenlclty of bromomethane
could not be located In the available literature.
3.3.2. Inhalation. The teratogenlclty of Inhaled bromomethane was evalu-
ated both In New Zealand White rabbits and female Wlstar rats (Hardln et
a!., 1981; Slkov et al., 1980). Groups of -20 pregnant rabbits were exposed
to 0, 20 or 70 ppm (0, 78 or 270 mg/m3) for 7 hours/day, on days 1-15 of
gestation. Beginning on day 9 of gestation, convulsive movements, hlndleg
paresis and death were observed 1n the high groups dams. By day 30 of
gestation, all but one were dead. Despite the signs of toxldty among
rabbits exposed to 70 ppm, no teratogenlc or fetotoxlc effects were reported
1n their fetuses. No evidence of maternal toxldty or fetal teratogenlclty
was observed In the rabbits exposed to 20 ppm. Although the number of dead
and resorped fetuses In the rabbits exposed to 20 ppm of bromomethane (19)
was nlgher than the number of dead and resorbed fetuses 1n the control group
(13), the number of Utters with resorptlons In the rabbits exposed to 20
ppm of bromomethane (6) was not significantly different from the number of
Utters with resorptlon In the controls (7).
In contrast to the rabbits, no adverse maternal or developmental effects
were observed In groups of -35 pregnant rats exposed to 0, 20 or 70 ppm (0,
78 or 270 mg/m3) of bromomethane, 7 hours/day on gestation days 1-19
0090h -8- 12/15/86
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(Hardln et al., 1981; S1kov et al., 1980). In addition, groups of -35 rats
were exposed to 20 or 70 ppm (78 or 270 rog/ra3) of bromomethane for 7
hours/day, 5 days/week for 3 weeks before mating. No maternal toxldty, no
teratogenlclty and no fetal toxldty were reported In the rats at any
exposure level.
3.4. TOXICANT INTERACTIONS
Pertinent data regarding the Interaction of bromomethane with other
chemicals Inhaled or Ingested could not be located In the available
literature.
0090h -9- 12/15/86
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4. CARCINOGENICITY
4.1. HUNAN DATA
4.1.1. Oral. Pertinent data regarding the human carclnogenlcHy of
bromomethane after oral exposure could not be located In the available
literature.
4.1.1. Inhalation. A study of workers potentially exposed to organic and
Inorganic bromlnated chemicals Indicated that the Incidence of death from
testlcular cancer was significantly higher (2/665) In workers exposed to
organic bromides than would be predicted based on the standardized mortality
ratio (0.11/655) (Wong et al., 1984). Bromomethane was the only common
potential exposure for the two men, but they may also have been exposed to
other chemicals. Exposures were not quantHated. No significant Increase
In the Incidence of any other type of tumor was observed 1n this study (Wong
et al., 1984).
4.2. BIOASSAYS
4.2.1. Oral. Bloassays on the carclnogenlclty of oral exposure to bromo-
methane could not be located 1n the available literature. In addition, no
bloassay on the carclnogenlclty of bromomethane associated with oral
exposure have been located.
4.2.2. Inhalation. Although no completed bloassay on the carclnogenlclty
of bromomethane after Inhalation exposure was located In the available
literature, a chronic Inhalation bloassay In mice 1s reported to be In
progress (NTP, 1986), and a chronic Inhalation bloassay on rats Is reported
to be 1n progress by the Dutch National Institute for Public Health (Danse
et al., 1984; U.S. EPA, 1985a).
0090h -10- 12/15/86
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4.3. OTHER RELEVANT DATA
Bromomethane Is mutagenlc to Salmonella typhlmurlum strains TA100 and
TA1535, but not to strain TA98 and TA1537, and to Escherlchla coll with and
without metabolic activation (Voogd et al., 1982; Morlya et a!., 1983;
Kramers et al., 1985; Simmon and Tardlff, 1978; Simmon et al., 1977).
Bromomethane Increased the frequency of lethal recessive mutations 1n Drosq-
phlla melanogaster (Voogd et al., 1982; McGregor, 1981; Kramers et al.,
1985). Bromomethane was mutagenlc In the mouse lymphoma cell assay, but not
In other assays performed on mammalian systems, such as unscheduled DNA
synthesis 1n rat liver cells (Voogd et al., 1982; Kramers et al., 1985) or
human flbroblasts (McGregor, 1981). I_n vivo dominant lethal chromosome
abnormality and sperm abnormality assays 1n rats and mice were also negative
(McGregor, 1981).
4.4. WEIGHT OF EVIDENCE
IARC has not evaluated the carcinogenic potential of bromomethane.
Applying the criteria described In the EPA's proposed guidelines for assess-
ment of carcinogenic risk (U.S. EPA, 1986c), bromomethane may be classified
In EPA Group D: not classifiable (U.S. EPA, 1986a). This category Is for
agents with Inadequate human and animal evidence of carclnogenldty or for
which no data are available. Bromomethane may also be classified In IARC
Group 3: cannot be classified.
0090h -11- 01/23/87
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5. REGULATORY STANDARDS AND CRITERIA
A TLV of 5 ppm (20 mg/m3) with a STEL of 15 ppm (60 mg/m3) was
recommended by the ACGIH (1980) and adopted by the ACGIH (1985) to protect
against the adverse neurotoxlc and pulmonary effects observed after acute
exposure 1s designated with the skin notation Indicating the potential
contribution of dermal absorption. The Occupational Safety and Health
Administration standard 1s 20 ppm (80 mg/m3) for an 8-hour TWA exposure
limit (OSHA, 1985). Tolerances for bromomethane on raw agricultural
commodities range from 5 ppm on pears, apples and quinces to 300 ppm on
asparagus and lettuce (U.S. EPA, 1982, 1983a,b).
The Inhalation NOAEL of 65 mg/m3 from the Irish et al. (1940) study In
which rabbits were exposed for up to 6 months has been used to derive oral
RfDs (ADIs) for bromomethane following two different methodologies. In the
first derivation, U.S. EPA (1980a, 1982) derived an oral RfD of 14.5 mg/day
by assuming that animal and human exposures at a given concentration are
equivalent and applying an absorption factor of 0.5 and an uncertainty
factor of 100.
In the second derivation (U.S. EPA, 1986b), an oral RfD of 0.0004
mg/kg/day was derived from an estimated equivalent absorbed dose with
application of an uncertainty factor of 10,000.
Recently, the U.S. EPA (1986a) more appropriately Identified an oral
NOAEL of 2 mg/kg/day from the Danse et al. (1984) study using rats. An RfD
of 0.0014 mg/kg/day of bromomethane was derived. The RfD for bromomethane
remains provisional until the results of the cardnogenldty studies
currently 1n progress (NTP, 1986) are completed.
0090h -12- 06/17/87
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6. RISK ASSESSMENT
6.1. SUBCHRONIC REFERENCE DOSE (RfO$)
6.1.1. Oral (RfDso). Treatment of groups of 10 male and 10 female
Wlstar rats by gavage with 0, 0.4, 2, 10 or 50 mg/kg of bromomethane 5
days/week for 13 weeks resulted In severe hyperplasla of the stratified
squamous epithelium 1n the forestomachs of male and female rats treated with
50 mg/kg/day of bromomethane, and slight epithelial hyperplasla 1n the
forestomachs of male and female rats treated with 10 mg/kg/day of
bromomethane (Danse et al., 1984). An RfDso of 0.014 mg/kg/day (1.0
mg/day for a 70 kg human) can be derived by multiplying the NOAEL of 2
mg/kg/day by 5/7 to provide continuous exposure and by dividing by an
uncertainty factor of 100 to account for Interspecles extrapolation and the
range of sensitivity to xenoblotlcs within the human population.
6.1.2. Inhalation (RfD..). -No adverse effects were observed In rabbits
exposed to 65 mg/m3 of bromomethane for 7.5 hours/day, 5 days/week for 6
months (Irish et al., 1940). The next higher dose level, 250 mg/m3,
resulted 1n paralysis and pulmonary damage In rabbits. An RfD§I of 0.076
mg/kg/day (5 mg/day for a 70 kg human) 1s derived by multiplying the NOAEL
of 65 mg/m3 by 7.5/24 and 5/7 to expand to continuous exposure and by the
reference dally Inhalation rate (2.0 mVday), and dividing by the refer-
ence body weight {3.8 kg) for rabbits (U.S. EPA, 1985b) and an uncertainty
factor of 100 to account for Interspecles extrapolation and the range of
sensitivity to xenoblotlcs within the human population.
6.2. REFERENCE DOSE (RfD)
6.2.1. Oral (RfDQ). Because oral data on the chronic toxlclty of
bromomethane are not available, the RfDQ of 0.0014 mg/kg/day (0.1 mg/day
0090h -13- 06/16/87
-------
for a 70 kg human) Is derived from the RfDSQ of 0.014 mg/kg/day by
dividing by an uncertainty factor of 10 to account for the use of a
subchronlc study to obtain an acceptable chronic Intake level.
Because there are no chronic oral data on bromomethane toxlclty, the CSs
for oral exposure are based on anemia and atelectasls of the lungs at 50
mg/kg and epithelial hyperplasla of the forestomach at 10 mg/kg In the
13-week gavage study 1n rats by Danse et al. (1984).
The CSs were obtained as Indicated In Table 6-1. An uncertainty factor
of 10 was used to account for the use of a subchronlc study to derive a
chronic CS. These CSs are Identified with those obtained In another recent
U.S. EPA (1986a.) analysis.
6.2.2. Inhalation (RfD.). Because there are no available Inhalation
data on the chronic toxlclty of bromomethane, the RfOj of 0.0076 mg/kg/day
(0.5 mg/day) Is derived from the RfOSI of 0.076 mg/kg/day by dividing by
an uncertainty factor of 10 to account for the use of a subchronlc study to
obtain an acceptable chronic Intake level.
Because there are no chronic Inhalation data on bromomethane toxlclty,
the CSs for Inhalation exposure are based on the paralysis observed In
rabbits at 130 mg/m3 and the convulsions observed In rats at 420 mg/m3
In the 6-month study by Irish et al. (1940).
The CSs were calculated as Indicated In Table 6-1. An uncertainty
factor of 10 was used to account for the use of a subchronlc study to derive
a chronic RQ. These CSs are Identified to those derived by U.S. EPA (1986a).
6.3. CARCINOGENICITY POTENTY (q^)
6.3.1. Oral. Data are not sufficient for estimation of carcinogenic
potential to bromomethane by oral exposure.
0090h -14- 06/16/87
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0090h
-15-
12/15/86
-------
6.3.2. Inhalation. No evidence of carclnogenlclty was observed In the
Inhalation studies reported In the literature (Irish et al., 1940; Russo et
al.t 1984). Their short duration, however, may have precluded detection of
tumors. Currently, two long-term Inhalation bloassays are In progress; one
with mice by NTP (1986) and one with rats at the Dutch National Institute
for Public Health (Danse et al., 1984; U.S. EPA, 1985a). Current data are
not sufficient for estimation of carcinogenic potential by Inhalation
exposure.
0090h -16- 09/15/86
-------
7. REFERENCES
ACGIH (American Conference of Governmental Industrial Hyglenlsts). 1980.
Documentation of the Threshold Limit Values, 4th ed. Cincinnati, OH.
p. 265-266.
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Brown, B.O. and D.E. Rolston. 1980. Transport and transformation of methyl
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Danse, L.H., F.L. van Velsen and C.A. vander Heljden. 1984. Methyl
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Davis, D.D., G. Machado, B. Conway, Y. Oh and R. Watson. 1976. A tempera-
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j O
CH2C12, CHC13, CH3BR. J. Chem. Phys. 65: 1268-1274.
0090H -17- 12/15/86
-------
Dllllng, H.L. 1982. Atmospheric environment. Chapter 5. In.: Environ-
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0090h -18- 12/15/86
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Kramers, P.G., C.E. Voogd, A.D. Knapp and C.A. Vander Heljden. 1985.
HutagenlcHy of methyl bromide 1n a series of short-term tests. Mutat. Res.
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chloroform, CH«CC1_, In January 1978 and estimates of the atmospheric
0 *j
residence times for hydrohalocarbons. Proc. Natl. Acad. Sc1. U.S.A.
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0090h -19- 06/17/87
-------
Medlnsky, M.A., J.S. Dutcher, 3.A. Bond, et al. 1985. Uptake and excretion
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0090h -20- 12/15/86
-------
S1kov, M.R., W.C. Cannon, D.B. Carr, R.A. Miller and L.F. Montgomery. 1980.
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0090h -21- 02/06/87
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U.S. EPA. 1980b. Guidelines and Methodology Used In the Preparation of
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0090h -22- 06/17/87
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U.S. EPA. 1985b. Reference Values for Risk Assessment. Prepared by the
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0090h -23- 06/17/87
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