National Toxicology Program

Selected toxicity information from HSDB, one of the National Library of Medicine's databases. ¹

Names (NTP)

• Methyl bromide
• BROMOMETHANE (9CI)

Human Toxicity Excerpts

• CHRONIC EXPOSURE CAN CAUSE CNS DEPRESSION OR KIDNEY INJURY ... . [Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989., p. 950]**PEER REVIEWED**
  
• In handling methyl bromide in drug industry: ... severe itching, dermatitis was observed. ... Liq ... can cause severe corneal burns but vapors do not appear to be irritating. [Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley & Sons Inc., 1993-1994., p. 4022]**PEER REVIEWED**
  
• Symptomatology (3-12 hr after inhalation of vapor): 1. Dizziness & headache. 2. Anorexia, nausea, vomiting, & abdominal pain. 3. Lassitude, profound weakness, slurring of speech, & staggering gait. 4. Transient blurring of vision, diplopia, sometimes strabismus & even temporary blindness. 5. Mental confusion, mania, tremors, & epileptiform convulsions. ... 6. Rapid respiration, associated with signs of severe pulmonary edema, cyanosis, pallor & collapse. ... 7. Coma, areflexia & death from respiratory or circulatory collapse. 8. Low-level subacute vapor exposures have produced a syndrome of persistent numbness in the hands & legs, impaired superficial sensation, muscle weakness, unsteadiness of gait & absent or hypoactive distal tendon reflexes. 9. Late sequelae incl bronchopneumonia after severe pulmonary lesions, renal failure with anuria due to tubular degeneration, & severe weakness with or without evidence of paralysis. These difficulties ... subside within a few wk or mo, & complete recovery is the rule. ... Jaundice & other evidence of mild hepatic injury are noted occasionally. [Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984., p. III-282]**PEER REVIEWED**
  
• SUFFICIENT PERCUTANEOUS ABSORPTION ... CAN OCCUR TO PRODUCE DEATH IN MAN, & IF EVAPORATION IS DELAYED ... IT IS INTENSE VESICANT ON ... SKIN. BLISTERS PRODUCED ... ARE ENORMOUS BUT RARELY DEEP ENOUGH TO DESTROY ENTIRE SKIN LAYER. [Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984., p. III-280]**PEER REVIEWED**
  
• AUTOPSY IN CASE IN WHICH THERE HAD BEEN BLURRING OF VISION & APPEARANCE OF FLICKERING LIGHTS, DOUBLE VISION, & PAIN BEHIND EYES SHOWED MANY MINUTE HEMORRHAGES THROUGHOUT BRAIN, HEART, SPLEEN, & KIDNEYS. [Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986., p. 609]**PEER REVIEWED**
  
• IN 35 METHYL BROMIDE FUMIGATORS EXAMINED, SLIGHT EEG CHANGES (IN 10 SUBJECTS) & SMALL INCR IN SERUM TRANSAMINASES WERE FOUND WHICH COULD BE RELATED TO BROMIDE CONCN IN BLOOD. [VERBERK MM ET AL; BR J IND MED 36 (1): 59-62 (1979)]**PEER REVIEWED**
  
• THREE CASES OF METHYL BROMIDE POISONING ARE DISCUSSED. A 6 YR OLD BOY HAD CONVULSIONS & BECAME COMATOSE FOLLOWING EXPOSURE TO METHYL BROMIDE. HIS INITIAL EEG SHOWED IRREGULAR WAVES BUT AFTER 3 WK RETURNED TO NORMAL. HIS GRANDMOTHER SHOWED SIGNS OF CONFUSION ACCOMPANIED BY NAUSEA, VOMITING, SEIZURES & COMA. HER EEG WAS AFFECTED BUT NORMALIZED 2 YR AFTER THE INCIDENT. GRANDFATHER'S SYMPTOMS CONSISTED OF NAUSEA & CONFUSION. HIS AWAKE EEG WAS INITIALLY IRREGULAR BUT THE SLEEP EEG WAS NORMAL. [JAMESON HD; ELECTROENCEPHALOGR CLIN NEUROPHYSIOL 46 (1): 2 (1979)]**PEER REVIEWED**
  
• AFTER SPRAYING METHYL BROMIDE IN STOREROOM OF A HOME, SPASMS OCCURRED IN ALL 4 RESIDENTS, A GIRL 11 YR OF AGE HAD FREQUENT APPEARANCE OF GENERAL MYOCLONIA WHICH WAS FOLLOWED BY COMA. AFTER THE DISAPPEARANCE OF MYOCLONIA, A PERIODIC HIGH AMPLITUDE SLOW WAVE DISCHARGE APPEARED ON THE ELECTROENCEPHALOGRAM. CHARACTERISTIC ACTION MYOCLONIA REMAINED ON THE RIGHT UPPER EXTREMITY. SERUM CONCN OF BROMIDE ION DID NOT SHOW ANY CORRELATION WITH CLINICAL PICTURE (SUGGESTING THAT TOXICITY ... IS DUE TO THE METHYL BROMIDE GROUP RATHER THAN THE BROMIDE ION.) [TAKAYAMA J, NUMAJIRI S; NIPPON SHONIKA GAKKAI ZASSHI (ACTA PEDIATR JPN) 83 (3): 332-3 (1979)]**PEER REVIEWED**
  
• Human experience indicates that acute fatal intoxication can result from exposures to vapor levels as low as 1164 to 1552 mg/cu m, and harmful effects can occur at 388 mg/cu m or more. Systemic poisoning has been reported to occur from a two week exposure (8 hr/day) at about 136 mg/cu m. Symptoms generally increase in severity with increasing levels of exposure and may vary somewhat according to exposure circumstances and individual susceptibility. In sublethal poisoning cases a latency period of 2 to 48 hr (usually about 4 to 6 hr) occurs between exposure and onset of symptoms. [USEPA; Ambient WaterQuality Criteria Doc: Halomethanes p.C-24 (1980) EPA 440/5-80-051]**PEER REVIEWED**
  
• A case of fatal methyl bromide poisoning in a 68 yr old male scrapdealer was reported. The subject discharged several obsolete fire extinguishers containing methyl bromide into the atmosphere & proceeded to scrap them. Several hrs later he developed twitching of the arms & became ataxic. On physical exam he had painful, epileptiform tonic, clonic spasms of the face, trunk, & limbs but was fully conscious during these episodes. Anticonvulsant treatment with diazepam, phenytoin, iv chlormethiazole & nitrous oxide by inhalation had no effect on convulsions. Muscle paralysis was induced with pancuronium & positive pressure ventilation begun. EEG showed centroencephalic spike discharges. After 7 days the generalized convulsions had ceased & ventilation was discontinued. There was some neurological improvement over the following week. Despite anticoagulant treatment the patient died 16 days after admission from pulmonary emboli. Serum bromide concn ranged from 130-480 mg/100 ml. [Behrens RH, Dukes DCD; Br J Ind Med 43: 561-62 (1986)]**PEER REVIEWED**
  
• Early medicinal: uses did not last long because of the tendency of methyl bromide to cause throat irritation, to induce vomiting, and to release free bromine, in addition, several deaths were attributed to its medicinal use. [USDA/Forest Service; Pesticide Background Statements Vol II Fungicides and Fumigants p.MB/C-12 (1986)]**PEER REVIEWED**
  
• The case of action myoclonus following acute methyl bromide intoxication was characterized by marked changes in the inferior colliculi & moderate or mild abnormalities of thalamus, griseum centrale mesencephali, nucleus centralis superior, nucleus reticularis tegmenti pontis, nuclei pontis, & dentatus. [Hauw JJ et al; Adv Neurol 43: 201-14 (1986)]**PEER REVIEWED**
  
• ... Exposure of human lymphocyte cultures to 4.3% methyl bromide for 100 sec increased the frequency of sister chromatid exchanges from 10.0 to 16.8%. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V41 199 (1986)]**PEER REVIEWED**
  
• Chronic methyl bromide toxicity usually is limited to CNS although mild elevation of serum hepatic aminotransferase levels has been reported in industrial workers. A fumigator chronically exposed to methyl bromide developed paresthesia of the extremities, dysesthesias, & visual impairment secondary to optic atrophy. Mild neurologic dysfunction (eg, decreased finger sensitivity, reduced cognitive performance, & behavioral abnormalities) was detected in a study of soil fumigators. [Ellenhorn, M.J. and D.G. Barceloux. Medical Toxicology - Diagnosis and Treatment of Human Poisoning. New York, NY: Elsevier Science Publishing Co., Inc. 1988., p. 981]**PEER REVIEWED**
  
• Bromomethane is a CNS depressant and may involve pyschic, motor and GI disturbances. In light poisoning cases effects may be limited to mild neurological and GI disturbances, with recovery in a few days. Moderate cases involve the CNS further, with more extensive neurological symptoms and usual disturbance. Recovery may be prolonged for weeks or months, with persisting symptoms and/or disturbed function. [USEPA; Ambient Water Quality Criteria Doc: Halomethanes p.C-34 (1980) EPA 440/5-80-051]**PEER REVIEWED**
  
• Severe poisoning cases also involve a latent period and similar initial symptoms, with development of disturbed speech and gait, incoordination, tremors that may develop to convulsions, psychic disturbances. Recovery can be quite protracted with persisting neurological disorders. [USEPA; Ambient Water Quality Criteria Doc: Halomethanes p.C-34 (1980) EPA 440/5-80-051]**PEER REVIEWED**
  
• In fatal cases the convulsions may become more intense and frequent, with unconscious periods. Death may occur in a few hours from pulmonary edema or in one to three days from circulatory failure. Pathology often includes hyperemia, edema, and inflammation in lungs and brain. Degenerative changes occur in the kidneys, liver and/or stomach, and perhaps the brain; although brain changes are usually more functional in character. [USEPA; Ambient Water Quality Criteria Doc: Halomethanes p.C-35 (1980) EPA 440/5-80-051]**PEER REVIEWED**
  
• A case of brief skin exposure (spray) to liquid bromomethane, quickly decontaminated, did not produce a burn, but resulted in severe, delayed neuromuscular disturbances (twitching, fits, convulsions) and permanent brain damage (cerebellum and pyranedal tract). [USEPA; Ambient Water Quality Criteria Doc: Halomethanes p.C-35 (1980) EPA 440/5-80-051]**PEER REVIEWED**
  
• The signs & symptoms of methyl bromide poisoning vary according to the degree of exposure. In most instances, the onset of the symptoms is delayed & this latent period varies from 1/2 to several hrs & occasionally 12, 24, or 48 hr. The symptoms may be fatigue, headache, dizziness, nausea & vomiting, disturbances of hearing, vision, mental confusion, muscular weakness, collapse, respiratory difficulties & coma. Death is usually due to lung damage, but damage to the CNS may accompany pulmonary damage. [Braker W, Mossman A; Matheson Gas Data Book 6th ed p.457 (1980)]**PEER REVIEWED**
  
• Exposure to low, but harmful, concns of methyl bromide over a period of time results in a varied picture of signs & symptoms. In order of frequency of occurrence, these symptoms are: visual disturbances, disturbances of speech, numbness of the extremities, mental confusion, hallucinations, tremors, coma & frequent fainting attacks. Most symptoms disappear in a few days /after/ the exposure /is terminated/, but numbness of the extremities & visual disturbances may persist from 2-5 mo. [Braker W, Mossman A; Matheson Gas Data Book 6th ed p.457 (1980)]**PEER REVIEWED**
  
• NO REASONS HAVE BEEN ADVANCED FOR COMPLETE SPARING OF LUNGS IN SOME CASES WHERE BRAIN DAMAGE HAS BEEN BOTH SEVERE & PERMANENT. SEVERE NEUROLOGICAL SIGNS SEEM TO BE DEPENDENT ON A SUDDEN EXPOSURE TO HIGH CONCN FOLLOWING CONTINUOUS SLIGHT EXPOSURE. [International Labour Office. Encyclopedia of Occupational Health and Safety. Vols. I&II. Geneva, Switzerland: International Labour Office, 1983., p. 330]**PEER REVIEWED**
  
• METHYL BROMIDE IS A DANGEROUS CUMULATIVE POISON WITH DELAYED SYMPTOMS OF CENTRAL NERVOUS SYSTEM INTOXICATION THAT MAY APPEAR AS LONG AS SEVERAL MONTHS AFTER EXPOSURE. [White-Stevens, R. (ed.). Pesticides in the Environment: Volume 1, Part 1, Part 2. New York: Marcel Dekker, Inc., 1971., p. 130]**PEER REVIEWED**
  
• Fatal poisoning has ... resulted from exposures to relatively high concn of methyl bromide vapors (from 8600 to 60000 ppm). [Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996., p. 2196]**PEER REVIEWED**
  
• When used as a fumigant for various foodstuffs in the past, methyl bromide caused more fatalities among California workmen than any other agricultural chemical. [Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984., p. III-280]**PEER REVIEWED**
  
• The toxic effects of aliphatic chlorinated, brominated, fluorinated & iodinated hydrocarbons, alcohols, acids, & thioacids, were reviewed, with emphasis on their action at the level of the CNS in both man & experimental animals as well as their metab & effects on other organs. Methyl iodide, methyl bromide, methyl chloride & ethyl chloride were shown to induce signs, symptoms, or lesions of the cerbellum in both humans & experimental animals. [O'Donoghue JL; Neurotoxicity of Industrial and Commerical Chemicals 2: 99-126 (1985)]**PEER REVIEWED**
  
• The effects of exposure of the skin to high concentrations of methyl bromide were studied in 6 cases, who had been unintentionally exposed. Exposure to high concentrations of methyl bromide (approximately 40 g/cu m) for 40 min can lead to redness and blistering of the skin. This cannot be prevented by wearing standard protective clothing. Skin lesions show a preference for relatively moist skin areas. Plasma bromide levels were highest immediately following exposure (mean 9.0 + or - 12.4 mg/l) and fell in subsequent hours (mean 6.8 + or - 2.3 mg/l 12 hr after the exposure). No systemic effects were noted in this series. [Zwaveling JH et al; Hum Toxicol 6 (6): 491-6 (1987)]**PEER REVIEWED**
  
• Neurobehavioral functions affected by methyl bromide exposure were evaluated in California structural and soil fumigators using methyl bromide and sulfuryl fluoride. Sampling data revealed that structural fumigators are exposed for up to 1.5 hr/day to 0-2.2 ppm methyl bromide and/or 10-200 ppm sulfuryl fluoride, and soil fumigators can be exposed to 2.3 ppm methyl bromide over an 8 hr day. Subjects were grouped for statistical analysis on the basis of exposure history: Those exposed primarily (80% or more of the work period with exposure potential) to methyl bromide (n= 32), primarily to sulfuryl fluoride (24), or to a combination of methyl bromide and sulfuryl fluoride (40-60% of each) for a minimum of one year (18), and those not exposed to high concentrations of any chemicals (29 Referents). Fumigators using methyl bromide reported a significantly higher prevalence of 18 symptoms consistent with methyl bromide toxicity than did referents. Methyl bromide fumigators did not perform as well as referents on 23 of 27 behaviorial tests (chosen to reflect methyl bromide effects), and were significantly lower on one test of finger sensitivity and one of cognitive performance. [Anger WK et al; Neurotoxicology 7(3): 137-56 (1986)]**PEER REVIEWED**
  
• A 32 year old fumigationassistant developed systemic and neuro-ophthalmic manifestation of methyl bromide poisoning, including increased serum bromide level (6.6 mg/100 ml), paresthesias and burning dysesthesia on his hands and feet, and visual impairment. Ocular examination showed mild bilateral decrease in vision, temporal optic nerve head pallor, severely attenuated visual-evoked response amplitudes and normal latencies, a normal electroetinogram, an abnormal electrooculogram, and a severe deuteranomalous (green) defect on Farnsworth-Munsell 100 hue testing. His vision had not improved 12 mo after the initial exposure. [Chavez CT et al; Am J Ophthalmol 99 (6): 715-9 (1985)]**PEER REVIEWED**
  
• A technique was described which used sister chromatid exchanges in human peripheral blood lymphocyte cultures to assess the genotoxic potential of vapors. Cultures were exposed to 4.3% methylbromide. Methylbromide increased sister chromatid exchange frequency from 9.90 to 16.84 per cell. [Tucker JD et al; Teratogenesis Carcinog Mutagen 6 (1): 15-21 (1986)]**PEER REVIEWED**
  
• High concns of methyl bromide can produce rapid unconsciousness during exposure, leading to a prompt "anesthetic" death. However, anesthesia plays no part in the great majority of cases, which are characterized by delayed onset, a great variety of symptoms, & delayed recovery, if death does not occur. The delay in onset usually is several hours, but a delay of only a few min & a delay of 48 hr have been observed. In fatal cases with delayed onset, death generally occurs within 4-6 hr but sometimes after 24-48 hr. In rare instances, death may be delayed as much as 18 days. The cause of death in these cases usually is circulatory failure. [Hayes, W.J., Jr., E.R. Laws, Jr., (eds.). Handbook of Pesticide Toxicology. Volume 2. Classes of Pesticides. New York, NY: Academic Press, Inc., 1991., p. 670]**PEER REVIEWED**
  
• ...Two cases of testicular cancer mortality versus 0.11 expected (SMR= 1.799, p <0.05) among workers exposed to organic bromides /were reported/. ...Based on the recorded work histories, the only known shared potential exposure was methyl bromide. [Hayes, W.J., Jr., E.R. Laws Jr., (eds.). Handbook of Pesticide Toxicology Volume 1. General Principles. New York, NY: Academic Press, Inc., 1991., p. 329]**PEER REVIEWED**
  
• Characteristically during exposure to the gas there are no warning sensations, but after a latent period of several hr the victim has headache, nausea, vomiting, vertigo, & staggering. He may then also have lacrimation from irritation of the eyes, & may experience blurring & diplopia. Transient dimming of vision & blindness for twelve hr has been reported associated with severe nausea & vomiting, but with recovery within a few days. In other cases, nystagmus on lateral gaze, diplopia, & blurring of vision, especially when attempting to read, have been associated with the general neurologic disturbances. In severe cases, convulsion, delirium, & sometimes mania ensue, followed by collapse & possible death. Patients who recover may have a protracted period of apathy & depression, incoordination, tremors, & bothersome visual complaints. As a rule those who recover eventually recover completely. [Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986., p. 607]**PEER REVIEWED**
  
• In a carefully studied case in 1937, a man exposed to methyl bromide while filling fire extinguishers did not develop symptoms until 48 hr later; then he began to have vertigo, aphasia, and ataxia. At the end of a week, when speech was improving, he noted that the contour of objects appeared blurred. His amblyopia became worse, approaching almost complete blindness in a few days. At the same time, vertigo became worse, and one arm was paralyzed. Three weeks after exposure he began to discern objects better, and there was general improvement. At a month, vision in both eyes could not be improved beyond 5/10 with glasses, but the pupils and fundi were normal. There appeared to be weakness of accommodation (requiring 3.5 D for near vision), and central scotomas were found for green, but not for white. By two months, vision in each eye improved to 8/10, and only 1.5 D was required for near vision. His other neurologic disturbances had also subsided. [Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986., p. 609]**PEER REVIEWED**
  
• ... A man exposed to pure methyl bromide gas for about half an hour became weak and stupified, unable to walk, but able to crawl out of the room. He saw lights doubled, and they appeared to dance in front of this eyes. He could not place his hands on things accurately. He had neither headache nor vomiting, but in the next few days ataxia increased so that he could scarely stand, and he had marked intention tremor of the hands. The eyes appeared normal externally, and he made no complaint of ocular irritation. The optic nerveheads were described as abnormally red. The retinal arteries seemed normal, but the veins were distended and tortuous. In one eye a retinal hemorrhage slightly larger than the disc extended from the nervehead inferiorly along the course of the verve fibers. Visual acuity varied from 3/4 to 1. There seemed to be slight paresis of abduction in each eye, but psychic disturbance made testing difficult, and the patient complained not only of doubled vision, but of seeing things four or five fold. Ataxia and psychic symptoms became more severe, wth hallucinations of hearing and vision, epileptiform attacks and periods of coma. The hemorrhage in the fundus spread, and it was postulated that the patient must have small hemorrhages in various parts of the central nervous system. [Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986., p. 608]**PEER REVIEWED**
  
• Local contact of methyl bromide with the eye either as concentrated vapor or as a splash of liquid has resulted in no more than transient irritation and conjunctivitis in the few cases in which this accident has been observed. [Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986., p. 616]**PEER REVIEWED**
  
• Methyl bromide is reported to be eight times more toxic on inhalation than ethyl bromide. Moreover, because of its volatility, it is a much more frequent cause of poisoning. Death following acute poisoning is usually caused by its irritant effect on the lungs. In chronic poisoning, death is due to injury to the CNS. ... In addn, to injury to the lung & CNS, the kidneys may be damaged, with development of albuminuria &, in fatal cases, cloudy swelling &/or tubular degeneration. The liver may be enlarged. There are no characteristic blood changes. [Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996., p. 2196]**PEER REVIEWED**
  
• Signs & symptoms of chronic exposures include those from acute exposure plus visual & hearing disorders, numbness or tingling in the extremities, incoordination, ataxia, & loss of consciousness. Psychologic symptoms have been associated with chronic exposure, including loss of initiative, depressed libido, personality changes, hallucinations, & an intolerance to alcohol. [Sullivan, J.B. Jr., G.R. Krieger (eds.). Hazardous Materials Toxicology-Clinical Principles of Environmental Health. Baltimore, MD: Williams and Wilkins, 1992., p. 1059]**PEER REVIEWED**
  
• The concn immediately dangerous to life & health (IDLH) is 2000 ppm, & at this concn, methyl bromide produces pulmonary edema, seizures, & death. [Sullivan, J.B. Jr., G.R. Krieger (eds.). Hazardous Materials Toxicology-Clinical Principles of Environmental Health. Baltimore, MD: Williams and Wilkins, 1992., p. 1059]**PEER REVIEWED**
  
• Both acute & chronic exposure can result in behavioral toxicity manifested by psychosis, delirium, hallucinations, aggression, & mania. Cases of homicidal ideation & acute psychosis have been described following serious exposures. [Sullivan, J.B. Jr., G.R. Krieger (eds.). Hazardous Materials Toxicology-Clinical Principles of Environmental Health. Baltimore, MD: Williams and Wilkins, 1992., p. 1059]**PEER REVIEWED**
  
• SUFFICIENT PERCUTANEOUS ABSORPTION ... CAN OCCUR TO PRODUCE DEATH IN MAN, & IF EVAPORATION IS DELAYED ... IT IS INTENSE VESICANT ON ... SKIN. BLISTERS PRODUCED ... ARE ENORMOUS BUT RARELY DEEP ENOUGH TO DESTROY ENTIRE SKIN LAYER. LIKE OTHER VESICANTS ... METHYL BROMIDE INHIBITS SKIN GLYCOLYSIS AT HEXOKINASE LEVEL. [Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984., p. III-280]**PEER REVIEWED**
  
• Methyl bromide poisoning is difficult to confirm because routine laboratory testing has not been reliable. Measurable levels of the parent agent are rapidly reduced, probably as a result of direct tissue chemical reaction. Serum bromide levels have been used as an indirect measure of exposure and/or toxicity but are inconsistent. Recently special testing has shown that protein adducts formed after exposure to methyl bromide may be a better measure of significant exposure. The S-methylcysteine adduct was used to confirm acute methyl bromide toxicity 10 weeks after an exposure. [Buchwald AL, Muller M; Vet Hum Toxicol 43 (4): 208-11 (2001)]**PEER REVIEWED**
  
• CASE REPORT: We describe a case of early peripheral neuropathy and central nervous system toxicity as a result of acute predominantly dermal exposure to methyl bromide. A 32-year-old male was admitted after an accidental predominantly dermal exposure to methyl bromide while fumigating soil for pest control. The patient suffered dermal burns and vesicles on the upper and lower limbs. One week following exposure, he developed progressive weakness of the lower limbs, ataxia, paresthesiae of both legs and the left arm, hyperactive tendon reflexes in the lower limbs, and left Babinski sign. Nerve conduction velocity testing was compatible with axonal neuropathy. The patient recovered gradually from his burns. Three months postexposure he showed no signs of central nervous system toxicity, but the peripheral neuropathy was still present. Neurological effects primarily referable to the central nervous system following severe inhalation of methyl bromide have frequently been reported. The patient described in this study developed an unusual early peripheral neuropathy following dermal exposure. Peripheral neuropathy can be an outcome of methyl bromide intoxication, but is usually a late sequela of acute central nervous system toxicity or an aftereffect of repetitively inhaled chronic exposure. In this case, exposure to methyl bromide through abraded skin caused early peripheral neuropathy and central nervous system toxicity. [Lifshitz M, Gavrilov V; J Toxicol Clin Toxicol 38 (7): 799-801 (2000)]**PEER REVIEWED**
  

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Non-Human Toxicity Excerpts

• INHALATION EXPOSURE AT 100 PPM FOR 2-3 WK RESULTED IN DEATH OR SERIOUS SYMPTOMS AMONG RATS, GUINEA PIGS & MONKEYS. ... RATS & GUINEA PIGS SHOWED NO DEMONSTRABLE TOXIC EFFECTS WHEN EXPOSED AT 64 PPM 7-8 HR A DAY OVER A PERIOD OF 6 MO. RABBITS RESPONDED WITH PULMONARY IRRITATION & PARALYSIS, WHEREAS MONKEYS DISPLAYED CONVULSIONS AT THE SAME DOSE. AT 33 PPM, RABBITS STILL SHOWED IRRITATION OF LUNGS & PARALYSIS, BUT OTHER SPECIES WERE NOT AFFECTED. ALL SPECIES TOLERATED 16 PPM WITHOUT EVIDENCE OF INJURY. [American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH, 1991., p. 945-946]**PEER REVIEWED**
  
• 8-hr survival dose for rats was ... approximately 1 mg/l (260 ppm). Rats survive 5200 ppm for 6 min & 2600 ppm for 24 min. The 6-hr survival dose for rabbits is approx 2 mg/l (520 ppm). ... These authors /also/ studied rats, rabbits, guinea pigs, & monkeys. They described the response of most animals as typically one of lung irritation. If exposure was severe enough, this resulted in lung edema & usually a typical confluent bronchial pneumonia. [Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley & Sons Inc., 1993-1994., p. 4024]**PEER REVIEWED**
  
• AT 0.25 MG/L (66 PPM) RATS SHOWED ... NO RESPONSE FROM 6 MO PERIOD OF REPEATED EXPOSURES. ... RABBITS, HOWEVER, DEVELOPED ... PARALYSIS & SOME PULMONARY DAMAGE. MONKEYS EXPOSED AT THIS LEVEL DEVELOPED A PARALYSIS COMPARABLE TO THAT SEEN IN RABBITS. [Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982., p. 3444]**PEER REVIEWED**
  
• Methyl bromide was mutagenic to Salmonella typhimurium TA100 when tested at concn of 0.02-0.2% in desiccators in absence of an exogenous metabolic system. ... A commercial prepn of methyl bromide (tested @ 0.5-5 g/cu m in a closed container) was mutagenic to Salmonella typhimurium TA1535 & TA100 (but not to TA1538 or TA98) & to Escherchia coli WP2 hcr in the absence of an exogenous metabolic system. An aqueous soln of methyl bromide (tested @ 0.5-6 mM) induced mutations to streptomycin independence in Escherchia coli SD-4. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V41 198 (1986)]**PEER REVIEWED**
  
• NEUROBEHAVIORAL EFFECTS OF CHRONIC & SUBCHRONIC EXPOSURE OF RABBITS & RATS TO METHYL BROMIDE WERE STUDIED. ONE GROUP OF RATS & RABBITS WAS EXPOSED TO 65 PPM FOR A TOTAL EXPOSURE OF FOUR 25 HR WEEKS, OR 100 HR, & RATS WERE EXPOSED TO 55 PPM FOR A TOTAL EXPOSURE OF THIRTYSIX 30 HR WEEKS. EXPOSURE TO 65 PPM FOR FOUR WK SIGNIFICANTLY REDUCED EYE BLINK RESPONSES & NERVE CONDUCTION VELOCITY IN RABBITS BUT HAD NO EFFECT ON RATS. [ANGER WK ET AL; SCAND J WORK ENVIRON HEALTH 7 (SUPPL 4): 40-7 (1981)]**PEER REVIEWED**
  
• TOXIC EFFECT IN RATS OF METHYL BROMIDE VAPOR WAS ASSESSED BY A CONDITIONED TASTE AVERSION REGIME. RATS KEPT UNDER A WATER DEPRIVATION SCHEDULE FOR 7 DAYS WERE PERMITTED ACCESS TO 0.3% (WT/VOL) SODIUM SACCHARIN SOLN & WERE EXPOSED TO METHYL BROMIDE AT 0, 25, 50 & 100 PPM FOR 4 HR. THREE DAYS AFTER EXPOSURE, A DOSE-DEPENDENT SACCHARIN AVERSION WAS NOTED IN THE TREATED ANIMALS. [MIYAGAWA M; TOXICOL LETT (AMST) 10 (4): 411-6 (1982)]**PEER REVIEWED**
  
• TEN WK OLD MALE WISTAR RATS WERE EXPOSED BY INHALATION TO 200 OR 300 PPM OF METHYL BROMIDE FOR 4 HR/DAY, 5 TIMES/WK FOR 3 WK. RELATIVELY PROLONGED DYSFUNCTION OF THE PERIPHERAL NERVES & DISTURBANCE IN SPONTANEOUS CIRCADIAN RHYTHM ACTIVITY WERE FOUND IN RATS EXPOSED TO THE 300 PPM DOSE. NO MACROSCOPIC OR MICROSCOPIC ABNORMALITIES WERE FOUND IN CNS OR IN THE PERIPHERAL NERVES. [IKEDA T ET AL; TOXICOL LETT 6 (4-5): 293-9 (1980)]**PEER REVIEWED**
  
• ... Exposing a rabbit eye to pure methyl bromide gas for 1 and 1/2 min resulted in an immediate loss of surface luster, followed in several hours by a loss of corneal epithelium and much edema of the conjunctivae and lids. The cornea became opaque ... . [Mackison, F. W., R. S. Stricoff, and L. J. Partridge, Jr. (eds.). NIOSH/OSHA - Occupational Health Guidelines for Chemical Hazards. DHHS(NIOSH) Publication No. 81-123 (3 VOLS). Washington, DC: U.S. Government Printing Office, Jan. 1981., p. 2]**PEER REVIEWED**
  
• Extremely phytotoxic. ... Not dangerous to bees when used as described. [Tomlin, C.D.S. (ed.). The Pesticide Manual - World Compendium. 10th ed. Surrey, UK: The British Crop Protection Council, 1994., p. 686]**PEER REVIEWED**
  
• It was reported ... that oral admin of 25 & 50 mg/kg body wt methyl bromide (purity unspecified) in peanut oil, admin by gavage for periods of 20, 60, 90 & 120 days, caused ulceration & epithelial hyperplasia of the forestomach in rats (number, strain, age, wt & sex unspecified) without evidence of malignancy. (The Working Group noted that the level of detail provided was inadequate for evaluation of carcinogenicity). [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V41 196 (1986)]**PEER REVIEWED**
  
• Toxic responses in rabbits administered bromomethane sc (in oil) at 20-120 mg/kg included limb paralysis, cessation of drinking, reduced urine excretion. Levels >50 mg/kg sharply increased the blood bromide level & reduced platelets, serotonin, & water content. [USEPA; Ambient Water Quality Criteria Doc: Halomethanes p.C-36 (1980) EPA 440/5-80-051]**PEER REVIEWED**
  
• Methyl bromide applied under plastic to soil organisms at concentrations of 300 g/cu m killed all insects. Some soil nematodes and mites survived in small numbers. [USDA/Forest Service; Pesticide Background Statements Vol II Fungicides and Fumigants p.MB/C-87 (1986)]**PEER REVIEWED**
  
• A 100% mortality rate occurred in Aspergillus ochraceus, Aspergillus flavus, Penicillium citrinum, Penicillium chrysogenum, and Penicillium cyclopium when fumigated with methyl bromide at a concentration of 120 mg/l for 4 hr. However 40% of an Aspergillus niger population retained its viability at this concentration. [USDA/Forest Service; Pesticide Background Statements Vol II Fungicides and Fumigants p.MB/C-32 (1986)]**PEER REVIEWED**
  
• Methyl bromide injected under plastic at 448 kg/ha did not eradicate nematodes or fanleaf virus carried by nematodes, but did reduce both /organisms/ to acceptable levels in a California vineyards. [USDA/Forest Service; Pesticide Background Statements Vol II Fungicides and Fumigants p.MB/C-31 (1986)]**PEER REVIEWED**
  
• Application of 300 and 400 lb/acre resulted in good control of Xiphinema index and the root rot nematode. [USDA/Forest Service; Pesticide Background Statements Vol II Fungicides and Fumigants p.MB/C-32 (1986)]**PEER REVIEWED**
  
• Methyl bromide at 436 lb/acre under plastic reduced nematode populations and resulted in increased wheat and barley yields. Methyl bromide at 857 kg/ha decreased nematode larvae in potato fields, and at 977 kg/ha in a greenhouse controlled nematodes to a depth of 40 cm and resulted in increased tomato yields. [USDA/Forest Service; Pesticide Background Statements Vol II Fungicides and Fumigants p.MB/C-30 (1986)]**PEER REVIEWED**
  
• Methyl bromide was found to be 0.81 times more toxic to Aonidiella aurantii than hydrogen cyanide. [USDA/Forest Service; Pesticide Background Statements Vol II Fungicides and Fumigants p.MB/C-27 (1986)]**PEER REVIEWED**
  
• Mutagenic effects were observed in Drosophila melanogaster exposed to concentrations of 0.004 and 0.002 mmole/l after 30 and 90 hr exposures. [USDA/Forest Service; Pesticide Background Statements Vol II Fungicides and Fumigants p.MB/C-25 (1986)]**PEER REVIEWED**
  
• Klebsiella pneumoniae tested in a fluctuation test, without metabolic activation showed mutagenic effects at concentrations in air of 4.75 g/cu m (0.05 mmole/l) and higher. [USDA/Forest Service; Pesticide Background Statements Vol II Fungicides and Fumigants p.MB/C-25 (1986)]**PEER REVIEWED**
  
• Cats fed fumigated peanuts /containing methyl bromide/ at 0.5 to 1.25 mg/day for 4 months showed no changes in motor responses. [USDA/Forest Service; Pesticide Background Statements Vol II Fungicides and Fumigants p.MB/C-19 (1986)]**PEER REVIEWED**
  
• Dogs fed fumigated pelleted food in doses equal to 35, 75 and 150 mg/kg/day for 6 to 8 wk were observed for 1 yr. Animals /which/ received 35 or 75 mg/kg/day showed no or minimal evidence of toxicity. Animals fed 150 mg/kg/day showed lethargy, occasional salivation, and diarrhea, but no changes in blood chemistry, hematology, urinary values, or histology. [USDA/Forest Service; Pesticide Background Statements Vol II Fungicides and Fumigants p.MB/C-19 (1986)]**PEER REVIEWED**
  
• A study on horses, goats and cattle fed hay contaminated with 6800 to 8400 ppm methyl bromide following fumigation showed difficulty in walking, locomotor impairment, listlessness, and /in some instances/ death. [USDA/Forest Service; Pesticide Background Statements Vol II Fungicides and Fumigants p.MB/C-19 (1986)]**PEER REVIEWED**
  
• Cattle fed pelleted food containing 170, 511, 1062, 2633, and 4650 ppm methyl bromide for 49 days showed signs of intoxication (uncoordinated movement and gait), and recumbency. [USDA/Forest Service; Pesticide Background Statements Vol II Fungicides and Fumigants p.MB/C-21 (1986)]**PEER REVIEWED**
  
• A laboratory study was conducted to determine the acute toxic effects in Swiss Webster mice after a one hr inhalation exposure to methyl bromide. Groups of 6 mice were exposed to 0, 0.87, 1.72, 2.20, 2.70, 3.50, 3.82, 4.70, 5.77, or 5.93 mg/l. Animals exposed to 3.50 mg/l or more exhibited kidney lesions. Animals with exposure to 2.20 or 2.70 mg/l showed decreased lung and liver weight. Liver lesions appeared in animals exposed to 4.70 mg/l. Animals exposed to 5.77 mg/l developed decreased motor coordination. The 1 hr LC50 for methyl bromide in mice was 4.68 mg/l (1200 ppm). The dose response curve was quite steep and the LC10 to LC90 of mortality was within a doubling of concentration. [Alexeef G et al; J Tox Env Health 15: 109-23 (1985)]**PEER REVIEWED**
  
• Methyl bromide was evaluated in the L5178Y mouse lymphoma cell TK gene mutation assay at a dose range of 0-2.5 ug/ml. The test protocol used met criteria established for this assay by the Gene Tox Program. The chemical was positive at the 2.5 ug/ml dose level without metabolic activation. [Kramers PGN et al; Mutat Res 155 (1-22): 41-7 (1985)]**PEER REVIEWED**
  
• Seeds of beans (Phaseolus vulgaris), with a moisture content of 8.10 and 13.80%, were treated with methyl bromide and placed in multiwall Kraft paper bags and stored at room temperature. Methyl bromide reduced both germination and vigor. Seeds with the higher moisture content were more susceptible than those with lower moisture. [Araujo EF et al; Rev Ceres 32 (180): 110-19 (1985)]**PEER REVIEWED**
  
• ... Micronuclei were induced in bone marrow cells of Fischer 344 rats & BDF1 mice & in peripheral blood cells of BDF1 mice exposed to methyl bromide by inhalation for 6 hr/day, 5 days/wk for 2 wk. In mice, the incidence of polychromatic erythrocytes with micronuclei in the bone marrow increased by 10 fold in males (200 ppm; 776 mg/cu m) & by 6 fold in females (154 ppm; 600 mg/cu m), & those in peripheral blood increased by 32 fold in males (200 ppm) & by 3 fold in females (154 ppm). In rats, the increases were 10 fold in males (338 ppm, 1211 mg/cu m) & 3 fold in females (338 ppm) /in bone marrow/. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V41 199 (1986)]**PEER REVIEWED**
  
• The available data for halomethanes indicate that acute toxicity to freshwater aquatic life occurs at concentrations as low as 11,000 ug/l. ... No data are available concerning the chronic toxicity of halomethanes to sensitive freshwater aquatic life. /Halomethanes/ [USEPA; Ambient Water Quality Criteria Doc: Halomethanes p.vi (1980) EPA 440/5-80-051]**PEER REVIEWED**
  
• The available data for halomethanes indicate that acute and chronic toxicity to saltwater aquatic life occur at concentration as low as 12000 and 6400 ug/l, respectively. ... A decrease in algal cell numbers occur at concentrations as low as 11,500 ug/l. /Halomethanes/ [USEPA; Ambient Water Quality Criteria Doc: Halomethanes p.vi (1980) EPA 440/5-80-051]**PEER REVIEWED**
  
• Groups of cattle were fed oat hay from a bromomethane fumigated field or pelleted ration containing sodium bromide added at various concentrations. The hay contained bromide ion at concentrations of 6800 to 8400 mg/l. Groups fed the hay and highest dose rate of bromide in pelleted ration developed signs of CNS toxicity (motor incoordination) at 10 to 12 days of exposure. Serum bromide levels and neurologic signs were markedly reduced two weeks after termination of exposure. /Bromide ion/ [USEPA; Ambient Water Quality Criteria Doc: Halomethanes p.C-36-7 (1980) EPA 440/5-80-051]**PEER REVIEWED**
  
• Methyl bromide (soil fumigant) administered by oral gavage as a solution in arachis oil was carcinogenic to rats in a 90 day experiment. In 13 of 20 animals of the highest dose group, 50 mg methyl bromide/kg body wt, squamous cell carcinomas of the forestomach developed. All animals of this group showed a marked diffuse hyperplasia of the epithelium of the forestomach. A less pronounced hyperplasia was observed in high and lower incidence with, respectively, 10 and 2 mg methyl bromide/kg body wt. The lowest dose, 0.4 mg methyl bromide/kg body wt was without effects. [Danse LHJC et al; Toxicol Appl Pharmacol 72(2): 262-71 (1984)]**PEER REVIEWED**
  
• Rats received a single 8 hr exposure to methyl bromide, and the amines and metabolities were separated by a reverse-phase HPLC and were quantified via native fluorescence. An exposure to 100 ppm methyl bromide decreased tissue levels of dopamine and norepinephrine in all brain areas at 0 or 2 hr following exposure. Homovanillic acid and 3-methoxy-4-hydroxyphenylglycol contents were significantly increased in almost all brain regions. In a second study, rats were exposed to four concentrations of methyl bromide ranging from 31-250 ppm, and monoamine and metabolite levels in brain regions measured immediately after the exposure. There were dose-dependent decreases of dopamine and norepinephrine, and increases in homovanillic acid and 3-methoxy-4-hydroxyphenylglycol. Less clear changes in serotonin and 5-hydroxyindoleacetic acid contents were observed. [Honma T et al; Neurotoxicol Teratol 9 (5): 369-76 (1987)]**PEER REVIEWED**
  
• Groups of 10 male F344 rats (11-13 wk old) were exposed to 0, 90, 175, 250, or 325 ppm methyl bromide 6 hr/day for 5 days. Animals were anesthetized with phenobarbital then perfusion fixed 1-2 hr after the last exposure or in extremis (325 ppm, 4 days) with Karnovsky's fixative and selected tissues were processed for light microscopy. With the exception of the nasal passages, tissues were selected on the basis of previous studies with methyl chloride. The principal clinical signs, confined to the 250 and 325 ppm groups, were diarrhea, hemoglobinuria, and, in a few cases, gait disturbances and convulsions. A dose-dependent vacuolar degeneration of the zona fasciculata of the adrenal glands, cerebellar granule cell degeneration, and nasal olfactory sensory cell degeneration were seen in all concn groups except at 90 ppm. Cerebral cortical degeneration and minor alterations in testicular histology were seen only in the 325 ppm group. Hepatocellular degeneration was confined to the 250 and 325 ppm groups. No changes were seen in the kidney or epididymis. [Hurtt ME et al; Fundam Appl Toxicology 9 (2): 352-65 (1987)]**PEER REVIEWED**
  
• The reproductive effects of methyl bromide in the male rat were studied. Adult male F344 rats (11-13 wk) were exposed by inhalation to 0 or 200 ppm methyl bromide 6 hr/day for 5 days (first day of exposure= day 1). Ten animals from each group were anesthetized with pentobarbital and terminated on days, 1, 3, 5, and 8. Additional, 5 males from each group were killed on days 6, 10, 17, 24, 38, 52, and 73. Plasma testosterone concn was reduced during and immediately following exposure (days 1, 3, 5, and 6), but returned to control levels by day 8. Nonprotein sulfhydryl content of the liver and testis was reduced during exposure but returned to control levels by day 8 (3 days postexposure). No other reproductive indexes, including testis wt, daily sperm production, cauda epididymal sperm count, sperm morphology, percentage motile sperm, linear sperm velocity, and epididymal and testicular histology were affected by methyl bromide exposure at any time point examined. [Hurtt ME, Working PK; Fundam Appl Toxicol 10 (3): 490-8 (1988)]**PEER REVIEWED**
  
• 1,2-Dichloroethane and methyl bromide were tested for mutagenicity in Drosophila melanogaster by inhalation exposure; both cmpd were mutagenic (standard sex-linked recessive lethal mutation) but the mutagenic affect of methyl bromide was most pronounced at the postmeiotic germ cell stage. Prolonged expsoure to the cmpd at lower concn caused mutation rates similar to those of higher concn at shorter exposure periods. [Kramers PGN et al; Environ Sci Res 32: 65-73 (1985)]**PEER REVIEWED**
  
• Methyl bromide concn which induce neurotoxic effects were studied in the rabbit, a species known to be sensitive to this cmpd. Rabbits were exposed via inhalation to 27 ppm methyl bromide over a period of 8 mo for a total exposure duration of 900 hr. Biweekly neurobehavioral tests failed to uncover any untoward consequences of the exposures. Long term exposures to methyl bromide, in the present concn range, are tolerated by this species. After subchronic exposures to 65 ppm methyl bromide, rabbits developed severe neuromuscular losses & had impaired blink reflexes & body weights. The symptoms partially subsided within 6-8 wk after removal from the exposure. [Russo JM et al; J Toxicol Environ Health 14 (2-3): 247-55 (1984)]**PEER REVIEWED**
  
• The acute toxicity of methyl bromide to carp was determined in experiments with a 4 hr exposure period. The 4 hr median lethal concn was calculated at approximately 17 mg/l ie, the order of magnitude of actually encountered peak concn in surface water. The concn effect curve was very steep and the response was somewhat delayed. Morphological damage to the gill epithelium, indicative of alkylation of cell membranes, was the most pronounced effect of methyl bromide. It consisted of initial swelling of the lymphatic space and vaculizaiton of the epithelial cells, followed by disintegration of the epithelium and invasion of leukocytes. [Segers JHL et al; Water Res 18 (11): 1437-41 (1984)]**PEER REVIEWED**
  
• Six week old male Wistar rats were treated with the agent by gavage at the rate of 50 mg/kg five times per week, either for 13 weeks with a 12 week recovery period or continuously for a period of 25 weeks. Treatment caused significant reduction in weight gain; stoppage of treatment resulted in significantly greater body weight gain as compared to rats on continuous treatment. The stomach of rats treated for 13 weeks had numerous abdominal adhesions. The forestomach at the greater curvature adhered to the liver, spleen and diaphragm and was extremely contracted. Animals treated up to 25 weeks presented similar features while the stop treatment group still had peritoneal adhesions, but the stomach was less contracted. In methyl bromide treated rats, microscopy revealed inflamation, fibrosis, acanthosis and pseudoepithelimatous hyperplasia of the forestomach. Mild acanthosis of the esophagus was evident after 25 weeks of continuous exposure. Discontinuation of methyl bromide was associated with a forestomach epithelium that had fewer cell layers than that of the continuous treatment group and a lower incidence of hyperplastic lesions. One animal in the 25 week group had a severe dysplastic lesion with high mitotic activity, which was classified as an early carcinoma. [Boorman GA et al; Toxicol Appl Pharmacol 86 (1): 131-9 (1986)]**PEER REVIEWED**
  
• Effects of methyl bromide on organ systems were measured with specific attention given to body weight changes, organ weight changes, general condition and hematological changes, residual bromide ion concentration and histopathological changes in male Sprague Dawley rats exposed to methyl bromide through inhalation at concentrations of 502, 622, 667, 699, and 896 ppm. Single exposures were for 4 hr periods. Additional rats were exposed to 701, 767, 808, 817, and 832 ppm concentration levels. Subacute toxicity exposures were at 150, 200, 300, or 400 ppm. The median lethal concentration for rats after 4 hr exposure was 780 ppm. In subacute and chronic toxicity studies neurological manifestations of paralysis of extremities and ataxia were noted after 300 ppm and 400 ppm exposure. Necrosis in the brain occurred at 400 ppm. Necrosis of the heart occurred at all concentrations. At 200, 300, and 400 ppm exposures, the kidney had the highest concentration. An unknown biochemical mechanism results in the metabolism of methyl bromide to bromide ion. Liver concentrations of methyl bromide were lower than either the liver or the brain. At 150 ppm levels the total lipid and nonesterified fatty acids in blood had decreased. Exposure to 150 ppm caused small focal necroses and fibrosis replacement in the heart muscle. [Kato W et al; Indust Health 24 (2): 87-103 (1986)]**PEER REVIEWED**
  
• The fumigant methyl bromide was evaluated for genotoxicity in the somatic wing spot assay of Drosophila melanogaster. Third instar larvae trans-dihybrid for mwh and flr3 were exposed to varying concentrations (0-16 mg/l) of the gas for 1 hr. Following this exposure via inhalation, the larvae were placed into vials containing Instant Medium. Seven days after the exposure, the adult flies in the vials were collected and their wings were scored under 400X magnification for the presence of clones appeared as mwh-flr3 twin spots and single spots of either mwh or flr3 phenotype. Exposure to methyl bromide was found to result in the positive induction of both twin spots and large (greater than 2 cells) single spots. For each endpoint, a significant exponential association was obtained between concentration and frequency of spots per wing. Methyl bromide was found to be a negative inducer of small (1-2 cells) single spots at all concentrations except 16 mg/l where a positive effect was observed. [Katz AJ; Mutat Res 192 (2): 131-5 (1987)]**PEER REVIEWED**
  
• The SOS umu test has been used for the detection of DNA damaging agents. The SOS function inducibility of volatile chemicals (propylene oxide, methyl bromide, and ethylene dibromide). All chemicals tested induced SOS function in a dose related manner. [Ong JM et al; Environ Mutagen 9 (2): 171-6 (1987)]**PEER REVIEWED**
  
• The subacute effects of continuous exposure to methyl bromide on the heart, liver, lung, and blood were examined in male Sprague Dawley rats. Animals were exposed through continuous inhalation for 3 weeks of 1, 5, or 10 ppm methyl bromide. Rats were sacrificed within 1 hr after end of exposure, and organs were weighed and biochemical examinations were performed on the blood and the homogenates of heart, liver, and lung. No differences were seen between rats given the 1 ppm concentration and control rats. Rats in the 5 ppm group showed several changes; blood glucose, thymus weight, and creatine phosphokinase decreased, while blood hemoglobin, reduced glutathione, serum total protein, and glutamic pyruvic transaminase increased after exposure. Animals receiving 10 ppm showed many changes. An increase was observed in: serum glutamic oxaloacetic transaminase, lactate dehydrogenase, total protein, blood hemoglobin, reduced glutathione, and glutamic pyruvic transaminase. Decreases were noted in: serm cholinesterase, creatine phosphokinase, triglyceride, free cholesterol lactate, blood glucose, heart lactate, glucose, free fatty acids and glyocgen. [Sato M et al; Indust Health 23 (3): 235-8 (1985)]**PEER REVIEWED**
  
• Methyl bromide was positive for induction of gene mutations in Salmonella typhimurium strain TA100, with & without exogenous metabolic activation; negative results were obtained with TA98 in this assay. In vivo, methyl bromide induced sister chromatid exchanges in bone marrow cells & micronuclei in periphral erythrocytes of female mice exposed by inhalation for 14 days. No significant incr in either sister chromatid exchanges or micronuclei was observed in male or female mice exposed to methyl bromide by inhalation for 4, 8, or 12 wk. [DHHS/NTP; Toxicology and Carcinogenesis Studies of Methyl bromide in B6C3F1 Mice (Inhalation Studies) p.9 (Year) Technical Rpt Series No. 385 NIH Pub No. 92-2840]**PEER REVIEWED**
  
• Decreased eyeblink reflex & hind limb paralysis associated with decreased sciatic & ulnar nerve conduction velocities were observed in rabbits exposed for 4 wk to 65 ppm methyl bromide. Only partial recovery was observed in these rabbits 6-8 weeks after cessation of exposure. [Hayes, W.J., Jr., E.R. Laws, Jr., (eds.). Handbook of Pesticide Toxicology. Volume 2. Classes of Pesticides. New York, NY: Academic Press, Inc., 1991., p. 669]**PEER REVIEWED**
  
• Methyl bromide was not teratogenic to rats exposed to 20 or 70 ppm for 7 hr/day, 5 days/wk, for 3 weeks prior to mating & daily through gestation day 19. In the same study, rabbits exposed to 70 ppm methyl bromide showed severe neurotoxicity & mortality. However at 20 ppm, no maternal toxicity, fetotoxicity, or teratogenic effects were elicited. [Hayes, W.J., Jr., E.R. Laws, Jr., (eds.). Handbook of Pesticide Toxicology. Volume 2. Classes of Pesticides. New York, NY: Academic Press, Inc., 1991., p. 670]**PEER REVIEWED**
  
• Experimental exposure of a rabbit's eye to pure methyl bromide gas at room temperature for one and one half minutes caused immediate loss of surface luster, followed in several hours by loss of corneal epithelium, and much edema of the conjunctivae and lids. A day later the corneal stroma was bluish, much swollen, and nearly opaque, but within five days the cornea started to clear. This was much more severe exposure than would occur by accident. [Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986., p. 610]**PEER REVIEWED**
  
• In the 29-month study male and female-rats were exposed to 0, 3, 30, or 90 ppm of methyl bromide gas 6 hr/days 5 days/week. Ten rats per sex were killed at 13, 52, and 104 weeks for interim information. Mortality was increased at week 114 but only in the 90 ppm group, which also had lowered body weights. Increased incidences of degenerative and hyperplastic changes in the nasal olfactory epithelium were observed in a dose-related manner in all groups. The lesions did not appear to progress with time. Exposure to 90 ppm was associated with an increased incidence of thrombi and myocardial degeneration-in the hearts and hyperkeratosis in the esophagus and forestomach. [Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley & Sons Inc., 1993-1994., p. 4026]**PEER REVIEWED**
  
• Groups of 50 male and 50 female Fischer 344/DuCrj rats, six weeks of age, were administered methyl bromide (purity, > 99.9%) by whole body inhalation at concentrations of 0 (controls), 4, 20 or 100 ppm (0, 16, 78 or 389 mg/cu m) for 6 hours per day on five days per week for 104 weeks. At week 105, all surviving animals were killed. Necropsy was performed on all animals and all organs were examined histologically. Survival at week 104 was 34/50, 34/50, 31/50 and 33/50 in control, low-, mid- and high-dose males and 42/49, 38/50, 39/50 and 41/50 in control, low-, mid- and high dose females, respectively. The incidence of adenomas of the pituitary gland was significantly increased in high-dose males compared with controls (16/50, 23/50, 19/50 and 30/50 in control, low-, mid-, and high-dose, respectively; p < 0.01, chi-square test). In females, no increase in the incidence of tumors related to treatment was observed. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V71 724 (1999)]**PEER REVIEWED**
  
• Alkylation of guanine-N-7 in DNA of liver & spleen was observed after treatment of male CBA mice with (14)C methyl bromide (4.9-5.0 mCi/mmole) by inhalation. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V41 199 (1986)]**PEER REVIEWED**
  
• Rats were exposed to 290 or 495 ppm methyl bromide gas for 6 h/day, 3 times/wk for 4 to 8 wk. Creatine kinase (CK), aspartate aminotransferase (ASAT), and lactate dehydrogenase (LDH) activities and bromide ion concentrations were measured in eight regions of the brain. Methyl bromide gas inhibited CK activities in all regions of the brain, though the inhibition tended to be smallest in the cerebellum (hemisphere and vermis) and largest in the brainstem (hypothalamus, midbrain, and medulla oblongata). The dose of methyl bromide to inhibit CK activities was lower than that to damage the central nervous system histologically. No inhibition of ASAT or LDH activities was seen except for a slight inhibition of these in striatum. Inhibition of CK activities did not increase clearly on increasing dose (290 to 495 ppm) or on prolonging exposure period (4 to 8 wk). Although 50% recovery of CK activities and the half-life of bromide ion agreed well in the medulla oblongata, changes in CK activities and bromide ion concentrations did not correlate otherwise. Thus, inhibition of CK activities in brain appears to be a sensitive indicator of methyl bromide intoxication, and may be related to genesis of its neurotoxicity. The inhibition seems to be caused by methyl bromide itself rather than by bromide ion. When effects on enzyme activities in brain homogenate were examined in vitro by bubbling with methyl bromide gas, CK inhibition was seen within 15 s of exposure. Dithiothreitol suppressed the CK inhibition, whereas N-acetylcysteine did not. These observations suggest that methyl bromide may attack sites in the CK molecule different from those attacked by ethylene oxide or acrylamide. [Hyakudo T et al; Inhal Toxicol 13 (8): 659-69 (2001)]**PEER REVIEWED**
  
• We used the inhalation of methyl bromide gas to produce a near-complete destruction of the rat olfactory epithelium and analyzed the reinnervation of the bulb during reconstitution of the epithelium. The degeneration of olfactory axons elicits a transient up-regulation of glial cell proliferation and glial fibrillary acidic protein expression in the olfactory nerve and olfactory nerve layer of the bulb. Anterograde transport after intranasal infusion of wheat germ agglutinin conjugated horseradish peroxidase demonstrates that the first nascent axons reach the bulb within the first week after lesion. Subsequently, a massive wave of fibers arrives at the bulb between 1 and 2 weeks postlesion, and enters the glomeruli between 2 and 3 weeks postlesion. However, the olfactory projection does not stabilize until 8 weeks after lesion judging from the return in growth associated protein-43 expression to control levels. The extent of reinnervation after lesion is correlated with the completeness with which the epithelium reconstitutes itself. In rats that are lesioned while fed ad libitum, there is near-complete reconstitution of the neuronal population, and the projection onto the bulb fills the glomerular layer in its entirety. However, in rats that are lesioned while food restricted, a significant fraction of olfactory epithelium becomes respiratory during its reconstitution, and the population of reinnervating fibers is less. As a consequence, the posterior half of the bulb remains hypoinnervated overall and denervated at its caudal margin. ... Accordingly, we hypothesize that the persistence of a significant population of pre-existing neurons is needed to preserve receptotopy during reinnervation. In addition, the results suggest that in the face of massive turnover and a reduced afferent population, there is a tendency for reinnervating axons to fill available synaptic space. [Schwob JE et al; J Comp Neurol 412 (3): 439-57 (1999)]**PEER REVIEWED**
  
• Methyl bromide, is neurotoxic in humans and other mammals. To study its short-term effects on neurons, it was applied in aqueous solution to hippocampal slices of young rats (1.4 and 0.7 mM; for 8 minutes). Extracellular field recordings and intracellular microelectrode recordings from CA1 pyramidal neurons showed that the neurons stay viable for at least one hour after application of the mono-halomethane. However, a moderate, but consistent, irreversible decrease in synaptic excitability was observed. The intracellular recordings indicate that this may be attributed to a decrease in excitatory postsynaptic potentials. No effects were observed at 0.7 mM methyl bromide. Bromide, in a dose-dependent, partly reversible manner (during one hour), produced a similar decrease in excitability. Quantitatively, the action of bromide at 0.5 mM resembled the one seen with methyl bromide at the concentration of 1.4 mM. Since methyl bromide did not induce electrophysiologic changes consistent with evidence of neurotoxicity during one hour of observation it is concluded that it lacks immediate toxic effects on hippocampal rat neurons. Its neurotoxicity may be entirely due to metabolites or other indirect effects. The slight decrease in excitability may be due to the effect of bromide that is set free as tissue proteins and other cell molecules are methylated. [Zeise ML et al; Neurotoxicology 20 (5): 827-32 (1999)]**PEER REVIEWED**
  
• Methyl bromide was experimentally exposed to a 12 cm2 area of the back skin of Wistar rats for 30 s, and for 1, 3, and 5 min, and time courses of both changes in plasma bromide concentration and of histopathological changes were examined. The concentration of plasma bromide ion showed a sharp increase immediately after the exposure in all exposed groups, reaching a peak level after 1 hr, then decreased rapidly. The ion level gradually decreased after 72 hr to 1 week, and returned to a normal level after 4 to 8 weeks. Calculating from a regressive curve, the biological half lives of plasma bromide ion were 5.0 days to 6.5 days. Histopathologically, the impairments to the epidermal cells, fibroblasts and blood vessels were observed in the early phase. These cellular changes could be due to the direct cytotoxicity of the compound. In the next phase, newly infiltrating cells showed degeneration and necrosis. Subsequently, an impairment of the collagen bundles was observed. [Yamamoto O et al; Arch Toxicol 73 (12): 641-8 (2000)]**PEER REVIEWED**
  
• Average human exposure resulting from consumption of methyl bromide (MB)-fumigated food has been estimated to be 0.00125 mg/kg/day. A 1-yr feeding study in beagle dogs was conducted as a safety study, in which the high-dose diet was intended to yield a methyl bromide dose of at least 100 times the calculated human dietary exposure. Diets were fumigated with MB and fed to the dogs daily, except for weekends and holidays. MB consumption each feeding day was calculated as a time weighted average (TWA) that accounted for the rate of degassing from the fumigated diet and the rate of feed consumption during the feeding period. TWA compound consumption in the low-, mid- and high-dose groups, respectively, averaged 0.06 + or - 0.02, 0.13 +/- 0.03 and 0.28 + or - 0.08 mg/kg/day in males and 0.07 + or - 0.03, 0.12 + or - 0.03 and 0.27 + or - 0.09 mg/kg/day in females. Clinical observations, body weight and feed consumption, ophthalmology, clinical pathology, urinalysis, organ weights and macroscopic and microscopic pathology were comparable in control and MB-treated dogs. Under the conditions of this study, the no-observed-effect level (NOEL) for MB was at least 0.28 mg/kg/day, or approximately 200 times the expected average human dietary exposure. [Wilson NH et al; Food Chem Toxicol 36 (7): 575-84 (1998)]**PEER REVIEWED**
  
• Teratogenicity studies of methyl bromide, a widely used fumigant, were conducted in rats and rabbits. Methyl bromide was dissolved in corn oil and administered orally to groups of 24 copulated female Crj:CD (SD) rats at dose levels of 0 (corn oil), 3, 10 or 30 mg/kg/day on days 6-15 of gestation and to groups of 18 artificially inseminated female Kbl:JW rabbits at 0, 1, 3 or 10 mg/kg/day on days 6-18 of gestation. Maternal rats and rabbits were euthanized on respective days 20 and 27 of gestation. Foetuses were examined for survival, growth and teratological alterations. Maternal toxicity was evident in the high-dose groups for both species. In these groups, maternal body weight gains and food consumption were significantly decreased during the dosing and post-dosing periods. Necropsy of maternal rats also revealed erosive lesions in the stomach and the surrounding organs. However, no treatment-related adverse effects were found in foetuses of the treated groups for both rat and rabbit studies. ... Methyl bromide was not foetotoxic or teratogenic to rat and rabbit foetuses up to dose levels of 30 and 10 mg/kg/day, respectively, at which maternal toxicity was evident for both species. [Kaneda M et al; Food Chem Toxicol 36 (5): 421-7 (1998)]**PEER REVIEWED**
  

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Human Toxicity Values

• None found

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Non-Human Toxicity Values

• LC100 Rat inhalation 0.63 mg/l air/6 hr [Tomlin, C.D.S. (ed.). The Pesticide Manual - World Compendium. 10th ed. Surrey, UK: The British Crop Protection Council, 1994., p. 686]**PEER REVIEWED**
  
• LC50 Mouse inhalation 4.68 mg/l/hr (1200 ppm/1 hr) [Alexeef GV et al; J Toxicol Environ Health 15 (1): 109-23 (1985)]**PEER REVIEWED**
  
• LC100 Guinea pig 7760-11640 mg/cu m [USEPA; Ambient Water Quality Criteria Doc: Halomethanes p.C-37 (1980) EPA 440/5-80-051]**PEER REVIEWED**
  
• LC50 Rat 780 ppm/4 hr [Kato W et al; Indust Health 24 (2): 87-103 (1986)]**PEER REVIEWED**
  
• LD50 Rat oral 214 mg/kg [Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996., p. 2196]**PEER REVIEWED**
  
• LC50 Rat inhalation 302 ppm/8 hr [Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996., p. 2196]**PEER REVIEWED**
  
• LC50 Mouse inhalation 1540 mg/cu m/2 hr [Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996., p. 2196]**PEER REVIEWED**
  

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Absorption, Distribution and Excretion

• Methyl bromide is absorbed readily through the lungs. There has been suggestions that it can be absorbed through the human skin, but experience so far has not shown absorption through the skin to be an important factor in methyl bromide intoxication. The major problem is inhalation. [Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley & Sons Inc., 1993-1994., p. 4026]**PEER REVIEWED**
  
• ... SERUM BROMIDE LEVELS ACHIEVED IN SERIOUS CASES OF METHYL BROMIDE POISONING ARE CONSIDERABLY LOWER THAN THOSE REQUIRED FOR POISONING BY INORGANIC BROMIDES. IT HAS BEEN SUGGESTED THAT THIS MAY BE DUE TO GREATER LIPID SOLUBILITY OF METHYL BROMIDE & HENCE GREATER PENETRATION INTO THE BRAIN. [Doull, J., C.D.Klassen, and M.D. Amdur (eds.). Casarett and Doull's Toxicology. 3rd ed., New York: Macmillan Co., Inc., 1986., p. 567]**PEER REVIEWED**
  
• Upon absorption, blood levels of residual nonvolatile bromide increase, indicating rapid uptake of bromomethane or its metabolites. Bromomethane is rapidly distributed to various tissues and is broken down to inorganic bromide. Storage, only as bromides, occurs mainly in lipid-rich tissues. [USEPA; Ambient Water Quality Criteria Doc: Halomethanes p.C-21 (1980) EPA 440/5-80-051]**PEER REVIEWED**
  
• Elimination of bromomethane is rapid initially, largely through the lung as bromomethane. The kidneys eliminate /most of the remaining bromomethane/ bromide in the urine. Final elimination may take longer, accounting in part for its prolonged toxicity. [USEPA; Ambient Water Quality Criteria Doc: Halomethanes p.C-22 (1980) EPA 440/5-80-051]**PEER REVIEWED**
  
• The disposition of methyl bromide was studied following various routes of exposure. Recoveries of oral and ip doses indicated little radioactivity persisted in the body after 3 days with urine being the major route of excretion. No changes in respiratory pattern occurred. Pulmonary absorption after inhalation exposure was linear over a dose range from 50 to 10,400 nmoles (14)C methyl bromide/l of air for 6 hr, decreasing only at higher doses. Expired CO2 was the dominant excretory product. After 60 hours 25% of the dose remained in the body of rats. [NTP; Fiscal Year 1985 Annual Plan p.148 (1985) NTP-85-055]**PEER REVIEWED**
  
• In rats fed bromomethane fumigated diets with residual bromide levels, higher tissue bromide levels were /found/ in their eyes, lung, blood, spleen, and testes, while /the/ lowest tissue levels were in /the/ fat, skeletal muscle, bone, and liver. [USEPA; Ambient Water Quality Criteria Doc: Halomethanes p.C-22 (1980) EPA 440/5-80-051]**PEER REVIEWED**
  
• Uptake of methyl bromide and pathways for excretion of (14)C were investigated in male Fischer 344 rats after nose only inhalation of 50, 300, 5700, or 10,400 nmoles (1.6 to 310 ppm) of (14)C methyl bromide/l of air for 6 hr. Fractional uptake of methyl bromide decreased at the highest concentrations, with 37 and 27% of the inhaled methyl bromide absorbed, compared to 48% at the lower levels. Total methyl bromide adsorbed was 9 or 40 umol/kg body wt after exposure to 50 or 300 nmol/l, respectively. Exhaled (14)CO2 was the dominant route of excretion, with from 1.2 to 110 umol (50% of amount absorbed) exhaled, and was described by a two component negative exponential function; 85% was exhaled with a half-life of 4 hr, & the remaining 15% was exhaled with a half-life of 17 hr. [Medinsky MA et al; Toxicol Appl Pharmacol 78 (2): 215-25 (1985)]**PEER REVIEWED**
  
• Male Fischer 344 rats were exposed nose only to a vapor concentration of 337 nmol (14)C methyl bromide/l air (9.0 ppm, 25 degrees C, 620 torr) for 6 hr. Urine, feces expired air, and tissues were collected for up to 65 hr after exposure. Elimination of (14)C as (14)CO2 was the major route of excretion with about 47% (3900 nmol/rat) of the total (14)C methyl bromide absorbed excreted by this route. Radioactivity was widely distributed in tissues immediately following exposure /with highest (14)C concentrations (in nmol equivalent/g) of: lung (250), adrenal (240), kidney (180), liver (130), and nasal turbinates (110)/. [Bond JA et al; Toxicol Appl Pharmacol 78 (2): 259-67 (1985)]**PEER REVIEWED**
  
• Absorption of methyl bromide by the lung was rapid & exhibited first order kinetics without a saturable component following exposure of rats to 100-3000 ppm (390-11640 mg/cu m). [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V41 198 (1986)]**PEER REVIEWED**
  
• After oral admin of 100 mg/kg body wt methyl bromide to rats, approx 45% was exhaled within 4 hr. Following ip admin to 120-180 mg/kg body wt in hourly divided doses, a total of 24-45% was exhaled. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V41 198 (1986)]**PEER REVIEWED**
  
• Following either oral or intraperitoneal admin of 250 umole/kg body wt (24 mg/kg body wt) (14)C methyl bromide to rats, 14-17% of the radioactivity remained in the body after 72 hr. Expiration of (14)C carbon dioxide amounted to 32% & 45%, respectively, & the respective urinary excretion of (14)C radioactivity was 43% & 16%. Less than 3% of the radioactivity was excreted in feces. In animals with bile duct cannulations, 46% of the radioactivity of the oral dose appeared in the bile over a 24 hr period. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V41 198 (1986)]**PEER REVIEWED**
  
• Male Fischer 344 rats were given 250 umol/kg of (14)C labeled methyl bromide by either oral or ip administration. Urine, feces, and expired air were collected and at the end of 72 hr the rats were sacrificed and tissues analyzed to determine (14)C excretion and tissue distribution. After ip administration of methyl bromide, the dominant route of excretion was exhalation of (14)CO2, with 46% of the dose exhaled as (14)CO2. In contrast, urinary excretion of (14)C was the major route of elimination (43% of the dose) when methyl bromide was given orally. Very little of the (14)C appeared in the feces (<3% of the dose) regardless of route of administration. In rats with bile duct cannulations, 46% of an oral dose appeared in the bile over a 24 hr period. Collection of bile significantly decreased the exhaltion of (14)CO2 and (14)C excreted in urine compared to controls. At 72 hr after oral or ip administration, 14-17% of the (14)C remained in the rats, with liver and kidney being the major organs of retention. [Medinsky MA et al; Toxicol 32 (3): 187-96 (1984)]**PEER REVIEWED**
  
• The effects of exposure to the skin to high concentrations of methyl bromide were studied in 6 cases, who had been unintentionally exposed. Expsoure to high concentrations of methyl bromide (approximately 40 g/cu m) for 40 min can lead to redness and blistering of the skin. ... Plasma bromide levels were highest immediately following exposure (mean 9.0 + or - 1.4 mg/l) and fell in subsequent hours (mean 6.8 + or - 2.3 mg/l 12 hr after the exposure). [Zwaveling JH et al; Hum Toxicol 6 (6): 491-6 (1987)]**PEER REVIEWED**
  
• Methyl bromide is one of the most important pesticides for the control of insects, fungi and nematodes. Serum bromide has been proposed as a biomonitor for occupational exposure to methyl bromide. Therefore, a ... novel, sensitive photometric method was developed for the determination of serum bromide at concentrations relevant for such exposure. Further possible applications are monitoring of intoxication victims and halothane narcosis. ... We have established a mean serum bromide level of 4.13 + or - S.D. 1.05 mg/l (n/64) in a group of healthy female and male volunteers not knowingly exposed to bromide or bromine containing organics. Serum of a subject accidently exposed to methyl bromide revealed a bromide level of 11.5 mg/l serum, while two individuals exposed to methyl iodide had no elevated levels. A group of 30 agricultural workers showed a mean serum bromide level of 15.33 + or - S.D. 1.90 mg/l at the end of the methyl bromide application season. [Muller M et al; Toxicol Lett 107 (1-3): 155-9 (1999)]**PEER REVIEWED**
  
• INTRODUCTION: Methyl bromide has been responsible for deaths that usually occur from its accidental inhalation during fumigation. ... /This study reports on/ ... an accidental fatality that occurred after methyl bromide seeped through underground conduits from a fumigated building to an adjacent guest house on the same property. The patient developed refractory seizures, intermittent fever, and multiorgan system failure before dying 19 days after exposure. The initial serum bromide was 27 mg/dl. Postmortem analysis detected methyl bromide concentrations of 2.9 mg/dl in the blood, 1.7 mg/dl in the bile, 24 micrograms/g in the liver, and 28 micrograms/g in the adipose tissue. [Horowitz BZ et al; J Toxicol Clin Toxicol 36 (4): 353-7 (1998)]**PEER REVIEWED**
  

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Metabolism/Metabolites

• ... EXCRETION IS ... BY LUNGS AS UNCHANGED METHYL BROMIDE. A SIGNIFICANT AMT OF METHYL BROMIDE, HOWEVER, IS METABOLIZED IN THE BODY AND APPEARS AS INORGANIC BROMIDE, WHICH IS EXCRETED IN URINE. [Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982., p. 3444]**PEER REVIEWED**
  
• Although the exact mechanism has not been well studied, part of the absorbed methyl bromide is ... metabolized to 5-methylcysteine, which is excreted in the urine. [Ellenhorn, M.J. and D.G. Barceloux. Medical Toxicology - Diagnosis and Treatment of Human Poisoning. New York, NY: Elsevier Science Publishing Co., Inc. 1988., p. 981]**PEER REVIEWED**
  
• The fat-soluble methyl bromide, methyl chloride, & methyl iodide enter cells, where hydrolysis to methanol & halogen ion occurs. [Dreisbach, R.H. Handbook of Poisoning. 12th ed. Norwalk, CT: Appleton and Lange, 1987., p. 150]**PEER REVIEWED**
  
• In human erythrocytes in vitro, methyl bromide is consumed, probably with formation of a glutathione conjugate. The reaction involves a glutathione S-transferase enzyme that metabolized methyl halides. This enzyme has not been found in erythrocytes of mouse, rat, cattle, sheep, pig or rhesus monkey. The enzyme is present only in part of the human population: among 45 people investigated, only 27 conjugated glutathione with methyl bromide. The enzyme is erythrocytes of conjugators is different from other glutathione S-transferases with respect to substrate specificity, affinity chromatography, and inhibition characteristics; it has been designated as glutathione S-transferase 0. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V71 725 (1999)]**PEER REVIEWED**
  

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TSCA Test Submissions

• Methyl bromide (CAS # 74-83-9) was evaluated for subchronic oral toxicity in male Wistar rats (10 rats/treatment group) administered gavage doses in peanut oil of 0, 25, or 50 mg/kg/day, 5 days/week for approximately 90 and 120 days (an additional rat was included in each 90- day treatment group). Two additional 90-day treatment groups (10 rats/dose level), respectively, were allowed 60- and 30-day recovery before necropsy. Supplemental groups (10 rats/dose level) of control and high dosed (50 mg/kg/day) rats also received treatment for approximately 30, 60, and 90 days, the 90-day groups undergoing gastrotomy prior to terminal necropsy. Relative to both control and low dose rats, 50 mg/kg/day oral dosing for 30 days was associated with lethargy, decreased feeding efficiency with weight loss, increased water consumption, soft stool, and some abdominal distention. Gross lesions predominated in the peritoneum and nonglandular stomach and included both nonspecific diffuse and focal changes of the gastric mucosa, atrophy of the surface squamous epithelium, and multiple adhesions of the gastric serosa to adjacent organs. Hyperplasia consisted of acanthosis and hyperkeratosis, with epithelial projections ("pegs") in all rats of this group; fibrotic lesions of the tunica muscularis and fibrotic serosa adhesions contained duct-like structures as well. These changes were statistically significant in association with treatment (irrespective of dose) relative to control and length of exposure, but did not demonstrate a dose-related significance (incidence differences between treated groups was not significant by Duncan's multiple range test). Increased fibrosis of the lamina propria and lymphocytic infiltrates of the glandular stomach were statistically significant (p
• In orientative study, methyl bromide (CAS # 74-83-9) was evaluated for subacute inhalation toxicity in male SPF Wistar rats (6/dose level) which received whole-body exposures to doses of 0, 150, 375, and 750 mg/cu m, 6 hours/day, on 5 and 3 days in 2 consecutive weeks. Exposure to 750 mg/cu m was associated with marked growth retardation, tremors, and motor incoordination. All treated rats had dose-related reduction in absolute and increase in relative brain weight compared with controls. Histologic examination showed pulmonary hyperemia with focal hemorrhage in 3/6 rats of 750 mg/cu m exposures. In range-finding tests, rats (6/sex/exposure level) were exposed to concentrations of 0, 70, 200, or 600 mg/cu m methyl bromide, 5 days/week for 3 weeks and 7 days of a fourth week. Exposures to 600 mg/m3 was associated with anorexia, stunted growth, and death (3/6 females, 5/6 males). This group also exhibited uprighting and balancing anomalies, while 3/6, 6/6, and 6/6 of low-, mid-, and high-concentration groups had abnormal gait. Elevated serum SGPT and alkaline phosphatase activity characterized the clinical chemistry and there was evidence of disrupted blood morphology. Histologic examination revealed lesions of the heart including diffuse fatty vacuolization and degeneration of myocardial fiber, and hyperemic lungs with marked alveolar dilation in 600 mg/cu m rats. Some animals exhibited interstitial pneumonia. This study reports a NOAEL of 70 mg/cu m.[Ethyl Corporation; Brief Inhalation Test with Methyl Bromide in Rats; 11/01/80; EPA Doc No. 86-870001201; Fiche No. OTS0516104]**UNREVIEWED**
  
• Methyl bromide (CAS # 74-83-9) was evaluated for chronic inhalation toxicity and carcinogenicity in Wistar rats (90/sex/group) which received whole-body exposure to nominal concentrations of 0, 3, 30, and 90 ppm for 6 hours/day, 5 days/week, for up to 29 months. Ten of each sex/group were sacrificed for interim pathology assessments at 13, 52 and 104 weeks, and 10 rats/sex/group removed from study at Week 41 received behavioral evaluation. High dose animals showed slightly increased mortality, slightly diminished bodyweights, and reduced brain weights in both males and females. The reduction in brain weight was statistically significant in females, but not in males. No other distinct clinical observations and no changes in hematology, biochemistry, or urine were noted throughout the study. Increased incidence of hemothorax was observed in dead and moribund 90 ppm rats. On microscopic evaluation, increased incidence of slight hyperplasia and degenerative lesions of the dorsomedial nasal epithelium was significantly (Fischer exact probability test) dose related. These changes did not appear to progress with time. Increased hyperkeratosis was observed in the esophagus of 30 ppm males and and both esophagus and forestomach of 90 ppm males and females, but the increase reached statistical significance in the esophagus of 90 ppm males. The incidence of cardiac thrombosis was also significantly increased in 90 ppm males and females, respectively, at 105 weeks and 29 months. The significantly increased myocardial degeneration with cartilaginous metaplasia (3 ppm females, 90 ppm males) also increased in severity with length of exposure, that change significant in 90 ppm females but not in the males. No dose or treatment-related neoplastic lesions were identified in any treatment group at any assessment throughout the study.[DuPont Chem Co; Chronic (29-Month) Inhalation Toxicity and Carcinogenicity Study of Methyl bromide in Rats; 01/01/87; EPA Doc No. 88-920008788; Fiche No. OTS0546338]**UNREVIEWED**
  
• Methyl bromide (CAS # 74-83-9) was evaluated for chronic inhalation toxicity and carcinogenicity in Wistar rats (90/sex/treatment level) administered exposures (protocol unspecified) to 0, 3, 30, or 90 ppm for 6 hours/day, 5 days/week, for up to 29 months. Ten of each sex/treatment group were sacrificed for interim assessments at 13, 52 and 104 weeks. This report by Dr. Jerry F. Hardisty of Experimental Pathology Laboratories, Inc. primarily constitutes confirmation of the original study pathologist's conclusions. Upon specific reexamination of nasal cavity specimens in groups sacrificed at 52 and 104 weeks, incidence of basal cell hyperplasia of olfactory epithelium in the dorsi-medial nasal cavity in low dose groups did not reach statistical significance (Fischer's exact probability test) relative to controls. Such changes in mid- and high-dose rats were significantly related to exposure level; however, a low level exposure established the inhalation NOEL of 3 ppm for this study, contrary to original study conclusions. The reviewer also found the incidence, but not the severity, of these lesions to increase with time.[Chem Mfgs Assn; Chronic (29-Month) Inhalation Toxicity and Carcinogenicity Study of Methyl Bromide in Rats, Reexamination of Nasal Cavity; 07/21/97; EPA Doc No. 88970000251; Fiche No. OTS0559186]**UNREVIEWED**
  
• Methyl bromide (CAS # 74-83-9) was evaluated in 2 rabbits (breed unspecified) for daily urinary excretion of Br associated with each of 5 initial daily 0 and 60 ppm exposures (exposure terms unspecified) in metabolic chambers. These values were compared to those of 2 rabbits from initial onset of exposure-related paralysis upon Days 14 and 20 of 60 ppm exposures, respectively. Values for mg Br/cc urine were initially comparable at 0.029 and 0.027, rose to 0.035 and 0.036 mg Br/cc following a first exposure, and rose again successively with each daily exposure to respective 5- and 3-day maximal values of 0.085 and 0.059 mg Br/cc. These values ranged from 0.011 to 0.019 ave. mg Br/cc/day in control rabbits. Initial values were 0.094 and 0.086 mg Br/cc in just-paralyzed rabbits, and 3- day values averaged 0.107 and 0.109 mg Br/cc/day. Subsequently, these animals deteriorated as to preclude their initial water and food consumption (and urination).[Dow Chem Co; Toxicity of Methyl bromide Vapors - Bromide Analyses on Urine from Control Rabbits and Rabbits Exposed to 60 ppm Methyl Bromide; 02/11/38; EPA Doc No. 86-870002140; Fiche No. OTS0515929]**UNREVIEWED**
  
• Methyl bromide (CAS # 74-83-9) was evaluated in rabbits (2/treatment group, breed unspecified) for urinary excretion of formic acid associated with daily 0 and 60 ppm atmospheric exposures (of unspecified duration). Relative to controls, rabbits administered daily methyl bromide exposures until paralyzed or moribund excreted no formic acid of significance in the urine.[Dow Chem Co; Toxicity of Methyl Bromide Vapors - Formic Acid Analyses on Urine from Control Rabbits and Rabbits Exposed to 60 ppm Methyl Bromide and to 5,000 ppm Methyl Alcohol; 02/14/38; EPA Doc No. 86-870002141; Fiche No. OTS0515930]**UNREVIEWED**
  
• Methyl bromide (CAS # 74-83-9) was evaluated in 5 and 9 rabbits (breed unspecified), respectively, of repeated 0 or 60 ppm atmospheric exposures, 8 hours/day, for toxicity-related methanol in blood, muscle, liver, kidney, lung, brain, and/or urine. The exposures were repeated until treatment-related paralysis or death ensued (18 to 26 exposures). No methanol of significance was detected in blood, tissues, or urine of controls or in rabbits of MeBr- associated paralysis or death.[Dow Chem Co; Toxicity of Methyl Bromide Vapors - Methanol Analyses on Blood, Tissues and Urine from Control Animals and from Animals Exposed to 60 ppm Methyl Bromide; 01/25/38; EPA Doc No. 86-870002142; Fiche No. OTS0515931]**UNREVIEWED**
  
• Methyl bromide (CAS # 74-83-9) was evaluated in 2 and 4 cavies (breed unspecified), respectively, of repeated 0 or 60 ppm inhalation exposures, 8 hours/day, for toxicity-related methanol in blood. The exposures were repeated to induce overt treatment-related toxicity; however, a total of 145-146 total exposures in 214-215 days produced no clinical toxicity and no methanol of significance in the sampled blood of MeBr-exposed cavies relative to controls.[Dow Chem Co; Toxicity of Methyl Bromide Vapors - Methanol Analyses on Blood, Tissues and Urine from Control Animals and from Animals Exposed to 60 ppm Methyl Bromide; 01/25/38; EPA Doc No. 86-870002142; Fiche No. OTS0515931]**UNREVIEWED**
  
• Methyl bromide (CAS # 74-83-9) was evaluated in 5 control and 8 MeBr-paralyzed rabbits (breed unspecified), respectively, of daily 0 and 60 ppm exposures (20-30 days' repeated inhalation exposures, protocol unspecified) for blood/tissue distribution of Br. Relative to average levels of 0.618 mg Br/100 cc blood, and 0.04, 0.50, 0.55, 0.44, and 0.00 mg Br/100 g dryweight muscle, liver, brain, kidney and lung of control rabbits, levels in the respective tissues of paralyzed rabbits were 11.1 mg/cc in the blood (approximately 20X), and 3.27, 11.3, 9.9, 22.7, and 26.0 mg/100 g tissue dryweights. Following cessation of treatment, the return of these values to normal in 2 paralyzed rabbits paralleled their improved general appearance and behavior on Recovery Days 27 and 64.[Dow Chem Co; Toxicity of Methyl Bromide Vapors - Bromide Analyses on Tissues from Control Animals and from Animals Exposed to 60 ppm Methyl Bromide; 12/10/37; EPA Doc No. 86-870002143; Fiche No. OTS0515932]**UNREVIEWED**
  
• Methyl bromide (CAS # 74-83-9) was evaluated for developmental toxicity in groups of 48, 25, 23, 23, and 23 pregnant RIV-TOX rats, respectively, administered daily gavage doses of 0, 0.5, 5, 25, and 50 mg/kg bodyweight from Gestational Days 5 through 20. Dose-related maternal toxicity associated with 25 and 50 mg/kg regimens was characterized by significantly (student's T test, p<0.05) diminished weight gain at Treatment Days 14 and 3, respectively. Otherwise, all clinical toxicity was confined to the high dose dams, including perivaginal blood, diarrhea, lethargy, piloerection, morbidity (4/23 dams killed in extremis), and death (1 dam). Pathologic inspection of the early lethalities revealed poor general condition with swollen abdomens and no changes in heart or lungs, their death apparently related to inflammation and perforation of the peritoneum arising in the stomach. Each dam had implantations or early resorptions, one with live embryos. No treatment-related reductions in bodyweight attended the clinical condition of pregnant females with live fetuses at caesarian, and placental weights, fetal weights, sex ratios, and gross morphology were comparable to controls in all dose groups; numbers of fetuses were comparable to controls in both pregnant and pregnant with live fetus determinations of all treated dams. Of the 43, 21, and 18 initially-pregnant dams in control, 25 mg/kg, and 50 mg/kg dose groups, 1, 3, and 18 (100%) were without live fetuses upon terminal caesarian. Relative to controls, the abortive pregnancies in 25 mg/kg (3/21) and 50 mg/kg (18/18) dams were associated with normal numbers of implantations and pre- implantation losses, and diminished maternal bodyweight, decreased corpora lutea, and increased early resorptions. Upon terminal necropsy, dams of the 2 highest treatment groups exhibited dose-related incidence and levels of plastic peritonitis arising from the stomach to involve diaphragm, liver, spleen, left adrenal gland, kidney, and pancreas. The nonglandular stomach had thickened walls characterized by hyperplasia and hyperkeratosis with ulceration and fibrosis of underlying tissues in extreme cases (50 mg/kg) and adhesions to the adjacent organs. Pending fetal skeletal and tissue analyses, the authors suggested that concurrence of dose-related maternal toxicity and early resorptions and otherwise normal reproductive parameters in treated pregnant rats indicated a lack of embryotoxicity.[Ethyl Corporation; Teratogenicity Study of Methyl Bromide Dosed Orally (translation from the German); 01/01/81; EPA Doc No. 86-870001186; Fiche No. OTS0516089]**UNREVIEWED**
  
• Methyl bromide (CAS # 74-83-9) was evaluated for developmental toxicity in female Wistar rats (38-42/treatment group) administered whole-body exposures to 0, 20, and 70 ppm, 7 hours/day, 5 days/week, for 3 weeks, mated, then exposed 7 hours/day for the initial 19 days of gestation. Additional groups received either low or high-level exposures pre- or post-conception, with exposure to filtered air only as the complement pre- or post-conception exposures. On Gestational Day 21, all rabbits were subjected to terminal necropsy with caesarian section. Significantly depressed bodyweights during post-conception high-level exposures in previously exposed dams resolved to near normal relative to air/air pre- and post-conception exposed controls; no further untoward effects or pathological change related to inhalation exposure of any concentration, with or without pretreatment. Histopathologic changes in lungs (25% random sampling) included mononuclear and focal granulomatous inflammatory lesions of questionable etiology, but the incidence was not related to exposure level. Other lesions included hydronephrosis, and hepatic inflammation and necrosis. Pregnancy rates, fetal size, sex ratio, fecundity, and embryotoxicity appeared comparable to air/air controls. The incidence of slight ossification reductions in fetuses did not correlate to exposure level. Authors reported minimal maternal toxicity and no notable embryotoxicity associated with repeated inhalation exposure to concentrations of 20 or 70 ppm in rats.[NIOSH; Teratologic Assessment of Butylene Oxide and Methyl Bromide, NIOSH Technical Report #81-124; 07/01/81; EPA Doc No. 40-8175008; Fiche No. OTS0509931]**UNREVIEWED**
  
• Methyl bromide (CAS # 74-83-9) was evaluated for developmental toxicity in artificially inseminated virgin female New Zealand rabbits (24/exposure group) administered whole-body exposures to 0, 20, and 70 ppm, 7 hours/day on the initial 24 days of gestation. All exposures were discontinued on Day 15 due to clinical toxicity in high dose animals, including marked anorexic weight loss and generalized signs of distress, progressing to convulsive movements, hind-limb paresis, and death (24/25 by GD 30). No maternal toxicity was noted in low dose does. On terminal necropsy, the solitary surviving high-level rabbit had a significantly small (relative and absolute) liver relative to controls. Microscopic examination revealed mononuclear and inflammatory lesions of the lungs, neither their incidence or severity correlated to dose level. No lesions of kidney, liver, or uterus were identified. Pregnancy rates (calculated among lethalities as well as survivors) were not significantly affected by treatment and no significant treatment-related differences in fetal weight or length were documented; however, the fetuses of the sole high-dose litter were dramatically smaller than those of both negative control and low dose groups. Since fetal effects accompanied severe maternal toxicity and were not noted in low-dose groups, the authors reported no treatment-related embryotoxicity per se.[NIOSH; Teratologic Assessment of Butylene Oxide and Methyl Bromide, NIOSH Technical Report #81-124; 07/01/81; EPA Doc NO. 40-8175008; Fiche No. OTS0509931]**UNREVIEWED**
  
• Methyl bromide (CAS # 74-83-9) was investigated for subhchronic inhalation toxicity in pregnant New Zealand White Rabbits in two range-finding tests for planned developmental toxicity study. Daily exposures to concentrations of 0, 50, 70, and 140 ppm in the second probe resulted in generalized moribund condition in high dose does, such that treatment was halted on Study Day 17. No clinical toxicity was noted at lower level exposures. Upon histologic examination of 7 brain and spinal cord tissue samples of each exposure group, all rabbits of the 140 ppm group exhibited multifocal brain lesions including bilateral necrosis or spongiosis and inflammation of the midbrain meninges; the spinal cords showed no treatment- related lesions. No neurologic lesions were identified among rabbits of other exposure groups. Gross lesions observed in 140 ppm rabbits included decreased ingesta, fecal soiling of the perineum, pulmonary atelectasis and congestion, focal hepatic blanching, erosions and/or ulcers of the gastric glandular mucosa, and distended bladder (urine). These lesions were not apparent at lower exposure levels. No reproductive data were presented.[Dow Chem Co; Methyl Bromide Inhalation Teratology Probe Study in New Zealand White Rabbits (Draft Pathology); 08/02/89; EPA Doc No. FYI-OTS-0889-0712; Fiche No. OTS0000712]**UNREVIEWED**
  
• Methyl bromide (CAS # 74-83-9) was evaluated for developmental toxicity in 2-part study with artificially inseminated rabbits (26/group) administered whole-body exposures to 0, 20, 40, or 80 ppm for 6 hours/day on gestational days 6-19. The initial trial reported significant maternal toxicity in 80 ppm does, and significant developmental toxicity (fetal malformations) consisting of agenesis of caudal lung lobes and gall bladders, and fused sternebrae. Potential confounding factors in assessing developmental toxicity included hereditary predisposition to malformations via the females or a common source of semen inseminating the 8 females of litters lacking gall bladders. In a second study, groups of 18 pregnant does (not inseminated with suspect semen) were exposed to either 0 or 80 ppm and 18 does (inseminated only with suspect semen) were an unexposed control group. Treatment-related maternal toxicity and reduced fetal bodyweights per litter were not associated with increased percent fetal malformation (fetal skeletal exams were not done) in the 80 ppm group, although incidence of missing gall bladders in 80 ppm fetuses was nearly 5X that in negative controls; the naive control group litters had fewer malformations than either the negative control or 80 ppm group litters. The protocol and findings were evaluated and validated by Dr. Rochelle Tyl, Senior Program Director, Reproductive and Developmental Toxicology, Research Triangle Institute. Both the study authors and Dr. Tyl concluded that fetal effects might be attributed to maternal toxicity at 80 ppm, as such fetal effects and maternal toxicity were not observed at lower concentrations. Dr. Tyl additionally provided historical control data regarding fetal fused sternebrae associated with maternal toxicity (irrespective of chemical, route, or dose). A NOAEL for both does and conceptuses was 40 ppm under the conditions of this study, and neither study authors nor reviewer considered the results indicative of developmental toxicity per se.[Methyl Bromide Industry Panel; Letter from the Methyl Bromide Industry Panel to USEPA Submitting Supplemental Information Concerning the 8EHQ-1189-0844S Submission on Methyl bromide; 02/26/91; EPA Doc No. 89-910000184; Fiche No. OTS0522340-2]**UNREVIEWED**
  
• Methyl bromide (CAS # 74-83-9) was evaluated for developmental toxicity in two-part study with artificially inseminated rabbits (26/group) administered whole-body exposures to nominal concentrations of 0, 20, 40, or 80 ppm for 6 hours/day on gestational days 6-19. On Day 28, all surviving does were necropsied for examination of maternal visceral organs, pregnancy status, and any fetal developmental anomalies. The initial trial reported significant (Dunnett's test, p < 0.05) clinical toxicity in 80 ppm does (13/26), including decreased feces, lethargy, right-sided head tilt, ataxia, and lateral recumbency with reductions of bodyweight and/or bodyweight gain. Treatment did not significantly affect relative or absolute maternal organ weights or reproductive parameters including pregnancy weight, gravid uterine weight, number of implantations, preimplantation loss, resorption rate, litter size, fetal sex ratio, or fetal body weights relative to controls. Fetal malformations (80 ppm litters only) included agenesis of caudal lung lobes and gall bladders, and fused sternebrae. Incidence of fused sternebrae and absence of gall bladders in 80 ppm fetuses was statistically significant. Of these, the former is historically attributable to maternal toxicity, while the significance of absent fetal gall bladders was potentially confounded by hereditary predisposition to malformations via the females and/or the common source of semen conceiving the litters lacking gall bladders. A second study employed groups of 18 pregnant does (inseminated with nonsuspect semen) exposed for 6 hours daily to either 0 or 80 ppm and 18 does (inseminated only with suspect semen) as a naive control group. The observed treatment-related maternal toxicity, reduced gravid uterine weights, and reduced fetal bodyweights per litter in 80 ppm litters were not associated with significantly increased percent total fetal malformation (skeletal examinations were not performed). The incidence of missing gall bladders in 80 ppm fetuses, however, was nearly 5X that in negative controls, and the naive control group litters had fewer malformations than either the negative control or 80 ppm group litters. Likewise, agenesis of caudal lung lobes could not be causally related to heredity factors of the suspect semen in the earlier study, but also was not decisively related to treatment since malformations also occurred among chamber control fetuses. As neither fetal effects nor maternal toxicity were observed at lower concentrations, the authors concluded that developmental effects were likely attributable to maternal toxicity at 80 ppm rather than developmental toxicity per se.[Methyl Bromide Industry Panel; Methyl Bromide Inhalation Teratology Study in New Zealand White Rabbits, Final Report; 06/18/90; EPA Doc No. 89-910000053; Fiche No. OTS0522340-3]**UNREVIEWED**
  
• Methyl bromide (CAS # 74-83-9) was evaluated for genotoxicity in cultured Chinese hamster ovary cells (3 x 375,000 cells/tube) gassed for 20 seconds at concentrations of 0, 1, 6, 13, and 26 ppm, sealed, and incubated for 18 hours. After transfer to fresh medium with bromodeoxyuridine, cells were gassed 3 times in 48 hours, until metaphase spreads could be examined for sister chromatid exchange (SCE). Exposure to MeBr vapor was associated with a significant (by linear regression analysis) dose-related increased rate of SCE in chinese hamster ovary cells.[Ethyl Corp; 01/28/80; Summary and Data on the Methyl Bromide Mutagenicity Study; 01/28/80; EPA Doc No. 86-870001200; Fiche No. OTS0516103]**UNREVIEWED**
  
• Methyl bromide (CAS # 74-83-9) was evaluated in 4 assays for mutagenicity in Saccharomyces cerevisiae D3 in modified protocol using methyl bromide in a gas-tight desiccator at concentrations ranging from 0.005 to 5.000%, 0.05 to 0.30%, 0.10 to 0.40%, and 0.075 to 0.40%. Toxicity in the first assay was associated with concentrations of 0.5% and above, but not with a 0.05% concentration. In the second assay, recombinations occurred at concentrations of 0.3%, the highest concentration, both in the presence and absence of metabolic activation (Aroclor 1254-induced mouse liver S-9 fraction). The third assay documented increased recombinations, both with and without metabolic activation, at concentrations of 0.2, 0.3, and 0.4%, but these were not clearly dose-related. In the final assay, a dose-related increase in mitotic recombinants was observed both with and without S-9 induction, and produced toxicity at the highest dose of 0.4%. The authors concluded that, MeBr induces mitotic recombination in Saccharomyces cerevisiae with and without metabolic activation in vitro.[SRI International; In Vitro Microbiological Mitotic Recombination Assay of Methyl bromide Using S.cerevisiae D3. (Final Report); 02/01/80; EPA Doc No. 86-870001203; Fiche No. OTS0516106]**UNREVIEWED**
  

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Footnotes

¹ Source: the National Library of Medicine's Hazardous Substance Database, 10/28/2007.