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0015

Bromomethane; CASRN 74-83-9

Human health assessment information on a chemical substance is included in the IRIS database only after a comprehensive review of toxicity data, as outlined in the IRIS assessment development process. Sections I (Health Hazard Assessments for Noncarcinogenic Effects) and II (Carcinogenicity Assessment for Lifetime Exposure) present the conclusions that were reached during the assessment development process. Supporting information and explanations of the methods used to derive the values given in IRIS are provided in the guidance documents located on the IRIS website.

STATUS OF DATA FOR Bromomethane

File First 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
of the forestomach

Rat Subchronic Gavage
Study

Danse et al., 1984

NOAEL: 1.4 mg/kg/day

LOAEL: 7.1 mg/kg/day

1000
1
1.4E-3
mg/kg/day

*Conversion Factors and Assumptions — 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 Studies/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
Database — 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

Screening-Level Literature Review Findings — A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the RfD for Bromomethane conducted in November 2001 identified one or more significant new studies. IRIS users may request the references for those studies from the IRIS Hotline at hotline.iris@epa.gov or (202)566-1676.

__I.A.7. EPA Contacts (Oral RfD)

Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (202)566-1676 (phone), (202)566-1749 (FAX) or hotline.iris@epa.gov (internet address).

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_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
proliferative lesions
of the olfactory
epithelium of the
nasal cavity

Rat 29-month
Inhalation Study

Reuzel et al., 1987, 1991

NOAEL: None

LOAEL: 11.7 mg/cu.m (3 ppm)
LOAEL (ADJ): 2.08 mg/cu.m
LOAEL (HEC): 0.48 mg/cu.m
100
1
5E-3
mg/cu.m

*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
Database — 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 database 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 database 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

Screening-Level Literature Review Findings — A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the RfC for Bromomethane conducted in November 2001 identified one or more significant new studies. IRIS users may request the references for those studies from the IRIS Hotline at hotline.iris@epa.gov or (202)566-1676.

__I.B.7. EPA Contacts (Inhalation RfC)

Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (202)566-1676 (phone), (202)566-1749 (FAX) or hotline.iris@epa.gov (internet address)

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_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 Human Carcinogenicity

__II.A.1. Weight-of-Evidence Characterization

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 studies.

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_II.B. Quantitative Estimate of Carcinogenic Risk from Oral Exposure

Not available

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_II.C. Quantitative Estimate of Carcinogenic Risk from Inhalation Exposure

Not available

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_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. EPA Review (Carcinogenicity Assessment)

Agency Work Group Review — 02/01/1989, 03/01/1989

Verification Date — 03/01/1989

Screening-Level Literature Review Findings — A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the cancer assessment for Bromomethane conducted in November 2001(revised May 2003) identified one or more significant new studies. IRIS users may request the references for those studies from the IRIS Hotline at hotline.iris@epa.gov or (202)566-1676.

__II.D.3. EPA Contacts (Carcinogenicity Assessment)

Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (202)566-1676 (phone), (202)566-1749 (FAX) or hotline.iris@epa.gov (internet address).

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_III.  [reserved]
_IV.  [reserved]
_V.  [reserved]


_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.

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_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.

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_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.

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_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 RfC 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
04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regultory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information.
12/03/2002 I.A.6., I.B.6., II.D.2. Screening-Level Literature Review Findings message has been added.

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_VIII.  Synonyms

Substance Name — Bromomethane
CASRN — 74-83-9
Primary Synonym — Methyl bromide
Last Revised — 01/31/1987

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