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SECTION 1. CHEMICAL IDENTIFICATION

CHEMINFO Record Number: 164
CCOHS Chemical Name: Methyl isocyanate

Synonyms:
Isocyanatomethane
Isocyanic acid, methyl ester
Methylcarboxylamine
MIC

Chemical Name French: Isocyanate de méthyle
Chemical Name Spanish: Isocianato de metilo
CAS Registry Number: 624-83-9
UN/NA Number(s): 2480
RTECS Number(s): NQ9450000
Chemical Family: Isocyanic acid ester / isocyanate / aliphatic isocyanate / monoisocyanate / aliphatic monoisocyanate
Molecular Formula: C2-H3-N-O
Structural Formula: CH3-N=C=O

SECTION 2. DESCRIPTION

Appearance and Odour:
Colourless liquid with a sharp, unpleasant, pungent odour; lachrymator (vapour irritates the eyes and causes tears).

Odour Threshold:
2.1 ppm.(26). Three out of 7 people could smell MIC at 5 ppm.(1,4)

Warning Properties:
NOT RELIABLE - odour threshold and eye irritation occur above the TLV.

Composition/Purity:
Usually contains inhibitors to prevent polymerization.

Uses and Occurrences:
MIC is used mainly in the manufacture of methylcarbamate pesticides such as carbaryl and aldicarb. Smaller quantities are used in the production of polyurethane foams, plastics and certain pharmaceuticals; used in organic synthesis.(1)


SECTION 3. HAZARDS IDENTIFICATION

EMERGENCY OVERVIEW:
Colourless liquid, with a sharp, unpleasant, pungent odour. Lachrymator. EXTREMELY FLAMMABLE LIQUID AND VAPOUR. Vapour is heavier than air and may spread long distances. Distant ignition and flashback is possible. Can decompose at high temperatures forming toxic gases, such as nitrogen oxides and hydrogen cyanide. Closed containers may develop pressure and rupture on prolonged exposure to heat. Reacts violently with water. May polymerize if heated or in contact with water. VERY TOXIC. May be fatal if inhaled or swallowed. Vapour is extremely irritating to eyes and respiratory tract. Causes lung injury--effects may be delayed. CORROSIVE to the eyes and skin. Can cause blindness and permanent scarring. SKIN SENSITIZER. May cause allergic skin reaction. MUTAGEN - may cause genetic damage, based on animal information.



POTENTIAL HEALTH EFFECTS

Effects of Short-Term (Acute) Exposure

Inhalation:
Methyl isocyanate is a very strong irritant and initial injury is largely confined to areas of direct contact such as the nose, mouth and respiratory tract.(2) Very serious and persistent respiratory system and lung damage can result. Rapid deaths following exposure to high concentrations and delayed deaths resulting from exposures to lower concentrations of methyl isocyanate have been caused by respiratory injury.(3)
In one laboratory test, people inhaled methyl isocyanate vapour for 1-5 minutes. At 0.4 ppm, no effect was detected; at 2 ppm, irritation of the nose and throat occurred; at 4 ppm irritation was stronger; and at 21 ppm, exposure was unbearable. In another study, 8 people breathed 1.75 ppm for 1 minute. Three people experienced nose and/or throat irritation. In most cases, the effects disappeared within 10 minutes after exposure.(1,4)
Much of the information about methyl isocyanate has been learned from the Bhopal tragedy, where a large concentration of methyl isocyanate accidentally escaped from a pesticide plant in Bhopal, India. Inhalation of very high levels of methyl isocyanate can be fatal due to severe respiratory tract and lung damage (pulmonary edema). Symptoms would include breathlessness, dry cough, throat irritation or choking, chest pain/tightness, and coughing up blood. Symptoms may appear immediately or may be delayed several hours after exposure, depending upon the concentration, and may continue for 3 to 7 days or longer. Many victims of Bhopal died or experienced permanent lung damage. There is no agreement over what concentration levels of methyl isocyanate were reached in Bhopal.(2,5)

Skin Contact:
Liquid methyl isocyanate is corrosive to the skin and can cause very severe irritation, redness, blistering (edema) and tissue death (necrosis). Permanent scarring could result.
Methyl isocyanate is considered capable of causing a severe allergic skin reaction, based on animal information. Refer to "Effects of Long-Term (Chronic) Exposure" for more information. Isocyanates, in general, can cause skin discolouration (staining) and hardening of the skin after repeated exposures.

Eye Contact:
Methyl isocyanate liquid and vapour is extremely irritating to the eyes.
In laboratory studies, people exposed to methyl isocyanate vapour at 1.75-2 ppm for 1-5 minutes experienced irritation with tearing. Six people exposed to 0.05 ppm for 10 minutes experienced irritation. All seven people exposed to 5 ppm for 1 minute had irritation with tearing. Effects lasted less than 3 minutes.(1,4) In the Bhopal disaster, exposure to extremely high concentrations for approximately 2 hours, resulted in severe eye injury. In most cases, complete recovery occurred. However, some victims continued to experience effects up to 2 years later. There were no cases of blindness. The risk of cataracts was greater among those with high exposures.(5,6)
Liquid methyl isocyanate is corrosive to the eyes and has caused severe permanent damage (tissue death and blindness) in animal studies.

Ingestion:
There have been no reports of people ingesting methyl isocyanate. Animal studies indicate that methyl isocyanate has high oral toxicity.(1) Ingestion would probably cause severe irritation and corrosive injury to the mouth, throat and digestive tract. Ingestion is unlikely to occur in the workplace.

Effects of Long-Term (Chronic) Exposure

Lungs/Respiratory System:
Animal evidence suggests that long-term, low-level exposure could result in significant damage to the respiratory system.

Exposure to isocyanates is likely to aggravate individuals with existing respiratory disease, such as chronic bronchitis, and emphysema.

Respiratory Sensitization:
In general, isocyanates are well known to cause respiratory sensitization. However, there are no reports of methyl isocyanate causing respiratory sensitization.
Isocyanate respiratory sensitization is usually caused by a very large exposure, or by multiple exposures.(7) Although varying periods of exposure (1 day to years) may elapse before sensitization occurs, it develops more often during the first few months of exposure. Sensitized individuals react to very low levels of airborne isocyanates that have no effect on unsensitized people.(7) At first, the symptoms may appear to be a cold or mild hay fever. However, severe asthmatic symptoms can develop and include wheezing, tightness of the chest, shortness of breath, difficulty breathing and/or coughing. Fever, chills, general feelings of discomfort, headache, and fatigue can also occur. Symptoms may occur immediately upon exposure (within an hour), several hours after exposure or both, and/or at night.(7,8) Typically, the asthma improves with removal from exposure (e.g. weekends or vacations) and returns, in some cases, in the form of an "acute attack", on renewed exposure.(8) Sensitized people who continue to be exposed to isocyanates at work may develop symptoms sooner after each exposure. The number and severity of symptoms may increase.
Following removal from isocyanate exposure, some sensitized people may continue to show a slow decline is lung function and have persistent respiratory problems, such as chronic bronchitis for months or years.(7) Others may recover fully and gradually lose their sensitivity within several years.
Cross-sensitization between different isocyanates may occur.(8)

Skin Sensitization:
Methyl isocyanate is an occupational skin sensitizer, based on animal evidence. Methyl isocyanate is a powerful skin sensitizer in guinea pigs and many other isocyanates are known skin sensitizers. There have been no reports of methyl isocyanate causing skin sensitization in humans.
Symptoms of skin sensitization include redness, scaling, rash, itching, hives and swelling of the arms and legs which can spread from the hands or arms to the face and body.

Carcinogenicity:

No human information is available on the carcinogenicity of methyl isocyanate. One animal study provides limited evidence of carcinogenicity after a very brief exposure.

The International Agency for Research on Cancer (IARC) has not evaluated the carcinogenicity of this chemical.

The American Conference of Governmental Industrial Hygienists (ACGIH) has not assigned a carcinogenicity designation to this chemical.

The US National Toxicology Program (NTP) has not listed this chemical in its report on carcinogens.

Teratogenicity and Embryotoxicity:
There is not enough information available to conclude that methyl isocyanate causes developmental toxicity in the absence of harmful effects in the mother. In a study of pregnant victims of the Bhopal accident, 49% did not give birth to live babies. This was a 3-4 fold greater incidence of fetal loss compared with the normal incidence in Bhopal. The miscarriage rate appeared to be higher in those exposed to methyl isocyanate in the first trimester of pregnancy. In another study, two surviving infants had multiple birth defects, such as spina bifida, limb deformities and heart disease. Autopsy revealed lung disease similar to that found in adults.(5,9) There was significant maternal toxicity in this population. Animal studies indicate that methyl isocyanate is embryotoxic at doses that are, or are expected to be, maternally toxic.

Reproductive Toxicity:
Women who resided within 10 km of the Bhopal plant, experienced significant gynecological symptoms. Semen samples taken 100-120 days after methyl isocyanate exposure showed normal sperm counts. However, this may be too late to detect damage to mature sperm, because it exceeds the duration of spermatogenesis.(5) The few animal studies available do not suggest that methyl isocyanate causes reproductive effects.

Mutagenicity:
Mutations (sister-chromatid exchange (SCE) frequencies and the incidence of chromosomal breaks) were increased in white blood cells of people exposed at Bhopal. Twelve months after exposure, 71% of the population showed evidence of chromosomal damage.(1,5,10) About 2-4 years after exposure, it was found that about 20% might possess some chromosomal abnormality.(10) In repeated exposure tests with mice, chromosomal damage in bone marrow and lung cells was attributed to methyl isocyanate exposure.

Toxicologically Synergistic Materials:
There is no information available.

Potential for Accumulation:
Probably does not accumulate. Reacts with water and tissues to form methylamine. In a study with guinea pigs and mice, methyl isocyanate and/or its breakdown products were detected in blood, the urine and bile within minutes from the start of exposure. It was thought that a large amount came from absorption on the nasal mucosa and upper respiratory tract. Clearance occurred gradually over 3 days. In exposed guinea pigs, methyl isocyanate and/or its products were distributed to all examined tissues and in pregnant mice, it was observed in the uterus, placenta and fetus.(11)


SECTION 4. FIRST AID MEASURES

Inhalation:
This product is flammable and very toxic. Take precautions to ensure your own safety before attempting rescue (e.g. wear appropriate protective equipment, use the buddy system and remove any sources of ignition). Remove source of contamination or move victim to fresh air. If breathing is difficult, oxygen may be beneficial if administered by trained personnel, preferably on a doctor's advice. DO NOT allow victim to move about unnecessarily. Symptoms of pulmonary edema can be delayed up to 48 hours after exposure. Immediately transport victim to an emergency care facility.

Skin Contact:
Avoid direct contact. Wear chemical protective clothing, if necessary. As quickly as possible, remove contaminated clothing, shoes, and leather goods (e.g. watchbands, belts) and place in a closed container. Quickly and gently blot or brush away excess chemical. Wash gently and thoroughly with water and non-abrasive soap for 20 minutes or until chemical is removed. If irritation persists, repeat flushing. Immediately transport victim to an emergency care facility. Discard contaminated clothing, shoes and leather goods before reuse or discard.

Eye Contact:
Avoid direct contact. Wear chemical protective gloves, if necessary. Quickly and gently blot or brush away excess chemical. Immediately flush the contaminated eye(s) with lukewarm, gently flowing water for 20 minutes or until the chemical is removed, while holding the eyelid(s) open. Take care not to rinse contaminated water into the unaffected eye or onto the face. If irritation persists, repeat flushing. Quickly transport victim to an emergency care facility.

Ingestion:
NEVER give anything by mouth if victim is rapidly losing consciousness, is unconscious or is convulsing. Have victim rinse mouth thoroughly with water. DO NOT INDUCE VOMITING. Have victim drink 240 to 300 mL (8 to 10 oz.) of water to dilute material in stomach. If milk is available, it may be administered AFTER the water is given. Quickly transport victim to an emergency care facility.

First Aid Comments:
Provide general supportive measures (comfort, warmth, rest).
Consult a doctor and/or the nearest Poison Control Centre for all exposures.
Some recommendations in the above sections may be considered medical acts in some jurisdictions. These recommendations should be reviewed with a doctor and appropriate delegation of authority obtained, as required.
All first aid procedures should be periodically reviewed by a doctor familiar with the material and its conditions of use in the workplace.



SECTION 5. FIRE FIGHTING MEASURES

Flash Point:
-7 deg C (19 deg F) (closed cup) (12)

Lower Flammable (Explosive) Limit (LFL/LEL):
5.3% (12)

Upper Flammable (Explosive) Limit (UFL/UEL):
26% (12)

Autoignition (Ignition) Temperature:
534 deg C (994 deg F) (12)

Sensitivity to Mechanical Impact:
Insufficient information. Probably not sensitive, since it is a stable material.

Sensitivity to Static Charge:
Insufficient information. Methyl isocyanate vapours in the flammable range may be ignited by a static discharge.

Combustion and Thermal Decomposition Products:
Nitrogen oxides, hydrogen cyanide.

Fire Hazard Summary:
Extremely flammable liquid. Material will readily ignite at room temperature. Vapour is heavier than air and may travel a considerable distance to a source of ignition and flash back to a leak or open container. During a fire, irritating/toxic nitrogen oxides and hydrogen cyanide may be generated. Vapour can cause death if it penetrates the firefighter's normal protective gear. Reacts violently with water. Can accumulate in confined spaces, resulting in an explosion and toxicity hazard. Closed containers may rupture violently when heated.

Extinguishing Media:
Carbon dioxide, dry chemical powder, alcohol foam (12). Water spray or fog can be used for cooling. Water-based extinguishers and foams should not be used on MIC, since the reaction is violent.(13)

Fire Fighting Instructions:
Evacuate area and fight fire from a safe distance or a protected location. Approach fire from upwind to avoid hazardous vapours and toxic decomposition products.
Stop leak before attempting to stop the fire. If the leak cannot be stopped, and if there is no risk to the surrounding area, let the fire burn itself out. If the flames are extinguished without stopping the leak, vapours could form explosive mixtures with air and reignite.
If possible, isolate materials not yet involved in the fire. Closed containers or tanks may explode in the heat of the fire. Move containers from fire area if this can be done without risk. Otherwise, keep fire- exposed tanks or containers cool by application of hose streams. Application of cooling streams should begin as soon as possible. If this is not possible, set up unmanned monitor nozzles and evacuate the area. Take care not to get water inside container.
Methyl isocyanate (MIC) can react violently with water and water-based fire extinguishers. For small fires, use dry chemical powder or carbon dioxide. Because of the hazards of MIC to personnel and the environment, it may be better to allow large fires to continue to burn, if there is no danger to the surrounding area.
Water can be used as a spray or fog to absorb heat and protect exposed material of structures. If a leak or spill has not ignited, use water spray in large quantities to disperse the vapours and to protect personnel attempting to stop a leak. However, proper care must be taken because of the violent reaction between water and MIC.
After the fire has been extinguished, the area should not be considered safe until a thorough inspection for residual isocyanate has been carried out by properly protected personnel.
MIC and its decomposition products, such as hydrogen cyanide and nitrogen oxides, are extremely hazardous to health. Do not enter without wearing specialized protective equipment suitable for the situation. Firefighter's normal protective clothing (Bunker Gear) will not provide adequate protection. A full-body encapsulating chemical resistant suit with positive pressure self-contained breathing apparatus (MSHA/NIOSH approved or equivalent) may be necessary.



NATIONAL FIRE PROTECTION ASSOCIATION (NFPA) HAZARD IDENTIFICATION

NFPA - Health: 4 - Very short exposure could cause death or major residual injury.
NFPA - Flammability: 3 - Liquids and solids that can be ignited under almost all ambient temperature conditions.
NFPA - Instability: 2 - Undergoes violent chemical change at elevated temperatures and pressures, or reacts violently with water, or may form explosive mixtures with water.
NFPA - Specific Hazards: Water-reactive.

SECTION 9. PHYSICAL AND CHEMICAL PROPERTIES

Molecular Weight: 57.05

Conversion Factor:
1 ppm = 2.33 mg/m3; 1 mg/m3 = 0.43 ppm at 25 deg C

Physical State: Liquid
Melting Point: -80 deg C (-112 deg F) (12); -45 deg C (-49 deg F) (27)
Boiling Point: 39 deg C (102 deg F) at 760 mm Hg (2)
Relative Density (Specific Gravity): 0.96 at 20 deg C (water = 1) (4)
Solubility in Water: Reacts with water.
Solubility in Other Liquids: Soluble in hydrocarbons, halogenated hydrocarbons and dimethyl sulfoxide. Decomposes in solvents containing an hydroxyl (-OH) group.(4)
Coefficient of Oil/Water Distribution (Partition Coefficient): Not applicable (reacts with water)
pH Value: Not applicable (reacts with water)
Vapour Density: 1.97 (air = 1)
Vapour Pressure: 46.4 kPa (348 mm Hg) at 20 deg C (2,27)
Saturation Vapour Concentration: Approx. 460,000 ppm or 46% at 20 deg C (calculated)
Evaporation Rate: 26.8 (butyl acetate = 1)
Critical Temperature: Not available

SECTION 10. STABILITY AND REACTIVITY

Stability:
Normally stable. It self-reacts at elevated temperatures to form trimers and polymers giving off carbon dioxide and heat.(28)

Hazardous Polymerization:
MIC may undergo uncontrolled exothermic trimerization and polymerization upon contact with incompatible materials, such as trialkyl phosphines, triphenylarsenic, potassium acetate and many metal compounds soluble in organic media, such as organotin compounds, or if heated.(28) The heat and products generated from this reaction can result in a pressure build-up in closed containers that is sometimes sufficient to rupture the container.

Incompatibility - Materials to Avoid:

NOTE: Chemical reactions that could result in a hazardous situation (e.g. generation of flammable or toxic chemicals, fire or detonation) are listed here. Many of these reactions can be done safely if specific control measures (e.g. cooling of the reaction) are in place. Although not intended to be complete, an overview of important reactions involving common chemicals is provided to assist in the development of safe work practices.


WATER - Reacts vigorously or violently, forming carbon dioxide gas and dimethylurea. The reaction may become progressively more vigorous at higher temperatures.(13,28) Closed containers can rupture explosively when contaminated with water.
STRONG OXIDIZING AGENTS - May react violently with the risk of fire and explosion.(13,27)
ALCOHOLS, ACIDS, BASES, AMINES - May react vigorously or violently with the generation of heat.(13,27)
IRON, STEEL, ZINC, TIN, COPPER (or salts of these metals) - may cause a violent reaction. (13,27)
CERTAIN CATALYSTS (e.g. triphenylarsenic oxide and tributyl tin oxide) - may cause a violent reaction. (28)

Hazardous Decomposition Products:
Methylamine (formed by reaction of MIC with water)

Conditions to Avoid:
Sparks, open flames, electrostatic discharge, heat, other ignition sources, moisture.

Corrosivity to Metals:
Attacks steel, iron, zinc, tin, copper and their alloys.(13,27)

Stability and Reactivity Comments:
Isocyanates are very reactive compounds and are especially highly reactive toward a large number of compounds with active hydrogens, particularly at high temperatures and in the presence of catalysts.(28) MIC attacks some forms of plastics, rubber and coatings. Fluorocarbon resins are resistant.(27) See reference 28 for some of the reactions of isocyanates.


SECTION 11. TOXICOLOGICAL INFORMATION

LC50 (rat): 5-17.5 ppm (4-hour exposure) (1,14)
LC50 (guinea pig): less than 5.2 ppm (4-hour exposure) (14)
LC50 (guinea pig): 6.6 ppm (4-hour exposure); cited as 5.4 ppm (6-hour exposure) (14)
LC50 (mouse): 14.9 ppm (4-hour exposure); cited as 12.2 ppm (6-hour exposure) (14)
Other LC50's with 2- and 6-hour exposure durations are similar when converted to 4-hour exposures.(1)

LD50 (oral, rat): 71 mg/kg (15); 140 mg/kg (16)
LD50 (oral, mouse): 120 mg/kg (16)

LD50 (dermal, rabbit): 211 mg/kg (cited as 0.22 mL/kg) (undiluted) (15); 1800 mg/kg (vehicle unknown) (16)

Eye Irritation:

Methyl isocyanate is corrosive and capable of causing permanent loss of sight.

Application of in excess of a 1% solution of methyl isocyanate cause corrosive injury in rabbits (scored over 5 where 5 is severe injury; graded 10/10).(15) Application of an unspecified volume of undiluted methyl isocyanate produced extensive injury to the conjunctiva and cornea in washed and unwashed rabbit eyes, resulting in a total loss of sight.(24)

Skin Irritation:

Methyl isocyanate is corrosive.

Application of 0.01 mL of undiluted methyl isocyanate produced tissue death (necrosis) in rabbits (graded 6/10). (15) Application of an unspecified volume of undiluted methyl isocyanate to the intact and abraded skin of rabbits, for an unspecified duration, resulted in severe irritation and tissue death (slight necrosis in intact skin; necrosis is abraded skin) following the first of 2 applications.(24) Application of an unspecified amount of undiluted methyl isocyanate to the earlap for 30 minutes caused redness and edema in rabbits, followed by tissue death (necrosis).(1 citing a report that is not available in English) There are no further details available.

Effects of Short-Term (Acute) Exposure:

Inhalation:
Damage to the respiratory tract and lungs is the most commonly observed effect. Deaths appear to be related to respiratory distress caused by severe lung damage, including pulmonary edema.(1) Single exposures to 2.4 ppm for 6 hours and 3 ppm for 2 hours caused minimal respiratory tract lesions in rats and mice.(1,5,17,18) Continued exposure at 3 ppm (6 hours on 4 consecutive days) resulted in severe injury and death in rats.(18) Respiratory difficulty was observed soon after exposure to concentrations as low as 5-10 ppm commenced.(1) In 2-hour studies, deaths occurred at 20-30 ppm, with few or no deaths at 10 ppm. Obstructive airway lesions were found in rats exposed to 10 ppm.(5) Deaths occurred within 10 minutes for guinea pigs and within a several hours for rats following exposure to very high concentrations (greater than 225 ppm for 15 minutes).(2) In addition to deaths observed immediately following exposure, a delayed or second phase of mortality has been observed in certain studies. Most deaths in the second phase are preceded by periods of respiratory distress more severe than those observed immediately following exposure.(2) Methyl isocyanate is a potent sensory and pulmonary irritant in mice and guinea pigs. The RD50 value (the concentration causing a 50% decrease in respiratory rate) in mice was 1.3 ppm for a 90 minute exposure (1,19) and 2.9 for a 30 minute exposure.(20) The RD50 value in mice is thought to be equivalent to an unbearable exposure level in humans. Fifteen and 22 ppm elicited an RD50 response in 3 and 2 minutes respectively which is approximately an intolerable concentration in humans.(20) There are mild alterations in hematology (increases in hemoglobin count, hematocrit, red blood cell count and decreases in lymphocyte count) following acute or repeated exposure. (1,2)

Skin Sensitization:
MIC is a powerful skin sensitizer in guinea pigs.
In a Landsteiner guinea pig test, positive reactions were observed 16/16 guinea pigs tested. A 0.01% solution (1/10th normal concentration) of methyl isocyanate in peanut oil was administered intradermally in 0.05 mL amounts for the initial and challenge doses and in 0.1 mL amount for the 7 sensitizing injections. The authors remarked that the sensitizing reaction was the highest scored of any chemical they had ever tested (234 at 24 hours/358 at 48 hours).(1,37,38) A single large dermal application of methyl isocyanate sensitized guinea pigs. One drop (about 0.06 mL) of undiluted methyl isocyanate was applied dermally to 9 animals. Three weeks later, an intradermal challenge produced a positive reaction in all 9 animals.(1,38) Guinea pigs (10/group) were exposed to methyl isocyanate with 5 animals receiving 9 applications of 5-25% on abraded skin during a 3-week induction period (Group 1) and the remainder receiving 2 intradermal injections of 1% in dimethyl phthalate 7 days apart (Group 2). All animals were then given a 14-day rest period followed by a challenge test, which produced positive reactions in 9/10 animals.(35) Positive responses were also observed in cross-sensitization studies with toluene diisocyanate and hexamethylene diisocyanate.(1)

Respiratory Sensitization:
Guinea pigs were exposed to 1 ppm MIC for 2 hours/day, 3 times/week for 3 weeks. After 3 weeks rest, no respiratory responses were seen when the animals were challenged with 1 or 5 ppm. An intradermal challenge produced a positive respiratory response in 11/19 animals.(1)

Carcinogenicity:
Rats and mice were exposed to 0, 1, 3 or 10 by inhalation for a single 2-hour period. Two years later, the rats were examined for carcinogenicity. This non-traditional study design was intended to replicate the Bhopal disaster. Two tumour types were seen at statistically significant levels in male rats, only, at the 3 and 10 ppm. The authors suggest that this experiment provides only very limited evidence of the carcinogenic potential of methyl isocyanate.(21)

Teratogenicity, Embryotoxicity and/or Fetotoxicity:
Methyl isocyanate does not appear to be teratogenic, but was embryotoxic in three studies. In one of the studies, maternal toxicity was not seen, but is expected to occur at the exposure concentrations used.
Pregnant mice (39-44/group) were exposed to 0, 1 or 3 ppm on days 14-17 of pregnancy (6 hr/d). There were no signs of maternal toxicity (survival, body weight, demeanor or gestational length) reported. However, it appears the evaluation of maternal toxicity was incomplete. The authors suggest that the dose-response curve is quite steep and that 3 ppm is close to lethal. A significant increase in the number of dead fetuses was observed at birth in animals exposed to both 1 and 3 ppm and in the mortality of pups through to lactation in animals exposed to 3 ppm.(22) Methyl isocyanate is a strong sensory irritant and harmful effects are expected to occur at concentrations as low as 1 ppm. In another study, pregnant mice (11-18/exposure group) were exposed once for 3 hours to 2-15 ppm on day 8 of pregnancy. There were clear signs of maternal toxicity at 9 and 15 ppm (2 deaths/group). The main effect was a concentration-dependent increase in embryo loss; at 9 and 15 ppm more than 75% of the animals lost all of their fetuses. A statistically significant decrease in fetal weight was observed at all concentrations. There is insufficient information available to assess maternal toxicity at the lower exposure concentrations.(23) The embryotoxic effects were confirmed in mice exposed to 9 ppm for 3 hours on day 8 of pregnancy (loss of all embryos in 70% of the animals) and in rats exposed to 9 ppm for 3 hours on day 10 or pregnancy. These effects were observed in the presence of maternal toxicity.(24)

Reproductive Toxicity:
No effect on reproduction was seen in mice in a mating trial in which both sexes were treated prior to mating and in a dominant lethal study where male mice were exposed to 1 or 3 ppm for 4 consecutive days (6 hr/d).(22)

Mutagenicity:
Positive results have been obtained in tests using live animals. Therefore, methyl isocyanate is considered mutagenic.
Male mice were exposed to 3, 10 and 30 ppm methyl isocyanate for a single 2-hour exposure, in two experiments. In the same study, male and female mice were exposed to 1 or 3 ppm in 3 experiments, or to 1, 3 or 6 ppm in one experiment, for 4 consecutive days (6 h/d). Negative results were obtained for chromosomal aberrations, micronuclei and sister chromatid exchanges in animals exposed for 2-hours, but significant delays in cell proliferation were observed. In the 4-day experiments, significant increases were observed for sister chromatid exchanges in mice exposed to 1 or 3 ppm (males in Experiment I and females in Experiment III) and in females exposed to 1, 3 or 6 ppm. Significant increases were also observed for chromosomal aberrations in mice exposed to 1, 3 or 6 ppm and in female mice exposed to 1 or 3 ppm (Experiment II). Significant delays in cell proliferation were observed in males in all experiments and in females exposed to 1, 3 or 6 ppm. Positive results were obtained for micronuclei in male mice exposed to 1, 3 or 6 ppm.(25) In a satellite experiment to a larger study, mice were exposed to 1 or 3 ppm methyl isocyanate for 4 consecutive days (6 hr/d). Peripheral blood lymphocytes (PBL) from males and lung cells from females were analyzed. Another experimental group of mice were exposed to 3 or 6 ppm methyl isocyanate for 4 consecutive days (6 hr/d). PBLs and lung cells were to be analyzed for both males and females. Females (4-5/group) exposed to 1, 3 or 6 ppm showed a statistically significant increase in sister chromatid exchange (SCE) frequencies in their lung cells. Within a week after exposure to 6 ppm, greater than 80% of the animals in the main experiment had died. None of the exposed male mice showed significant increases in SCE frequencies in their PBLs. However, cultures from only 2/5 males exposed to 6 ppm could be analyzed. In addition, due to an experimental problem (incubator failure), SCEs could not be scored in the lung cells of male mice or PBLs from female mice.(36) Negative results were obtained in a dominant lethality study using mice.(22)
Methyl isocyanate gave negative results in 5 strains of Salmonella typhimurium, both with and without metabolic activation (Ames test).(1,3,4) Positive results were obtained in three cultured mammalian cell tests, both with and without metabolic activation.(1,3,4).
Methyl isocyanate gave negative results in the Drosophila sex-linked recessive lethal test.(1,3,4)


SECTION 16. OTHER INFORMATION

Selected Bibliography:
(1) Dodd, D.E. Toxicology of methyl isocyanate. Reviews of Environmental Contamination and Toxicology. Vol. 105 (1988). p. 71-98
(2) Bucher, J.R. Methyl isocyanate: a review of health effects research since Bhopal. Fundamental and Applied Toxicology. Vol. 9, no. 3 (Oct. 1987). p. 367-379.
(3) Bucher, J.R. The toxicity of methyl isocyanate: where do we stand? Environmental Health Perspectives. Vol. 72 (June 1987). p. 197-198
(4) Methyl isocyanate. In: Documentation of the threshold limit values and biological exposure indices. 6th ed. Vol. II. ACGIH, 1991. p. 1022-1024
(5) Mehta, P.S., et al. Bhopal tragedy's health effects: a review of methyl isocyanate toxicity. Journal of the American Medical Association. Vol. 264, no. 21 (Dec. 5, 1990). p. 2781-2787
(6) Grant, W.M., et al. Toxicology of the eye. 4th ed. Charles C. Thomas, 1993. p. 982-984
(7) Karol, M.H. Respiratory effects of inhaled isocyanates. CRC Critical Reviews in Toxicology. Vol. 16, no. 4 (1986). p. 349-379
(8) Musk, A.W., et al. Isocyanates and respiratory disease: current status. American Journal of Industrial Medicine. Vol. 13, no. 3 (1988). p. 331-349
(9) Varma, D.R. Pregnancy complications in Bhopal women exposed to methyl isocyanate vapor. Journal of Environmental Science and Health. Part A: Environmental Science and Engineering. Vol. A26, no. 8 (1991). p. 1437- 1447
(10) Goswami, H.K., et al. Search for chromosomal variations among gas- exposed persons in Bhopal. Human Genetics. Vol. 84 (1990). p. 172-176
(11) Ferguson, J.S., et al. Uptake and distribution of 14C during and fol- lowing exposure to [14C]methyl isocyanate. Toxicology and Applied Pharmacology. Vol. 94, no. 1 (June 15, 1988). p. 104-117
(12) Fire protection guide to hazardous materials. 13th ed. Edited by A.B. Spencer, et al. National Fire Protection Association, 2002. NFPA 325; NFPA 49
(13) Chemical safety sheets: working safely with hazardous chemicals. Kluwer Academic Publishers, 1991. p. 606
(14) Dodd, D.E., et al. Acute inhalation studies with methyl isocyanate vapour. I. Methodology and LC50 determinations in guinea pigs, rats, and mice. Fundamental and Applied Toxicology. Vol. 6, no. 4 (May 1986). p. 747-755
(15) Smyth, H.F., Jr., et al. Range-finding toxicity data: list VII. American Industrial Hygiene Association Journal. Vol. 30, no. 5 (Sept.-Oct. 1969). p. 470-476
(16) Vernot, E.H., et al. Acute toxicity and skin corrosion data for some organic and inorganic compounds and aqueous solutions. Toxicology and Applied Pharmacology. Vol. 42, no. 2 (Nov. 1977). p. 417-423
(17) Fowler, E.H., et al. Acute inhalation studies with methyl isocyanate vapour. II. Respiratory tract changes in guinea pigs, rats and mice. Fundamental and Applied Toxicology. Vol. 6, no. 4 (May 1986). p. 756-771
(18) Bucher, J.R., et al. The toxicity of inhaled methyl isocyanate in F344/N rats and B6C3F1 mice. II. Repeated exposure and recovery studies. Environmental Health Perspectives. Vol. 72 (June, 1987). p. 133-138
(19) Ferguson, J.S., et al. Sensory and pulmonary irritation with exposure to methyl isocyanate. Toxicology and Applied Pharmacology. Vol. 82, no.2 (Feb. 1986). p. 329-335
(20) James, J.T., et al. Sensory irritation of methylisocyanate vapor. Journal of Applied Toxicology. Vol. 7, no. 2 (Apr. 1987). p. 147-148
(21) Bucher, J.R., et al. Carcinogenicity and pulmonary pathology associated with a single 2-hour inhalation exposure of laboratory rodents to methyl isocyanate. (Letter). Journal of the National Cancer Institute. Vol. 81, no. 20 (Oct. 18, 1989). p. 1586-1587
(22) Schwetz, B.A., et al. Methyl isocyanate: reproductive and developmental toxicology studies in Swiss mice. Environmental Health Perspectives. Vol. 72 (June 1987). p. 149-152
(23) Varma, D.R., et al. Epidemiological and experimental studies on the effects of methyl isocyanate on the course of pregnancy. Environmental Health Perspectives. Vol. 72 (June 1987). p. 153-157
(24) Varma, D.R., et al. Dissociation between maternal and fetal toxicity of methyl isocyanatein mice and rats. Journal of Toxicology and Environmental Health. Vol. 30 (1990). p. 1-14
(25) Tice, R.R., et al. Methyl isocyanate: an evaluation of in vivo cytogenetic activity. Environmental Mutagenesis. Vol. 9 (1987). p. 37-58
(26) Odor thresholds for chemicals with established occupational health standards. American Industrial Hygiene Association, 1989. p. 24, 68
(27) HSDB record for methyl isocyanate. Date of last update: 9308
(28) Kirk-Othmer encyclopedia of chemical technology. rd.edition. Vol. 13. John Wiley and Sons, 1981. p. 789-818
(29) NIOSH pocket guide to chemical hazards. NIOSH, June 1994. p. 212-213
(30) Berardinelli, S.P. et al. Methyl isocyanate liquid and vapor permeation through selected respirator diaphragms and chemical protective clothing. American Industrial Hygiene Association Journal. Vol. 48, no. 4 (1987). p. 324-329
(31) Forsberg, K., et al. Quick selection guide to chemical protective clothing. 4th ed. Van Nostrand Reinhold, 2002
(32) European Economic Community. Commission Directive 93/72/EEC. Sept. 1, 1993
(33) Emergency response planning guidelines for methyl isocyanate. American Industrial Hygiene Association, 1996
(34) Results of range finding toxicological tests on methyl isocyanate with cover letter and attachments (Sanitized). Dow Chemicals Co. Date produced: n.d. EPA/OTS 86-910000361S. NTIS/OTS0530132.
(35) Initial submission: Dermal irritation and sensitization tests of methyl isocyanate in guinea pigs with cover letter dated 101592. Dupont Chemicals. Date produced: Sept. 1968. EPA/OTS 88-920009582. NTIS/OTS0571239.
(36) Kligerman, A.D., et al. Sister chromatid exchange analysis in lung and peripheral blood lymphocytes of mice exposed to methyl isocyanate by inhalation. Environmental Mutagenesis. Vol. 9 (1987). p. 29-36
(37) Mellon Institute. Range finding tests on methyl isocyanate with cover sheets and letter dated 012591 (Declassified). Date produced: Sept. 1963. Rhone-Poulenc. EPA/OTS 86-910000658D. NTIS/OTS0529151.
(38) Mellon Institute. Acute inhalation toxicity, human response to low concentrations, guinea pig sensitization, and cross sensitization to other isocyanates with cover sheets and letter dated 120790. Date produced: May 1970. Rhone-Poulenc. EPA/OTS 86-910000268. NTIS/OTS0528500.

Information on chemicals reviewed in the CHEMINFO database is drawn from a number of publicly available sources. A list of general references used to compile CHEMINFO records is available in the database Help.


Review/Preparation Date: 1995-05-04

Revision Indicators:
EU class 1995-10-01
EU risk 1995-10-01
EU safety 1995-10-01
Sampling 1995-10-01
Respiratory guidelines 1995-10-01
ERPG 1996-09-01
US transport 1998-03-01
Resistance of materials 1998-06-01
Extinguishing media 2003-04-14
WHMIS disclosure list 2003-07-08
Bibliography 2003-09-19
Long-term exposure 2003-09-19
PEL transitional comments 2003-11-06
PEL-TWA final 2003-11-06
PEL final comments 2003-11-06
Toxicological info 2004-01-06
Short-term skin contact 2004-01-06
Short-term eye contact 2004-01-06
Short-term ingestion 2004-01-06
Teratogenicity/embryotoxicity 2004-01-06
Reproductive toxicity 2004-01-06
WHMIS detailed classification 2004-01-06
WHMIS proposed classification 2004-01-06
WHMIS health effects 2004-01-06
Emergency overview 2004-01-06
First aid inhalation 2004-01-06
First aid skin 2004-01-06
First aid eye 2004-01-06
First aid ingestion 2004-01-06
First aid comments 2004-01-06
Handling 2004-01-10
Engineering controls 2004-01-10
Handling 2004-01-10
Resistance of materials for PPE 2004-03-29
ERPG-2 2005-07-01
ERPG-3 2005-07-01



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