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SECTION 1. CHEMICAL IDENTIFICATION

CHEMINFO Record Number: 650
CCOHS Chemical Name: Chloroform

Synonyms:
Formyl trichloride
Methane trichloride
Methenyl trichloride
Methyl trichloride
Trichloroform
Trichloromethane

Chemical Name French: Chloroforme
Chemical Name Spanish: Cloroformo
CAS Registry Number: 67-66-3
UN/NA Number(s): 1888
RTECS Number(s): FS9100000
EU EINECS/ELINCS Number: 200-663-8
Chemical Family: Halogenated aliphatic hydrocarbon / saturated halogenated hydrocarbon / halocarbon / halogenated alkane / haloalkane / haloform / trihaloalkane / chloroalkane / trichloroalkane / chlorinated methane
Molecular Formula: C-H-Cl3
Structural Formula: CHCl3

SECTION 2. DESCRIPTION

Appearance and Odour:
Clear, colourless liquid with a characteristic pleasant, sweet, ethereal odour.(28,29)

Odour Threshold:
A wide range of values have been reported; 0.6 to 1413 ppm. The range of acceptable values is 133 to 276 ppm (geometric mean air odour threshold: 192 ppm) (detection).(30)

Warning Properties:
POOR - odour threshold is above the TLV.

Composition/Purity:
Chloroform is available commercially in a number of grades and typically has a purity above 99%.(31) Impurities include other halogenated hydrocarbons, such as dichloromethane, bromochloromethane, bromodichloromethane, bromodichloroethane, carbon tetrachloride, dichloroethane, 1,2- dichloroethylene, trichloroethylene, tetrachloroethane and vinylidene chloride.(7,28) Stabilizers are added to prevent oxidation by air and light, and to prevent chloroform from becoming acidic and corrosive. The most common stabilizer used is 50 ppm 2-methyl-2-butene. Others include ethanol (0.5-1.0%), amylenes (0.006%), industrial methylated spirits (0.2%), methanol, thymol, t-butylphenol and n-octylphenol.(3,28)

Uses and Occurrences:
It is mainly used (about 90%) as a starting material in the production of chlorodifluoromethane (fluorocarbon 22) which is used as a refrigerant, aerosol propellant, and as a starting material in the production of polytetrafluoroethylene (PTFE) plastics. Other uses include extraction and purification of penicillin, alkaloids, vitamins and flavours, as an intermediate in the preparation of dyes and pesticides, in fire extinguishers, and as a fumigant and insecticide. Due to its toxicity, many of the historical uses of chloroform (e.g. as an anesthetic and its use in some pharmaceuticals, toothpastes, cosmetics, and food packaging products) are banned or have been discontinued.(7,28,32)


SECTION 3. HAZARDS IDENTIFICATION

EMERGENCY OVERVIEW:
Clear, colourless liquid with a characteristic pleasant, sweet, ethereal odour. Will not burn. Can decompose at high temperatures forming toxic and corrosive gases such as phosgene, hydrogen chloride and chlorine. Closed containers may rupture and explode if heated, releasing toxic gases or vapours. TOXIC. Can accumulate in low lying areas. Can be harmful if inhaled or swallowed. Central nervous system depressant. Vapour may cause headache, nausea, dizziness, drowsiness, incoordination, and confusion. May cause liver and kidney damage, based on animal information. Causes skin and eye irritation. Aspiration hazard. Swallowing or vomiting of the liquid may result in aspiration (breathing) into the lungs. POSSIBLE CANCER HAZARD - may cause cancer, based on animal information.



POTENTIAL HEALTH EFFECTS

Effects of Short-Term (Acute) Exposure

Inhalation:
Chloroform easily forms very high vapour concentrations and poses a high inhalation hazard, especially in poorly ventilated areas. No immediate symptoms were experienced by volunteers exposed to 160 or 205 ppm for less than 30 minutes. Harmful effects on the central nervous system (CNS) (mainly dizziness) were experienced after 3 minutes exposure to 920 ppm and sooner at higher exposure levels.(1)
Harmful effects on the liver and kidneys, and some deaths, have been reported from historical use of chloroform as an anesthetic agent, at concentrations between 8000 and 20000 ppm.(1,2) Liver and kidney effects have also been observed in animal studies following exposure to low airborne concentrations.

Skin Contact:
Contact with the liquid can cause severe irritation, based on human and animal information. Prolonged exposure may result in corrosive effects (blisters, burns and scarring). A burning and prickling sensation was experienced after 3 minutes and redness and irritation occurred following application of undiluted chloroform to the uninjured skin of five volunteers for 3-6 minutes. Small blisters were observed five hours later.(1)
Chloroform can be absorbed through the skin, based on animal information.(1,3)

Eye Contact:
Chloroform liquid can cause serious eye damage, based on animal information. Permanent injury including blindness could result. The severity of the effect depends on several factors including the amount of chloroform entering the eye and the duration of contact. No human information was located. For airborne chloroform, no human or animal information was located.

Ingestion:
Chloroform can cause irritation of the stomach and intestines, central nervous system (CNS) depression with symptoms such as nausea, vomiting, dizziness and incoordination and liver and kidney damage, based on human and animal information. Vomiting, irregular heart beat, effects on the CNS and harmful effects on the liver and kidneys were observed in a person who accidentally ingested approximately 2410 mg/kg.(2) Liver damage, sometimes resulting in death, has occurred following non-occupational ingestion of chloroform.(2)
Chloroform can probably be aspirated, based on its physical properties. Aspiration is the inhalation of the chemical into the lungs during ingestion or vomiting. Severe lung irritation, damage to the lung tissues and death may result.
Ingestion is not a typical route of occupational exposure.

Effects of Long-Term (Chronic) Exposure

The evidence is limited but studies of employees with long-term exposure to chloroform suggests that it can cause harmful effects on the liver, kidneys and central nervous system (CNS).

Nervous System:
Symptoms of CNS depression and indigestion were also experienced in 17/68 employees exposed regularly to airborne concentrations of 2-218 ppm chloroform for 1-4 years. Other solvents were also present, but in small amounts.(4)
Symptoms of CNS depression, as well as indigestion, were reported following the exposure of a small number of employees to 23-71 ppm chloroform for 4 hours/day for an average of 15 months.(5)
Evidence of harmful effects on the CNS was observed in an individual exposed to an airborne concentrations of approximately 725-758 ppm for periods of about 45 minutes, twice a week for 3 or 4 weeks. This individual was also exposed to other potentially harmful chemicals at the same time.(6)

Kidneys/Urinary System:
Frequent urination and a burning sensation upon urination were reported following the exposure of a small number of employees to 23-71 ppm chloroform for 4 hours/day for an average of 15 months.(5)
Evidence of harmful effects on the kidneys was observed in an individual exposed to an airborne concentrations of approximately 725-758 ppm for periods of about 45 minutes, twice a week for 3 or 4 weeks. This individual was also exposed to other potentially harmful chemicals at the same time.(6)

Liver:
In one study, jaundice was observed in 31 employees exposed to chloroform for 5 months or less. Symptoms included lack of appetite, nausea and vomiting. Concentrations of at least 400 ppm were present in one plant, based on limited air sampling. In the second plant, no conclusions can be drawn about exposure levels, since air sampling was not conducted until 1 year later.(1)
Liver enlargement was observed in 17/68 employees exposed regularly to airborne concentrations of 2-218 ppm chloroform for 1-4 years. An increased incidence of viral hepatitis with jaundice was also observed. Other solvents were also present, but in small amounts.(4)
Evidence of harmful effects on the liver was observed in an individual exposed to an airborne concentrations of approximately 725-758 ppm for periods of about 45 minutes, twice a week for 3 or 4 weeks. This individual was also exposed to other potentially harmful chemicals at the same time.(6)

NOTE: The above studies are limited by factors such as the small number of people studied, incomplete exposure information and possible exposure to other potentially harmful chemicals at the same time. Nevertheless, the findings are consistent with observations made in animal studies.

Carcinogenicity:

Chloroform is possibly carcinogenic to humans, based on animal evidence.
There have been numerous human population studies which have examined the possible association of exposure to chlorinated drinking water (chloroform is a by-product) and risk of cancer, especially cancer of the urinary bladder and rectum, and possibly the colon. Evaluation of these studies suggests there may be a mild excess in cancer related to consumption of chlorinated drinking water. However, it cannot be concluded that chloroform is the chemical responsible because of lack of control for other possible causes, as well as the use of surrogate indicators for exposure to chloroform.(2,8) No firm conclusions can be drawn from the limited studies available which have examined the relationship between occupational exposures to chloroform and cancer.(3,8) The International Agency for Research on Cancer (IARC) has determined that there is inadequate evidence for the carcinogenicity of chloroform to humans. There is sufficient evidence for the carcinogenicity of chloroform to experimental animals.(8)

The International Agency for Research on Cancer (IARC) has concluded that this chemical is possibly carcinogenic to humans (Group 2B).

The American Conference of Governmental Industrial Hygienists (ACGIH) has designated this chemical as an animal carcinogen (A3).

The US National Toxicology Program (NTP) has listed this chemical as reasonably anticipated to be a human carcinogen.

Teratogenicity and Embryotoxicity:
In a human population study, it was reported that there was a weak association between women working with chloroform in a laboratory and miscarriage (odds ratio 2.3). This study is limited by factors such as self-reporting biases, a lack of exposure information and concurrent exposure to other chemicals.(46) A few studies have investigated the potential association between chloroform in drinking water and developmental effects. It is difficult to draw conclusions from these studies due to the fact that chloroform is one of many water disinfection by-products. Chloroform is teratogenic, fetotoxic and embryotoxic in animals at exposure levels causing significant toxicity in the mothers.

Reproductive Toxicity:
No conclusions can be drawn from a report of two cases of harmful effects (toxemia) during pregnancy in women with occupational exposure to chloroform, since there was exposure to other solvents at the same time.(1) Two animal studies did not show effects on fertility. In the one study that did show effects, there was other significant toxicity in the animals.

Mutagenicity:
There is insufficient information available to conclude that chloroform is mutagenic. A large number of mutagenicity tests have been conducted using chloroform showing both positive and negative results. Experiments that have shown positive results in tests using live animals exposed by relevant routes of exposure have limitations. There no information available from people occupationally exposed to chloroform.

Toxicologically Synergistic Materials:
The toxicity of chloroform can be increased by alcohols.(10) The liver toxicity of chloroform is increased by corn oil.(41)

Potential for Accumulation:
Chloroform is rapidly absorbed by inhalation, dermal and oral routes of exposure, and distributed to all body tissues, particularly body fat, blood, liver, kidneys and the nervous system. Placental transfer has been shown in animal and human studies. Chloroform can be stored temporarily in all tissues of the body, but once exposure stops, it is eliminated relatively quickly (within several days in rats). Some chloroform is metabolized to trichloromethanol, which spontaneously decomposes to phosgene, which in turn is converted to carbon dioxide, hydrochloric acid and other products. Absorbed chloroform is mainly eliminated unchanged or as carbon dioxide in the expired air. Small amounts are eliminated (2-11%) as metabolites in the urine and feces. The fraction of the amount eliminated as carbon dioxide varies with the dose and the species.(1,2,3)


SECTION 4. FIRST AID MEASURES

Inhalation:
This chemical is toxic and carcinogenic. Take proper precautions to ensure your own safety before attempting rescue (e.g. wear appropriate protective equipment, use the buddy system). Remove source of contamination or move victim to fresh air. If breathing has stopped, trained personnel should begin artificial respiration (AR) or, if the heart has stopped, cardiopulmonary resuscitation (CPR) or automated external defibrillation (AED) immediately. Immediately obtain medical attention.

Skin Contact:
Avoid direct contact with this chemical. Wear chemical protective clothing, if necessary. As quickly as possible, remove contaminated clothing, shoes and leather goods (e.g. watchbands, belts). Immediately flush with lukewarm, gently flowing water for 15-20 minutes. Immediately obtain medical attention immediately. Completely decontaminate clothing, shoes and leather goods before re-use or discard.

Eye Contact:
Avoid direct contact. Wear chemical resistant gloves, if necessary. Immediately flush the contaminated eye(s) with lukewarm, gently flowing water for 15-20 minutes. If a contact lens is present, DO NOT delay irrigation or attempt to remove the lens. Take care not to rinse contaminated water into the unaffected eye or onto the face. Immediately obtain medical attention.

Ingestion:
NEVER give anything by mouth if victim is rapidly losing consciousness, is unconscious or convulsing. Have victim rinse mouth thoroughly with water. DO NOT INDUCE VOMITING. Have victim drink 60 to 240 mL (2 to 8 oz) of water. If vomiting occurs naturally, have victim rinse mouth with water again. If breathing has stopped, trained personnel should begin artificial respiration (AR) or, if the heart has stopped, cardiopulmonary resuscitation (CPR) or automated external defibrillation (AED) immediately. Immediately obtain medical attention.

First Aid Comments:
Provide general supportive measures (comfort, warmth, rest).
Consult a doctor and/or the nearest Poison Control Centre for all exposures except minor instances of inhalation or skin contact.
All first aid procedures should be periodically reviewed by a doctor familiar with the material and its conditions of use in the workplace.

Note to Physicians:
Chloroform may cause liver or kidney damage.



SECTION 5. FIRE FIGHTING MEASURES

Flash Point:
None measured by conventional test methods. Not combustible (does not burn).(2,33)

Lower Flammable (Explosive) Limit (LFL/LEL):
Not applicable

Upper Flammable (Explosive) Limit (UFL/UEL):
Not applicable

Autoignition (Ignition) Temperature:
Not applicable; chemicals formed during decomposition may ignite above 1000 deg C (above 1832 deg F).

Sensitivity to Mechanical Impact:
Not sensitive. Stable material.

Sensitivity to Static Charge:
Chloroform will not be ignited by a static discharge because it does not burn. The reported electrical conductivity of chloroform is less than 10(4) pS/m to less than 2 X 10(6) pS/m at 25 deg C.(34,35)

Combustion and Thermal Decomposition Products:
Phosgene, chlorine, hydrogen chloride gases and other toxic and irritating compounds.(29,36)

Fire Hazard Summary:
Chloroform does not burn. It is stable at temperatures up to 290 deg C.(3) At higher temperatures, chloroform vapour decomposes forming toxic and/or corrosive phosgene, chlorine, hydrogen chloride and tetrachloroethylene. Closed containers may explode if exposed to excess heat for a sufficient period of time releasing large quantities of toxic gases or vapours.

Extinguishing Media:
Chloroform is not combustible. Use extinguishing media suitable for surrounding fire.(36)

Fire Fighting Instructions:
If a fire occurs in the vicinity of containers of chloroform, evacuate area and fight fire from a safe distance or a protected location. Approach fire from upwind to avoid toxic decomposition products.
If possible, isolate materials not yet involved in the fire, move containers from the fire area if this can be done without risk, and protect personnel. Otherwise, fire-exposed containers or tanks should be cooled by application of water spray. Application should begin as soon as possible and should concentrate on any unwetted portions of the container. Apply water from the side and from a safe distance until well after the fire is out.
Stay away from the ends of tanks involved in the fire, but be aware that flying material from ruptured tanks may travel in any direction. Withdraw immediately in case of rising sound from venting safety device or any discolouration of tank due to fire.
For a massive fire, it may be prudent to use unmanned hose holder or monitor nozzles.
Chloroform is a possible cancer hazard and its decomposition products are extremely toxic. 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 (NIOSH approved or equivalent) may be necessary.



NATIONAL FIRE PROTECTION ASSOCIATION (NFPA) HAZARD IDENTIFICATION

NFPA - Health: 2 - Intense or continued (but not chronic) exposure could cause temporary incapacitation or possible residual injury.
NFPA - Flammability: 0 - Will not burn under typical fire conditions.
NFPA - Instability: 0 - Normally stable, even under fire conditions, and not reactive with water.

SECTION 9. PHYSICAL AND CHEMICAL PROPERTIES

Molecular Weight: 119.38

Conversion Factor:
1 ppm = 4.87 mg/m3; 1 mg/m3 = 0.205 ppm at 25 deg C (calculated)

Physical State: Liquid
Melting Point: FREEZING POINT: -63.5 deg C (-82.3 deg F) (29,33,35)
Boiling Point: 61.3 deg C (142.3 deg F) (3,28,32)
Relative Density (Specific Gravity): 1.484 (3,35); 1.489 (32,33) at 20 deg C (water = 1); 1.481 at 25 deg C (water = 1) (28)
Solubility in Water: Slightly soluble (0.822 g/100 g at 20 deg C) (7,28,35)
Solubility in Other Liquids: Soluble in all proportions in the principal organic solvents, including ethanol, diethyl ether, acetone, benzene, carbon tetrachloride, carbon disulfide, petroleum ether and solvent naphtha, as well as fixed oils and volatile oils.(2,7,28)
Coefficient of Oil/Water Distribution (Partition Coefficient): Log P(oct) = 1.97 (2,3,38)
pH Value: Not available
Viscosity-Dynamic: 0.563 mPa.s (0.563 centipoise) at 20 deg C (28,31,33)
Viscosity-Kinematic: 0.379 m2/s (0.379 centistokes) at 20 deg C (calculated)
Saybolt Universal Viscosity: 26.8 Saybolt Universal Seconds at 37.8 deg C (100 deg F) (calculated)
Surface Tension: 27.14 mN/m (27.14 dynes/cm) at 20 deg C (28,32,33)
Vapour Density: 4.12 (air = 1) (33)
Vapour Pressure: 21.28 kPa (159.6 mm Hg) at 20 deg C (3,28,32); 26 kPa (195 mm Hg) at 25 deg C (33)
Saturation Vapour Concentration: 210,000 ppm (21%) at 20 deg C; 257,000 ppm (25.7%) at 25 deg C (calculated)
Evaporation Rate: 7.6 (n-butyl acetate = 1) (33); 11.6 (n-butyl acetate = 1) (31)
Critical Temperature: 263.4 deg C (506 deg F = 536.4 deg K) (3,28,35)

SECTION 10. STABILITY AND REACTIVITY

Stability:
Unstabilized chloroform slowly decomposes in sunlight or in the dark, in the presence of air, forming toxic and corrosive phosgene, hydrogen chloride and chlorine.(3,7,28,29)

Hazardous Polymerization:
Not reported

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.


STRONG BASES (e.g. sodium hydroxide, potassium hydroxide or sodium methoxide) - react vigorously, violently or explosively in the presence of a solvent like acetone or methanol.(37,39)
ALKALI METALS (e.g. lithium, potassium, sodium or sodium-potassium alloy) - form impact sensitive compounds, resulting in weak explosions with lithium, strong explosions with potassium and sodium, and violent explosions with sodium-potassium alloy.(37,39)
REACTIVE METAL POWDERS (e.g. aluminum, magnesium), FLUORINE, DINITROGEN TETROXIDE or NITROMETHANE - can react explosively.(37,39)
STRONG OXIDIZING AGENTS (e.g. chromic acid) - react to form highly toxic and corrosive phosgene and chlorine gases.(3,7,28)
POTASSIUM TERT-BUTOXIDE - ignition occurs on contact.(39)
DISILANE or TRIISOPROPYLPHOSPINE- react vigorously.(37,39)

Hazardous Decomposition Products:
Phosgene, hydrogen chloride and chlorine.

Conditions to Avoid:
Excessive heat, open flames, electrical arcs, welding arcs, sunlight, depletion of stabilizers.

Corrosivity to Metals:
Dry, stabilized chloroform is not corrosive to any of the common construction materials, such as cast iron, steel, stainless steel, aluminum, copper, bronze, brass, nickel and its alloys.(40) Dry, unstabilized chloroform reacts with aluminum and zinc at the rate of 250 micrometres (um)/year, and iron at 25 um/year. Wet, unstabilized chloroform reacts completely with aluminum, and attacks zinc at a rate of greater than 250 um/year and iron at less than 250 um/year.(28) It is also corrosive to steel and type 304 stainless steel, but the rate has not been reported.(40)

Stability and Reactivity Comments:
Chloroform decomposes on prolonged heating with water at 260 deg C forming formic acid, carbon monoxide and hydrochloric acid.(28)
Chloroform attacks some plastics, rubber and coatings.(29)


SECTION 11. TOXICOLOGICAL INFORMATION

LC50 (rat): 2265 ppm (4-hour exposure); cited as 1849 ppm (6-hour exposure) (1)
LC50 (mouse): 1540 ppm (4-hour exposure); cited as 1260 ppm (6-hour exposure) (1)

LD50 (oral, rat): 908 mg/kg (12)
LD50 (oral, young rat): 450 mg/kg (1)
LD50 (oral, male mouse): 36 mg/kg (13)
LD50 (oral, female mouse): 353 mg/kg (13)
NOTE: In reference 13 , chloroform was administered orally to several different strains of mice. The LD50 (oral) values ranged from 36 to 460 mg/kg for males and from 353 to 1366 mg/kg for females. The strain for which the lowest values were obtained (males and females) appears to be particularly susceptible to the effects of chloroform. Of 12 LD50 (oral, mouse) values obtained, only 1 value was below 50 mg/kg; 6 values ranged between 101 to 460 mg/kg and 5 values ranged from 679 to 1366 mg/kg.(13)

Eye Irritation:

Corrosive effects have been observed.

Severe irritation and corrosive injury was observed in 6/6 rabbits following application of undiluted chloroform in a Draize test (average score at 24, 48 and 72 hours: 41/110). Corneal opacity was still present 3 weeks after the test.(52) Slight irritation of the inner eyelids and slight, but definite, corneal damage was observed in another study. Effects cleared within one week.(14)

Skin Irritation:

Chloroform is a severe skin irritant. Corrosive effects have also been observed, but usually following prolonged contact (24-hour application).

Application of 0.5 mL, to intact skin for 24 hours, produced severe irritation in (average score at 24 and 72 hours: 5.2/8).(52) Severe irritation and corrosive effects (tissue death and blistering) were observed in rabbits after one or two 24-hour applications of a pad wetted with chloroform.(14) Moderate to severe redness and swelling with some tissue death were observed following application of undiluted chloroform for 24 hours.(1, unconfirmed) In a study designed to measure skin absorption, application of 350 microL of undiluted chloroform to the intact skin of hairless rats caused chemical burns when applied for 2 minutes or longer.(53) Application of 0.01 mL of undiluted chloroform produced mild irritation (graded 2/10).(15)

Effects of Short-Term (Acute) Exposure:

Short-term inhalation has produced liver injury in animals exposed to concentrations as low as 30 ppm for 5-6 hours and kidney injury in male mice exposed to 30 ppm for 7 days or 246 ppm for 2 hours. Higher concentrations have produced signs and symptoms of central nervous system (CNS) depression.(2,3)

Inhalation:
Temporary effects on the nasal passages have been observed in male rats and female mice, following inhalation of 10 ppm or higher for 4 days.(2,3,16) Harmful effects on the liver (death of liver cells) were observed after exposing mice to 800 ppm for 4 hours, or as low as 30 ppm for 5-6 hours.(1) Other liver effects have been observed in rats and mice following exposure to concentrations as low as 121 ppm for 4 hours or 103 ppm for 24 hours.(1,3,17) Harmful effects on the kidneys have been observed in male mice in a number of studies following inhalation of concentrations as low as 246 ppm for 2 hours or 30 ppm for 7 days.(2,3) Symptoms of CNS depression (including incoordination) were observed in rats following exposure to 16000 ppm for 10 minutes and in cats following exposure to 9000 ppm for 32 minutes.(1)

Skin Contact:
Corrosive skin effects and harmful effects on the kidneys were observed in rabbits following a 24-hour dermal exposures to 1000, 2000 or 4000 mg/kg, under a patch.(14)

Ingestion:
Dose-related effects on the liver and kidneys were observed in mice given oral doses ranging from 35 to 148 mg/kg/day for up to 14 days. Effects ranged from changes in enzyme levels and organ weights to degenerative cellular changes.(2,3,18) In most cases, the reversibility of these effects was not assessed. However, in one study, even fairly severe liver changes were reversible within 8 days.(2) Higher doses have also caused CNS depression, effects on body weight, harmful effects on the kidneys, liver and stomach, and deaths.(1,2,3,14,19,20)

Effects of Long-Term (Chronic) Exposure:

Inhalation:
Temporary harmful effects on the liver and kidneys were observed in rats exposed to airborne concentrations as low as 25 ppm for up to 6 months. Harmful effects on the liver and kidneys were also observed in rabbits and guinea pigs, but no dose-response relationship was observed. Reversibility of these effects was not evaluated. Pneumonia was observed in male rats exposed to 85 ppm and in male rabbits exposed to 50 ppm for 6 months.(2,14)

Ingestion:
Several studies have shown liver and/or kidney effects in rats and mice exposed to oral doses. Some studies have shown mild, reversible changes at doses up to 150 mg/kg/day for 90 days. Other studies have shown fatty changes, tissue death and increased organ weights at higher doses. Administration of chloroform with corn oil increases the liver toxicity of chloroform and some studies which used corn oil as a carrier have reported significant effects at less than 100 mg/kg/day. Another study reported cellular necrosis in the livers and kidneys of mice exposed to 86 mg/kg/day or 258 mg/kg/day for 52 weeks. However, statistical analysis of the data was not presented and reversibility of the effects was not evaluated.(1,2,41,42) Harmful effects on the lungs (inflammatory lesions) and thyroid gland have also been observed at higher doses.(1,3,21) Signs and symptoms of CNS depression were observed in mice and rats following oral administration of 20 to 400 mg/kg for 90 days.(3)

Carcinogenicity:
The International Agency for Research on Cancer (IARC) has concluded that there is sufficient evidence for the carcinogenicity of chloroform to experimental animals.(7,8) The American Conference of Governmental Industrial Hygienists (ACGIH) has designated chloroform as an A3 (animal carcinogen).
A number of studies have shown kidney and liver tumours in rats and mice following oral administration.(2,20-24) Kidney tumours have also been observed in male mice in one inhalation study, but only at the highest exposure level (90 ppm). Tumours were not observed in female mice or in rats of either sex.(16) There is evidence that these carcinogenic effects may be secondary to other significant toxic effects on the liver and kidneys and that the risk may vary considerably depending on which route of exposure is used.(1,3,16)

Teratogenicity, Embryotoxicity and/or Fetotoxicity:
Developmental effects have been observed in the presence of maternal toxicity in animals exposed by inhalation or ingestion.
A number of studies have shown fetotoxic (e.g. reduced body weight), embryotoxic (e.g. deaths) and/or teratogenic (e.g. skeletal malformations) effects in rats, mice and/or rabbits exposed by inhalation or ingestion to doses which also produced significant harmful effects in the mothers.(1,3) No harmful effects were observed in another oral study using mice.(1) No conclusions can be drawn from another study using rats and mice exposed by inhalation because no information was provided regarding maternal toxicity.(1)

Reproductive Toxicity:
Reduced fertility was observed in mice exposed to large oral doses. This effect was observed in the presence of significant other toxicity in the animals.
Harmful effects on fertility were not observed in mice orally exposed to up to 41 mg/kg/day for 1 week prior to cohabitation and for 14 weeks during cohabitation or to 31 mg/kg/day for 21 days prior to mating.(1,2) Harmful effects on fertility were observed in mice following ingestion of approximately 1000 (to 1250) mg/kg/day (cited as 5 mg/mL in drinking water) in a 3-generation study. These effects were observed in the presence of significant other toxicity.(3) In one study, harmful effects on the ovaries and testes (atrophy) were observed in rats following oral administration of 410 mg/kg/day for 13 weeks.(1) No conclusions can be drawn from two studies which evaluated sperm abnormalities due to high mortality and use of a non-relevant route of exposure.(1)

Mutagenicity:
There is insufficient information available to conclude that chloroform is mutagenic. A large number of mutagenicity tests have been conducted using chloroform showing both positive and negative results. Experiments that have shown positive results in tests using live animals exposed by relevant routes of exposure have limitations.
Changes in sperm head shape (morphological changes) were observed in spermatozoa following inhalation exposure of mice to chloroform for 5 days (4 hr/d).(25,49) Although changes in sperm head shape may be genetically determined, it is uncertain whether they are due to genotoxicity or to other toxic effects. Therefore, this effect cannot be taken as evidence of germ cell mutagenicity. Male rats (3/group) were orally exposed to 1.2, 12 or 119.4 mg/kg chloroform (analytical grade) for 5 days. There was a dose-related increase in chromosome aberrations, with statistical significance at 119.4 mg/kg.(26) This study is limited by small number of animals/group and the relatively high exposure level. Sister chromatid exchanges (SCEs) were induced in the bone marrow cells of male mice following oral exposure to 50, 100 or 200 mg/kg/day chloroform for 4 days. There was a dose-related response, but statistical evaluation of the data for chloroform is not clearly presented.(27) This study is limited by poor reporting and design deficiencies (a small number of cells were scored). Conclusions cannot be drawn from another non-standard test because the administered dose was very high and expected to produce significant other toxicity in the animals.(50) In another study, a low level of DNA binding was observed in male rats exposed to 47.8 mg/kg (cited as 0.4 mmol/kg) chloroform dissolved in corn oil.(51) This study is not considered sufficient evidence for classification of chloroform as a mutagen.
Positive and negative results have been obtained in studies using cultured mammalian cells, both with and without metabolic activation. Inconsistent results were obtained in yeast. However, overall, the studies are considered negative. Negative results were obtained in bacteria, both with or without metabolic activation.(1,3)
Negative results were obtained in fruit flies.(1,3)


SECTION 16. OTHER INFORMATION

Selected Bibliography:
(1) Meldrum, M. Chloroform. In: Health and Safety Executive. Part 1 carbon tetrachloride, part 2 chloroform. HMSO (U.K.), 1992
(2) Agency for Toxic Substances and Disease Registry. Toxicological profile for chloroform (update). US Department of Health and Human Services, Sept. 1997
(3) International Programme on Chemical Safety (IPCS). Chloroform. Environmental Health Criteria; 163. World Health Organization, 1994
(4) Bomski, H., et al. Toxic damage of the liver by chloroform in chemical industry workers. English translation. Internationales Archiv fur Gewerbepathologie und Gewerbehygiene. Vol. 24 (1967). p. 127-134 (NIOSHTIC Control Number: 00041982)
(5) Challen, P.J.R., et al. Chronic chloroform intoxication. British Journal of Industrial Medicine. Vol. 15 (1958). p. 243-249
(6) Belotti, L., et al. Acute hepatonephritis in a subject with occupational exposure to chloroform. English translation. Giornale Italiano di Medicina del Lavoro. Vol. 10 (1988). p. 73-75. (HSE Translation No. 13944 A)
(7) International Agency for Research on Cancer. Chloroform. In: IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Vol. 20. Some halogenated hydrocarbons. World Health Organization, Oct. 1979. p. 401-427
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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: 1998-03-26

Revision Indicators:
TLV comments 1998-08-01
ERPG 2001-03-01
Long-term exposure 2002-04-03
Carcinogenicity 2002-04-03
Saybolt Universal Viscosity 2002-04-03
Teratogenicity/embryotoxicity 2002-04-22
TDG 2002-05-15
WHMIS proposed classification 2002-06-11
TLV basis 2002-06-12
PEL transitional comments 2004-01-22
Resistance of materials for PPE 2004-04-09
Passive Sampling Devices 2005-04-02
Sampling/analysis 2005-04-02
WHMIS classification comments 2005-06-23
Mutagenicity 2005-06-23
WHMIS detailed classification 2005-06-23
WHMIS health effects 2005-06-23
Emergency overview 2005-06-23
Note to physicians 2005-06-23
Handling 2005-07-07
Bibliography 2006-02-22
Toxicological info 2006-03-01
Short-term skin contact 2006-03-01
Short-term eye contact 2006-03-01



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