NOTE: Although the toxicity values presented in these toxicity profiles were correct at the time they were produced, these values are subject to change. Users should always refer to the Toxicity Value Database for the current toxicity values.
Prepared by: Rosmarie A. Faust, Ph.D, Chemical Hazard Evaluation and Communication Group, Biomedical and Environmental Information Analysis Section, Health and Safety Research Division, *, Oak Ridge, Tennessee.
Prepared for: OAK RIDGE RESERVATION ENVIRONMENTAL RESTORATION PROGRAM.
*Managed by Martin Marietta Energy Systems, Inc., for the U.S. Department of Energy under Contract No. DE-AC05-84OR21400.
Chloroform is a colorless, volatile liquid that is widely used as a general solvent and as an intermediate in the production of refrigerants, plastics, and pharmaceuticals (Torkelson and Rowe, 1976; IARC, 1976). Chloroform is rapidly absorbed from the lungs and the gastrointestinal tract, and to some extent through the skin. It is extensively metabolized in the body, with carbon dioxide as the major end product. The primary sites of metabolism are the liver and kidneys. Excretion of chloroform occurs primarily via the lungs, either as unchanged chloroform or as carbon dioxide (ATSDR, 1989).
Target organs for chloroform toxicity are the liver, kidneys, and central nervous system. Liver effects (hepatomegaly, fatty liver, and hepatitis) were observed in individuals occupationally exposed to chloroform (Bomski et al., 1967). Several subchronic and chronic studies by the oral or inhalation routes of exposure documented hepatotoxic effects in rats, mice, and dogs (Palmer et al., 1979; Munson et al., 1979; Heywood et al., 1979). Renal effects were reported in rats and mice following oral and inhalation exposures (Roe et al., 1979; Reuber, 1976; Torkelson et al., 1976), but evidence for chloroform-induced renal toxicity in humans is sparse. Chloroform is a central nervous system depressant, inducing narcosis and anesthesia at high concentrations. Lower concentrations may cause irritability, lassitude, depression, gastrointestinal symptoms, and frequent and burning urination (ATSDR, 1989).
Developmental toxicity studies with rodents indicate that inhaled and orally administered chloroform is toxic to dams and fetuses. Possible teratogenic effects were reported in rats and mice exposed to chloroform by inhalation (Schwetz et al.; 1974; Murray et al., 1979). Chloroform may cause sperm abnormalities in mice and gonadal atrophy in rats (Palmer et al, 1979; Reuber, 1979; Land et al., 1981).
A Reference Dose (RfD) of 0.01 mg/kg/day for subchronic and chronic oral exposure was calculated from a lowest-observed-adverse-effect level (LOAEL) of 15 mg/kg/day based on fatty cyst formation in the liver of dogs exposed to chloroform for 7.5 years (Heywood et al., 1979). Development of an inhalation Reference Concentration (RfC) is presently under review (U.S. EPA, 1992b).
Epidemiological studies indicate a possible relationship between exposure to chloroform present in chlorinated drinking water and cancer of the bladder, large intestine, and rectum. Chloroform is one of several contaminants present in drinking water, but it has not been identified as the sole or primary cause of the excess cancer rate (ATSDR, 1989; U.S. EPA, 1985). In animal carcinogenicity studies, positive results included increased incidences of renal epithelial tumors in male rats, hepatocellular carcinomas in male and female mice, and kidney tumors in male mice (Jorgensen et al., 1985; Roe et al., 1979; NCI, 1976).
Based on U.S. EPA guidelines, chloroform was assigned to weight-of-evidence Group B2, probable human carcinogen, on the basis of an increased incidence of several tumor types in rats and in three strains of mice. The carcinogen slope factor (q1*) for chloroform is 6.1E-3 (mg/kg/day)-1 for oral exposure (U.S. EPA, 1992b) and 8.1E-2 (ug/m3)-1 for inhalation exposure (U.S. EPA, 1992a). An inhalation unit risk of 2.3E-5 (µg/m3)-1 is based on hepatocellular carcinomas in mice in an oral gavage study (U.S. EPA, 1992b).
Chloroform (CHCl3; CAS No. 67-66-3), also known as trichloromethane, is a colorless, volatile liquid with a pleasant ethereal odor (DeShon, 1979; IARC, 1979). It has a molecular weight of 119.38, a density of 1.485 g/cm3 at 20C (Hawley, 1981), and an octanol/water partition coefficient of 1.97 (Hansch and Leo, 1985). It is only slightly soluble in water, but is miscible with alcohol, benzene, ether, petroleum ether, carbon tetrachloride, carbon disulfide, and oils (Budavari et al., 1989). Chloroform is widely used as an intermediate in the production of refrigerants, plastics, and pharmaceuticals, and as a general solvent or constituent of solvent mixtures (Torkelson and Rowe, 1981; IARC, 1979). In the past, chloroform has been extensively used as a surgical anesthetic, but this use was discontinued because exposure to narcotic concentrations resulted in adverse side effects. The Food and Drug Administration has banned the use of chloroform as an ingredient in human drug and cosmetic products as of July, 1976 (U.S. FDA, 1976).
Human exposure to chloroform can occur orally, dermally, or by inhalation. Chloroform is the principal trihalomethane generated as by-products during the chlorination of drinking water. The primary sources of chloroform in the environment are chlorinated drinking water and wastewater, pulp and paper mills, and chemical and pharmaceutical manufacturing plants. Most of the chloroform released to the environment eventually enters the atmosphere, while much smaller amounts enter groundwater as a result of filtration through the soil (ATSDR, 1989).
Chloroform is rapidly absorbed through the lungs and the gastrointestinal tract, and to some extent through the skin (Torkelson and Rowe, 1981). In humans, the respiratory absorption of chloroform ranges from 49 to 77% (ATSDR, 1989) and absorption from the gastrointestinal tract approximates 100%, with peak blood levels being reached within 1 hour (Fry et al., 1972). Essentially complete oral absorption has also been reported in rats, mice, and monkeys (Brown et al., 1974; Taylor et al., 1974).
Following its absorption, chloroform is distributed to all organs (IARC, 1979). Humans exposed to chloroform by inhalation exhibited a three-component decrease of blood chloroform levels, with a rapid phase having a half-life of 14 min, a slower phase with a half-life of 90 min, and a very slow phase with an undetermined half-life (Fry et al., 1972). A number of studies have shown that chloroform accumulates in the body fat of humans and animals. It is lipid soluble, readily passes through cell membranes, reaching relatively high concentrations in nervous tissue. Chloroform concentrations in tissues are dose-related and occur in the following order: adipose > brain > liver > kidney > blood (ATSDR, 1989). Chloroform passes through the placenta and has been detected in fetal blood at levels equal to or greater than those in maternal blood (Dowty et al., 1976).
Chloroform is metabolized by oxidative dehydrochlorination of its carbon-hydrogen bond to form phosgene (CCl2O). The reaction is P450-mediated and occurs in both the liver and the kidney. The major end product of chloroform metabolism is carbon dioxide (CO2), most of which is eliminated via the lungs, but some is incorporated into endogenous metabolites and may be excreted as bicarbonate, urea, methionine and other amino acids, inorganic chloride ion, and carbon monoxide (ATSDR, 1989).
Fry et al. (1972) studied a group of volunteers who ingested 500 mg of 14C-labelled chloroform. More than 96% of the administered isotope was exhaled within 8 hours, 18-67% of which was excreted unchanged by this route; less than 1% appeared in urine. Lean subjects eliminated a greater percentage of the dose via the lungs than overweight subjects. The fraction reported metabolized to CO2 was 46% for a male and 58% for a female (Fry et al., 1972; Chiou, 1975). Rats, mice, and monkeys excreted 6, 20, and 78%, respectively, of an oral 60-mg/kg dose as unchanged parent compound in air (Torkelson and Rowe, 1981).
Chloroform is acutely toxic to the liver although damage may not be fully apparent until 12-48 hours after exposure. Liver effects include centrilobular necrosis and reduced prothrombin formation (ATSDR, 1989). Schroeder (1965) reported that a fatal oral dose of chloroform may be as little as 10 mL (14.8 g), with death due to respiratory or cardiac arrest. Gosselin et al. (1984) estimate that the mean lethal oral dose is 44 g for humans.
Oral LD50 values range from 444 to 2000 mg/kg for rats and from 118 to 1400 mg/kg for mice (U.S. Air Force, 1989). Torkelson et al. (1976) reported that 250 mg/kg of orally administered chloroform produced fatty infiltration and necrosis of the liver as well as kidney damage in rats. Liver and kidney damage was also reported in CD-1 mice treated daily for 14 days with 148 mg/kg chloroform in corn oil by gavage (Condie et al., 1983).
The long-term use of a dentrifice containing 3-4% chloroform and a mouthwash containing 0.43% chloroform was investigated in a study involving 299 subjects (DeSalva et al., 1975). Ingestion was estimated to be 0.3-0.96 mg/kg/day over a 1- to 5-year period. There were no statistical differences between experimental and control subjects in any of the parameters [alanine aminotransferase (ALT), aspartate aminotransferase (AST), and blood urea nitrogen] monitored as tests for liver and kidney function.
Chu et al. (1982) exposed Sprague-Dawley rats to 5, 50, 500, or 2500 ppm chloroform in drinking water for 90 days. Increased mortality, decreased growth rate, and decreased food intake were reported at the highest dose. Histological examination of treated animals showed mild to moderate fatty infiltration of the liver and reduction in follicular size and colloid density of the thyroid. These lesions were not significantly different from controls, with the exception of thyroid effects observed in the highest-dosed males.
Chloroform administered by gavage in toothpaste at a dose of 15, 30, 150, or 410 mg/kg/day, 6 days/week for 13 weeks to Sprague-Dawley rats produced increased liver weight and fatty changes with necrosis in the high-dose group. Increased liver weights were seen at 150 mg/kg/day, but no effects were seen at the lower doses (Palmer et al., 1979).
Munson et al. (1982) administered 0, 50, 125, or 250 mg/kg/day chloroform by gavage to male and female CD-1 mice for 90 days. Chloroform-treated male and female mice exhibited increased liver weights and slight histologic changes in liver and kidneys.
Liver effects were also observed in beagle dogs administered chloroform in gelatin capsules at doses ranging from 30 to 120 mg/kg/day for up to 18 weeks (Heywood et al., 1979). At >= 60 mg/kg/day, hepatocyte enlargement with vacuolization, fatty deposits of the liver, and increased ALT, AST, and serum alkaline phosphatase (SAP) activity were observed.
Hepatitis and kidney nephrosis were reported in a patient who had ingested a chloroform-containing cough-suppressant over a ten-year period. Chloroform intake was estimated at 1.6-2.6 g/day (Wallace, 1950). Although the investigator attributed the effects to chloroform, the patient had ingested moderate amounts of alcohol daily, a known liver toxicant, until about a year prior to the examination.
Palmer et al. (1979) administered 3.5% chloroform in toothpaste by gavage for 80 weeks to male and female Sprague-Dawley rats. Retardation in weight gain and decreases in relative liver weights were observed in female rats. Decreased plasma cholinesterase activity was observed in both sexes.
Reuber (1979) re-examined histological sections from an NCI (1976) carcinogenesis bioassay in which rats received 90 mg/kg/day chloroform by gavage for 78 weeks. Interstitial fibrosis of the kidneys, polyarteritis of the mesenteric, pancreatic, and other arteries, and testicular atrophy were observed in rats receiving this dose.
Roe et al. (1979) administered chloroform in toothpaste, by gavage, to mice at doses of 0, 17, or 60 mg/kg/day, 6 days/week for 80 weeks, followed by 16-24 weeks of observation. There was an increased incidence of moderate to severe renal disease and benign and malignant tumors in the group treated with 60 mg/kg/day. No adverse effects occurred in the lower-dose group.
Male and female beagle dogs were fed capsules containing 0, 15, or 30 mg/kg/day chloroform in a toothpaste base, 6 days/week for 7.5 years, followed by 20 to 24 weeks of observation (Heywood et al., 1979). Fatty cysts were found in the liver of all groups; however, they were larger and more numerous in chloroform-treated dogs. There was also a moderate dose-related increase in serum ALT activity and other serum enzymes, indicative of liver damage.
Information on the developmental and reproductive toxicity of chloroform following oral exposure in humans was unavailable.
Thompson et al. (1974) orally administered chloroform to rats (20, 50, or 126 mg/kg/day) and rabbits (20, 35, or 50 mg/kg/day) on gestation days 6-15 and 6-18, respectively. In rats, no adverse effects occurred at 20 mg/kg/day, but maternal toxicity, characterized by decreased body weight gain and mild fatty change in the liver, was evident at >= 50 mg/kg. Fetal body weights were significantly decreased at 126 mg/kg/day. In rabbits, maternal weight gain was decreased at 50 mg/kg, and mean fetal body weight was decreased at 20 and 50 mg/kg/day, but not at 35 mg/kg/day.
Testicular atrophy was one of the effects observed in SD rats administered chloroform at a dose of 410 mg/kg/day by gavage for 13 weeks (Palmer et al., 1979) and in Osborne-Mendel rats administered 90 mg/kg/day by gavage for 78 weeks (Reuber, 1979).
Chloroform is a central nervous system (CNS) depressant. Concentrations of 20,000 to 40,000 ppm were formerly used to induce anesthesia with lower concentrations used to maintain it. Delayed toxic effects observed after use as an anesthetic included drowsiness, restlessness, vomiting, fever, elevated pulse rate, jaundice, liver enlargement, abdominal tenderness, abnormal liver and kidney function, delirium, and coma. Chloroform may sensitize the heart to epinephrine, causing arrhythmias (ATSDR, 1989). In experimental human exposures to chloroform vapors, approximately 14,000-16,000 ppm caused narcosis. Dizziness, intracranial pressure, and nausea resulted after a 7-minute exposure to 1000 ppm, with fatigue and headache as after effects. A 30-minute exposure to 390 ppm caused no adverse effects (Torkelson and Rowe, 1981).
An inhalation LC50 of 10,000 ppm for rats exposed to chloroform for 4 hours was reported by Lundberg et al. (1986). Exposure to 2500 ppm for 2 hours caused no obvious CNS effects in mice; 3100 ppm for 1 hour induced slight narcosis; and 4000 ppm induced deep narcosis within 30 minutes. Cats exposed to 7200 ppm experienced disturbed equilibrium after 5 minutes and narcosis as exposure duration increased (U.S. EPA, 1985).
Nine of ten female individuals occupationally exposed for approximately 5 years to chloroform vapors at an average breathing zone concentration of 128 ppm experienced various symptoms, including irritability, lassitude, depression, gastrointestinal distress, and frequent and burning urination (Challen et al., 1958). Workers exposed to lower concentrations and shorter time periods experienced less severe symptoms. No evidence of liver injury was seen in either exposure group.
Workers at a pharmaceutical plant, where chloroform was used as the main solvent, were exposed to an estimated air concentration of 2-205 ppm of chloroform as well as to small amounts of other solvents (Bomski et al., 1967). Enlarged livers were seen in 17/68 workers exposed regularly to chloroform for 1-4 years and still in contact with chloroform; in 5/39 workers with past exposure to chloroform; in 2/23 with hepatitis but no exposure to chloroform (positive controls); and in 2/164 workers with no hepatitis and no exposure to chloroform. Of the 17 workers still exposed who had enlarged livers, 4 had toxic hepatitis (based on increased alanine aminotransferase, aspartate aminotransferase, and serum gamma globulin levels) and 14 had fatty degeneration of the liver. Also reported was a high incidence of enlargement of the spleen as well as complaints of headache, nausea, eructation, and loss of appetite.
Torkelson et al. (1976) exposed rats, rabbits, and guinea pigs to 0, 25, 50, or 85 ppm chloroform vapor, 7 hours/day, 5 days/week for 6 months. Dogs (1/sex) were similarly exposed to 25 ppm. Increased relative kidney weights, cloudy swelling of the renal tubular epithelium, and lobular, granular degeneration with necrosis of the liver were seen in male rats at all three exposure concentrations. Also seen in male rats were decreased body weights at 50 and 85 ppm, and increased relative liver weights at 85 ppm. In female rats at 25 ppm, there was only an increase in relative kidney weights. At 50 and 85 ppm, liver and kidney pathology was similar to that seen in males. Experiments with rabbits and guinea pigs gave inconsistent results. Histological lesions were observed in the liver and kidneys of rabbits and guinea pigs at 25 ppm but not at 50 ppm in either species. At 85 ppm, histological lesions were observed in rabbits but not in guinea pigs. Histological changes in the kidneys were seen in the female but not the male dog at 25 ppm.
Information on the chronic inhalation toxicity of chloroform in humans or animals was unavailable.
Information on the developmental and reproductive toxicity of chloroform following inhalation exposure in humans was unavailable.
Schwetz et al. (1974) exposed Sprague-Dawley rats to chloroform at concentrations of 0, 30, 100, or 300 ppm, 7 hours/day, on days 6-15 of gestation. Exposure to 30 ppm caused significantly increased incidences of fetal abnormalities, such as delayed skull ossification and wavy ribs compared with controls. At 100 ppm, there was a significantly increased incidence of missing ribs, short or missing tail, imperforate anus, subcutaneous edema, and delayed ossification of sternebrae. A decrease in pregnancy rate, number of live fetuses/litter, and an increased percentage of litters with absorptions was seen at 300 ppm. Subcutaneous edema and skull abnormalities were also observed, but their incidence was not statistically significant, possibly due to the small number of surviving fetuses. Decreased maternal weight gain occurred at all dose levels.
Murray et al. (1979) observed an increased incidence of cleft palate, decreased fetal body weight, and decreased crown to rump length in CF-1 mice exposed to 100 ppm on days 8-15 of gestation.
Male mice exposed to 0.04 or 0.08% (400 or 800 ppm) chloroform, 4 hours/day for 5 days exhibited a significant increase in the percentage of abnormal sperm (Land et al., 1981).
A subchronic or chronic reference concentration/dose for chloroform was not available at this time. However, a risk assessment for chloroform is under review by an EPA work group (U.S. EPA, 1992b).
Liquid chloroform in the eye causes tearing and conjunctivitis (Grant, 1974).
Dermal applications of 1000 mg/kg for 24 hours caused degenerative changes in kidney tubules of rabbits (Torkelson et al., 1976).
Information on the subchronic toxicity of chloroform by other routes of exposure in humans or animals was unavailable.
Information on the chronic toxicity of chloroform by other routes of exposure in humans or animals was unavailable.
Information on the developmental and reproductive toxicity of chloroform by other routes of exposure in humans or animals was unavailable.
Enlargement of the spleen was reported in humans occupationally exposed to chloroform.
Several epidemiological and case control studies of populations consuming chlorinated drinking water, containing chloroform as well as numerous other contaminants, showed small but significant increases in the incidence of cancer of the large intestine, rectum, and/or bladder. However, chloroform was not identified as the sole or primary cause for excess cancer (ATSDR, 1989). According to U.S. EPA (1985), the human data suggest a possible increased risk of cancer at these three sites because chloroform is the predominant trihalomethane in drinking water, but the data are too weak to draw a conclusion about the carcinogenic potential of chloroform.
In a carcinogenesis bioassay (NCI, 1976), Osborne-Mendel rats and B6C3F1 mice were treated by gavage with chloroform in corn oil 5 times/week for 78 weeks. Male rats received 90 or 125 mg/kg/day; females were treated initially with 125 or 250 mg/kg/day for 22 weeks, and then with 90 or 180 mg/kg/day thereafter. Male and female mice initially received 100 or 200 mg/kg/day and 200 or 400 mg/kg/day, respectively. These levels were increased after 18 weeks to 150 or 300 and 250 or 500 mg/kg/day, respectively. In male rats, there was a significant dose-related increase in the incidence of kidney epithelial tumors; in male and female mice, there was a significant dose-related increase of hepatocellular carcinomas.
Jorgensen et al. (1985) administered 0, 200, 400, 900, or 1800 ppm chloroform (pesticide quality and distilled) in drinking water to male Osborne-Mendel rats and female B6C3F1 mice for 104 weeks. In male rats, there was a significant (p < 0.01), dose-related increase in the incidence of renal tubular cell adenomas and/or adenocarcinomas that was slightly lower than that seen in the NCI (1976) study. However, in contrast to the NCI (1976) study, there was no increased incidence of hepatocellular tumors in female mice.
Roe et al. (1979) administered toothpaste containing chloroform (60 mg/kg/day, 6 days/week for 80 weeks, by gavage) to four strains of male mice. The incidence of kidney tumors was not increased in treated C57BL, CBA, or CF/1 mice. However, benign and malignant kidney tumors were seen in ICI mice.
According to IARC (1979), there is sufficient evidence that chloroform is carcinogenic in animals.
Information on the carcinogenicity of chloroform following inhalation exposure in humans or animals was unavailable.
U.S. EPA (1992b) reported negative results in pulmonary tumor bioassays in which two strains of mice were treated subcutaneously with chloroform.
Classification -- B2; probable human carcinogen
Basis -- Increased incidence of several tumor types in rats and three strains of mice (U.S. EPA, 1992b).
ATSDR (Agency for Toxic Substances and Disease Registry). 1989. Toxicological Profile for Chloroform. Prepared by Syracuse Research Corporation, under Contract 68-C8-0004. U.S. Public Health Service. ATSDR/TP-88/09.
Bomski, H., A. Sobolweska and A. Strakowski. 1967. Toxic damage to the liver by chloroform in chemical industry workers. Arch. Gewerbepathol. Gewerbehyg. 24: 127-134. (In German; cited in ATSDR, 1989; Torkelson and Rowe, 1981; IARC, 1979)
Brown, D.M., P.F. Langley, D. Smith, et al. 1974. Metabolism of Chloroform. I. The metabolism of [14C]-chloroform by different species. Xenobiotica 4: 151-163.
Budavari, S., M.J. O'Neil and A. Smith (Eds). 1989. The Merck Index. Merck & Co., Inc., Rahway, NJ, p. 2137.
Challen, P.J.R., D.E. Hickish and J. Bedford. 1958. Chronic chloroform intoxication. Br. J. Ind. Med. 15: 243-249.
Chiou, W.L. 1975. Quantitation of hepatic and pulmonary first-pass effects and its implication in pharmacokinetic study. I. Pharmacokinetics of chloroform in man. J. Pharmacokinet. Biopharm. 3: 193-201. (Cited in ATSDR, 1989)
Chu, I., D.C. Villeneuve, V.E. Secours, et al. 1982. Toxicity of trihalomethanes. II. Reversibility of toxicological changes produced by chloroform, bromodichloromethane, chlorodibromomethane and bromoform in rats. J. Environ. Sci. Health B17: 225-240.
Condie, L.W., C.L. Smallwood and R.D. Laurie. 1983. Comparative renal and hepatotoxicity of halomethanes: Bromodichloromethane, bromoform, chloroform, dibromochloromethane, and methylene chloride. Drug Chem. Toxicol. 6: 564-578.
DeSalva, S., A. Volpe, G. Leigh, et al. 1975. Long-term safety studies of a chloroform-containing dentrifice and mouth-rinse in man. Food Cosmet. Toxicol. 13: 529-532.
Deshon, H.D. 1979. Chloroform. In: Grayson, M. and D. Eckroth, Eds. Kirk-Othmer Encyclopedia of Chemical Technology, 3rd. ed., Vol. 5. John Wiley & Sons, New York, pp. 693-703.
Dowty, B.J., J.L. Laseter and J. Storer. 1976. Transplacental migration and accumulation in blood of volatile organic constituents. Pediatr. Res. 10: 696-375.
Fry, B.J., T. Taylor and D.E. Hathway. 1972. Pulmonary elimination of chloroform and its metabolites in man. Arch. Int. Pharmacodyn. 196: 98-111.
Gosselin, R.E., R.P. Smith, H.C. Hodge, et al. 1984. Clinical Toxicology of Commercial Products. Acute Poisoning, 5th ed. Williams and Wilkins, Baltimore, MD, p. II-161.
Grant, W.M. 1974. Toxicology of the Eye, 2nd ed. Charles C. Thomas Publisher, Springfield, IL, pp. 267-268.
Hansch, C. and A.J. Leo. 1985. Medchem Project Issue 26. Pomona College, Claremont, CA. (Cited in ATSDR, 1989)
Hawley, G.G. 1981. The Condensed Chemical Dictionary, 10th ed. Van Nostrand Reinhold, New York, NY, p. 237.
Heywood, R., R.J. Sortwell, P.R.B. Noel, et al. 1979. Safety evaluation of toothpaste containing chloroform. III. Long-term study in beagle dogs. J. Environ. Pathol. Toxicol. 2: 835-851.
IARC (International Agency for Research on Cancer). 1979. Chloroform. In: Some Halogenated Hydrocarbons. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans, Vol. 20. World Health Organization, Lyon, France, pp. 401-427.
Jorgenson, T.A., E.F. Meierhenry, C.J. Rushbrook, et al. 1985. Carcinogenicity of chloroform in drinking water to male Osborne-Mendel rats and female B6C3F1 mice. Fund. Appl. Toxicol. 5: 760-769.
Land, P.D., E.L. Owen and H.W. Linde. 1981. Morphological changes in mouse spermatozoa after exposure to inhalational anesthetics during early spermatogenesis. Anesthesiology 54: 53-56.
Lundberg, I., M. Ekdahl, T. Kronevi, et al. 1986. Relative hepatotoxicity of some industrial solvents after intraperitoneal injection or inhalation exposure to rats. Environ. Res. 40: 411-420. (Cited in ATSDR, 1989)
Munson, A.E., L.E. Sain, V.M. Sanders, et al. 1982. Toxicology of organic drinking water contaminants: Trichloromethane, bromodichloromethane, dibromochloromethane, and tribromomethane. Environ. Health Perspect. 46: 117-126.
Murray, A.E., B.A. Schwetz, J.G. McBride and R.E. Staples. 1979. Toxicity of inhaled chloroform in pregnant mice and their offspring. Toxicol. Appl. Pharmacol. 50: 515-522.
NCI (National Cancer Institute). 1976. Report on Carcinogenesis Bioassay of Chloroform. National Cancer Institute, Washington, DC. NTIS PB 264018.
Palmer, A.K., A.E. Street, F.J.C. Roe, et al. 1979. Safety evaluation of toothpaste containing chloroform. II. Long term studies in rats. J. Environ. Path. Toxicol. 2: 821-833.
Reuber, M.D. 1979. Carcinogenicity of chloroform. Environ. Health Perspect. 31: 171-182. (Cited in U.S. EPA, 1985)
Roe, F.J.C., A.A.K. Palmer, A.N. Worden, et al. 1979. Safety evaluation of toothpaste containing chloroform. I. Long-term studies in mice. J. Environ. Toxicol. 2: 799-819.
Schroeder, H.G. 1965. Acute and delayed chloroform poisoning. A case report. Br. J. Anaesth. 37: 972-975.
Schwetz, B.A., B.K.L. Leong and P.J. Gehring. 1974. Embryo- and fetotoxicity of inhaled chloroform in rats. Toxicol. Appl. Pharmacol. 28: 442-451.
Taylor, D.C., D.M. Brown, R. Keeble, et al. 1974. Metabolism of chloroform. II. A sex difference in the metabolism of [14C]-chloroform in mice. Xenobiotica 4: 165-174.
Thompson, D.J., S.D. Warner and V.B. Robinson. 1974. Teratology studies on orally administered chloroform in the rat. Toxicol. Appl. Pharmacol. 29: 348-357.
Torkelson, T.R. and V.K. Rowe. 1981. Halogenated aliphatic hydrocarbons containing chlorine, bromine and iodine. In: G.D. Clayton and E. Clayton, Eds. Patty's Industrial Hygiene and Toxicology, Vol. 2B. John Wiley & Sons, New York, pp. 3462-3469.
Torkelson, T.R., F. Oyen and V.K. Rowe. 1976. The toxicity of chloroform as determined by single and repeated exposure of laboratory animals. Am. Ind. Hyg. Assoc. 37: 697-704.
U.S. Air Force. 1989. Chloroform. In: The Installation Restoration Program Toxicology Guide, Vol. 1. Wright-Patterson Air Force Base, Ohio, pp. 4-1 to 4-41.
U.S. EPA. 1985. Health Assessment Document for Chloroform. Final Report. Office of Health and Environmental Assessment, Washington, DC. EPA/600/8-84/004F, NTIS PB86-105004/XAB.
U.S. EPA. 1992a. Health Effects Assessment Summary Tables. Annual FY-92. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH, for the Office of Emergency and Remedial Response, Washington, DC.
U.S. EPA. 1992b. Chloroform. Integrated Risk Information System (IRIS). Environmental Criteria and Assessment Office, Office of Health and Environmental Assessment, Cincinnati, OH.
U.S. FDA (U.S. Food and Drug Administration). 1976. Chloroform as an ingredient of human drug and cosmetic products. Fed. Reg. 41: 26842-26845.
Last Updated 8/29/97