|
Bromomethane
CASRN 74-83-9
Contents
0015
Bromomethane; CASRN 74-83-9
Health assessment information on a chemical substance is included in IRIS only
after a comprehensive review of chronic toxicity data by U.S. EPA health
scientists from several Program Offices and the Office of Research and
Development. The summaries presented in Sections I and II represent a
consensus reached in the review process. Background information and
explanations of the methods used to derive the values given in IRIS are
provided in the Background Documents.
STATUS OF DATA FOR Bromomethane
File On-Line 01/31/1987
Category (section) Status Last Revised
----------------------------------------- -------- ------------
Oral RfD Assessment (I.A.) on-line 07/01/1991
Inhalation RfC Assessment (I.B.) on-line 10/01/1992
Carcinogenicity Assessment (II.) on-line 08/01/1990
_I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS
__I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD)
Substance Name -- Bromomethane
CASRN -- 74-83-9
Primary Synonym -- Methyl bromide
Last Revised -- 07/01/1991
The oral Reference Dose (RfD) is based on the assumption that thresholds exist
for certain toxic effects such as cellular necrosis. It is expressed in units
of mg/kg-day. In general, the RfD is an estimate (with uncertainty spanning
perhaps an order of magnitude) of a daily exposure to the human population
(including sensitive subgroups) that is likely to be without an appreciable
risk of deleterious effects during a lifetime. Please refer to the Background
Document for an elaboration of these concepts. RfDs can also be derived for
the noncarcinogenic health effects of substances that are also carcinogens.
Therefore, it is essential to refer to other sources of information concerning
the carcinogenicity of this substance. If the U.S. EPA has evaluated this
substance for potential human carcinogenicity, a summary of that evaluation
will be contained in Section II of this file.
___I.A.1. ORAL RfD SUMMARY
Critical Effect Experimental Doses* UF MF RfD
-------------------- ----------------------- ----- --- ---------
Epithelial hyperplasia NOAEL: 1.4 mg/kg/day 1000 1 1.4E-3
of the forestomach mg/kg/day
LOAEL: 7.1 mg/kg/day
Rat Subchronic Gavage
Study
Danse et al., 1984
*Conversion Factors: doses adjusted for gavage schedule (5 days/week)
___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD)
Danse, L.H.J.C., F.L. van Velsen and C.A. van der Heijden. 1984.
Methylbromide: Carcinogenic effects in the rat forestomach. Toxicol. Appl.
Pharmacol. 72: 262-271.
Treatment of groups of 10 male and 10 female Wistar rats by gavage 5 days/week
for 13 weeks with bromomethane at 0, 0.4, 2, 10, or 50 mg/kg resulted in
severe hyperplasia of the stratified squamous epithelium in the forestomach at
a dose of 50 mg/kg/day and slight epithelial hyperplasia in the forestomach at
a dose of 10 mg/kg/day (Danse et al., 1984). At the 50 mg/kg/day dose level,
decreased food consumption, body weight gain and anemia were observed in the
male rats. Slight pulmonary atelectasis was observed, at the two higher dose
levels, in both male and female rats; however, the investigators stated that
the possible inhalation of bromomethane-containing oil during the gastric
intubation procedure might have been responsible for this effect. No
neurotoxic effects were observed at any dose level tested. Renal
histopathology was not evaluated. Adverse effects were not observed at 0.4 or
2 mg/kg.
___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD)
UF -- The UF includes the standard uncertainty factors for interspecies and
intrahuman variability and a factor of 10 for extrapolation to lifetime
exposure from an intermediate exposure duration.
MF -- None
___I.A.4. ADDITIONAL COMMENTS (ORAL RfD)
The current RfD is based on the Danse et al. (1984) study, which uses the
preferred oral route of exposure for deriving an oral RfD. The previous oral
RfD (4E-4 mg/kg/day) was based on the inhalation studies by Irish et al.
(1940). Inhalation studies are inappropriate for oral risk assessment
extrapolation for bromomethane because portal-of-entry effects are observed
for both the inhalation route (lung pathology) and oral route (stomach
hyperplasia). In addition, neurological effects reported after inhalation
exposures have not been reported after oral exposures.
Beagle dogs of either sex were fed methyl bromide fumigated food ad libitum
for 1 year so that groups of four dogs each ingested approximately 35, 75, or
150 mg/kg/day of bromide, or adjusting for molecular weight, 41.6, 89.1, or
178.2 mg/kg/day of methyl bromide, assuming all the bromide was present as
methyl bromide (Rosenblum et al., 1960). The control group consisted of three
male and three female dogs fed only dog chow, ad libitum. The dogs ingesting
178.2 mg/kg/day methyl bromide gained more weight than the controls or the two
lower treatment groups; they also became lethargic and displayed excessive
salivation and occasional diarrhea. Methyl bromide was reported to have no
effect on hematological values, urinalysis, blood chemistry (including BUN
levels) or mortality rate. Mild chronic renal inflammation was reported in
two dogs in the high-dose group and in one dog in the control group. Mild
hepatic focal inflammation was reported in three dogs in the high-dose group,
two dogs in the low-dose group and one dog in the control group. No other
histological lesions were reported.
No adverse developmental effects were observed in the fetuses of Wistar rats
exposed to 20 ppm (78 mg/cu.m) or 70 ppm (272 mg/cu.m) of bromomethane for 7
hours/day on days 1-19 of gestation (Hardin et al., 1981; Sikov et al., 1980).
Exposure to 20 ppm (78 mg/cu.m) or 70 ppm (272 mg/cu.m) for 7 hours/day, 5
days/week for 3 weeks prior to mating, and gestation, did not result in
developmental toxicity in the offspring. No maternal toxic effects were
observed.
Bromomethane was highly toxic to pregnant New Zealand White rabbits exposed to
70 ppm (272 mg/cu.m) for 7 hours/day, 5 days/week on days 1 to 15 of
gestation; 24/25 rabbits died by day 30 of gestation (Hardin et al., 1981;
Sikov et al., 1980). No adverse developmental effects were observed in the
one remaining litter or in a group of rabbits exposed to 20 ppm (78 mg/cu.m)
of bromomethane for 7 hours/day, 5 days/week on days 1 to 30 of gestation.
___I.A.5. CONFIDENCE IN THE ORAL RfD
Study -- Medium
Data Base -- Medium
RfD -- Medium
The study by Danse et al. (1984) used the preferred route of administration
for derivation of an oral RfD. The study was adequately conducted, and the
determination of epithelial hyperplasia of the forestomach was independently
confirmed.
___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD
U.S. EPA. 1986. Health and Environmental Effects Profile for Methyl Bromide.
Prepared by the Office of Health and Environmental Assessment, Environmental
Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste
and Emergency Response, Washington DC.
U.S. EPA. 1987. Drinking Water Health Advisory for Bromomethane. Prepared
by the Office of Health and Environmental Assessment, Environmental Criteria
and Assessment Office, Cincinnati, OH for the Office of Drinking Water,
Washington DC.
Agency Work Group Review -- 12/02/1985, 02/05/1986, 09/29/1986, 04/15/1987, 05/26/1988
Verification Date -- 05/26/1988
___I.A.7. EPA CONTACTS (ORAL RfD)
Please contact the Risk Information Hotline for all questions concerning this
assessment or IRIS, in general, at (513)569-7254 (phone), (513)569-7159 (FAX)
or RIH.IRIS@EPAMAIL.EPA.GOV (internet address).
__I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC)
Substance Name -- Bromomethane
CASRN -- 74-83-9
Primary Synonym -- Methyl bromide
Last Revised -- 10/01/1992
The inhalation Reference Concentration (RfC) is analogous to the oral RfD and
is likewise based on the assumption that thresholds exist for certain toxic
effects such as cellular necrosis. The inhalation RfC considers toxic effects
for both the respiratory system (portal-of-entry) and for effects peripheral
to the respiratory system (extrarespiratory effects). It is expressed in
units of mg/cu.m. In general, the RfC is an estimate (with uncertainty
spanning perhaps an order of magnitude) of a daily inhalation exposure of the
human population (including sensitive subgroups) that is likely to be without
an appreciable risk of deleterious effects during a lifetime. Inhalation RfCs
were derived according to the Interim Methods for Development of Inhalation
Reference Doses (EPA/600/8-88/066F August 1989) and subsequently, according to
Methods for Derivation of Inhalation Reference Concentrations and Application
of Inhalation Dosimetry (EPA/600/8-90/066F October 1994). RfCs can also be
derived for the noncarcinogenic health effects of substances that are
carcinogens. Therefore, it is essential to refer to other sources of
information concerning the carcinogenicity of this substance. If the U.S. EPA
has evaluated this substance for potential human carcinogenicity, a summary of
that evaluation will be contained in Section II of this file.
___I.B.1. INHALATION RfC SUMMARY
Critical Effect Exposures* UF MF RfC
-------------------- --------------------------- ----- --- ---------
Degenerative and NOAEL: None 100 1 5E-3
proliferative lesions mg/cu.m
of the olfactory LOAEL: 11.7 mg/cu.m (3 ppm)
epithelium of the LOAEL(ADJ): 2.08 mg/cu.m
nasal cavity LOAEL(HEC): 0.48 mg/cu.m
Rat 29-month
Inhalation Study
Reuzel et al., 1987, 1991
*Conversion Factors: MW = 94.95. Assuming 25 degrees C and 760 mmHg,
LOAEL(mg/cu.m) = 3 ppm x 94.95/24.45 = 11.7 mg/cu.m. LOAEL(ADJ) = 11.7 x 6
hours/24 hours x 5 days/7 days = 2.08 mg/cu.m. The LOAEL(HEC) was calculated
for a gas:respiratory effect in the extrathoracic region. MVa (chronic,
female Wistar rats) = 0.30 cu.m/day, MVh = 20 cu.m/day, Sa(ET) = 11.6 sq. cm.,
Sh(ET) = 177 sq. cm. RGDR(ET) = (MVa/Sa)/(MVh/Sh) = 0.23. LOAEL(HEC) =
LOAEL(ADJ) x RGDR = 0.48 mg/cu.m.
___I.B.2. PRINCIPAL AND SUPPORTING STUDIES (INHALATION RfC)
Reuzel, P.G.J., C.F. Kuper, H.C. Dreef-van der Meulen and V.M.H. Hollanders.
1987. Chronic (29-month) inhalation toxicity and carcinogenicity study of
methyl bromide in rats. Report No. V86.469/221044. Netherlands Organization
for Applied Scientific Research, Division for Nutrition and Food Research,
TNO. EPA/OTS Document No. 86-8700001202.
Reuzel, P.G.J., H.C. Dreef-van der Meulen, V.M.H. Hollanders, C.F. Kuper, V.J.
Feron and C.A. van der Heijden. 1991. Chronic inhalation toxicity and
carcinogenicity study of methyl bromide in Wistar rats. Fd. Chem. Toxic.
29(1): 31-39.
A series of inhalation toxicity studies of bromomethane were conducted
under the sponsorship of the National Institute of Public Health and
Environmental Hygiene of the Netherlands. In a chronic inhalation study
conducted by Reuzel et al. (1987, 1991), 50 male and 60 female Wistar rats
were exposed to 0, 3, 30, or 90 ppm (0, 11.7, 117, or 350 mg/cu.m,
respectively) 98.8 % pure bromomethane 6 hours/day, 5 days/week (duration-
adjusted concentrations are 0, 2.08, 20.9, or 62.5 mg/cu.m, respectively) for
up to 29 months. Three satellite groups of 10 animals/sex/exposure level were
sacrificed at 14, 53, and 105 weeks of exposure. Animals were observed daily,
and body weight was recorded weekly for the first 12 weeks and monthly
thereafter. Hematology, clinical chemistry, and urinalyses were conducted at
12-14 weeks and 52-53 weeks in the satellite groups. Eleven organs were
weighed at necropsy, and approximately 36 tissues, including the lungs with
trachea and larynx; 6 cross-sections of the nose; heart; brain; and adrenal
glands were examined histopathologically. The test atmosphere was measured by
gas chromatography every 30 minutes during exposure.
Males and females exposed to 90 ppm exhibited decreased body weight gains;
no treatment-related changes in hematological, biochemical, or urine
parameters were observed. A significant concentration-related decrease in
relative kidney weights was reported in the 30- and 90-ppm males. A decrease
in mean absolute brain weight was reported to occur in the 90-ppm females at
weeks 53 and 105, but there was no change in relative brain weight or in brain
histology. Microscopic evaluation revealed that the nose, the heart, and the
esophagus and forestomach were the principle targets of bromomethane toxicity
in this study. Very slight to moderate hyperplastic changes in the basal
cells accompanied by degeneration in the olfactory epithelium in the dorso-
medial part of the nasal cavity were observed in all exposed groups of both
sexes at 29 months of exposure. At the lowest concentration, the lesion is
described as very slight. These changes were concentration-related in both
incidence and severity and were statistically significant at 29 months.
Incidence of basal cell hyperplasia in control, 3-, 30-, and 90-ppm groups
were 4/46, 13/48, 23/49, and 31/48 in males and 9/58, 19/58, 25/59, and 42/59
in females, respectively. Slight increases in incidence of basal cell
hyperplasia in the 30- and 90-ppm groups (n=7-10) at 53 and 105 weeks were not
statistically significant. Lesions in the heart were statistically
significant in the males (cartilaginous metaplasia and thrombus), and the
females (myocardial degeneration and thrombus) exposed to 90 ppm. The authors
attributed part of the increased mortality in the high-concentration animals
to the cardiac lesions. A statistically significant increase in
hyperkeratosis of the esophagus was observed in the 90-ppm males after 29
months of exposure. Slight increases in forestomach lesions were not
statistically significant. No effects were observed in the tracheobronchial
or pulmonary regions of the respiratory tract. No other exposure-related
effects were noted. Based on these results, a LOAEL of 3 ppm (HEC = 0.48
mg/cu.m) for nasal effects is established.
___I.B.3. UNCERTAINTY AND MODIFYING FACTORS (INHALATION RfC)
UF -- The uncertainty factor of 100 reflects a factor of 10 for intraspecies
uncertainty, a factor of 3 for the use of a LOAEL for a mild effects and a
factor of 3 for interspecies extrapolation because dosimetric adjustments have
been applied. The factors of 3 represent operational application of a
geometric half of the standard factor of 10, rounded to a single significant
figure. As a result, multiplication of two factors of 3 results in a
composite factor of 10.
MF -- None
___I.B.4. ADDITIONAL STUDIES / COMMENTS (INHALATION RfC)
NTP conducted a 13-week subchronic study in B6C3F1 mice and F344 rats and
a 6-week target organ study (Eustis et al., 1988; NTP, 1990). A chronic study
on the toxicology and carcinogenesis of bromomethane following inhalation
exposure to B6C3F1 mice was also conducted (NTP, 1990).
In the 13-week study, 18 rats/sex/group were exposed to target
concentrations of 0, 30, 60, or 120 ppm (0, 117, 233, or 466 mg/cu.m,
respectively) bromomethane 6 hours/day, 5 days/week (duration-adjusted
concentrations are 0, 20.9, 41.6, and 83.2 mg/cu.m, respectively). Mice (18-
27/sex/group) were exposed to 0, 10, 20, 40, 80, or 120 ppm (0, 38.8, 77.6,
155, 311, or 466 mg/cu.m, respectively) bromomethane 6 hours/day, 5 days/week
(duration-adjusted concentrations are 0, 6.93, 13.9, 27.7, 55.5, or 83.2
mg/cu.m, respectively). Hematological parameters were measured and organ
weights were determined for the adrenals (rats only), brain, heart, kidney,
lung, spleen (rats only), testis, and thymus (mice only).
Pseudocholinesterase activity was measured in the mice only. Neurobehavioral
testing was conducted on 8 rats and 8 mice/sex/group at weeks 0, 6, and 12,
and neuromorphological studies were conducted on 4 rats/sex from the control
and 120-ppm group and on 4 mice/sex for each concentration. Histopathological
examination of approximately 40 tissues from control and 120-ppm animals were
carried out, including lungs, bronchi, and nasal turbinates. Exposure-related
changes seen in the mice were a significant (58%) body weight gain reduction
and a 17% increase in mortality in mice exposed to 120 ppm bromomethane. Mice
exposed to this level exhibited severe curling and crossing of the hindlimbs
and twitching of the forelimbs; these effects were more severe in the males.
Hematological parameters that were found to be statistically significantly
different from control values in mice included decreased mean cell hemoglobin,
decreased mean cell count, and increased erythrocyte count in males exposed to
40, 80, and 120 ppm; and increased hemoglobin in males exposed to 120 ppm. No
exposure-related effects were seen upon histopathological examination. In the
rats there was no increase in mortality, but the males exposed to 120 ppm and
the females exposed to 60 and 120 ppm bromomethane exhibited significant
decreases in body weight gain. Mild neurobehavioral effects were noted in the
high-concentration rats of both sexes. Females exposed to 120 ppm were found
to have significantly lower hematocrit, hemoglobin, and erythrocytes counts,
but the males did not exhibit these changes. The only exposure-related effect
noted at histopathological examination was an increase in the incidence of
olfactory epithelial dysplasia and cysts in the rats of both sexes exposed to
120 ppm [LOAEL(HEC) = 12 mg/cu.m]. Based on these results a NOAEL of 80 ppm
[NOAEL(HEC) = 8 mg/cu.m] for nasal olfactory epithelial changes in rats is
established.
Because no significant target organ toxicity was noted in the 14-day or
13-week studies, a special 6-week target organ toxicity study at a near lethal
concentration was conducted in F344 rats and B6C3F1 mice (Eustis et al., 1988;
NTP, 1990). Groups of 5 animals/sex were exposed to 0 or 160 ppm (621
mg/cu.m) bromomethane 6 hours/day for either 3 consecutive days (rats), or 5
days/week over 2 weeks (rats and mice) or 6 weeks (rats). Fifteen
mice/sex/dose were exposed to 0 or 160 ppm (621 mg/cu.m) 6 hours/day, 5
days/week, for 6 weeks. Endpoints studied included clinical observations,
mortality, body and organ weights, hematology, clinical chemistry, urinalysis,
gross pathology, and histopathology of a standard set of tissues, including
the lungs and nasal turbinates. The female rats were the only group to
demonstrate more than 50% survival, with mice being more sensitive than rats
(mortality exceeded 50% after 6-8 exposures in both the male and female mice
and after 14 exposures in the male rats). Because of the high mortality, the
male and female mice and male rats were killed after 10, 8, or 14 exposures,
respectively. Neurological signs exhibited by both rats and mice, but to a
lesser extent in the rats, included lethargy and curling and crossing of
hindlimbs, forelimb twitching, and tremors. Decreases in body weight gain
were observed in the exposed animals as compared to controls (18% in the mice
and 32% in the rats). The mean organ weights of most organs were
significantly reduced in both species. Notable hematological effects were
seen mostly in the female mice and included decreased RBC and increased WBC
counts. Target organs affected by exposure to 160 ppm bromomethane were the
brain, kidney, nasal cavity, heart, adrenal gland, liver, and testes. Species
differences were noted in the responses of these organs. For example,
neuronal necrosis in the cerebral cortex, hippocampus, and thalamus of the
brain were seen in the rats whereas neuronal necrosis was seen predominantly
in the internal granular layer of the cerebellum of the mice. Nephrosis,
characterized by degeneration, necrosis, and sloughing of the epithelium of
the cortical convoluted tubules was seen in all of the exposed mice and was
considered by the authors to be partially responsible for the increase in
mortality, but these lesions were not observed in the rats. Degeneration and
atrophy of the seminiferous tubules was observed in several of the exposed
rats and mice, but was less severe in the mice. Olfactory epithelial
degeneration was observed in the rats of both sexes, and this was seen to a
lesser degree in the male mice, with only one female mouse exhibiting this
lesion. Myocardial degeneration was seen in rats of both sexes, and to a
lesser degree in the male mice. Atrophy of the inner zone of the adrenal
cortex was observed in the female mice, and cytoplasmic vacuolation of the
adrenal cortex was seen in rats.
In the chronic study (NTP, 1990), a total of 86 mice/sex/concentration
were exposed to 0, 10, 33, or 100 ppm (0, 38.8, 128, or 388 mg/cu.m,
respectively) bromomethane 6 hours/day, 5 days/week (duration-adjusted
concentrations are 0, 6.93, 22.9, or 69.3 mg/cu.m, respectively). Exposures
to 10 and 33 ppm were for 103 weeks, with interim sacrifices at 6 and 11
months. Exposure to 100 ppm produced 47% mortality in the males and 10%
mortality in the females by 20 weeks, so exposure was discontinued in this
group at this time and the surviving animals were observed for an additional
84 weeks, except for the females scheduled for the 15-month sacrifice. The
endpoints studied were the same as those described for the 6-week target organ
toxicity study in addition to neurobehavioral assessments in 16 mice/sex/group
and neuropathological examination on 3-8 animals/sex/group at 20 weeks and 6,
15, and 24 months. Body weights were significantly depressed in the animals
exposed to 100 ppm (33% in the males and 31% in the females) beginning at week
11 and persisting until study termination. Significant body weight changes
were not observed in the lower exposure groups. Because of the reduced body
weight in the 100-ppm animals, organ weight changes were difficult to
interpret, but reduced absolute and relative thymus weights were observed in
both the males and females exposed to 100 ppm bromomethane. Clinical signs of
toxicity observed almost exclusively in the 100-ppm animals that persisted
throughout the 103 weeks included tremors, abnormal posture, and limb
paralysis. Functional neurobehavioral changes consisting of hypoactivity, a
heightened startle response, and higher hindlimb grip scores and hot plate
latency were observed in both sexes exposed to 100 ppm at various times during
exposure, but were more pronounced in the males. The target organs of
toxicity identified in this study were the brain, bone (sternum), heart, and
nose, with lesions in these organs occurring more frequently in the males. In
the brain, there was a statistically significant increase in the incidence of
cerebellar degeneration in the animals exposed to 100 ppm. Cerebral
degeneration was also observed in these animals, but the incidence of this
lesion was statistically significant in the males only. Because this lesion
was observed more frequently in the animals that died prior to study
termination, it may have contributed to the early mortality in this group.
Dysplasia of the sternal bone marrow was observed at a statistically
significantly increased rate in both the males and the females exposed to 100
ppm, but because it was observed more frequently in the animals that survived
to study termination than in those that died early, it was not considered to
be a contributing factor to the death of these animals. Myocardial
degeneration and chronic cardiomyopathy were also observed at a statistically
higher incidence in both males and females exposed to 100 ppm bromomethane,
and occurred at a higher incidence in those animals dying early. Finally, a
statistically significant increase in the incidence of olfactory epithelial
necrosis and metaplasia was seen in the nasal cavities of both the male and
female mice exposed to 100 ppm. Necrosis was seen only in the animals dying
early, whereas metaplasia was exhibited mainly in those animals surviving
until study termination. Histopathological changes in other organs were
observed and considered to be secondary to stress and weight loss rather than
a direct toxic effect of bromomethane. Animals exposed to lower
concentrations did not exhibit significant increases in any of the lesions
described above. Based on the results of this study, a NOAEL of 33 ppm (HEC =
4.4 mg/cu.m for respiratory effects and 23 mg/cu.m for extrarespiratory
effects) and a LOAEL of 100 ppm (HEC = 13 mg/cu.m for respiratory effects and
69 mg/cu.m for extrarespiratory effects) are established based on toxicity in
multiple organs.
Male Fischer 344 rats (10/group) were exposed to 0, 90, 175, 250, or 325
ppm (0, 350, 680, 971, or 1,262 mg/cu.m, respectively) bromomethane (99.9%
pure) 6 hours/day for 5 days (Hurtt et al., 1987). The brain, nasal cavity,
liver, kidney, adrenal glands, testes, and epididymides were examined
histopathologically. The lungs were not examined. Three animals exposed to
325 ppm died after the fourth exposure. Diarrhea, hemoglobinuria, gait
disturbances, convulsions and hepatocellular degeneration were observed in
animals exposed to 250 ppm or greater; vacuolar degeneration of the zona
fasciculata of the adrenal gland and cerebellar granule cell degeneration were
observed in rats exposed at 175 ppm and greater. Minor alterations in
testicular histology and cerebrocortical degeneration were observed in the
350-ppm exposure group. A concentration-dependent degeneration of the nasal
olfactory sensory cells was observed in rats exposed to 175 ppm bromomethane
or greater. This degeneration affected 50-80% of the olfactory mucosa, and
was characterized by complete or partial destruction of the olfactory
epithelium at the higher concentrations. Small foci of hepatocellular
coagulative necrosis were observed in animals exposed to the two highest
concentrations. No exposure-related lesions were noted in the kidneys.
In a subsequent study, Hurtt et al. (1988) investigated the ability and
time-course of the olfactory epithelium to regenerate following acute exposure
to bromomethane. Male Fischer 344 rats were exposed to 0 (n=5) or 200 ppm
(n=40) 99.9% pure bromomethane (777 mg/cu.m) 6 hours/day for 1-5 days. Five
animals/group were killed after 1, 3, or 5 days of exposure and 1, 2, 3, 5, or
10 weeks after cessation of treatment. In a companion study, 6 animals/group
were exposed to 0, 90, or 200 ppm (0, 350, or 777 mg/cu.m) bromomethane for 6
hours and olfactory function was studied by determining the effects of
bromomethane on the ability of food-deprived animals to locate buried food
pellets. Additional animals similarly exposed were killed at various times
following the single 6-hour exposure to assess the state of morphological
regeneration at the time of functional recovery. Only the nasal cavities were
examined histopathologically in these studies. No clinical signs of toxicity
were observed in the exposed animals. Extensive destruction of the olfactory
epithelium, characterized by epithelial disruption, fragmentation, and
exfoliation, was evident after a single 6-hour exposure to 90 or 200 ppm, with
the most severe effects observed in the sustentacular and mature sensory
cells, and the basal cell remaining intact. Regeneration of the olfactory
epithelium, characterized at first by replacement with a squamous cell layer
that increased in thickness, began by the third day of exposure and was
essentially complete by 10 weeks after the last exposure. It is important to
note that regeneration began even though exposure to bromomethane was still
ongoing. Olfactory function was impaired in animals exposed to 200 ppm
bromomethane, but not 90 ppm. Recovery of this function was evident by 4-6
days after exposure, which preceded morphological regeneration.
Similar results were obtained by Hastings (1990). In this study, rats
were exposed to 200 ppm (777 mg/cu.m) bromomethane 4 hours/day 2 days/week for
2 weeks. Prior to exposure, rats were food-deprived and trained to find
buried food pellets. Morphological as well as biochemical (carnosine content
in the olfactory bulb, which is an indication of the integrity of the
olfactory primary sensory neurons) studies were performed as well to assess
the integrity of the olfactory epithelium. Extensive damage to the olfactory
epithelium was seen, as evidenced by both morphological analysis and decreased
carnosine content after a single 4-hour exposure. Olfactory function was also
impaired after 4 hours, as evidenced by the inability of the rats to find the
buried food pellets. However, olfactory function began to return after the
second week of exposure and the animals performed as well as their controls by
the end of the exposure period whereas regeneration of the olfactory
epithelium, as indicated by morphological and biochemical analysis was not
complete until 30 days from the start of exposure.
The most common signs of acute intoxication with bromomethane in humans
are neurotoxic in nature and include headache, dizziness, fainting, apathy,
weakness, tiredness, giddiness, delirium, stupor, psychosis, loss of memory,
mental confusion, speech impairment, visual effects, limb numbness, tremors,
muscle twitching, paralysis, ataxia, seizures, convulsions, and unconscious.
Several studies have been conducted on the longer-term effects of occupational
exposure to bromomethane. None of these studies can serve as the basis for
the derivation of an RfC for bromomethane because of concurrent exposures to
other chemicals, inadequate quantitation of exposure levels and/or durations,
and other deficits in study design.
In a cross-sectional occupational study conducted by Anger et al. (1986),
soil and structural fumigators underwent a neurological examination. The
exposure group was blinded to the physician giving the examination. Most of
the structural fumigators used both bromomethane (MB) and sulfuryl fluoride
(SF). The formation of the study groups was based on the estimated time
devoted to bromomethane and sulfuryl fluoride fumigation activities, and
estimated length of time in the occupation. Four groups were formed: the MB
group (n=32) consisted of structural fumigators using MB 80% or more of the
time and soil fumigators using the mixture MB and chloropicrin; the SF group
(n=24) consisted of structural fumigators who used SF 80% or more of the time;
group COMB (n=18) consisted of workers using both MB and SF 40-60% of the
time, the reference group (Group R, n=29) consisted of those workers who were
not directly exposed to fumigants, but worked in the fumigation industry. The
workers in the exposed groups had been in the profession for 1 or more years
and had fumigated a house or field within the last 50 days. More symptoms
were reported in the exposed groups than in the reference population: 78-83%
and 41% respectively showed symptoms. The difference was significant for the
MB and COMB groups when compared to Group R. The MB group did not perform as
well as referents on several behavioral tests, including tests of cognitive
function, reflexes, sensory and visual effects. Although this study suggests
mild neurological effects of exposure to methyl bromide, it is difficult to
draw any conclusions between exposure and effect because of the confounding
factors. The exposed and reference groups were not well matched for age; use
of prescription medication, alcohol, or illegal drugs within 2 days of the
testing; education; or ethnic group. In addition, participation in the study
was voluntary and no information is provided on the use of personal protective
equipment in these groups.
Herzstein and Cullen (1990) reported on 4 cases of bromomethane toxicity
at a nursery following the removal of polyethylene sheets covering soil
fumigated with 98% bromomethane and 2% chloropicrin. Four workers involved in
removing the tarp wore no respiratory protection, and had no training in the
handling or hazards of bromomethane. On the second day, all four workers
noted fatigue and lightheadedness. After arriving home, three of the workers
developed severe coughing, chest tightness, nausea, vomiting, headaches, and
tremulousness during the night. Three workers were found to have either
ataxia, tremor, or both. Blood bromide levels were not performed. The
symptoms continued to improve without treatment. Upper- and lower-extremity
paresthesias and reduced hand dexterity were reported in two workers at 3
weeks post-exposure. There were no long-term adverse effects after 18 months
of follow-up.
The first reported study on the effects of short-term and repeated
exposure to bromomethane in experimental animals was conducted by Irish et al.
(1940). In the first set of experiments, rats and rabbits were exposed once
to 420-50,000 mg/cu.m bromomethane for varying lengths of time.
Concentrations of bromomethane greater than or equal to 10,000 mg/cu.m were
lethal to 100% of the animals within 6-132 minutes. Deaths also occurred at
6-36 hours after exposure to concentrations less than 10,000 mg/cu.m.
Clinical signs observed in rats exposed to less than 10,000 mg/cu.m included
roughening of the fur, hunching of the back, drowsiness, heavy breathing, and
lacrimation. Nasal irritation and lacrimation were observed, in addition to
the signs mentioned above, at higher concentrations. Rabbits did not exhibit
these signs. However, in rats exposed to greater than 1000 mg/cu.m for 20
hours, a hyperexcitable state was observed, whereas rabbits exposed to the
same concentration exhibited paralysis. Evidence of pulmonary irritation
(congestion and edema) was found (predominantly in the rat) following
exposures to 1,000-20,000 mg/cu.m.
In subsequent studies, rats (n=135), rabbits (n=104), guinea pigs (n=98)
and female rhesus monkeys (n=13) were exposed to 0, 17, 33, 66, 100, or 220
ppm (0, 66, 128, 256, 388, or 853 mg/cu.m, respectively) 7-8 hours/day, 5
days/week for 6 months or until the majority exhibited severe reactions or
died. The frank-effect-levels (increased mortality) were 100 ppm for rats,
guinea pigs, and monkeys and 133 ppm for rabbits (Irish et al., 1940).
Rabbits and monkeys exhibited paralysis after exposure to 66 ppm whereas rats
and guinea pigs exhibited no adverse effects. Pulmonary damage was still seen
in rabbits exposed to 33 ppm, but the monkeys appeared normal. None of the
species exhibited adverse effects following repeated exposure to 17 ppm (66
mg/cu.m; Irish et al. 1940).
The brain and heart also appeared to be target organs following inhalation
exposure to bromomethane in a study conducted by Kato et al. (1986). Male
Sprague-Dawley rats (10-12/group) were exposed to 150 ppm (583 mg/cu.m)
bromomethane (purity unspecified) 4 hours/day, 5 days/week for 11 weeks
(duration-adjusted to 69.3 mg/cu.m). Focal necrosis and fibrosis of coronary
ventricles and papillary muscle disorders were observed in the exposed
animals. In the same study, male Sprague-Dawley rats (10-12/group) were
exposed to 0, 200, 300, or 400 ppm (0, 777, 1,165, or 1,553 mg/cu.m) 4
hours/day, 5 days/week for 6 weeks (duration-adjusted concentrations are 0,
92.5, 139, and 185 mg/cu.m, respectively). Focal necrosis and fibrosis of
coronary ventricles and papillary muscle were observed in all exposed animals.
Neurological dysfunction (ataxia, paralysis) were reported at levels at and
exceeding 300 ppm; necrosis in the bilateral regions of the dorso-external
cortex of the cerebral hemisphere was observed in animals exposed at 400 ppm.
Testicular atrophy with suppression of spermatogenesis was apparent in 6 of
the 8 the animals exposed to 400 ppm. Although the lungs appeared to be one
of the tissues examined histopathologically, respiratory effects were not
addressed in the descriptions of either experiment.
Neurobehavioral effects of bromomethane inhalation were studied in rats
and rabbits by Anger et al. (1981). In one set of experiments, Sprague-Dawley
rats and New Zealand white rabbits were exposed to 0 (n=2) or 65 ppm (252
mg/cu.m, n=6) 7.5 hours/day, 4 days/week for 4 weeks. Neurobehavioral
testing, consisting of conduction velocity in the sciatic and ulnar nerves
(rats and rabbits), eye-blink reflex (rabbits), open field activity (rats),
and grip/coordination (rats) were conducted weekly. Exposed rabbits exhibited
depressed body weight gain as compared with the controls, and signs of hind
limb paralysis were evident during the last week of exposure. Statistically
significant decreases in the eyeblink reflex magnitude and in nerve conduction
velocity were also observed in the exposed rabbits. In contrast, no effects
on weight gain, grip/coordination, or nerve conduction velocity were observed
in the rats exposed to 65 ppm for 4 weeks. The LOAEL for neurological effects
in rabbits and the NOAEL for rats is 65 ppm. In another experiment that was
performed as part of this study, Sprague-Dawley rats were exposed to 0 or 55
ppm (214 mg/cu.m) bromomethane 6 hour/day, 5 day/week for 36 weeks.
Neurobehavioral tests (conduction velocity in the sciatic and ulnar nerves,
open-field activity, and grip/coordination) conducted at 25- to 30-day
intervals did not reveal any exposure-related effects.
In a subsequent study performed by this group (Russo et al., 1984) that
was designed to assess the neurotoxic effects of bromomethane in rabbits
following longer-term exposure at lower concentration, male New Zealand white
rabbits were exposed to 0 (n=2) or 26.6 ppm (103 mg/cu.m, n=6) 99% pure
bromomethane 7.5 hours/day, 4 days/week for 8 months (Russo et al., 1984).
Exposure concentrations were monitored every 12 minutes by an infrared
analyzer. Neurobehavioral tests examined the latency rates of the sciatic and
ulnar nerves and the amplitude of the eyeblink reflex of the orbicularis oculi
muscle. No other parameters, including respiratory effects, were monitored.
No exposure-related neurological effects were observed [NOAEL(HEC) = 23
mg/cu.m]. As part of this study, the animals exposed to 252 mg/cu.m
bromomethane for 4 weeks (previously discussed; Anger et al., 1981) were
allowed to recover for 6-8 weeks and the neurological tests were repeated.
The animals demonstrated partial, but not complete recovery within the 6-week
period. Therefore rabbits, which are sensitive to the neurotoxic effects of
high-level exposure to bromomethane, can tolerate long-term low-level exposure
to bromomethane, and appear to be able to recover from severe neurological
effects after cessation of exposure.
Morrissey et al. (1988), using data obtained from the 13-week NTP (1990)
study in rats and mice, evaluated testis, epididymis, and cauda epididymis
weights; caudal sperm motility and count; sperm head morphology; average
estrous cycle length; and relative frequency of different estrous stages to
assess the potential reproductive effects of bromomethane. In mice, they
found that inhalation exposure to bromomethane resulted in an increase in the
relative weights of the epididymis and testis, a decrease in sperm density,
and an increase in the percentage of abnormal sperm. In the rats, a decrease
in absolute cauda epididymis and absolute and relative epididymis weights, an
increase in relative testis weight, and a decrease in sperm motility occurred
as a result of subchronic inhalation exposure to bromomethane. No effects on
estrous cycle length were noted. This study is an evaluation of a screening
method for reproductive toxicants and was applied to 50 subchronic studies
carried out by the NTP. The exposure levels at which these effects were found
were not specified.
Male Fischer 344 rats (75/group) were exposed to 0 or 200 ppm bromomethane
(777 mg/cu.m) 6 hours/day for 5 consecutive days and sacrificed on various
days beginning on day 1 of exposure through 68 days after termination of
exposure. Plasma testosterone and testicular glutathione levels were
depressed, but returned to control levels within 3 days after exposure had
ended. No effects on spermatogenesis, sperm quality, or testicular weight or
histology were noted (Hurtt and Working, 1988).
Female Wistar rats (n=39-45) were exposed to 0, 20, or 70 ppm (0, 78, or
272 mg/cu.m, respectively) bromomethane 7 hours/day, 5 days/ week for 3 weeks,
mated and exposed during gestational days 1-19. The study design included
groups at each exposure level exposed pregestationally, during gestation, and
both, as well as a control. At gestational day 21, litters were evaluated for
fetotoxicity and live fetuses were examined for external, visceral (about 1/2
of fetuses), and skeletal abnormalities. Maternal organ weights for liver,
kidney, and lung, and histopathology on 8 animals/group on ovaries, uterus,
kidney, lung, and trachea were performed. No mortality or change in organ
weights were observed and body weight was decreased during gestation but was
not different than controls at full term. Histological effects observed in
the lung and kidney were not clearly exposure-related due to the small sample
size and high control incidence. There was no effect on pregnancy rate or
fetal size. There were 31-38 litters/group examined and no effect on
embryotoxicity, fetal viability, or fecundity measures was observed. There
was no increase in malformations. The NOAEL for reproductive toxicity
(changes in fertility rate) and maternal and fetal toxicity in rats is 70 ppm
(Sikov et al., 1981; Hardin et al., 1981).
Female New Zealand white rabbits (25/group) were exposed to 0, 20, or 70
ppm (0, 78, or 272 mg/cu.m, respectively) bromomethane 7 hours/day, 5
days/week for 3 weeks during gestational days 1-24. Evaluation of
developmental effects was the same as in the rat study except that all fetuses
were evaluated for visceral abnormalities. In the 70-ppm group, severe
neurotoxic effects occurred and 24/25 animals died. No effects on body
weight, organ weight, or histology were observed in maternal animals exposed
to 20 ppm. There was no effect on pregnancy rate or fetal size. There were
13 litters in the group exposed to 20 ppm examined and no effect on
embryotoxicity, fetal viability, or fecundity measures was observed. There
was no increase in malformations. The NOAEL for maternal and fetal toxicity
in rabbits is 20 ppm (Sikov et al., 1981; Hardin et al., 1981).
Breslin et al. (1990) performed a developmental study in rabbits in which
New Zealand rabbits (26/group) were exposed to 0, 20, 40, or 80 ppm (0, 78,
155, or 311 mg/cu.m, respectively) methyl bromide 6 hours/day on gestation
days 6-19. Maternal toxicity at 80 ppm included reduced body weight and
weight gain. Clinical signs of central nervous system toxicity were observed
at 80 ppm. There was no effect on pre- or postimplantation loss, litter size,
or fetal body weights. There was an increase in agenesis of the gall bladder
and fused sternebrae at 80 ppm. The NOAEL for maternal toxicity and
developmental effects in this study is 40 ppm [NOAEL(HEC) = 155 mg/cu.m].
American Biogenics Corporation (1986) conducted a two-generation
reproduction study in Sprague-Dawley rats. Groups of 25 rats/sex/dose were
exposed by inhalation to methyl bromide vapor at 0, 3, 30, or 90 ppm (0, 12,
117, or 350 mg/cu.m) 6 hours/day, 5 days/week during the premating, gestation,
and lactation periods for 2 generations. In F0 male rats, exposure at 90 ppm
caused statistically significant decreases in body weight gain during the
premating period, final body weight, and total weight gain. No treatment-
related changes in reproductive organs were noted. Also, no adverse effects
were found on the progeny and reproductive parameters examined. In second
generation (F1) animals, no adverse effects were found on body weights,
histopathology of reproductive organs, or reproductive parameters measured.
However, a statistically significant concentration-related reduction in body
weights at 28 days was noted in F2 males and females at 30 ppm and 90 ppm.
Although significant changes were seen in some of the mean organ weights and
organ-to-body weight ratios in F0, F1, and F2 generation animals, no
histopathology changes were seen in these organs. Therefore, the biological
significance of these findings if any is not clear. Under the conditions of
the study, exposure to methyl bromide did not affect fertility in rats but
decreased the body weights of parental rats and reduced the growth of neonatal
rats. The NOAEL and LOAEL for these effects were 30 and 90 ppm for adult rats
and 3 and 30 ppm for neonates, respectively.
Medinsky et al. (1985) and Bond et al. (1985) conducted a series of
experiments to assess the uptake, distribution, and excretion of bromomethane
in rats following inhalation exposure. In one experiment, F344 rats were
exposed to 1.6, 9, 170, or 310 ppm (6, 35, 660, or 1,203 mg/cu.m) radiolabeled
bromomethane (nose-only) for 6 hours (Medinsky et al., 1985), and in the
other, F344 rats were exposed to 9 ppm radiolabeled bromomethane for 6 hours
(Bond et al., 1985). The percentage of total volume of inhaled radiolabeled
bromomethane that was absorbed decreased in a concentration-related manner
from 48+/-2% at the two lower concentrations to 27+/-4% at the highest
concentration, which indicates that uptake of bromomethane is a saturable
process. In both studies, inhaled bromomethane was distributed quickly
throughout the body, and the highest concentrations were found in the lung,
adrenal, kidney, liver, and nasal turbinates. By 65-66 hours after exposure,
75% of the radiolabel had been eliminated. The amount of bromomethane
eliminated was linearly related to the amount absorbed (Medinsky et al.,
1985). Excretion of bromomethane and its metabolites does not appear to be a
concentration dependent (i.e., saturable) process, once absorbed.
___I.B.5. CONFIDENCE IN THE INHALATION RfC
Study -- Medium
Data Base -- High
RfC -- High
The Reuzel et al. (1987, 1991) chronic study was well conducted, used an
appropriate number of animals and exposure levels, and included thorough
histopathological examination of the respiratory tract; however, it is given a
medium confidence rating because it did not identify a NOAEL. The LOAEL
identified in this study is supported by the effects seen in rats in the
subchronic NTP (1990) study and mice in the chronic NTP (1990) study, as well
as in subacute and subchronic studies in rats (Hastings, 1990; Hurtt et al.,
1987, 1988). The data base is given a high confidence rating because there is
a chronic inhalation study in two species supported by subchronic inhalation
studies in several species, and because data are available on the
developmental and reproductive effects of bromomethane as well as its
pharmacokinetics following inhalation exposure. Based on the confidence in
the data base and study, high confidence in the RfC follows.
___I.B.6. EPA DOCUMENTATION AND REVIEW OF THE INHALATION RfC
Source Document -- This assessment is not presented in an existing U.S. EPA
document.
Other EPA Documentation -- U.S. EPA, 1986, 1987
Agency Work Group Review -- 10/13/1988, 09/19/1989, 08/15/1991, 12/10/1991
Verification Date -- 12/10/1991
___I.B.7. EPA CONTACTS (INHALATION RfC)
Please contact the Risk Information Hotline for all questions concerning this
assessment or IRIS, in general, at (513)569-7254 (phone), (513)569-7159 (FAX)
or RIH.IRIS@EPAMAIL.EPA.GOV (internet address).
_II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE
Substance Name -- Bromomethane
CASRN -- 74-83-9
Primary Synonym -- Methyl bromide
Last Revised -- 08/01/1990
Section II provides information on three aspects of the carcinogenic
assessment for the substance in question; the weight-of-evidence judgment of
the likelihood that the substance is a human carcinogen, and quantitative
estimates of risk from oral exposure and from inhalation exposure. The
quantitative risk estimates are presented in three ways. The slope factor is
the result of application of a low-dose extrapolation procedure and is
presented as the risk per (mg/kg)/day. The unit risk is the quantitative
estimate in terms of either risk per ug/L drinking water or risk per ug/cu.m
air breathed. The third form in which risk is presented is a drinking water
or air concentration providing cancer risks of 1 in 10,000, 1 in 100,000 or 1
in 1,000,000. The rationale and methods used to develop the carcinogenicity
information in IRIS are described in The Risk Assessment Guidelines of 1986
(EPA/600/8-87/045) and in the IRIS Background Document. IRIS summaries
developed since the publication of EPA's more recent Proposed Guidelines for
Carcinogen Risk Assessment also utilize those Guidelines where indicated
(Federal Register 61(79):17960-18011, April 23, 1996). Users are referred to
Section I of this IRIS file for information on long-term toxic effects other
than carcinogenicity.
__II.A. EVIDENCE FOR CLASSIFICATION AS TO HUMAN CARCINOGENICITY
___II.A.1. WEIGHT-OF-EVIDENCE CLASSIFICATION
Classification -- D; not classifiable as to human carcinogenicity
Basis -- Inadequate human and animal data: a single mortality study from which
direct exposure associations could not be deduced and studies in several
animal species with too few animals, too brief exposure or observation time
for adequate power. Bromomethane has shown genotoxicity.
___II.A.2. HUMAN CARCINOGENICITY DATA
Inadequate. A prospective mortality study was reported for a population
of 3579 white male chemical workers. The men, employed between 1935 and 1976,
were potentially exposed to 1,2-dibromo-3-chloropropane, 2,3-dibromopropyl
phosphate, polybrominated biphenyls, DDT, and several brominated organic and
inorganic compounds (Wong et al., 1984). Overall mortality for the cohort, as
well as for several subgroups, was less than expected. Of the 665 men exposed
to methyl bromides (the only common exposure to organic bromides), two died
from testicular cancer, as compared with 0.11 expected. This finding may be
noteworthy as testicular cancer is usually associated with a low mortality
rate. Therefore, there could be more cancer cases than there appear to be
based on mortality. The authors noted that it was difficult to draw
definitive conclusions as to causality because of the lack of exposure
information and the likelihood that exposure was to many brominated compounds.
___II.A.3. ANIMAL CARCINOGENICITY DATA
Inadequate. Bromomethane was administered by gavage to groups of 10 male
and female Wistar rats (Danse et al., 1984). Animals were administered doses
of 0, 0.4, 2, 10, or 50 mg/kg/day bromomethane in arachis oil 5 days/week for
13 weeks, at which time the experiment was terminated. There was an apparent
dose-related increase in diffuse hyperplasia of the forestomach. The authors
reported a forestomach papilloma incidence of 2/10 in the high-dose males and
forestomach carcinoma incidences of 7/10 and 6/10 in the high-dose males and
females, respectively. These results were subsequently questioned (U.S. EPA,
1985; Schatzow, 1984). A panel of NTP scientists reevaluated the histological
slides and concluded that the lesions were hyperplasia and inflammation
rather than neoplasia.
Rosenblum et al. (1960) reported a 1-year study in which beagle dogs
(4/treatment group, 6/control) were provided diets fumigated to residue
levels of 0, 35, 75, or 150 ppm bromomethane. No tumors were observed at any
dose level; however, there was no indication that the dogs were examined for
tumors. In addition, 1-year observation is considered to be inadequate by the
EPA for tumor induction in dogs.
In an earlier study (Irish et al., 1940) small numbers of rats, guinea
pigs, rabbits and monkeys were exposed by inhalation to bromomethane at doses
ranging from 0.065 to 0.85 mg/L air. Exposures were for 7.5 to 8 hours/day, 5
days/week for up to 6 months. The authors reported that the highest dose
produced acutely toxic effects in all species, but no tumors were observed at
any dose level. The short duration of exposure and observation are
considered inadequate by the EPA.
Bromomethane is currently on test at NTP.
___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY
Bromomethane has been shown to produce mutations in Salmonella strains
sensitive to alkylating agents and to E. coli both with and without the
addition of a metabolic activation system (Voogd et al., 1982; Moriya et al.,
1983; Kramers et al.,1985; Djalali-Behzad et al., 1981). Bromomethane was
also mutagenic in a modification of the standard Salmonella assay employing
vapor phase exposure (Simmon and Tardiff, 1978; Simmon, 1978, 1981; Simmon et
al., 1977). Bromomethane was observed to be mutagenic for Drosophila and for
mouse lymphoma cells (Voogd et al., 1982; Kramers et al., 1985).
Bromomethane is structurally related to bromoethane which, when tested in
mice and rats of both sexes, has shown clear evidence of carcinogenicity in
some cases and equivocal in others. NTP (1988) conducted an inhalation
bioassay on bromoethane, and the results were recently released in a draft
report. Groups of F344/N rats (50/sex) and B6C3F1 mice (50/sex) were exposed
to 0, 100, 200 or 400 ppm bromoethane 6 hours/day for 5 days/week. A
statistically significant increase in uterine adenomas, adenocarcinomas, or
squamous cell carcinomas was observed in female mice exposed to 200 and 400
ppm, indicating clear evidence of carcinogenic activity. Equivocal evidence
of carcinogenic activity was reported for male and female rats and male mice.
While alveolar/bronchiolar adenomas or carcinomas and pheochromocytomas were
observed in male rats, the incidences were not dose-related and were within
the historical ranges for NTP studies. Granular cell tumors of the brain were
also observed in male rats and, although not statistically significant, the
incidence was higher than historical incidence in either the study lab or NTP
studies. The incidence of alveolar/bronchiolar neoplasms in exposed male mice
was marginally greater than control or historical incidence. An increased
incidence of gliomas in exposed female rats was significant by the trend test;
however, the incidence was not significantly greater when compared with the
controls in the study and the controls used in NTP stuides.
__II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE
Not available.
__II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE
Not available.
__II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT)
___II.D.1. EPA DOCUMENTATION
Source Document -- U.S. EPA, 1985, 1986, 1987
The Health and Environmental Effects Profile for Methyl Bromide and the Health
Effects Assessment for Bromoethane received Agency review.
___II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT)
Agency Work Group Review -- 02/01/1989, 03/01/1989
Verification Date -- 03/01/1989
___II.D.3. U.S. EPA CONTACTS (CARCINOGENICITY ASSESSMENT)
Please contact the Risk Information Hotline for all questions concerning this
assessment or IRIS, in general, at (513)569-7254 (phone), (513)569-7159 (FAX)
or RIH.IRIS@EPAMAIL.EPA.GOV (internet address).
_VI. BIBLIOGRAPHY
Substance Name -- Bromomethane
CASRN -- 74-83-9
Primary Synonym -- Methyl bromide
Last Revised -- 04/01/1992
__VI.A. ORAL RfD REFERENCES
Danse, L.H.J.C., F.L. van Velsen and C.A. van der Heijden. 1984.
Methylbromide: Carcinogenic effects in the rat forestomach. Toxicol. Appl.
Pharmacol. 72: 262-271.
Hardin, B.D., G.P. Bond, M.R. Sikov, F.D. Andrew, R.P. Beliles and R.W.
Niemeier. 1981. Testing of selected workplace chemicals for teratogenic
potential. Scand. J. Work Environ. Health. 7: 66-75.
Irish, D.D., E.M. Adams, H.C. Spencer and V.K. Rowe. 1940. The response
attending exposure of laboratory animals to vapors of methyl bromide. J. Ind.
Hyg. Toxicol. 22: 218-230.
Rosenblum, I., A.A. Stein, and G. Eisinger. 1960. Chronic ingestion by dogs
of methyl bromide-fumigated food. Arch. Environ. Health. 1: 316-323.
Sikov, M.R., W.C. Cannon, D.B. Carr, R.A. Miller, L.F. Montgomery and D.W.
Phelps. 1980. Teratologic assessment of butylene oxide, styrene oxide and
methyl bromide. NTIS PB 81-16851. 87 p.
U.S. EPA. 1986. Health and Environmental Effects Profile for Methyl Bromide.
Prepared by the Office of Health and Environmental Assessment, Environmental
Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste
and Emergency Response, Washington DC.
U.S. EPA. 1987. Drinking Water Health Advisory for Bromomethane. Prepared
by the Office of Health and Environmental Assessment, Environmental Criteria
and Assessment Office, Cincinnati, OH for the Office of Drinking Water,
Washington DC.
__VI.B. INHALATION RfC REFERENCES
American Biogenics Corporation. 1986. Two-generation reproduction study via
inhalation in albino rats using methyl bromide. Final Report. American
Biogenics Corporation Study 450-1525, OTS 0515364, sponsored by the Methyl
Bromide Panel.
Anger, W.K., J.V. Setzer, J.M. Russo, W.S. Brightwell, R.G. Wait and B.L.
Johnson. Neurobehavioral effects of methyl bromide inhalation exposures.
Scand. J. Work Environ. Health. 7(Suppl. 4): 40-47.
Anger, W.K., L. Moody, J. Burg, W.S. Brightwell, B.J. Taylor, J.M. Russo, et
al. 1986. Neurobehavioral evaluation of soil and structural fumigators using
methyl bromide and sulfuryl fluoride. Neurotoxicology. 7(3): 137-156.
Bond, J.A., J.S. Dutcher, M.A. Medinsky, R.F. Henderson and L.S. Birnbaum.
1985. Disposition of [14C]methyl bromide in rats after inhalation. Toxicol.
Appl. Pharmacol. 78: 259-267.
Breslin, W.J., C.L. Zablotny, G.J. Brabley and L.G. Lomax. 1990.
Methylbromide inhalation teratology study in New Zealand white rabbits.
Toxicology Research Laboratory, Health and Environmental Sciences, The Dow
Chemical Company, Midland, MI. Study No. K-000681-033. OTS Number 8EHQ-1189-
0844 S.
Eustis, S.L., S.B. Haber, R.T. Drew and R.S.H. Yang. 1988. Toxicology and
pathology of methyl bromide in F344 rats and B6C3F1 mice following repeated
inhalation exposure. Fund. Appl. Toxicol. 11: 594-610.
Hardin, B.D., G.P. Bond, M.R. Sikov, F.D. Andrew, R.P. Beliles and R.W.
Niemeier. 1981. Testing of selected workplace chemicals for teratogenic
potential. Scand. J. Environ. Health. 7(Suppl. 4): 66-75.
Hastings, L. 1990. Sensory neurotoxicology: Use of the olfactory system in
the assessment of toxicity. Neurotoxicol. Teratol. 12: 455-459.
Herzstein, J. and M.R. Cullen. 1990. Methyl bromide intoxication in four
field-workers during removal of soil fumigation sheets. Am. J. Ind. Med. 17:
321-326.
Hurtt, M.E. and P.K. Working. 1988. Evaluation of spermatogenesis and sperm
quality in the rat following acute inhalation exposure to methyl bromide.
Fund. Appl. Toxicol. 10(3): 490-498.
Hurtt, M.E., K.T. Morgan and P.K. Working. 1987. Histopathology of acute
toxic responses in selected tissues from rats exposed by inhalation to methyl
bromide. Fund. Appl. Toxicol. 9: 352-365.
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: 311-328.
Irish, D.D., E.M. Adams, H.C. Spencer and V.K. Rowe. 1940. The response
attending exposure of laboratory animals to vapors of methyl bromide. J. Ind.
Hyg. Toxicol. 22(6): 218-230.
Kato, N., S. Morinobu and S. Ishizu. 1986. Subacute inhalation experiment
for methyl bromide in rats. Indust. Health. 24: 87-103.
Medinsky, M.A., J.S. Dutcher, J.A. Bond, R.F. Henderson, J.L Mauderly, M.B.
Snipes, et al. 1985. Uptake and excretion of [14C]methyl bromide as
influenced by exposure concentration. Toxicol. Appl. Pharmacol. 78: 215-225.
Morrissey, R.E., B.A. Schwetz, J.C. Lamb IV, M.D. Ross, J.L. Teague and R.W.
Morris. 1988. Evaluation of rodent sperm, vaginal cytology, and reproductive
weight data from National Toxicology Program 13-week studies. Fund. Appl.
Toxicol. 11: 343-358.
NTP (National Toxicology Program). 1990. Toxicology and carcinogenesis
studies of methyl bromide (CAS No. 74-83-9) in B6C3F1 mice (inhalation
studies). NTP TR 385, NIH Publication No. 91-2840. Peer Review Draft.
Reuzel, P.G.J., C.F. Kuper, H.C. Dreef-van der Meulen and V.M.H. Hollanders.
1987. Chronic (29-month) inhalation toxicity and carcinogenicity study of
methyl bromide in rats. Report No. V86.469/221044. Netherlands Organization
for Applied Scientific Research, Division for Nutrition and Food Research,
TNO. EPA/OTS Document No. 86-8700001202.
Reuzel, P.G.J., H.C. Dreef-van der Meulen, V.M.H. Hollanders, C.F. Kuper,
V.J. Feron and C.A. van der Heijden. 1991. Chronic inhalation toxicity and
carcinogenicity study of methyl bromide in Wistar rats. Fd. Chem. Toxic.
29(1): 31-39.
Russo, J.M., W.K. Anger, J.V. Setzer and W.S. Brightwell. 1984.
Neurobehavioral assessment of chronic low-level methyl bromide exposure in the
rabbit. J. Toxicol. Environ. Health. 14: 247-255.
Sikov, M.R., W.C. Cannon, D.B. Carr, R.A. Miller, L.F. Montgomery and D.W.
Phelps. 1981. Teratologic assessment of butylene oxide, styrene oxide and
methyl bromide. Battelle Pacific Northwest Laboratory, Richland, WA, for the
National Institute for Occupational Safety and Health, Cincinnati, OH.
U.S. EPA. 1986. Health and Environmental Effects Profile for Methyl Bromide.
Final Draft. Prepared by the Office of Health and Environmental Assessment,
Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of
Solid Waste and Emergency Response, Washington, DC.
U.S. EPA. 1987. Health Effects Assessment for Bromomethane. Final Draft.
Prepared by the Office of Health and Environmental Assessment, Environmental
Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste
and Emergency Response, Washington, DC.
__VI.C. CARCINOGENICITY ASSESSMENT REFERENCES
Danse, L.H.D.C., F.L. van Velsen and C.A. Van der Heijden. 1984.
Methylbromide: Carcinogenic effects in the rat forestomach. Toxicol. Appl.
Pharmacol. 72: 262-271.
Djalali-Behzad, G., S. Hussain, S. Osterman-Golker and D. Segerback. 1981.
Estimation of genetic risks of alkylating agents. VI. Exposure of mice and
bacteria to methyl bromide. Mutat. Res. 84(1): 1-10.
Irish, D.D., E.M. Adams, H.C. Spencer and V.K. Rowe. 1940. The response
attending exposure of laboratory animals to vapors of methyl bromide. J. Ind.
Hyg. Toxicol. 22: 218-230.
Kramers, P.G.N, C.E. Voogd, A.G.A.C. Knaap and C.A. Van der Heijden. 1985.
Mutagenicity of methyl bromide in a series of short-term tests. Mutat. Res.
155(1-2): 41-47.
Moriya, M., T. Ohta, K. Watanabe, T. Miyazawa, K. Kato and Y. Shirasu. 1983.
Further mutagenicity studies on pesticides in bacterial reversion assay
systems. Mutat. Res. 116(3-4): 185-216.
NTP (National Toxicology Program). 1988. NTP technical report on the
toxicology and carcinogenesis studies of bromomethane (CAS No. 74-96-4) in
F344/N rats and B6C3F1 mice (inhalation studies). NIH Publication No. 89-
2818. Peer Review Date: October 3, 1988.
Rosenblum, I., A.A. Stein and G. Eisinger. 1960. Chronic ingestion by dogs
of methyl bromide-fumigated food. Arch. Environ. Health. 1: 316-323.
Schatzow, S. 1984. Memorandum to D. Clay, November 9, 1984. FXI-OTS-1184-
0327. Supplement, Sequence D.
Simmon, V.F. 1978. Structural correlations of carcinogenic and mutagenic
alkyl halides. FDA Publ(US); (FDA-78-1046): 163-171.
Simmon, V.F. 1981. Applications of the Salmonella/Microsome Assay. Short-
Term Tests. Chem. Carcinog. p.\120-126.
Simmon, V.F. and R.G. Tardiff. 1978. The mutagenic activity of halogenated
compounds found in chlorinated drinking water. Water Chlorination: Environ.
Impact Health Eff. Proc. Conf. 2: 417-431.
Simmon, V.F., K. Kauhanen and R.G. Tardiff. 1977. Mutagenic activity of
chemicals identified in drinking water. Dev. Toxicol. Environ. Sci. 2:
249-258.
U.S. EPA. 1985. Chemical Hazard Information Profile. Draft Report. Methyl
Bromide. Rev. Feb. 20, 1985. U.S. EPA, OTS, Washington, DC.
U.S. EPA. 1986. Health and Environmental Effects Profile for Methyl Bromide.
Final Draft. ECAO-CIN-P182, June, 1986.
U.S. EPA. 1987. Health Effects Assessment for Bromoethane. Final Draft.
ECAO-CIN-H090. June, 1987.
Voogd, C.E., A.G.A.C. Knaap, C.A. Van der Heijden and P.G. Kramers. 1982.
Genotoxicity of methylbromide in short-term assay systems. Mutat. Res. 97:
233.
Wong, O., W. Brocker, H.V. Davis and G.S. Nagle. 1984. Mortality of workers
potentially exposed to organic and inorganic brominated chemicals, DBCP, TRIS,
PBB, and DDT. Br. J. Ind. Med. 41: 15-24.
_VII. REVISION HISTORY
Substance Name -- Bromomethane
CASRN -- 74-83-9
Primary Synonym -- Methyl bromide
-------- -------- --------------------------------------------------------
Date Section Description
-------- -------- --------------------------------------------------------
09/30/1987 I.A.1. MF changed to UF -- no change in RfD
09/30/1987 I.A.2. Text changes
09/30/1987 I.A.3. Text changes
09/30/1987 I.A.4. Study descriptions added
09/30/1987 I.A.5. Text change
09/30/1987 I.A.6. Secondary contact changed
03/01/1988 I.A.1. Critical effect added
06/30/1988 I.A. Withdrawn; new RfD verified (in preparation)
09/26/1988 I.A. Oral RfD summary replaced
05/01/1989 II. Carcinogen assessment now under review
06/01/1989 II. Carcinogen summary on-line
06/01/1989 VI. Bibliography on-line
08/01/1989 VI.A. Oral RfD references added
10/01/1989 I.B. Inhalation RfD now under review
06/01/1990 I.A.2. Dosing clarified
06/01/1990 IV.F.1. EPA contact changed
08/01/1990 I.A. Text edited
08/01/1990 II. Text edited
08/01/1990 III.A. Health Advisory on-line
08/01/1990 VI.D. Health Advisory references added
07/01/1991 I.A.7. Secondary contact changed
01/01/1992 IV. Regulatory actions updated
04/01/1992 I.B. Inhalation RfC summary on-line
04/01/1992 VI.B. Inhalation RfC references added
05/01/1992 I.B.6. Deleted incorrect work group review date
10/01/1992 I.B.1. 'NOAEL' corrected to LOAEL
VIII. SYNONYMS
Substance Name -- Bromomethane
CASRN -- 74-83-9
Primary Synonym -- Methyl bromide
Last Revised -- 01/31/1987
74-83-9
Brom-o-gas
Bromomethane
Curafume
Dowfume MC-2 Soil Fumigant
Dowfume MC-33
Edco
Embafume
Halon 1001
Haltox
Iscobrome
Kayafume
MB
MBX
MEBR
Metafume
Methane, Bromo-
Methogas
Methyl bromide
Monobromomethane
Pestmaster
Profume
R40B1
Rotox
Terabol
Terr-o-gas 100
Zytox
Last updated: 5 May 1998
URL: http://www.epa.gov/iris/SUBST/0015.HTM
|
