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Methyl bromide

1. NAME
   1.1 Substance
   1.2 Group
   1.3 Synonyms
   1.4 Identification numbers
      1.4.1 CAS Number
      1.4.2 Other numbers
   1.5 Main brand names/main trade names
   1.6 Main manufacturers/main importers
2. SUMMARY
   2.1 Main risks and target organs
   2.2 Summary of clinical effects
   2.3 Diagnosis
   2.4 First-aid measures and management principles
3. PHYSICO-CHEMICAL PROPERTIES
   3.1 Origin of the substance
   3.2 Chemical structure
   3.3 Physical properties
      3.3.1 Colour
      3.3.2 State/Form
      3.3.3 Description
   3.4 Other characteristics
4. USES/CIRCUMSTANCES OF POISONING
   4.1 Uses
      4.1.1 Uses
      4.1.2 Description
   4.2 High risk circumstance of poisoning
   4.3 Occupational exposed populations
5. ROUTES OF ENTRY
   5.1 Oral
   5.2 Inhalation
   5.3 Dermal
   5.4 Eye
   5.5 Parenteral
   5.6 Others
6. KINETICS
   6.1 Absorption by route of exposure
   6.2 Distribution by route of exposure
   6.3 Biological half-life by route of exposure
   6.4 Metabolism
   6.5 Elimination by route of exposure
7. TOXICOLOGY
   7.1 Mode of action
   7.2 Toxicity
      7.2.1 Human data
         7.2.1.1 Adults
         7.2.1.2 Children
      7.2.2 Relevant animal data
      7.2.3 Relevant in vitro data
      7.2.4 Workplace standards
      7.2.5 Acceptable daily intake (ADI)
   7.3 Carcinogenicity
   7.4 Teratogenicity
   7.5 Mutagenicity
   7.6 Interactions
8. TOXICOLOGICAL AND BIOMEDICAL INVESTIGATIONS
9. CLINICAL EFFECTS
   9.1 Acute poisoning
      9.1.1 Ingestion
      9.1.2 Inhalation
      9.1.3 Skin exposure
      9.1.4 Eye contact
      9.1.5 Parenteral exposure
      9.1.6 Other
   9.2 Chronic poisoning
      9.2.1 Ingestion
      9.2.2 Inhalation
      9.2.3 Skin exposure
      9.2.4 Eye contact
      9.2.5 Parenteral exposure
      9.2.6 Other
   9.3 Course, prognosis, cause of death
   9.4 Systematic description of clinical effects
      9.4.1 Cardiovascular
      9.4.2 Respiratory
      9.4.3 Neurological
         9.4.3.1 Central Nervous System
         9.4.3.2 Peripheral nervous system
         9.4.3.3 Autonomic nervous system
         9.4.3.4 Skeletal and smooth muscle
      9.4.4 Gastrointestinal
      9.4.5 Hepatic
      9.4.6 Urinary
         9.4.6.1 Renal
         9.4.6.2 Others
      9.4.7 Endocrine and reproductive systems
      9.4.8 Dermatological
      9.4.9 Eye, ears, nose, throat: local effects
      9.4.10 Hematological
      9.4.11 Immunological
      9.4.12 Metabolic
         9.4.12.1 Acid-base disturbances
         9.4.12.2 Fluid and electrolyte disturbances
         9.4.12.3 Allergic reactions
      9.4.14 Other clinical effects
      9.4.15 Special risks
   9.5 Others
10. MANAGEMENT
   10.1 General Principles
   10.2 Relevant laboratory analyses and other investigations
      10.2.1 Sample collection
      10.2.2 Biomedical analysis
      10.2.3 Toxicological analysis
      10.2.4 Other investigations
   10.3 Life supportive procedures and sympomatic treatment
   10.4 Decontamination
   10.5 Elimination
   10.6 Antidote treatment
      10.6.1 Adults
      10.6.2 Children
   10.7 Management discussion
11. ILLUSTRATIVE CASES
   11.1 Case reports from literature
   11.2 Internally extracted data on cases
   11.3 Internal cases
12. ADDITIONAL INFORMATION
   12.1 Availability of antidotes
   12.2 Specific preventive measures
   12.3 Other
13. REFERENCES
14. AUTHOR(S), REVIEWER(S), ADDRESS(ES), UPDATE(S)
    1.  NAME
 
        1.1  Substance  
 
             Methyl bromide
 
        1.2  Group  
 
             Halogenated hydrocarbon
 
        1.3  Synonyms
 
             CH3 Br
             Bromomethane
             Monobromomethane
             MBX
 
        1.4  Identification numbers
 
             1.4.1  CAS Number
 
                    74-83-9
 
             1.4.2  Other numbers
 
                    RTECS    PA 4900000
                    IN - UN/NA  1062
                    EEC N    602-002-00-2
                    EINECS N  200-813-2
 
        1.5  Main brand names/main trade names
 
             Dowfume MC-2
             Dowfume MC-33
             Embafume
             Meth-O-Gas
 
        1.6  Main manufacturers/main importers
 
    2.  SUMMARY
 
        2.1  Main risks and target organs
 
             Methyl bromide is a very toxic fumigant gas with  poor 
             olfactory warning properties.  Severe poisoning and death 
             have occured during application due to inadvertent spread, 
             clean-up operations, and premature entry into fumigated 
             places.
             
             The target organs are:
             
             The central nervous system,  the respiratory system, kidneys, 
             eyes and skin.
 
 
 
             
             The local exposure to the eyes can cause severe irritation, 
             blurred vision, temporary blindness and severe corneal 
             burns.
             
             Methyl bromide can cause severe irritation and corrosive 
             injury of the skin in particular when the gas or liquid is 
             trapped in gloves, boots or other clothing.
 
        2.2  Summary of clinical effects
 
             Symptoms may only appear after a delay of several 
             hours.
             
             A delayed onset of symptoms is typical and serious symptoms 
             can develop from a few minutes to as long as 48 hours 
             postexposure.
             
             Methyl bromide has local and systemic effects. It is a severe 
             eyes, skin and mucous membrane irritant.   Exposure to high 
             concentrations causes pulmonary oedema.
             
             Prolonged skin contact may cause blisters and vesicles 
             resembling a  second-degree burn.
             
             The most important systemic effects are: neurological: 
             headaches, dizziness, coma,  tremors, prolonged and 
             generalized seizures and permanent brain damage.
             
             Several neuropsychiatric signs and symptoms may be observed 
             during acute and chronic methyl bromide poisonings. Low level 
             subacute exposure to the vapour have produced 
             polyneuropathy.
             
             Late sequelae include: bronchopneumonia, renal failure with 
             anuria, severe weakness with or without evidence of 
             paralysis, disturbances of gait, blurred vision and 
             neuropsychiatric disorders.
 
        2.3  Diagnosis
 
             Diagnosis is made primarily on a history of exposure to 
             the compound and typical symptoms.  Serum bromide levels may 
             be useful to make the diagnosis but do not necessarily 
             correlate with the severity of poisoning.
 
        2.4  First-aid measures and management principles
 
             Exposed people should be monitored for a minimum of 24 
             to 48 hours to detect delayed symptoms especially pulmonary 
             edema.
             
 
 
 
             In case of poisoning, management is  primarily 
             supportive.
             
             Measures for decontamination include: In case of inhalation 
             remove source of contamination or remove the victim from the 
             site of exposure to the fresh air. Take proper precautions to 
             ensure that the rescuers guard  their own safety before 
             attempting rescue. e.g. wear appropriate protective equipment 
             and use breathing apparatus.
             
             Remove all contaminated clothing and wash affected skin with 
             soap and water.
             
             Copiously irrigate exposed eyes with water.
             
             In case of respiratory and cardiac arrest  initiate 
             cardiopulmonary resuscitation inmediately. 
             
             Administer supplemental oxygen and treat bronchospasm, 
             pulmonary edema, seizures and coma.
 
             High dose thiopental anaesthesia seems effective in the 
             treatment of CH3Br induced generalised seizures that have 
             proved to be unresponsive to regular treatment with 
             antiepileptic drugs.
             
             The usage of Dimercaprol (BAL) and acetylcysteine have not 
             been critically tested in controlled studies and their 
             reported effectiveness concerned only less severely poisoned 
             patients
 
    3.  PHYSICO-CHEMICAL PROPERTIES
 
        3.1  Origin of the substance
 
             Synthetic
 
        3.2  Chemical structure
 
             CH3 Br
                     H
                     |
                   H-C-Br
                     |
                     H
 
        3.3  Physical properties
 
             3.3.1  Colour
 
             3.3.2  State/Form
 
 
 
             3.3.3  Description
 
                    It is a colorless gas at room temperature  and 
                    standard pressure with a boiling point of about 4C. 
                    It is heavier than air. It is odourless except at high 
                    concentrations when it has a burning taste and a sweet 
                    chloroform-like smell.
                    Molecular weight:  94.95
                    Relative density( specific gravity): 1.73 at 0C
                    Flash point:   none
                    
                    194C burns with difficulty
                    Critical temperature:  194C
                    
                    Autoignition temperature: 536.7C
                    
                    Vapor pressure at 20C : 1420 mm Hg
                    
                    Solubility in water at 20C ; 1.75 g/100 g of 
                    solution
                    
                    Methyl bromide is freely soluble in alcohol, 
                    chloroform, ether, carbon disulfide, carbon 
                    tetrachloride, and benzene.   It is stable and non 
                    corrosive  (EHC,1994). 
                    
                    Melting point :  -93.6 C
                    Boiling point:  3.56  C
                    (Windholz, 1983).
 
        3.4  Other characteristics
 
             Methyl bromide hydrolyses to methanol and hydrobromic 
             acid in aqueous solution.
 
    4.  USES/CIRCUMSTANCES OF POISONING
 
        4.1  Uses
 
             4.1.1  Uses
 
             4.1.2  Description
 
                    Methyl bromide is commercially available as a 
                    liquefied gas and used  as a fumigant for the control 
                    of nematodes, fungi and weeds. The formulations also 
                    may contain chloropicrin or amyl acetate as warning 
                    agents. 
                    
                    It is used widely as a fumigant for all types of dry 
                    foodstuffs, in grain elevators, mills, ships, 
                    warehouses, greenhouses and  food-processing 
                    facilities.
 
 
 
                    
                    It is also used as a soil fumigant applied prior to 
                    planting either being injected into the soil  as a 
                    liquid or applied to the soil under sheeting in the 
                    liquid form using evaporating jars and allowed to 
                    vaporize in situ (cold method) or by heating (hot 
                    method). The methods permitted in various countries 
                    differ. The type of plastic sheeting is also important 
                    (EHC, 1994)
                    
                    The industrial uses of methyl bromide include: 
                    methylating agent in chemical manufacture and as a 
                    low-boiling solvent e.g. for extracting oils from 
                    nuts, seeds and flowers.
                    
                    It has also been used as a refrigerant and fire 
                    extinguishers (Baselt 1982; Hayes  and Laws, 
                    1992).
 
        4.2  High risk circumstance of poisoning
 
             Earlier poisoning incidents involving the general public 
             were mainly from the methyl bromide in fire extinguishers. 
             More poisoning incidents have involved unauthorized entry 
             into fumigated buildings or persons living near fumigated 
             buildings, greenhouses or fields being fumigated with methyl 
             bromide.
             
             Most of occupational poisonings have arisen from its 
             manufacture or from its use as a fumigant  (Hustinx et al, 
             1993).
 
        4.3  Occupational exposed populations
 
             Up to 1955. the majority of methyl bromide poisoning 
             incidents resulted from chemical manufacture and filling 
             operations. Since 1955, fumigation has become the major 
             source of fatalities.  The highest risk group are fumigators 
             and greenhouse workers.  In many countries the use of methyl 
             bromide is restricted to trained and licensed personnel 
             (EHC,1994).
 
    5.  ROUTES OF ENTRY
 
        5.1  Oral
 
             No data available.
 
 
 
        5.2  Inhalation
 
             Inhalation is the primary route of exposure.  Acute, 
             subchronic and chronic poisonings have ocurred following 
             inhalation of methyl bromide. It is readily absorbed through 
             the lungs (Hayes and Laws, 1991). An inhalation study in 
             humans was carried out to determine systemic uptake of low 
             concentrations of methyl bromide from air during nasal or 
             oral breathing. Two male and two female volunteer subjects 
             inhaled about 0.1 mg/m3 (25 ppb) 14C-labelled methyl 
             bromide once through the nose and once through the mouth. The 
             uptake (% of methyl bromide inhaled) was 55.4% nasal and 52.1 
             % oral (Raabe, 1988)
 
        5.3  Dermal
 
             Dermal exposure can result from direct contact with 
             liquid methyl bromide e.g. from accidental splashing or 
             through contact with contaminated boots,clothing, bandages or 
             gloves.  These articles are often made of rubber which can 
             absorb methyl bromide (Alexeef and Kilgore, 1983). Dermal 
             exposure to gaseous methyl bromide can also cause poisoning. 
             Methyl bromide may be absorbed through the skin provoking 
             the same symptoms as described for inhalation  (Baselt 1982, 
             Gosselin et al, 1984). 
             
             When liquid methyl bromide is spilled on the skin, it 
             evaporates rapidly producing a cool or burning 
             sensation.
 
        5.4  Eye
 
             Methyl bromide may cause irritation and tearing. It may 
             also cause severe burns of the cornea.
 
        5.5  Parenteral
 
             No data available
 
        5.6  Others
 
             No data available
 
    6.  KINETICS
 
        6.1  Absorption by route of exposure
 
             Methyl bromide may be absorbed by inhalation or dermal 
             contact. Inhalation experiments in rats, beagles and humans 
             have shown that methylbromide is rapidly absorbed through the 
             lungs. It is also rapidly absorbed in rats following oral 
             administration (EHC, 1994)
 
 
 
        6.2  Distribution by route of exposure
 
             After  absorption, methyl bromide or metabolites are 
             rapidly distributed to many tissues including the lungs, 
             adrenals, kidneys, liver, brain, testis and adipose 
             tissue.
             
             The disposition of 14C-methyl bromide has been evaluated in 
             rats by several authors after oral,intraperitoneal and 
             inhalation exposure.  Following oral or inhalation exposure, 
             75 to 85%  of the body burden was eliminated by rats 65 to 72 
             hours post exposure.
             
             The major organs of distribution of radioactivity observed 
             immediatly after exposure included fat, lungs, liver, 
             adrenals and kidneys concentrations of one-third to one-tenth 
             less were found in the brain. More than 90% of the tissue 
             radioactivity was attributed to metabolized methyl bromide 
             (Hayes and Laws, 1991).
             
             Methylation of proteins and lipids has been observed in 
             tissues from several species, including humans, exposed by 
             inhalation.
             
             Methylated DNA adducts have also been detected following  in 
              vivo and  in vitro exposure of rodents or rodents cells 
             (EHC, 1994).
 
        6.3  Biological half-life by route of exposure
 
             The biological half-life of the bromide ion is 10 to12 
             days (Hustinex et al, 1993).  No data are available about 
             methyl bromide half-life.
 
        6.4  Metabolism
 
             The metabolism of methyl bromide has not been 
             elucidated.  It is known to be partially converted to 
             inorganic bromide in man.  The contribution of this 
             metabolite to the toxicity of the parent is not clear but it 
             is felt that methyl bromide itself is the primary toxic agent 
             (Baselt, 1982).
             
             Bromide concentrations in blood and target organs were 
             reported to be increased in humans and in laboratory animals 
             after exposure to methyl bromide (Hine, 1969)
 
 
 
        6.5  Elimination by route of exposure
 
             Depending on the route of exposure, 30 to 50% of the 
             absorbed methyl bromide was recovered as 14CO2, 16 to 40% 
             was recovered as metabolized methyl bromide in the urine and 
             only 4 to 20% was recovered in the expired air as parent 
             compound.
             
             Medinsky et al observed extensive biliary excretion of 14C 
             activity as indicated by the fact that 46% of the dose was 
             recovered in bilis within 24 hours following oral 
             administration of 14C-methyl bromide (Hayes and Laws, 
             1991).
 
    7.  TOXICOLOGY 
 
        7.1  Mode of action
 
             The mode of action of methyl bromide is still not 
             understood. Proposed mechanisms of toxicity include  the 
             direct cytotoxic effect of the intact methyl bromide molecule 
             or toxicity due to one of its metabolites. The bromide ion 
             concentration are insufficient to explain methyl bromide 
             toxicity.  Methyl bromide reacts  in vitro with a number of 
             SH enzymes and causes progressive and irreversible inhibition 
             interfering with microsomal metabolism. Its ability to 
             methylate sulfhydryl groups and thus inactivate enzymes has 
             been postulated to play an important role in its toxicity 
             (Baselt, 1982; Gosselin et al, 1984).
             
             Honma et al (1985) concluded that CNS toxicity seems to be 
             due to the methyl bromide molecule itself or the methyl 
             moiety incorporated into the tissue and does not appear to be 
             attributable to inorganic bromide or methyl alcohol.
 
        7.2  Toxicity
 
             7.2.1  Human data
 
                    7.2.1.1  Adults
 
                             Fatal poisoning have resulted from 
                             exposures to relatively high concentrations ( 
                             from 33000 mg/m3 or 8600 ppm onwards) of 
                             methyl bromide vapours. Nonfatal poisoning 
                             has resulted from exposure to concentrations 
                             as low as 390 to 1950 mg/m3 (100 to 500 
                             ppm) (EHC, 1994).
 
                    7.2.1.2  Children
 
                             No data available
 
 
 
             7.2.2  Relevant animal data  
 
                    Methyl bromide is very toxic to all animals 
                    species by all routes of administration studied.
                    
                    Acute inhalation studies have shown:
                    
                    LC50  rat, 30 minutes exposure = 2800 ppm ( NIOSH, 
                    1984)
                    
                    LC50  rat, 30 minutes exposure = 11000 mg/ m3 
                    (NIOSH,1984)
                    
                    LC50 rat, 8 hours exposure = 302 ppm 
                    (NIOSH,1984)
                    
                    LC50, rat , 24 hours exposure = 50 mg/m3 , about 13 
                    ppm
                    
                    (NIOSH, 1984)
                    
                    LC50, mouse, 1 hour exposure = 4.68 mg/L, about 1200 
                    ppm
                    
                    (ACGIH, 1986; USEPA, 1985) 
                    
                    LC50 mouse, 2 hour exposure = 1540 mg/L, about 393 pp. 
                    (USEPA, 1985)
                    
                    Oral experimental studies have shown:
                    
                    LD50, rat: 214 mg/kg (IARC, 1986, USEPA, 1985)
                    
                    Long-term inhalation studies:
                    
                    Rats, rabbits and guinea pigs were exposed for 7.5  to 
                    8 hours/day, 5 days/week for up to 6 months to methyl 
                    bromide at 65, 130, 250, 420  and 850 mg/m3. 
                    Increased mortality occured early in the study at 
                    concentrations of 130 mg/m3 (34 ppm) in rabbits and 
                    420 mg/m3 (108 ppm) in rats and guinea pigs. 
                    Surviving animals exhibited signs of severe injury to 
                    the nervous system such as paralysis of the legs, 
                    hyperexcitability and convulsions. These signs were 
                    also seen in monkeys exposed at 250 mg/m3. Lung, 
                    liver and kidney damage were observed in high-dose 
                    animals (IARC, 1986).
                    
                    Cysteine has been shown  to reduce the toxicity of 
                    methyl bromide when administered to rats, mice and 
                    rabbits orally or s.c. 30 minutes before or s.c. 
 
 
 
                    within 5 minutes after acure poisoning. Cysteine 
                    prevented the death, paralysis, paresis and spasms 
                    which developed on the 3rd to 4th days after methyl 
                    bromide inhalation in other animals (EHC, 
                    1994)
 
             7.2.3  Relevant in vitro data
 
                    No data available
 
             7.2.4  Workplace standards
 
                    Time-weighted average (TLV-TWA)  5 ppm (20 
                    mg/m3)
                    
                    Threshold limit values  TLV /ACGIH  1987-88
 
             7.2.5  Acceptable daily intake (ADI)
 
                    In 1988, the JMPR evaluated the toxicology of 
                    the bromide ion (FAO/WHO, 1988a; 1988b) and concluded 
                    that the level causing no toxicological effect 
                    was:
                    
                    Rat-240 ppm, equivalent to 12 mg bromide/kg bw/day
                    
                    Human-9 mg bromide/kg bw/day
                    
                    The acceptable daily intake (ADI) of 1 mg/kg bw was 
                    confirmed
 
        7.3  Carcinogenicity
 
             Groups of males and female rats were given oral doses of 
             methyl bromide (0, 0.4, 2, 10 or 50 mg/kg body weight) in oil 
             5 times/week for 13 weeks. There was incresed incidence of 
             cancers of the forestomach in high-dose animal groups (ACGIH, 
             1986 , IARC, 1986).  In a second study, daily oral 
             administration of methyl bromide at 25 or 50 mg/kg bw did not 
             cause tumours (IARC 1986).
             
             Human data is limited and inconclusive. According to the IARC 
             (1986) the evidence for the carcinogenicity of methyl bromide 
             to humans is inadequate and the evidence in experimental 
             animals is limited. NIOSH, (1984) has recommended that methyl 
             bromide be considered as a potential occupational 
             carcinogen.
 
 
 
        7.4  Teratogenicity
 
             Methyl bromide did not cause birth defects or 
             fetotoxicity in rats or rabbits which were exposed daily by 
             inhalation at 20 or 70 ppm during gestation or prior to 
             breeding (rats only) (IARC, 1986).
             
             No human data is available.
 
        7.5  Mutagenicity
 
             Methyl bromide was mutagenic in several short-term tests 
             using bacteria, cultured mammalian cells, insects and whole 
             animals. Micronuclei (chromosome fragments) were observed in 
             bone marrow and blood cells of rats and mice repeatedly 
             exposed to methyl bromide by inhalation. Alkylation of DNA in 
             liver and spleen was detected in mice exposed to methyl 
             bromide by inhalation or injection (IARC 1986)   
 
        7.6  Interactions
 
             No data available.
 
    8.  TOXICOLOGICAL AND BIOMEDICAL INVESTIGATIONS
 
    9.  CLINICAL EFFECTS
 
        9.1  Acute poisoning
 
             9.1.1  Ingestion
 
                    No cases of ingestion have been reported.
 
             9.1.2  Inhalation
 
                    Mild and moderate exposure may cause headache, 
                    dizziness, abdominal pain, nausea, vomiting, chest 
                    pain and difficulty breathing. Visual disturbances 
                    such as blurred or double vision may also appear.  A 
                    characteristic delay of more than 1 hour up to 48 
                    hours in the onset of symptoms has been described in 
                    several human exposures. Severe poisoning may cause 
                    tremors, convulsions, unconsciousness,and permanent 
                    brain damage.
                    
                    A great variety of central nervous system 
                    manifestations have been described: numbness, ataxia, 
                    tremor, myoclonus, positive Romberg' sign, great 
                    agitation, change of personality. Whereas convulsions 
                    generally occur in fatal cases, death usually is the 
                    result of pulmonary edema leading to respiratory 
                    failure or cardiovascular collapse.
                    
 
 
 
                    Liver and kidney damage have also been described 
                    (Ellenhorn and Barceloux, 1988, Baselt 1982, Hayes and 
                    Laws,1992).
                    
                    Inhalation of more than 10000 ppm for more than a few 
                    minutes may cause death (Hayes and Laws, 1992)
 
             9.1.3  Skin exposure
 
                    Methyl bromide can cause severe irritation and 
                    corrosive skin injury, blisters and vesicles 
                    resembling second-degree burns.  In particular, severe 
                    injury may occur if gas or liquid is trapped in 
                    gloves, boots or other clothing.
                    
                    Methyl bromide can be absorbed through the skin and 
                    produce the same symptoms described for inhalation 
                    (CCHOS, 1992)
 
             9.1.4  Eye contact
 
                    Irritation and tearing. Blurred vision. 
                    Temporary blindness and retinal bleeding have been 
                    reported. Severe burns of the cornea have also been 
                    described (Chavez et al, 1985).
 
             9.1.5  Parenteral exposure
 
                    No data available
 
             9.1.6  Other
 
                    No data available
 
        9.2  Chronic poisoning
 
             9.2.1  Ingestion
 
                    No data available
 
             9.2.2  Inhalation
 
                    Chronic exposure is characterized by lethargy, 
                    muscular pains; visual, speech and sensory 
                    disturbances and mental confusion. More severe effects 
                    include tremors, hallucinations, fainting spells and 
                    seizures due to permanent brain damage.
                    
 
 
 
                    Kidney and liver damage have also been reported 
                    (Ellenhorn and Barceloux,1988). A fumigator 
                    chronically  exposed to methyl bromide developed 
                    paresthesia of the extremities, dysesthesias and 
                    visual impairment secondary to optic atrophy (Chavez 
                    et al, 1985)
 
             9.2.3  Skin exposure
 
                    Prolonged or repeated contact with liquid may 
                    cause skin burns and lesions.
 
             9.2.4  Eye contact 
 
                    No data available
 
             9.2.5  Parenteral exposure
 
                    No data available
 
             9.2.6  Other
 
                    No data available
 
        9.3  Course, prognosis, cause of death
 
             A delayed onset of symptoms is typical and serious 
             symptoms can develop within a few minutes to as long as 48 
             hours  postexposure.
             
             Death usually is the result of pulmonary edema, 
             cardiovascular  collapse or intratable status epilepticus 
             (Hayes and Laws, 1991, Hustinx et al, 1993).
             
             In severely poisoned patients  recovery is frequently 
             prolonged and convalescence may take months. Permanent 
             sequelae are frequent, they are: psychiatric, motor and 
             sensory impairment ataxia, muscular weakness, irritability, 
             blurred vision, myoclonus and EEG disturbances.
 
        9.4  Systematic description of clinical effects
 
             9.4.1  Cardiovascular
 
                    Tachycardia is very common in mild and moderate 
                    cases. Cardiovascular collapse has been described in 
                    fatal cases (Gosselin et al, 1984).
 
 
 
             9.4.2  Respiratory
 
                    Methyl bromide produces irritation of the 
                    respiratory tract.  Cough, chest pain, difficulty in 
                    breathing and bronchospasm have been described. 
                    Development of non-cardiogenic pulmonary oedema may be 
                    immediately or delayed leading to respiratory failure. 
                    Chest X-ray may show uni or bilateral infiltrative 
                    changes with or without pleural effusion. 
                    Pathological findings at autopsy include: pulmonary 
                    oedema, bronchopneumonia, congestion and haemorrhage 
                    (Hine, 1969)
 
             9.4.3  Neurological
 
                    9.4.3.1  Central Nervous System
 
                             A great variety of manifestations 
                             may appear, nearly every type of nervous 
                             disturbance has been reported: numbness, 
                             twitching of all limbs, ataxia, tremor, 
                             myoclonus, great agitation, coma and tonic- 
                             clonic generalized convulsions (status 
                             epilepticus).  Exageration of the patellar 
                             reflexes and a positive Babinski's sign may 
                             develop ( Hustinx et al, 1993).
                             
                             Other manifestations are: headache, 
                             dizziness, visual, speech and sensory 
                             disturbances,sensation described as 
                             "floating".
                             
                             Remarkable abnormalities of the EEG have been 
                             reported: runs of very  sharp spikes of short 
                             duration followed by a short wave. Myoclonic 
                             jerks coincide these polyspike and wave 
                             complexes (Hustinx et al, 1993).  Uncini et 
                             al (1990) were able to show that the status 
                             mioclonicus as seen in some cases of serious 
                             methyl bromide poisoning may represent a form 
                             of cortical reflex myoclonus.
                             
                             Brain stem damage was described in a man who 
                             died 30 days after unconsciousness following 
                             methyl bromide exposure. At postmorten 
                             examination the brain showed mild generalized 
                             swelling, normal ventricles and well defines 
                             symmetrical lesions, including loss of 
                             neurones in the mammilary bodies and inferior 
 
 
 
                             colliculi.  The cerebellar dentate nuclei had 
                             occasional foci of neuronal loss;other brain 
                             regions were normal. The spinal cord was 
                             normal but dorsal root ganglia had scattered 
                             nodules of neuronal loss (Cavanagh, 
                             1992)
 
                    9.4.3.2  Peripheral nervous system
 
                             Distal muscular weakness, painful 
                             plantar dysaesthesia and alteration of tendon 
                             reflexes due to axonal neuropathy have been 
                             described  after acute poisoning (Hustinx et 
                             al, 1993).
                             
                             Low-level subacute exposure to the vapour 
                             have produced a syndrome of polyneuropathy 
                             characterized by persistent numbness in the 
                             and legs, impaired superficial sensation, 
                             muscle weakness, unsteadiness of gait and 
                             absent or hypoactive distal tendon reflexes 
                             (Kantarjian, 1963).
 
                    9.4.3.3  Autonomic nervous system
 
                             No data available
 
                    9.4.3.4  Skeletal and smooth muscle
 
                             High serum CPK has been seen 
                             returning to normal soon after suppression of 
                             seizures (Hustinx et al, 1993)
 
             9.4.4  Gastrointestinal
 
                    Acute exposure may cause: nausea, vomiting, 
                    abdominal pain.
 
             9.4.5  Hepatic
 
                    Rise in ALAT - ASAT and LDH have been described 
                    several days after an acute episode  suggestive of 
                    mild hepatotoxicity (Verberk et al, 1979).
 
             9.4.6  Urinary
 
 
 
                    9.4.6.1  Renal
 
                             Transient proteinuria has been 
                             described (Hustinx et al, 1993).  Renal 
                             failure due to tubular necrosis may be a late 
                             sequela, but this is  uncommon and usually 
                             mild (Benatt, 1948).
 
                    9.4.6.2  Others
 
                             No data available
 
             9.4.7  Endocrine and reproductive systems
 
                    No data available
 
             9.4.8  Dermatological
 
                    Methyl bromide is a potent skin irritant and an 
                    intense vesicant. Prolonged skin contact may cause 
                    blisters and vesicles resembling a second-degree burn 
                    (Gosselin et al, 1984; CCOHS, 1992).
 
             9.4.9  Eye, ears, nose, throat: local effects
 
                    Methyl bromide has local irritant  effects. It 
                    is  a severe eye, nose, skin and mucous membrane 
                    irritant.
                    
                    Various visual disturbances have been described: 
                    blurring of vision, diplopia, lacrymation and 
                    accommodative disturbance
                    
                    Burning sensation of the throat has also been 
                    reported.
 
             9.4.10  Hematological
 
                    Varying degrees of leucocytosis with or 
                    without left shift have been described (Hustinx et al, 
                    1993).
 
             9.4.11  Immunological
 
                    No data available
 
             9.4.12  Metabolic
 
 
 
                    9.4.12.1 Acid-base disturbances
 
                             Metabolic acidosis has been 
                             observed in moderate and severe 
                             poisoning.
 
                    9.4.12.2 Fluid and electrolyte disturbances
 
                             Raise in serum chloride 
                             concentrations has been observed in some 
                             patients (Hustinx et al, 1993).
 
                    9.4.12.3 Allergic reactions
 
                             No data available
 
             9.4.14 Other clinical effects
 
                    An employee habitually not wearing a mask in a 
                    fumigating plant spraying fruits and vegetables was 
                    initially treated for psychosis as the early symptoms 
                    of methyl bromide poisoning are similar (Zatuchni  and 
                    Hong, 1981) 
 
             9.4.15 Special risks
 
                    No data available
 
        9.5  Others
 
             No data available
 
    10. MANAGEMENT
 
        10.1 General Principles
 
             Exposed people should be monitored for a minimum of 24 
             to 48 hours to detect delayed symptoms especially pulmonary 
             edema.
             
             Management is primarily supportive. 
             
             In case of respiratory and cadiac arrest initiate 
             cardiopulmonary resuscitation immediately.
             
             Administer supplemental oxygen and treat bronchospasm, 
             pulmonary edema, seizures and coma.
             
             High dose thiopental anaesthesia seems effective in the 
             treatment of CH3Br induced generalised seizures that have 
             proved to be unresponsive to regular treatment with 
             antiepileptic drugs.
 
 
 
             
             The usage of Dimercaprol (BAL) and acetylcysteine have not 
             been critically tested in controlled studies and their 
             reported effectiveness concerned only less severely poisoned 
             patients.
 
        10.2 Relevant laboratory analyses and other investigations
 
             10.2.1 Sample collection 
 
             10.2.2 Biomedical analysis
 
                    The following analysis may be useful in the 
                    management of CH3Br poisoning :
                    
                    Arterial blood gases
                    Acid base balance
                    Serum  electrolytes
                    Urine analysis
                    Creatinine
                    Total haemoglobin, blood cell count
                    Hepatic enzymes
                    Chest x-ray
                    ECG
                    EEG
 
             10.2.3 Toxicological analysis
 
                    Measurement of blood  CH3Br and serum bromide 
                    (Br-) by induction coupled plasma mass spectrometry 
                    should be performed (Hustinx et al, 1993).
                    
                    Methyl bromide itself has been detected in human 
                    tissue on only one occasion.  This observation may be 
                    due to the absence of methyl bromide or more probably 
                    its very  short half-life in tissues as well as 
                    difficulties in analysis (EHC 1994).  Data on 
                    concentrations of bromide in various human tissues 
                    after methyl bromide poisoning are scarce.
                    
                    There is an inconsistency in the data as to whether 
                    there is a correlation between bromide  levels and the 
                    symptoms of methyl bromide.  Serum Br- concentrations 
                    are considered by some authors to correlate poorly 
                    with clinical symptoms and outcome (Bradford, 
                    1990)
                    
                    Cases of fatal CH3Br poisoning have reportedly 
                    occurred in association with serum Br- concentrations 
                    of only 30 mg/L whereas concentrations of more than 
                    200 mg/L were found in  professional fumigators 
                    without any accompanying symptoms (Hustinx et al, 
                    1993).
 
 
 
                    
                    In four lethal cases of people exposed to methyl 
                    bromide, Marraccini et al (1983) found bromide ion 
                    concentrations in serum or plasma ranging from 40 to 
                    583 mg/L. Methyl bromide was detected in the brain of 
                    one patient (detection limit < 1 ppm).
 
             10.2.4  Other investigations
 
                    Haemoglobin adducts as a biological index to 
                    methyl bromide exposureMethyl bromide reacts with 
                    cysteine to form S-methylcysteine (MeCys) in 
                    haemoglobin. Iwasaki and Kagawa (1989) determined the 
                    haemoglobin adduct in methyl bromide manufacturing 
                    workers and examined its effectiveness as a biological 
                    index of exposure to methyl bromide. Haemoglobin 
                    adducts have a life span of about 2 months, so workers 
                    only intermittently exposed to methyl bromide would 
                    also be detected in such a survey.
 
        10.3  Life supportive procedures and sympomatic treatment
 
             Treatment with diazepam, clonazepam, diphenylhydantoin 
             or paraldehyde is often not sufficient to supress convulsive 
             activity. In these cases high dose thiopental anaesthesia 
             seems to be effective.
             
             The drug resistant status epilepticus , also described by 
             some authors as status myoclonicus is associated with a high 
             mortality (Hustinx et al, 1993).
 
        10.4 Decontamination
 
             Measures for decontamination.  In case of inhalation 
             remove the source of contamination or remove victim from 
             exposure  to the fresh air. Take proper precaution to ensure 
             the rescuers their own safety before attempting recue. e.g. 
             wear appropriate protective equipment. Use breathing 
             apparatus.
             
             Remove all contaminated clothing and wash affected skin with 
             soap and water.
             
             Irrigate exposed eyes with copious water.
 
        10.5 Elimination
 
             No data indicating the benefit of forced diuresis, 
             alkalinization, haemodialysis or haemoperfusion is 
             available.
 
 
 
        10.6 Antidote treatment
 
             10.6.1 Adults
 
                    Although BAL has been used for treating methyl 
                    bromide  poisoning  there is no evidence that it was 
                    beneficial (Hayes and Laws, 1991).
 
             10.6.2 Children
 
                    No data available
 
        10.7 Management discussion
 
             In the past chelating agents as Dimercaprol and N- 
             acetylcysteine have been used. None of these drugs were used 
             in the context of controlled prospective trials and their 
             reported effectiveness concerned only less severely poisoned 
             patients (Hustinx et al, 1993). 
 
    11. ILLUSTRATIVE CASES
 
        11.1 Case reports from literature
 
             Systemic methyl bromide (CH3Br) poisoning with signs 
             and symptoms of varying severity developed in nine greenhouse 
             workers after acute inhalational exposure on two consecutive 
             days.
             
             Measurements of CH3Br, carried out at the site within hours 
             after the accident suggest that exposure on the second day 
             may have been in excess of 200 ppm (800 mg/m3). All workers 
             were admitted for observation. Seven of them were discharged 
             after an uneventful overnight observation and residual 
             symptoms if any, subsided within  three weeks of the 
             accident. Two patients needed intensive care for several 
             weeks because of severe reactive myoclonus and tonic-clonic 
             generalised convulsions. These conditions were unresponsive 
             to repeated doses of diazepam, clonazepam and 
             diphenylhydantoin but could be suppressed effectively by 
             induction of a thiopental coma that had to be continued for 
             three weeks.
             
             In some of the patients previous subchronic exposure to CH3Br 
             as shown by their occupational histories and high serum 
             bromide  concentrations is likely to have been a factor 
             contributing to the severity of their symptoms. A direct 
             association between serum bromide concentrations and the 
             severity of neurological symptoms, however, seemed to be 
 
 
 
             absent. An on site investigation into the circumstances 
             leading to the accident showed the presence of an empty and 
             out of use drainage system that covered both sections of the 
             greenhouse. This was probably the most important factor 
             contributing to the rapid and inadvertent spread of CH3Br 
             (Hustinx et al, 1993).
 
        11.2 Internally extracted data on cases
 
        11.3 Internal cases 
 
    12. ADDITIONAL INFORMATION
 
        12.1 Availability of antidotes
 
             No antidote available.
 
        12.2 Specific preventive measures
 
             Personal protective equipment: Wear suitable personal 
             protective equipment including approved respiratory 
             protection.
             
             Have appropriate equipment available for use in emergencies 
             such as spills or fire. Respiratory protection: NIOSH 
             recommendations: positive pressure, full-facepiece SCBA; or 
             positive pressure, full-facepiece SCBA.
             
             Eye/face protection: Chemical safety goggles. A face shield 
             may also be necessary.
             
             Skin protection: Impervious gloves, coveralls, boots and/or 
             other resistant protective clothing. Have a safety 
             shower/eye-wash fountain readily available in the immediate 
             work area. 
             
             Personal protection comments:  Remove contaminated clothing 
             promptly. Keep contaminated clothing in closed containers. 
             Discard or launder before rewearing. Inform laundry personnel 
             of contaminant's hazards. Discard contaminated leather goods 
             (shoes,belt, watchband).
             
             Do not smoke, eat or drink in work areas.
             
             Wash hands thoroughly after handling this material.  Maintain 
             good housekeeping (CCOHS, 1992).
 
 
 
        12.3 Other
 
             Spill and leak procedures: Precautions
             
             Restrict access to area until completion of clean-up. Ensure 
             clean-up is conducted by trained personnel only. Wear 
             adequate personal protective equipment. Ventilate area. 
             Extinguish or remove all ignition sources.
             
             Clean-up:  Do not touch spilled material. Prevent material 
             from entering sewers or confined spaces. Stop or reduce leak 
             if safe to do so. Contain spilled liquid with earth, sand or 
             absorbent material which does not react with spilled 
             material.
             
             Large spills: Contact fire and emergency services and 
             supplier for advice.
 
    13. REFERENCES
 
        ACGIH (1986) Threshold limit values for chemical substances 
        and physical changes and biological exposure indices. Cincinnati, 
        Ohio, American Conference of Governmental Industrial Hygienist, 
        pp 26.
        
        Alexeef GV, Kilgore WW (1983)  Methyl bromide In: Gunther FA., & 
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        Verlag , pp 102-153. 
        
        Baselt R (1982)  Disposition of Toxic Drugs and Chemicals in Man, 
        2nd. Ed. Biochemical Publications, Davis, California, 
        pp 516-517.
        
        Benatt, AJ,Courtney TRB (1948)  Uraemia in methyl bromide 
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        Bradford JC (1990)  Methyl bromide and related compounds. In: 
        Haddad LM  and Winchester JF, eds. Clinical Management of 
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        Company.
        
        Cavanagh JB (1992)  Methyl bromide intoxication and acute energy 
        deprivation syndromes . Neuropathol. Appl. Neurobiol, 
        18: 573-578.
        
        Chavez CT, Hepler RS, Straatsma BR (1985)  Methyl Bromide optic 
        atrophy. Am J Ophthalmol 99: 715-19
        
        CCOHS (1992)  CHEMINFO Canadian Centre for Occupational Health and 
        Safety
        
 
 
 
        EHC (1994)  Environmental Health Criteria (EHC) for Methyl 
        bromide, draft for Editor, IPCS/UNEP/ILO/WHO 
        
        Ellenhorn MJ & Barceloux DG (1988) Medical Toxicology. Diagnosis 
        and Treatment of Human Poisoning. New York, Elsevierr, p957.
        
        FAO/WHO (1988a)  Pesticide residues in food.  Report of the Joint 
        Meeting of the FAO Panel of Experts on Pesticide Residues in Food 
        and the Environment and the WHO Expert Group on Pesticide 
        Residues. FAO Plant Production and Protection  Paper 92. 
        
        FAO/WHO (1988b)  Pesticide residues in food - 1988 evaluations. 
        Part II- Toxicology. FAO Plant Production and Protection Paper 
        93/2.
        
        Gosselin RE, Smith RP and Hodge HC (1984) Clinical toxicology of 
        commercial products . 5th ed. William & Wilkins, 
        pp III-280, III-284, II-158.
        
        Hayes W Jr, Laws E Jr (1991)  Handbook of Pesticide Toxicology, 
        Vol 2 , Chapter 14, Academic Press Inc, pp 668-671.
        
        Hine CH (1969)  Methyl bromide poisoning - a review of ten cases. 
        J. Occup. Med, 11(1): 1-10.
        
        Honma T., Miyagawa M, Sato M, & Hasegawa H (1985)  Neurotoxicity 
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        Pharmacol., 81: 183-191
        
        Hustinx  WNM, Van de Laar RTH, Van Huffelen AC, Verwey JC, 
        Meulenbelt J, Savelkoul TJF (1993)  Systemic effects of 
        inhalational methyl bromide poisoning: a study ot nine cases 
        occupationally exposed due to inadvertent spread during 
        fumigation. Br J Indus Med, 50: 155-159 
        
        IARC (1986)  Monographs on the evaluation of the carcinogenic risk 
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        Iwasaki K, Ito I, Kagawa J (1989)  Biological exposure monitoring 
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        Kantarjian AD, Shaheen AS (1963)  Methyl bromide poisoning with 
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        13: 1054-1058.
        
        Marraccini JV, Thomas GE, Ongley JP, Pfaffenberger D, Davis JH, 
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        an insecticide fumigant. J. Foren. Sci. Soc. 28: 601-607
        
 
 
 
        NIOSH (1984) Current Intelligence Bulletin : monohalomethanes: 
        methyl chloride, methyl bromide, methyl iodide. National Institute 
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        Raabe OG (1986)  Inhalation uptake of selected vapors by people. 
        Laboratory for Energy-related Health Research, University of 
        California, Davis, (ISS ARB-R 88/338) Order-No PB-88 202726  Final 
        Report August 1986 - March 1988) 94 pages
        
        Uncini A, Basciani M, Di Muzio A, Antonini D, Onofri M (1990) 
        Methyl bromide myoclonus: an electro physiological study. Acta 
        Neurol Scand. 81: 159-164  
        
        Verberk MM, Rooyakkers-Beemster T, De Vlieger M, Van Vliet AGM 
        (19??)  Bromine in blood, EEG and transaminases in methyl bromide 
        workers. Br. J. Ind. Med. 36: 59-62
        
        Windholz  M  (1983)  Merck Index: an encyclopedia of chemicals, 
        drugs, and  biologicals. 10th Edition, Merck & Co., Inc. Rahway, 
        N.J.
         
        Zatuchni J, Hong K (1981)  Methyl bromide poisoning seen initially 
        as psychosis.  Arch Neurol, 38:529-530
 
    14. AUTHOR(S), REVIEWER(S), ADDRESS(ES), UPDATE(S)
 
        Author:     Dr M.C. Alonzo
                    Departamento de Toxicologia & Centro de Informacion y 
                    Asesoramiento Toxicologico
                    Hospital de Clinicas "Dr. M. Quintela"
                    7piso
                    Avda. Italia s/n
                    Montevideo
                    Uruguay
                    
                    Tel:     598-2-470300/804000
                    Fax:     598-2-470300
                    
        Date:                March 1995
        
        Peer review:         Cardiff, United Kingdom, March 1995
                             (Group members: Dr C. Alonzo, Dr M. Balali- 
                             Mood,
                             Dr R. Fernando, Dr Z. Kolacinski, Ms M. 
                             McFarland,
                             Dr J. Szajewski, Dr W. Temple)
        
        Finalised:           IPCS, September 1996
 
    
 


    See Also:
       Toxicological Abbreviations
       Methyl Bromide (EHC 166, 1995)
       Methyl bromide (ICSC)
       Methyl bromide (FAO Meeting Report PL/1965/10/2)
       Methyl bromide (FAO/PL:CP/15)
       Methyl bromide (FAO/PL:1967/M/11/1)
       Methyl bromide (FAO/PL:1968/M/9/1)
       Methyl bromide (WHO Pesticide Residues Series 1)
       Methyl bromide (SIDS)
       Methyl Bromide (IARC Summary & Evaluation, Volume 71, 1999)