Testing Information

Testing Status of Agents at NTP

CAS Registry Number: 67-66-3 Toxicity Effects

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

Names (NTP)

  • Chloroform
  • CHLOROFORM (WATER DISINFECTION BYPRODUCTS)
  • TRICHLOROMETHANE
  • Water disinfection byproducts (Chloroform)

Human Toxicity Excerpts

  • ACUTE ... RESPONSES FROM EXPOSURE AT VARIOUS CONCN OF CHLOROFORM IN MAN HAVE BEEN REPORTED TO BE: FAINTING SENSATION & VOMITING FROM 4096 PPM; DIZZINESS & SALIVATION AFTER FEW MIN AT 1475 PPM; INCR INTRACRANIAL PRESSURE & NAUSEA IN 7 MIN; AFTER-EFFECTS, FATIGUE & HEADACHE FOR SEVERAL HR FROM 1024 PPM. [American Conference of Governmental Industrial Hygienists. Documentation of the Threshold Limit Values for Substances in Workroom Air. Third Edition, 1971. Cincinnati, Ohio: American Conference of Governmental Industrial Hygienists, 1971. (Plus supplements to 1979), p. 413]**PEER REVIEWED**
  • RESPONSES ASSOC WITH EXPOSURE TO /CHLOROFORM/ CONCN BELOW ANESTHETIC OR PREANESTHETIC LEVEL ARE TYPICALLY INEBRIATION & EXCITATION PASSING INTO ... /CNS DEPRESSION/. VOMITING AND GI UPSETS MAY BE OBSERVED. EXPOSURE INCL RESP DEPRESSION, COMA, RENAL DAMAGE, & LIVER DAMAGE AS MEASURED BY ELEVATED SERUM ENZYME LEVELS. [Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley & Sons Inc., 1993-1994., p. 4054]**PEER REVIEWED**
  • SPLASH OF LIQ CHLOROFORM IN THE EYES CAUSES IMMEDIATE BURNING PAIN, TEARING, & REDDENING OF CONJUNCTIVA. THE CORNEAL EPITHELIUM IS USUALLY INJURED & MAY BE PARTIALLY LOST. HOWEVER, REGENERATION IS PROMPT, AND AS A RULE THE EYE RETURNS TO NORMAL IN 1 TO 3 DAYS. [Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986., p. 213]**PEER REVIEWED**
  • CHLOROFORM EXPOSURE HAS REPEATEDLY BEEN FATAL TO MAN. RAPID DEATH WAS ATTRIBUTABLE TO CARDIAC ARREST & DELAYED DEATH TO LIVER & KIDNEY DAMAGE. SYMPTOMS OF CHLOROFORM EXPOSURE INCL RESP DEPRESSION, COMA, RENAL DAMAGE, & LIVER DAMAGE AS MEASURED BY ELEVATED SERUM ENZYME LEVELS. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V20 415 (1979)]**PEER REVIEWED**
  • CHLOROFORM WITH METABOLIC ACTIVATION FAILED TO INDUCE CHROMOSOME BREAKAGE OR SISTER-CHROMATID EXCHANGES IN HUMAN LYMPHOCYTES. [KIRKLAND DJ ET AL; FD COSMET TOXICOL 19: 651 (1981)]**PEER REVIEWED**
  • ... Twenty-five percent of 68 workers handling chloroform in a chemical plant had enlarged livers. The lengths of employment were between 1 and 4 yr. Concn of chloroform in air ranged from 10-200 ppm. [American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH, 1991., p. 290]**PEER REVIEWED**
  • 33-year-old male who habitually inhaled chloroform for 12 yr, had psychiatric and neurologic symptoms of depression, loss of appetite, hallucination, ataxia, and dysarthria. Other symptoms from habitual use are moodiness, mental and physical sluggishness, nausea, rheumatic pain, and delirium. [NIOSH; Criteria for a Recommended Standard Occupational Exposure to Chloroform (1974) DHEW Pub NIOSH 75-114]**PEER REVIEWED**
  • Signs of chloroform poisoning in humans include a characteristic sweetish odor on the breath, dilated pupils, cold and clammy skin, initial excitation alternating with apathy, loss of sensation, abolition of motor functions, prostration, unconsciousness and eventual death. [Kayser, R., D. Sterling, D. Viviani (eds.). Intermedia Priority Pollutant Guidance Documents. Washington, DC: U.S.Environmental Protection Agency, July 1982., p. 2-1]**PEER REVIEWED**
  • Worker exposure to concn of chloroform of over 112 mg/cu m have been reported to result in depression, ataxia, flatulence, irritability, and liver and kidney damage. [Kayser, R., D. Sterling, D. Viviani (eds.). Intermedia Priority Pollutant Guidance Documents. Washington, DC: U.S.Environmental Protection Agency, July 1982., p. 2-1]**PEER REVIEWED**
  • Toxic blood level: 70.0 to 250 mg/l; Lethal blood level: 390.0 mg/l. [Winek, C.L. Drug and Chemical Blood-Level Data 1985. Pittsburgh, PA: Allied Fischer Scientific, 1985., p. ]**PEER REVIEWED**
  • An increased incidence of cardiac arrhythmias has been demonstrated during surgery in patients anesthetized with chloroform as compared with other anesthetic agents at vapor concn of 22,500 ppm. [Mackison, F. W., R. S. Stricoff, and L. J. Partridge, Jr. (eds.). NIOSH/OSHA - Occupational Health Guidelines for Chemical Hazards. DHHS(NIOSH) Publication No. 81-123 (3 VOLS). Washington, DC: U.S. Government Printing Office, Jan. 1981., p. 2]**PEER REVIEWED**
  • ... Produces CNS depression ... Can sensitive the heart to arrhythmias produced by catecholamines. The hepatotoxic potential is highest with chloroform ... [Hardman, J.G., L.E. Limbird, P.B. Molinoff, R.W. Ruddon, A.G. Goodman (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill, 1996., p. 1681]**PEER REVIEWED**
  • Fatal doses of liquid anesthetic agents by ingestion or inhalation are approx as follows: ... chloroform, 10 ml ... . [Dreisbach, R.H. Handbook of Poisoning. 12th ed. Norwalk, CT: Appleton and Lange, 1987., p. 314]**PEER REVIEWED**
  • Concentrations /of chloroform/ up to about 400 ppm can be endured for 30 min without complaint; 1000 ppm exposure for 7 min can cause dizziness and GI upset; 14,000 ppm can cause /CNS depression/. [Klaassen, C.D., M.O. Amdur, Doull J. (eds.). Casarett and Doull's Toxicology. The Basic Science of Poisons. 5th ed. New York, NY: McGraw-Hill, 1995., p. 748]**PEER REVIEWED**
  • Chloroform causes: local irritation (hyperemia, erythema, moisture loss) at the site of skin absorption. [Malten KE et al; Berufsdermatosen 16: 135 (1968)]**PEER REVIEWED**
  • Both di- and tri-halogenated methane derivatives have been found to produce increased blood levels of methemoglobin; the greatest increase caused by iodo-, followed by bromo- and chloro- compounds. CNS functional disturbances are reported, including depression of rapid eyemovement sleep, as seen in carbon monoxide exposures. /Di- and tri-halogenated methane derivatives/ [USEPA; Ambient Water Quality Criteria Doc: Halomethanes p.C-40 (1980) EPA 440/5-80-051]**PEER REVIEWED**

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Non-Human Toxicity Excerpts

  • MICE EXPOSED TO 8,000 PPM OF CHLOROFORM DIED AFTER 3 HR OF EXPOSURE, RABBITS DIED AFTER A 2-HR EXPOSURE TO 12,500 PPM ... DOGS SURVIVED MUCH HIGHER CONCN. ACUTE CHLOROFORM EXPOSURE MAY RESULT IN DEATH BY RESP ARREST. PRIMARY TOXIC RESPONSE AT LOWER LEVELS OF EXPOSURE IS HEPATOTOXICITY LEADING TO FATTY LIVER & CENTRILOBULAR NECROSIS. [Doull, J., C.D. Klaassen, and M. D. Amdur (eds.). Casarett and Doull's Toxicology. 2nd ed. New York: Macmillan Publishing Co., 1980., p. 471]**PEER REVIEWED**
  • ... 40% INHIBITION OF MICROSOMAL DRUG-METABOLIZING ENZYME ACTIVITY IN RATS FED 1.05 ML/KG OF CHLOROFORM 24 HR PRIOR TO SACRIFICE /IS REPORTED/. THIS MAY BE RELATED TO DEGREE OF HEPATIC NECROSIS PRODUCED BY CHLOROFORM OR TO MORE SUBTLE EFFECT ON MICROSOMAL ENZYME SYSTEM. [Doull, J., C.D. Klaassen, and M. D. Amdur (eds.). Casarett and Doull's Toxicology. 2nd ed. New York: Macmillan Publishing Co., 1980., p. 471]**PEER REVIEWED**
  • GROUPS OF 5 STRAIN A MICE OF EACH SEX, 3 MO OLD AT THE BEGINING OF THE EXPERIMENT WERE GIVEN 30 ORAL DOSES OF 0.1, 0.2, 0.4, 0.8 OR 1.6 ML/KG (0.15-2.4 G/KG BODY WT) CHLOROFORM IN OLIVE OIL AT 4-DAY INTERVALS. SURVIVORS WERE KILLED 1 MO AFTER LAST TREATMENT. ALL FEMALES AT THE 3 HIGHEST DOSES AND ALL MALES AT THE 3 HIGHEST DOSES DIED EARLY IN THE EXPERIMENT. NONMETASTASIZING HEPATOMAS & CIRRHOSIS WERE FOUND IN ALL SURVIVING FEMALES GIVEN 0.8 OR 0.4 ML/KG BODY WEIGHT PER DOSE. NO HEPATOMAS WERE OBSERVED IN THOSE AT THE TWO LOWEST DOSE LEVELS OR IN THE CONTROLS. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V20 408 (1979)]**PEER REVIEWED**
  • GROUPS OF 50 MALE & 50 FEMALE B6C3F1 MICE, 5 WK OF AGE, RECEIVED 2-5% SOLN OF CHLOROFORM (USP GRADE) IN CORN OIL BY GAVAGE 5 TIMES/WK FOR 78 WK. THE INITIAL DOSE LEVELS FOR MALES WERE 100 AND 200 MG/KG BODY WT, AND THOSE FOR FEMALES 200 AND 400 MG/KG BODY WT. THESE DOSES WERE INCREASED AFTER 18 WEEKS TO 150 AND 300 MG/KG BODY WT FOR MALES AND 250 AND 500 MG/KG BODY WT FOR FEMALES, SO THAT THE AVERAGE LEVELS WERE 138 AND 277 MG/KG BODY WT FOR MALES AND 238 AND 477 MG/KG BODY WT FOR FEMALES. POOLED CONTROL GROUPS, CONSISTING OF 77 MALE AND 80 FEMALE MICE, AND MATCHED CONTROL GROUPS, CONSISTING OF 20 MALES AND 20 FEMALES, WERE TREATED WITH CORN OIL ONLY. THE EXPERIMENT WAS TERMINATED AT 92-93 WEEKS. THE INCIDENCE OF HEPATOCELLULAR CARCINOMAS IN ALL TREATED GROUPS OF MICE WAS STATISTICALLY SIGNIFICANT (P < 0.0001) WHEN COMPARED WITH THAT IN CONTROLS. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V20 411 (1979)]**PEER REVIEWED**
  • GROUPS OF 50 MALE & 50 FEMALE OSBORNE-MENDEL RATS, 52 DAYS OLD, RECEIVED A 10% SOLUTION OF CHLOROFORM (USP GRADE) IN CORN OIL BY GAVAGE 5 TIMES WEEKLY. MALES WERE GIVEN DOSES OF 90 AND 180 MG/KG BODY WT FOR 78 WEEKS; FEMALE RATS STARTED ON DOSE LEVELS OF 125 AND 250 MG/KG BODY WT, BUT THESE WERE LOWERED TO 90 AND 180 MG/KG BODY WT AFTER 22 WEEKS, GIVING AN AVERAGE LEVEL OF 100 AND 200 MG/KG BODY WT FOR THE STUDY. POOLED CONTROL GROUPS OF 100 MALES AND 100 FEMALES AND MATCHED CONTROL GROUPS OF 20 MALES AND 20 FEMALES WERE TREATED WITH THE VEHICLE ONLY. THE EXPERIMENT WAS TERMINATED AT 111 WEEKS. THE INCIDENCE OF KIDNEY EPITHELIAL TUMOURS IN MALE RATS WAS STATISTICALLY GREATER (P= 0.0016) THAN THAT IN CONTROLS. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V20 411 (1979)]**PEER REVIEWED**
  • RATS WERE EXPOSED TO SUBANESTHETIC DOSES OF CHLOROFORM: 150, 500 & 1500 MG/CU M (30, 100 & 300 PPM), IN AIR BY INHALATION FOR 7 HR/DAY ON DAYS 6-15 OF GESTATION. 100 PPM DOSE CAUSED LOW INCIDENCE OF ACAUDATE FETUSES WITH IMPERFORATED ANUSES. ALL DOSES OF CHLOROFORM WERE FETOTOXIC & RETARDED DEVELOPMENT. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V20 414 (1979)]**PEER REVIEWED**
  • CLINICAL SIGNS OBSERVED IN RATS FOLLOWING SINGLE ORAL DOSES OF CHLOROFORM WERE SEDATION, FLACCID MUSCLE TONE, ATAXIA, PILOERECTION, & PROSTRATION. MALES WERE MORE SUSCEPTIBLE THAN FEMALES. [CHU I ET AL; TOXICOL APPL PHARMACOL 52 (2): 351-3 (1980)]**PEER REVIEWED**
  • MALE & FEMALE MICE WERE GAVAGED WITH VEHICLE OR CHLOROFORM 31.1 MG/KG/DAY FOR 21 DAYS PRIOR TO MATING, THROUGHOUT MATING & DAMS THROUGHOUT GESTATION & LACTATION. PUPS GAVAGED WITH SAME DOSE DAILY BEGINNING ON DAY 7. NO DIFFERENCES IN CONTROL & TREATED MICE. [BURKHALTER JE ET AL; NEUROBEHAV TOXICOL 1 (3): 199-205 (1979)]**PEER REVIEWED**
  • CELLS OF SACCHAROMYCES CEREVISIAE, HARVESTED FROM LOG-PHASE CULTURES, CONTAIN CYTOCHROME P450 & ARE CAPABLE OF METAB PROMUTAGENS TO GENETICALLY ACTIVE PRODUCTS. THE ACTIVITIES OF 7 HALOGENATED ALIPHATIC HYDROCARBONS IN THE YEAST SYSTEM WERE INVESTIGATED. CHLOROFORM INDUCED MITOTIC GENE CONVERTANTS & RECOMBINANTS &, TO A LESSER EXTENT, GENE REVERTANTS WHEN INCUBATED WITH LOG-PHASE CELLS OF YEAST STRAIN D7. CHLOROFORM CONCN USED RANGED FROM 21 TO 54 MM. [CALLEN DF ET AL; MUTAT RES 77 (1): 55-63 (1980)]**PEER REVIEWED**
  • THE TOXIC EFFECTS OF A SINGLE ORAL DOSE OF CHLOROFORM WERE EVALUATED IN C57BL, DBA, AND F1 MALE MICE. SOLN OF CHLOROFORM IN PEANUT OIL (FINAL VOL= 0.1 ML/10 G BODY WT) WERE ADMIN ONCE BY GAVAGE TO 9-WK-OLD MICE. DBA/2J MALE MICE ARE MORE SENSITIVE TO THE 10-DAY LETHAL EFFECT OF CHLOROFORM THAN ARE C57BL/6J MALES, WHEREAS B6D2F1/J ARE INTERMEDIATE. THIS RELATIVE ORDER OF SENSITIVITY IS PRESERVED FOLLOWING SUBLETHAL DOSES IN REGARD TO RADIOLABEL ACCUMULATION INTO SUBCELLULAR BIOCHEMICAL FRACTIONS AND RENAL, BUT NOT HEPATIC, DYSFUNCTION. KIDNEYS FROM MICE OF ALL THREE GENOTYPES ARE ABLE TO REPAIR TUBULAR DAMAGE FROM CHLOROFORM. [CLEMENS TL ET AL; TOXICOL APPL PHARMACOL 48 (1 PART 1): 117-30 (1979)]**PEER REVIEWED**
  • CHLOROFORM WAS NEGATIVE IN THE SPERM MORPHOLOGY ASSAY WHEN ADMIN TO GROUPS OF 5 (CBAXBALB/C)F1 MALE MICE IP 5 TIMES/DAY @ 5.0 ML/KG/DAY. [TOPHAM JC; PROGRESS IN MUTATION RESEARCH 1: 718-20 (1981)]**PEER REVIEWED**
  • EPIDIDYMAL SPERMATOZOA OF (C57BL/C3H)F1 MICE SHOWED SIGNIFICANT INCREASES IN ABNORMALITIES AFTER /28 DAYS OF/ EXPOSURE TO CHLOROFORM /NEAR 0.1 MAC AND GREATER CONCN/ 4 HR/DAY FOR 5 DAYS. [LAND PC ET AL; ANESTHESIOLOGY 54 (1): 53-6 (1981)]**PEER REVIEWED**
  • MICE WERE GIVEN ACCESS TO DEIONIZED WATER FOR 30 MIN DAILY. WHEN FLUID CONSUMPTION STABILIZED, THEY WERE GIVEN 30 MIN ACCESS TO 0.3% SACCHARIN FOLLOWED BY ORAL DOSES OF 3, 10 OR 30 MG/KG CHLOROFORM OR VEHICLE (EMULPHOR). BEGINNING 24 HR LATER SUBJECTS WERE GIVEN 2-BOTTLE CHOICE TEST SACCHARIN VS WATER FOLLOWED BY ADMIN OF CHLOROFORM. 30 MG/KG PRODUCED TASTE AVERSION ON 1ST CHOICE TEST & REDUCTION OF TOTAL FLUID INTAKE. DOSES OF 3 & 10 MG/KG OR VEHICLE DID NOT AFFECT EITHER MEASURE. ALSO IT PRODUCED TASTE AVERSIONS WHEN GIVEN AT RELATIVELY LOW DOSES BY IP ROUTE. [LANDAUER MR ET AL; NEUROBEHAV TOXICOL TERATOL 4 (3): 305-10 (1982)]**PEER REVIEWED**
  • NO EVIDENCE OF POTENTIAL MUTAGENICITY WAS OBSERVED WHEN TESTED IN 5 STRAINS OF SALMONELLA TYPHIMURIUM WITH & WITHOUT S-9 MICROSOMAL-ENZYME PREPN. S-9 PREPN WAS DERIVED FROM LIVERS & KIDNEYS OF RATS & MICE PREVIOUSLY EXPOSED TO AROCLOR 1254. [VAN ABBE NJ ET AL; FOOD CHEM TOXICOL 20 (5): 557-61 (1982)]**PEER REVIEWED**
  • In mice, immature males, castrated adult males, and estrogen treated males were resistant to chloroform renal toxicity, whereas mature males and testosterone treated females were sensitive. [Vessel ES; Fed Proc 35 (8): 1125-32 (1976)]**PEER REVIEWED**
  • Rabbits developed slight hyperemia with moderate necrosis and scar tissue formation following one to two, 24 hr dermal applications of chloroform on shaven skin. [Torkelson TR; Amer Ind Hyg Assoc J 37 (12): 697-705 (1976)]**PEER REVIEWED**
  • Cultured Chinese hamster fibroblasts when exposed to 1-2.5% chloroform did not demonstrate mutagenic changes. However, fibroblast multiplication rate was depressed in a dose-dependent pattern. [Sturrock JE; Anesthesiology 43 (1): 21-30 (1975)]**PEER REVIEWED**
  • Chloroform: did not induce sister chromatid exchanges in Chinese hamster ovary cells when tested at 0.71% vol/vol. [White AE et al; Anesthesiology 50: 426-30 (1979)]**PEER REVIEWED**
  • Exposure to chloroform for 1-5 min caused a gradual browning of the surfaces of Phaseolus vulgaris cotyledons during subsequent incubation for 10-72 hr; this was accompanied by isoflavanoid accumulation in the cotyledons. ... The amts of phytoalexin produced increased with increasing damage, phaseollin, phaseollinisoflavan, and kievitone (< or = to 96 ug/g cotyledon). ... Cotyledons treated with chloroform for > 10 min became entirely flaccid and did not become pigmented or produce any of the above compounds. No isoflavanoids were detected in undamaged cotyledons. Hence, accumulation of phytoalexins may be a direct consequence of the death of superficial cells of the bean cotyledons. [Bailey JA, Berthier M; Phytochemistry 20 (1): 187-8 (1981)]**PEER REVIEWED**
  • 40 and 160 ppm /chloroform/ caused no mortality in goldfish after 4 days while at 300 ppm a 30% mortality was observed. 40 ppm caused no mortality in guppies while at 160 and 300 ppm, 30 and 50% mortality, respectively, was observed. At 160 and 300 ppm the fish acquired darker pigmentation, retarded reproduction rate and growth, and caused an equilibrium loss (especially at 300 ppm). 40 ppm caused five-fold incr in leukocytes after a six month exposure. [Hazdra JJ et al; 9th Proc Int Symp: Adv Comp Leuk Res p.215-7 (1980)]**PEER REVIEWED**
  • The effects of lifetime exposure to chloroform ... were studied in Wistar rats. ... Treatment was initiated with weanlings at 2 ml chlorofrom per liter of water. Concentrations were halved at 72 weeks because of increasing water intake among the test animals. ... Treated rats weighed less than unexposed controls at all ages. At about 15 to 17 weeks, females had a high consumption of water and ... /chloroform/ than males. The incidence of neoplastic nodules was significantly increased in females. ... /Both/ males /and females/ treated with chlorofrom had a high incidence of hepatic adenofibrosis. [Tumasonis CF et al; Ecotoxicol Environ Safety 9 (2): 233-40 (1985)]**PEER REVIEWED**
  • Characteristics of chloroform (CHCl3) nephrotoxicity and of 2-hexanone potentiation were evaluated in adult male Fischer 344 rats pretreated with vehicle (oil, 10 ml/kg, po) or 2-hexanone (10 mmol/kg, po) 18 hr prior to chloroform exposure. ... Little metabolism of (14)C-chloroform by renal cortical microsomes from vehicle or 2-hexanone pretreated rats was detected. However, chloroform produced a concn-related dysfunction when added to renal cortical slices from Fischer 344 or Sprague-Dawley rats. The degree of chloroform toxicity in vitro was not altered when renal cortical slices were preincubated with chloroform (8.5 microliter) under an atmosphere of carbon monoxide. In renal cortical slices, deuterated-chloroform was less toxic than chloroform. Although 2-hexanone pretreatment increased renal slice metabolism of (14)C-chloroform twofold, this incr was not associated with an incr in nephrotoxicity after direct exposure of slices to chloroform (0 to 10 microliter) in vitro. Chloroform (0.5 ml/kg, ip) did not alter renal cortical glutathione concn in vehicle or 2-hexanone pretreated rats. The association of (14)C-chloroform-derived radiolabel was incr over control by 2-hexanone pretreatment in protein, lipid, and acid soluble fractions from the renal cortex by approx two-, two-, and five-fold, respectively. In conclusion, renal cytochrome p450 did not appear to mediate chloroform metabolism and nephrotoxicity in the rat to the extent observed previously in mice. 2-Hexanone appeared to potentiate nephrotoxicity by a mechanism different than that observed in rat liver. [Smith JH et al; Toxicol Appl Pharmacol 79 (1): 166-74 (1985)]**PEER REVIEWED**
  • The genetic damage caused by ... chloroform ... was studied in rodents (Rattus norvegicus and Mus musculus). ... Aneuploidy, stages of fuzziness, despiralization and stickiness of the chromosomes were observed. Some metaphases with gaps, breaks and translocations, were also encountered. [Sharma GP, Anand RK; Proc Natl Acad Sci India Sect B (Biol Sci) 54 (1): 61-7 (1984)]**PEER REVIEWED**
  • The carcinogenic activity of chloroform administered at 0, 200, 400, 900, and 1800 mg/l in drinking water was studied in male Osborne-Mendel rats and female B6C3F1 mice. A second control group was included in the study and was restricted to the water consumption of the high-dose group. Animals were maintained on study for 104 weeks. ... Chloroform increased the yield of renal tubular adenomas and adenocarcinomas in male rats in a dose-related manner. For the high-dose group, which corresponded to a time-weighted average dose of 160 mg/kg per day for 104 weeks, there was a 14% incidence of renal tubular adenomas and adenocarcinomas, vs 1% in the control group. This compares to a 24% incidence observed when 180 mg/kg per day of chloroform was administered for 78 weeks in earlier studies. In contrast, chloroform in the drinking water of mice failed to increase the incidence of hepatocellular carcinomas in female B6C3F1 mice. The highest dose group received a time-weighted average dose of 263 mg/kg per day for 104 weeks, resulting in a 5% combined incidence of hepatocellular adenomas and carcinomas relative to a 6% incidence in the control groups. In a prior National Cancer Institute study an 80% incidence of hepatocellular carcinomas was observed at 270 mg/kg per day for 78 weeks. Chloroform administered in drinking water evidently is capable of inducing cancer in the rat kidney. However, the lack of response in the mouse liver when chloroform is supplied in the drinking water suggests that earlier reports of chloroform hepatocarcinogenesis may be related to some interaction with the mode of administration (corn oil gavage). [Jorgenson TA et al; Fundam Appl Toxicol 5 (4): 760-9 (1985)]**PEER REVIEWED**
  • The acute toxicity of chloroform in experimental animals is species-, strain-, sex- and age-dependent. [Kayser, R., D. Sterling, D. Viviani (eds.). Intermedia Priority Pollutant Guidance Documents. Washington, DC: U.S.Environmental Protection Agency, July 1982., p. 2-1]**PEER REVIEWED**
  • Pregnant C57B1 mice were administered chloroform, (14)C-chloroform, by inhalation on days 11, 14, and 17 of gestation. In another experiment, six 4-day-old mice received an ip dose of 2 uCi of (14)C-chloroform dissolved in maize oil. The pregnant mice and the exposed newborns were killed for autoradiography studies. A high uptake of (14)C-chloroform was noted in the pregnant mice after inhalation, especially in the respiratory epithelium, liver, fat, lung, brain, and renal cortex. Metabolites of chloroform accumulated in the amniotic fluid. In the newborn mice, a notable accumulation of chloroform was noted in the respiratory epithelium, oral/esophageal mucosa, liver, salivary glands, and the conjunctiva of the eye. [Danielson BRG et al; Biol Res Pregnancy Perinatol 7: 77-83 (1986)]**PEER REVIEWED**
  • ... Male and female B6C3F1 mice were administered chloroform at 60, 130, and 270 mg/kg per day for 90 days. At sacrifice, body and organ weights were measured, and blood was recovered to perform the following serum chemistry measurements (in order of priority): glutamate oxalacetate transaminase, lactate dehydrogenase, blood urea nitrogen and triglyceride levels. The liver was sectioned for histopathological examination. Chloroform increased glutamate oxalacetate transaminase levels significantly only when administered in corn oil at a dose of 270 mg/kg in both male and female mice. It had no effect on lactate dehydrogenase (LDH) activity. There was a small increase in BUN when chloroform was administered in corn oil, but not when adminsitered in 2% Emulphor. When administered in corn oil, chloroform significantly decreased serum triglyceride levels but was without effect on this parameter when administered in 2% Emulphor. Chloroform decreased body weight and increased liver weight with both vehicles, but the effects were significantly greater when it was administered in corn oil. [Bull RJ et al; Environ Health Perspect 69: 49-58 (1986)]**PEER REVIEWED**
  • In C57 male black mice, renal tubular necrosis was produced by ip admin of 300 mg of chloroform/kg; an ip injection of 445 mg/kg caused necrosis in the liver and the kidneys. [American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH, 1991., p. 289]**PEER REVIEWED**
  • NCI strain A mice, receiving chloroform repeatedly (30 doses by stomach tube at 4-day intervals) developed hepatomas. ... Hepatomas and cirrhosis of the liver were induced only if the dosage was large enough to produce necrosis of the liver (individual doses greater than 300 mg/kg). [American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH, 1991., p. 289]**PEER REVIEWED**
  • ... Negative results of /chloroform/ carcinogenicity were obtained in beagle dogs after 7.5 yr, in Sprague-Dawley rats, and in 3 of 4 strains of mice. In the fourth strain (ICI Swiss), renal tumors occurred only in males at the 60 mg/kg/day dose, but not at the 17 mg dose. In the male mouse CBA strain, survival was better than in controls, and fewer liver tumors were seen in the treated than the control mice. The lack of toxicity was attributed to the small doses used in these studies (15 and 30 mg/kg/day, dogs; 60 mg/kg/day in mice and rats). The hepatocellular degeneration and necrosis and the abdominal distention ... were induced by several times higher dosage. [American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH, 1991., p. 289]**PEER REVIEWED**
  • ... The hepatotoxic effect of chloroform is 20 times greater than the hepatotoxic effect of trichloroethylene and 10 times greater than that of tetrachloroethylene. [American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH, 1991., p. 289]**PEER REVIEWED**
  • Two studies in rats exposed repeatedly to chloroform /conclude that/ ... 25-30 ppm, 7 hr/day, 5 days/wk for 6 mo does not produce organ injury; liver and kidney injury start to appear at 50 ppm exposure; and the severity of the injury is concentration dependent. Data ... also indicates that rats are more sensitive to chloroform than other species (mice, rabbits, guinea pigs, dogs). [American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH, 1991., p. 289]**PEER REVIEWED**
  • Chloroform 0.1 to 0.5% was an effective bactericide against small inocula of Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa; against large inocula chloroform 0.1% was effective against Pseudomonas aeruginosa, but higher concn were needed against the other organisms. Spores of Bacillus pumilus were not killed. [Reynolds, J.E.F., Prasad, A.B. (eds.) Martindale-The Extra Pharmacopoeia. 28th ed. London: The Pharmaceutical Press, 1982., p. 745]**PEER REVIEWED**
  • ... Abnormal mitosis has occurred in /plant/ cells exposed to chloroform concn of 0.025%. Toxic effects also occur at this level. Concn greater than 0.25% have been shown to be lethal. [Kayser, R., D. Sterling, D. Viviani (eds.). Intermedia Priority Pollutant Guidance Documents. Washington, DC: U.S.Environmental Protection Agency, July 1982., p. 2-2]**PEER REVIEWED**
  • ... Rabbits, rats, guinea pigs, and dogs /were exposed/ to 25, 50, or 85 ppm chloroform, 7 hr/day, 5 days/wk for six months. Histopathological evaluation of animals indicated centrilobular necrosis and cloudy swelling of the kidneys. The effects of the 25 ppm dose were characterized as mild and reversible. [Klaassen, C.D., M.O. Amdur, Doull J. (eds.). Casarett and Doull's Toxicology. The Basic Science of Poisons. 5th ed. New York, NY: McGraw-Hill, 1995., p. 748]**PEER REVIEWED**
  • ANESTHESIA WITH DEUTERATED CHLOROFORM AT 0.36% PRODUCED A 35% DECR IN SERUM GLUTAMIC PYRUVIC TRANSAMINASE IN RATS. THUS, DEUTERATION OF VOLATILE ANESTHETICS CHANGES THEIR METABOLISM, IN MOST CASES PRODUCING DECR IN METABOLISM. THIS MAY LESSEN ORGAN TOXICITY. [MCCARTY LP ET AL; ANESTHESIOLOGY 51 (2): 106-10 (1979)]**PEER REVIEWED**
  • ... Rats pretreated with phenobarbital, but not untreated rats, will produce conjugated dienes during chloroform anesthesia; depression of glucose-6-phosphatase activity also occurs after chloroform only in phenobarbital-pretreated rats. ... Since chloroform-induced liver injury is more severe in phenobarbital-pretreated rats, the possibility exists that the initial lesion induced by chloroform in these animals is only aggravated by the appearance of lipid peroxidation. These findings cast doubt on the general applicability of lipid peroxidation as a mechanism for necrogenic haloalkanes. [Doull, J., C.D.Klassen, and M.D. Amdur (eds.). Casarett and Doull's Toxicology. 3rd ed., New York: Macmillan Co., Inc., 1986., p. 296]**PEER REVIEWED**
  • STUDIES WERE DONE USING MALE B6C3F1 MICE TO INVESTIGATE POTENTIAL OF CHLOROFORM TO INDUCE GENETIC DAMAGE &/OR ORGAN TOXICITY AT SITES WHERE TUMORS HAVE BEEN OBSERVED IN VARIOUS BIOASSAYS. THEY REVEALED THAT CARCINOGENIC DOSES PRODUCED SEVERE NECROSIS AT SITES WHERE TUMORS DEVELOPED. NONCARCINOGENIC DOSES FAILED TO INDUCE THIS RESPONSE. STUDIES OF DNA ALKYLATION & DNA REPAIR IN VIVO FAILED TO GIVE ANY INDICATION THAT IT HAD PRODUCED GENETIC ALTERATIONS ASSOC WITH KNOWN GENOTOXIC CHEMICALS. DATA SUGGEST THAT PRIMARY MECHANISM OF CHLOROFORM-INDUCED CARCINOGENESIS IS NONGENETIC. [REITZ RH ET AL; ENVIRON HEALTH PERSPECT 46: 163-8 (1982)]**PEER REVIEWED**
  • RELATIONSHIP BETWEEN ACUTE TOXICITY FROM ORAL ADMIN & LONG-TERM TUMORIGENIC POTENTIAL WAS STUDIED IN MALE CFLP OUTBRED SWISS ALBINO MOUSE STRAIN. SINGLE DOSE OF CHLOROFORM, APPROX 18 MG/KG HAD NO DETECTABLE ACUTE TOXIC EFFECT ON LIVER OR KIDNEYS & DID NOT STIMULATE REGENERATIVE ACTIVITY. TOXICITY & TISSUE REGENERATION WERE OBSERVED WITH SINGLE 60 MG/KG OR HIGHER DOSE. IN EARLIER LONG-TERM STUDIES IN MICE OF SAME STRAIN, KIDNEY TUMORS OCCURRED IN MALES GIVEN 60 MG/KG/DAY THROUGHOUT LIFE BUT NOT IN MICE GIVEN 17 MG/KG/DAY. FINDINGS ARE CONSISTENT WITH HYPOTHESIS THAT EARLY ACUTE TOXIC CHANGE & SUBSEQUENT REPAIR ARE ESSENTIAL FOR TUMORIGENESIS IN KIDNEY & LIVER. [MOORE DH ET AL; FOOD CHEM TOXICOL 20 (6): 951-4 (1982)]**PEER REVIEWED**
  • CHLOROFORM INDUCED DOSE-DEPENDENT INCR OF HEPATIC ORNITHINE DECARBOXYLASE AT 100 MG/KG BODY WT IN FISCHER 344 RATS. FEMALES WERE 2 TO 4 TIMES MORE SUSCEPTIBLE THAN MALES. NUCLEAR RNA POLYMERASE I ACTIVITY WAS ALSO INDUCED. IT REDUCED RENAL ORNITHINE DECARBOXYLASE BY 35% RATHER THAN INCREASING IT. INDUCTION OF HEPATIC ORNITHINE DECARBOXYLASE ACTIVITY MIGHT BE ASSOC WITH REGENERATIVE HYPERPLASIA. [SAVAGE RE JR ET AL; ENVIRON HEALTH PERSPECT 46: 157-62 (1982)]**PEER REVIEWED**
  • RATS WERE DOSED 1, 5, OR 10 TIMES WITH CHLOROFORM (0.5 TO 50 MG/KG) AND THE LIVER ENZYME ACTIVITIES DETERMINED. CHLOROFORM INDUCED CHANGES IN THE 24 ENZYMES INVESTIGATED BUT CAUSED ONLY MINIMAL LIVER ENLARGEMENT. THE MAIN ENZYMATIC CHANGES WERE: STIMULATION OF GLYCOLYSIS & OXIDATIVE PHOSPHORYLATION, INCR BREAKDOWN OF PROTEIN & NUCLEIC ACIDS, REDUCED HEXOSE PHOSPHATE SHUNT ACTIVITY LEADING TO A SHORTAGE OF NADPH IN THE CELL, AND STIMULATION OF ADRENAL MEDULLARY & CORTICAL SECRETION. SOME OF THE CHANGES ARE SIMILAR TO THOSE SEEN WITH LARGER AND ANESTHETIC DOSES. [GROGER WK ET AL; TOXICOLOGY 14 (1): 23-38 (1979)]**PEER REVIEWED**
  • Hepatocytes isolated from male Sprague-Dawley rats (Harlan, 200-275 g) were exposed to halogenated hydrocarbons including chloroform. Cell suspensions contained 2-3X10+6 cells/ml and were viable for 6 hr as indicated by a < 10% increment in the fractional release of aspartate aminotransferase (AST) activity. The addition of chloroform (20 mM) caused a rapid release of AST into the incubation medium. The release peaked within 20 min and approximately 20% (n= 4) of the total activity was found in the medium. Only 3% of the activity was in the medium of control cells. Untreated cells or cells treated with vehicle did not exhibit an increase of AST release with time. The amount of AST release was concentration dependent (tested at 10 and 20 mM) and related to the oil/water partition coefficient. Cellular oxygen consumption was reduced by approximately 50% (n= 8) by 20 mM chloroform, and the reduction was dose dependent. The effects of cellular respiration were completely reversible within one hr. A dose-related decrease of DNP stimulated oxygen consumption was observed when chloroform was present. Succinate-stimulated oxygen consumption was not abolished by up to 10 mM chloroform. [Berger ML, Sozeri T; Toxicology 45 (3): 319-30 (1987)]**PEER REVIEWED**
  • ... Chloroform was administered to rats and mice by inhalation. High doses (300 ppm/6 hr/day for 7 days) caused significant hepatotoxicity and mild renal toxicity. Both hepatotoxicity and renal toxicity were observed in rats. The rats developed a series of nasal lesions involving degeneration of Bowman's glands and osseous hyperplasia. [Klaassen, C.D., M.O. Amdur, Doull J. (eds.). Casarett and Doull's Toxicology. The Basic Science of Poisons. 5th ed. New York, NY: McGraw-Hill, 1995., p. 749]**PEER REVIEWED**
  • The primary cellular target /of chloroform/ is the proximal tubule with no primary damage to the glomerulus or the distal tubule. Proteinuria, glucosuria, and increased blood urea nitrogen levels are all characteristic of chloroform-induced nephrotoxicity. [Klaassen, C.D., M.O. Amdur, Doull J. (eds.). Casarett and Doull's Toxicology. The Basic Science of Poisons. 5th ed. New York, NY: McGraw-Hill, 1995., p. 432]**PEER REVIEWED**
  • ... Castration of male mice decreased renal cytochrome p450 and chloroform-induced nephrotoxicity. Likewise, testosterone pretreatment of female mice increased cytochrome p450 content and rendered female mice susceptible to the nephrotoxic effects of chloroform. [Klaassen, C.D., M.O. Amdur, Doull J. (eds.). Casarett and Doull's Toxicology. The Basic Science of Poisons. 5th ed. New York, NY: McGraw-Hill, 1995., p. 432]**PEER REVIEWED**
  • ... Chloroform ... /administered ip/ produced moderate increases in mouse striatal p-tyramine. /Dose not specified/ [Juorio AV, Yu PH; Biochem Pharmacol 34 (9): 1381-8 (1985)]**PEER REVIEWED**

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Human Toxicity Values

  • None found

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Non-Human Toxicity Values

  • LD50 Rat intragastric 2000 mg/kg [Torkelson TR et al; Am Ind Hyg Assoc J 37: 697 (1976)]**PEER REVIEWED**
  • LD50 White rat oral 2180 mg/kg [Larson, L.L., Kenaga, E.E., Morgan, R.W. Commercial and Experimental Organic Insecticides. 1985 Revision. College Park, MD: Entomological Society of America, 1985., p. 25]**PEER REVIEWED**
  • LD50 Rabbit oral 9827 mg/kg [Larson, L.L., Kenaga, E.E., Morgan, R.W. Commercial and Experimental Organic Insecticides. 1985 Revision. College Park, MD: Entomological Society of America, 1985., p. 25]**PEER REVIEWED**
  • LD50 Dog oral 2250 mg/kg [Larson, L.L., Kenaga, E.E., Morgan, R.W. Commercial and Experimental Organic Insecticides. 1985 Revision. College Park, MD: Entomological Society of America, 1985., p. 25]**PEER REVIEWED**
  • LD50 RAT MALE ORAL 908 MG/KG [CHU I ET AL; TOXICOL APPL PHARMACOL 52 (2): 351-3 (1980)]**PEER REVIEWED**
  • LD50 RAT FEMALE ORAL 1117 MG/KG [CHU I ET AL; TOXICOL APPL PHARMACOL 52 (2): 351-3 (1980)]**PEER REVIEWED**
  • LC50 Rat ihl 47,702 mg/cu m/4 hr [Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996., p. 775]**PEER REVIEWED**
  • LD50 Mouse oral 36 mg/kg [Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996., p. 775]**PEER REVIEWED**
  • LD50 Mouse ip 623 mg/kg [Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996., p. 775]**PEER REVIEWED**
  • LD50 Mouse sc 704 mg/kg [Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996., p. 775]**PEER REVIEWED**
  • LD50 Dog ip 1000 mg/kg [Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996., p. 775]**PEER REVIEWED**

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Absorption, Distribution and Excretion

  • CHLOROFORM CAN BE ABSORBED THROUGH LUNG, FROM GI TRACT & TO SOME EXTENT THROUGH SKIN. INHALATION ROUTE IS ... PRIMARY SOURCE OF ... ABSORPTION IN MAN. [Doull, J., C.D. Klaassen, and M. D. Amdur (eds.). Casarett and Doull's Toxicology. 2nd ed. New York: Macmillan Publishing Co., 1980., p. 47]**PEER REVIEWED**
  • CHLOROFORM IS RAPIDLY ABSORBED & DISTRIBUTED TO ALL ORGANS, WITH RELATIVELY HIGH CONCN IN NERVOUS TISSUE. AFTER INTRADUODENAL INJECTION OF (14)C-CHLOROFORM TO RATS, 70% ... WAS FOUND UNCHANGED IN EXPIRED AIR & 4% AS (14)CO2 (CARBON DIOXIDE) DURING 24 HR. ... LIVER &, TO MUCH LESSER EXTENT, KIDNEY WERE MAIN ORGANS IN WHICH CO2 WAS FORMED. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V20 414 (1979)]**PEER REVIEWED**
  • IN MAN, PULMONARY EXCRETIONS OF CHLOROFORM & ITS CO2 (CARBON DIOXIDE) METAB ACCOUNT SUBSTANTIALLY FOR SINGLE ORAL DOSE OF 0.5 OR 1.0 G. AMONGST 9 SUBJECTS, UP TO 68% OF DOSE IS EXCRETED UNCHANGED & UP TO 51% OF CO2; NOT MORE THAN 4% OF DOSE IS EXCRETED UNCHANGED AFTER 8 HR. [The Chemical Society. Foreign Compound Metabolism in Mammals Volume 3. London: The Chemical Society, 1975., p. 329]**PEER REVIEWED**
  • ... /CHLOROFORM CROSSES/ PLACENTA RAPIDLY & ENTERS FETAL CIRCULATION. [The Chemical Society. Foreign Compound Metabolism in Mammals Volume 3. London: The Chemical Society, 1975., p. 635]**PEER REVIEWED**
  • Long-term retention of chloroform occurred in body fat, with incr levels occurring in liver during the post-exposure period. Thus, there is redistribution of chloroform in body tissues as it slowly builds up in fatty tissues during the post exposure period. [Cohen EN, Hood N; J Chloroform Anesthesiol 30: 306 (1969)]**PEER REVIEWED**
  • Chloroform is well absorbed via the respiratory system (94% to 77%). ... Absorption from the gastrointestinal tract approximates 100%. [USEPA; Ambient Water Quality Criteria Doc: Chloroform p.C-5 (1980) EPA 440/5-80-033]**PEER REVIEWED**
  • Distribution of radioactivity in pregnant mice was registered at different time intervals (0-24 hr) after a 10 min period of inhalation of (14)C-labeled chloroform and methyl chloroform. Autoradiographic and liquid scintillation methods were used to make possible the distinction between volatile (non-metabolized), water-soluble and firmly tissue-bound radioactivity. Methyl chloroform was retained longer in fat as compared to chloroform. Metabolites of chloroform were present in a much greater abundancy than those of methyl chloroform and they were found preferentially in the respiratory tract (nasal mucosa, trachea and bronchi), liver and excretory organs. Tissue-bound activity after Chloroform inhalation or ip injection to newborn mice was found in the respiratory tract and centrilobular areas of the liver. Volatile radioactivity was observed in the placenta and fetuses at short time intervals after inhalation of both chloroform and methyl chloroform at all stages of gestation. ... Metabolites accumulated in the embryonic neural tissues. Tissue-bound metabolites of chloroform were observed in the fetal respiratory epithelium. [Danielson BRG et al; Biol Res Pregnancy Perinatol 7 (2): 77-83 (1986)]**PEER REVIEWED**
  • By using the (14)C-labeled compounds, the absorption, distribution, and excretion of trichloromethane ... was determined in rats (100 mg/kg) or in mice (150 mg/kg) after intragastric intubation; most or all the compound was eliminated in both rats and mice by the lung in the expired air. In rats, 40-81% of the compound was expired as (14)C-carbon dioxide and approximately 5-26% as unmetabolized parent. In mice, 4-18% was expired as (14)C-carbon dioxide and approximately 41-67% as parent. [Mink FL et al; Bull Environ Contam Toxicology 37 (5): 752-8 (1986)]**PEER REVIEWED**
  • In 6 acute fatalities due to the intentional or forced inhalation of chloroform, blood levels of 10-48 mg/l and urine levels of 0-60 mg/l were observed. [Baselt, R.C. Biological Monitoring Methods for Industrial Chemicals. 2nd ed. Littleton, MA: PSG Publishing Co., Inc. 1988., p. 81]**PEER REVIEWED**

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Metabolism/Metabolites

  • WHEN (14)C-CHLOROFORM WAS ADMIN ORALLY TO MICE, RATS, & MONKEYS, RADIOACTIVITY WAS FOUND IN EXPIRED AIR. MOST OF DOSE WAS EXCRETED UNCHANGED BY MONKEYS, AS (14)CO2 (CARBON DIOXIDE) BY MICE, & AS BOTH BY RATS. THREE METABOLITES WERE DETECTED IN URINE OF RATS & MICE, ONE OF WHICH WAS IDENTIFIED AS UREA. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V20 414 (1979)]**PEER REVIEWED**
  • HALOFORMS ARE METABOLIZED TO CARBON MONOXIDE BY HEPATIC MICROSOMAL MIXED FUNCTION OXIDASES & THIS REACTION IS MARKEDLY STIMULATED BY SULFHYDRYL CMPD. MAX STIMULATION OCCURRED AT 0.5 MMOL GLUTATHIONE. A MECHANISM FOR CONVERSION TO CARBON MONOXIDE IS PROPOSED. [STEVENS JL ET AL; BIOCHEMICAL PHARMACOLOGY 28: 3189 (1979)]**PEER REVIEWED**
  • TRIHALOMETHANES (HALOFORMS) WERE METAB TO CARBON MONOXIDE BY RAT LIVER MICROSOMAL FRACTION REQUIRING NADPH & MOLECULAR OXYGEN. METABOLISM FOLLOWED HALIDE ORDER; THUS, CHLOROFORM YIELDED SMALLEST AMT. RESULTS SUGGEST CYTOCHROME P450 DEPENDENT SYSTEM. [AHMED AE ET AL; DRUG METABOLISM DISPOSITION 5 (2): 198 (1976)]**PEER REVIEWED**
  • Deuterium-labeled chloroform was less toxic and less readily metabolized than /normal/ chloroform, suggesting that the cleavage of the C-H bond is the rate-limiting step in the process resulting in hepatotoxicity. [Pohl LR; Rev Biochem Toxicol 1: 79 (1979)]**PEER REVIEWED**
  • Whether chloroform-induced nephrotoxicity might be due to its metabolism to phosgene in the kidney was studied. Kidney homogenates from mice in the presence of glutathione metabolize chloroform to 2-oxothiazolidine-4-carboxylic acid (OTZ) This product appears to be formed by the initial trapping of COCl2 by 2 molecules of glutathione to form diglutathionyl dithiocarbonate. Kidney gamma-glutamyl transpeptidase can rapidly metabolize diglutathionyl dithiocarbonate to N-(2-oxothiazolidine-4-carbonyl)glycine which is then hydrolyzed, possibly by cysteinyl glycinase to 2-oxothiazolidine-4-carboxylic acid. The finding that deuterium-labeled chloroform was less nephrotoxic and depleted less renal glutathione than did chloroform suggests that the metabolism of chloroform to phosgene also occur in the kidney in vivo and lead to nephrotoxicity. [Branchflower RV et al; Toxicol Appl Pharmacol 72 (1): 159-68 (1984)]**PEER REVIEWED**
  • While the liver is the primary site for chloroform metabolism, other tissues, including the kidney, can also metabolize chloroform to carbon dioxide. [USEPA; Health Assessment Document: Chloroform (Draft) p.1-3 (1984) EPA-600/8-84-004A]**PEER REVIEWED**
  • ... Relation between metabolism and toxicity of chloroform in the kidney of rabbits, a species in which renal cytochrome p450 is induced by phenobarbital. Pretreatment with phenobarbital enhanced the toxic response of renal cortical slices to chloroform in vitro as indicated by decreased p-aminohippurate and tetraethylammonium (+1) accumulation. Phenobarbital pretreatment also potentiated in vitro (14)C-chloroform metabolism to (14)carbon dioxide and covalently bound radioactivity in rabbit renal cortical slices and microsomes. Addition of L-cysteine significantly reduced covalent binding in renal microsomes from phenobarbital-treated and control rabbits and was associated with the formation of 2-oxothiazolidine-4-carboxylic acid. Formation of 2-oxothiazolidine-4-carboxylic acid was enhanced in renal microsomes from phenobarbital-treated rabbits. Thus, the kidney metabolizes chloroform to phosgene. [Bailie MB et al; Toxicol Appl Pharmacol 74 (2): 285-92 (1984)]**PEER REVIEWED**
  • Studies were made with male Wistar rats on the effects of 50% food restriction on the metabolism of ... chloroform. ... The activities of liver drug-metabolizing enzymes for this solvent was enhanced almost equally without exception by one-day food restriction, although the restriction produced no significant increase in the microsomal protein and cytochrome p450 contents. Thus, food restriction enhances metabolism of chloroform in the liver. [Koyama Y, Sato A; Jpn J Ind Health 28 (2): 96-100 (1986)]**PEER REVIEWED**
  • Rats were injected iv or ip with (14)C chloroform and the localization and binding of metabolites in the tissues were studied by whole-body and microautoradiography. Based on the the autoradiographic findings various tissues were tested for their capacity to form (14)CO2 and to incorporate (14)C into tissue-macromolecules from the (14)C chloroform. Autoradiography in vitro was used to localize the sites of (14)C chloroform metabolism under in vitro conditions. The results of the in vitro metabolism studies showed that several tissues had a capacity to metabolize the (14)C chloroform. Further, the results showed that there was a correlation between the ability of various tissues to accumulate metabolites in the rats injected with the (14)C chloroform and the ability of the same tissues to metabolize the (14)C chloroform in vitro. The in vitro autoradiography showed an accumulation of radioactivity at sites corresponding to the ones accumulating metabolites in vivo. It is concluded that many tissues have a capacity to metabolize chloroform in vivo and in vitro. The structures identified to have a marked chloroform-metabolizing capacity were, besides the liver, the kidney cortex, the mucosa of the bronchial tree, the tracheal mucosa, the olfactory and respiratory nasal mucosa. Bowman's glands in the olfactory lamina propria mucosae, Steno's gland (the lateral nasal gland), the mucosa of the oesophagus, the larynx, the tongue, the gingiva, the cheek, the nasoparyngeal duct, the pharynx and the soft palate (but not the hard palate). [Lofberg B, Tjalve H; Toxicology 39 (1): 13-36 (1986)]**PEER REVIEWED**
  • Hepatic lipoperoxidation by highly reactive metabolites produced during biodegradation of chloroform is believed to cause delayed hepatic necrosis. Chemilluminescence occurs during interaction of these metabolites with a lipid membrane. We have made continuous in vivo measurements of hepatic light output in the phenobarbital-induced rat breathing either air or chloroform vaporized in air. The data permitted direct estimation of the time course of chloroform-induced lipoperidoxidation. These potentially toxic events began 15 minutes after initiation of anesthesia and continued for the duration of the study. Chemiluminescence did not occur with inhalation of isoflurane, an anesthetic undergoing minimal biodegradation. [Cohen PJ, Chance B; Biochim Biophys Acta 884 (3): 517-9 (1986)]**PEER REVIEWED**
  • IN VITRO ... FINDING OF 2-OXO-THIAZOLIDINE-4-CARBOXYLIC ACID IN INCUBATES WAS STRONG EVIDENCE FOR FORMATION OF PHOSGENE; REACTIVE METABOLITE, PHOSGENE IS FORMED BY MIXED-FUNCTION OXIDATION OF CHLOROFORM TO TRICHLOROMETHANOL ... /WHICH UNDERGOES/ DEHYDROCHLORINATION. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V20 414 (1979)]**PEER REVIEWED**

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TSCA Test Submissions

  • The toxicokinetics of chloroform (CAS # 67-66-3, CHCl3) was systematically evaluated and interpreted in various species including B6C3F1 mice, Fischer 344 and male Osborne-Mendel rats, and male Syrian Golden hamsters for development and validation of a physiologically-based pharmacokinetic (PB-PK) model of prospective dose-, species- and route-specific disposition of CHCl3. This model assumes total chloroform metabolism within target organs, liver and kidney, solely by a mixed function oxidase (MFO) metabolic pathway following Michaelis-Menten kinetics. Metabolic rate constants (Vmax, Km, and V/S), calculated by computer optimization of multispecies enzyme activity and kinetics studies in liver and kidney, allowed extrapolation of results between species. The model facilitates determination of a "delivered dose" (macromolecular binding, MMB) of chloroform metabolites to chloroform-sensitive internal organs to imply a potential cytotoxicity and tumorigenicity associated with chronic CHCl3 exposure. Toxicologically-significant descending relative rates of chloroform sensitivity in mice, rats, and humans were revealed. In chronic inhalation study with B6C3F1 mice, tumorigenicity correlated better with the rate of MMB (and a cellular regenerative response) than with absolute metabolite or MMB levels. Inclusion of historical absorption rates through digestive, respiratory, and circulatory compartments in the mammalian model allowed toxicological simulations based on route of administration. A homologous biochemical response provides a basis for the extrapolation of toxicity associated with the relatively high chronic exposures in studies with laboratory animals to that expected in humans chronically exposed to lower levels of chloroform typically encountered in the environment. Phase two studies will attempt to correlate rates of cytotoxicity and cell death to MMB. The authors offered that such a PB-PK model might be used for quantification of the potential biohazard to humans chronically exposed to low level trichloromethane found in chlorine-pretreated drinking water.[Dow Chem Co; Chloroform - A Physiologically-Based Pharmacokinetic Model Including Cytotoxicity as an Endpoint, Part A - Development of the PB-PK Model (Final Report); EPA Document No. 86-890000091; Fiche No. OTS0516654]**UNREVIEWED**
  • Chloroform (CAS # 67-66-3) bioactivation and toxicity in the kidney and liver was investigated in B6C3F1 mice and in male Osborne-Mendel rats exposed in an environmental chamber to target vapor concentrations of 0, 10 (mice only), 100 (mice only), 400, and 1100 ppm for approximately 6 hours. Groups of 4 mice and 4 rats from each treatment level were sacrificed for quantification of nonprotein sulfhydryl (NPSH, to approximate glutathione) levels in liver and kidney tissues at 0, 2, 4, and 6 hours into the exposures and at 6, 12, 24, 46, and 48 hours following final exposures. In mice, treatment was associated with significant mortality 36 hours following 400 and 1100 ppm exposures, lethargy and perineal staining (400, 1100 ppm), and light anesthesia (1100 ppm). Upon necropsy, livers and kidneys appeared pale as compared to those of sham controls. In rats, light anesthesia upon 1100 ppm exposures alone characterized the clinical toxicity and no gross pathology was identified upon terminal necropsy. Renal NPSH levels were statistically significantly (Winer's paired t-test) depressed for prolonged periods following exposures of 100 ppm and above in mice, while NPSH levels either equalled or slightly exceeded those of sham control animals in rats of exposures below 1100 ppm. Conversely, mouse hepatic NPSH levels dropped markedly at isolated sampling times only, the NPSH depressions inconsistent and not dose related, but more profound in association with 400 and 1100 ppm than with 10 and 100 ppm exposures. In rats, both renal and liver NPSH levels were statistically significantly (Winer's paired t-test) depressed at 4-hour sampling following 1100 ppm exposures. These studies contributed to derivation of metabolic and bioactivation rate constants in design of a physiologically-based pharmacokinetic (PB-PK) model of chloroform toxicity.[Dow Chem Co; Chloroform - A Physiologically-Based Pharmacokinetic Model Including Cytotoxicity as an Endpoint, Part A - Development of the PB-PK Model (Final Report); EPA Document No. 86-890000091; Fiche No. OTS0516654]**UNREVIEWED**
  • The metabolic disposition of chloroform (CAS # 67-66-3, CHCl3) was evaluated in male B6C3F1 mice (4/group) and Osborne-Mendel rats (3/group) exposed under dynamic flow-through conditions in a Roth-type metabolism chamber to target vapor concentrations of 10 (mice only), 100, 400 and 1100 (rats only) ppm 14CHCl3 for 6 hours. Urine, feces, and CO2 were collected and analyzed for radioactive label both during and after exposure. Likewise, aqueous samples of carcass homogenates (33-50% w/w) and skin, harvested during terminal sacrifice of all test animals 48 hours post exposure, were analyzed to quantify fixed radiolabel. At exposures of 400 ppm, metabolism of 14CHCl3 appeared to become saturating (non-linear) in both mice and rats, with the radioactive body burden recovered as metabolites (mice 92%; rats 80%) diminished relative to that at 100 ppm (98-99%). Additionally, post-exposure metabolism and unmetabolized 14CHCl3 collected following exposures in excess of 100 ppm increased disproportionately. Exhaled 14CO2, urine, and feces, respectively, accounted for approximately 85%, 10%, and 1-1.5% of the total radiolabeled CHCl3 metabolized; the carcass and skin accounted for approximately 3% and 1%, respectively. On comparison, elimination routes and rates were highly consistent in mice and rats, although the total body burden (mg/kg) in mice was 2-4X that in rats. These studies contributed to derivation of metabolic rate constants in design of a physiologically-based pharmacokinetic (PB-PK) model of chloroform toxicity.[Dow Chem Co; Chloroform - A Physiologically-Based Pharmacokinetic Model Including Cytotoxicity as an Endpoint, Part A - Development of the PB-PK Model (Final Report); EPA Document No. 86-890000091; Fiche No. OTS0516654]**UNREVIEWED**
  • The metabolic disposition of chloroform (CAS # 67-66-3, CHCl3) was evaluated in male B6C3F1 mice (4/group) and Osborne-Mendel rats (3/group) exposed under dynamic flow-through conditions in a Roth- type metabolism chamber to target vapor concentrations of 10 (mice only), 100, 400, and 1100 (rats only) ppm 14CHCl3 for 6 hours. All animals were sacrificed at 6 hours post exposure for harvest and assay of liver and kidneys to assess the degree of irreversible macromolecular binding (MMB), or the "delivered dose" (Anderson, 1987) of radiolabel chloroform or its metabolites. At low exposure levels (10, 100 ppm), mouse kidney MMB (1.06, 4.01 nmol Eq/mg protein) was 4-10 fold greater than liver MMB (0.10, 1.05 nmol Eq/mg protein), while these values converged at 400 ppm (4.99 and 4.48 nmol Eq/mg protein for liver and kidney, respectively). Conversely, at exposure levels of 100 and 400 ppm, rat liver MMB (0.60, 1.33 nmol Eq/mg protein) and kidney MMB (0.66, 0.89 nmol Eq/mg protein) were roughly equivalent, while these values diverged between 400 and 1100 ppm, such that liver MMB after a 1100 ppm exposure (1.70 nmol Eq/mg protein) was approximately 2X kidney MMB (0.78 nmol Eq/mg protein). Mouse MMB was higher, on comparison, than that in the rat at the same exposure levels, consistent with a higher rate of CHCl3 metabolism. These values became an integral component of a physiologically-based pharmacokinetic (PB-PK) model of chloroform toxicity.[Dow Chem Co; Chloroform - A Physiologically-Based Pharmacokinetic Model Including Cytotoxicity as an Endpoint, Part A - Development of the PB-PK Model (Final Report); EPA Document No. 86-890000091; Fiche No. OTS0516654]**UNREVIEWED**
  • The rate of chloroform (CAS # 67-66-3, CHCl3) metabolism was evaluated in 6-hour in vitro bioassay with microsomal fractions of liver and kidney from B6C3F1 mice, F344 rats, Syrian Golden hamsters, and humans. Microsomal protein preparations of each species were incubated for 30 minutes with labeled 14CHCl3 in dimethyl formamide, a NADPH regenerating system and a potassium phosphate buffer (pH 7.4). Boiled enzyme preparations containing equivalent amounts of protein served as controls. The reaction terminated at 30 minutes, CO2 generated by the enzymatic reaction was measured and the solution's unreacted substrate (14CHCl3) and water-soluble reaction products separated by solvent extraction (unlabeled CHCl3). Liquid scintillation assay in combined species analysis (mice, rats, hamsters, and humans) documented a rate of 14CHCl3 biotransformation to water-soluble metabolite proportional to time for 10-30 min and proportional to protein concentration up to 1-2 mg protein per incubation. This reaction was wholly inhibited by boiling the enzyme prior to incubation. Reaction rates or MFO (mixed function oxidase) activities (nmoles oxidized/min/mg protein at 0.049-0.058 mM CHCl3) in liver microsomes of mouse, rat, and hamster ranged from 0.0199 (rat) to 0.133 (hamster) nmoles/min/mg protein. Human liver microsomes demonstrated a broad activity range from 0.003 - 0.017 nmoles/min/mg protein (mean +/- s.d. = 0.00816 +/- 0.00448), the slowest rates among tested mammals. Descending rates of CHCl3 metabolism in the kidney were found in mice (0.0102 nmoles/min/mg protein), hamsters (0.00562 nmoles/min/mg protein), and rats (0.000928 nmoles/min/mg protein). Human kidney samples were limited and failed to demonstrate microsomal rates of CHCl3 metabolism above the minimal detection limit (0.0003 nmoles/min/mg protein at 0.06 mM CHCl3). Species-specific metabolic indices were subsequently derived by computer optimization of kinetics study data associated with 1-20 mM 14CHCl3 for development of a physiologically-based pharmacokinetic (PB-PK) model of chloroform toxicity.[Dow Chem Co; Chloroform - A Physiologically-Based Pharmacokinetic Model Including Cytotoxicity as an Endpoint, Part A - Development of the PB-PK Model (Final Report); EPA Document No. 86-890000091; Fiche No. OTS0516654]**UNREVIEWED**
  • Chloroform (CAS # 67-66-3) was evaluated for developmental toxicity in pregnant Wistar rats (23-25/group) exposed by inhalation at concentrations of 0, 30, 100, and 300 ppm for 7 hours/day during Days 7-16 postconception. Treatment was associated with dose-related depression of maternal food consumption and bodyweight gains, primarily during the first week of treatment; no further signs of maternal toxicity and no gross pathology were observed. Signs of embryotoxicity included dose-dependent early intrauterine loss of primordia with slightly stunted development (slightly reduced crown-rump length) among the remaining live fetuses at all treatment levels. No toxicologically significant incidence of malformations was observed on Day 21 terminal necropsy of treated and control fetuses relative to spontaneous occurrence in experimental controls.[Halogenated Solvents Industry; Two Genotoxicity Studies on Chloroform and One Embryotoxicity Study on Chloroform; 07/28/88; EPA Document No. FYI-OTS-0988-0635; Fiche No. OTS0000635]**UNREVIEWED**
  • Chloroform (CAS # 67-66-3) was evaluated for clastogenicity in Chinese Hamsters (5/sex/treatment group) exposed by oral gavage to doses of 0 (solvent control), 40, 120, and 400 mg/kg bw with subsequent harvest, preparation and analysis of metaphase bone marrow cells (100 cells/animal) at 6 (high dose), 24 (all doses), and 48 (high dose) hours post-treatment. Hamsters of 400 mg/kg doses exhibited signs of toxicity including hypoactivity, closed eyes, and arrested food consumption. Slight enhancement of chromosomal aberrations was statistically significant (Mann-Whitney-U-test) 6 and 24 hours after doses of 400 mg/kg, although the rate was still within the range of historical negative controls. Further, outside the range of historical controls, no dose-response relationship was demonstrated. The study authors noted an inference of chloroform mutagenicity, however, based on the nature of marked damage (multiple aberrations, chromosomal disintegration, and exchanges) associated with oral chloroform at doses of 120 and 400 mg/kg (6-, 24-, and 48-hour assessments). In repeat study, exposing groups of hamsters to doses of 0 (solvent control), 120, and 400 mg/kg bw, 24-hour cytogenetic assay again revealed a slight but statistically significant increase in chromosome aberrations in association with 400 mg/kg doses, failing again to demonstrate a dose-response relationship for rates of damage (chromosome breaks) beyond the range of historical controls. Distinctly heavy damage (multiple aberrations and exchanges) characterized the chloroform-induced aberrations at 400 mg/kg in 6/6000 metaphase bone marrow cells.[Dow Chem Co; Chloroform - Chromosome Aberrations in Chinese Hamster Bone Marrow Cells; 03/09/88; EPA Document No. 88-920005773; Fiche No. OTS0544556]**UNREVIEWED**

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Footnotes

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

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