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Toxicological information

Carcinogenicity

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Description of key information

Chloroform administered via the oral route can induce the formation of kidney tumours in male ICI mice receiving the substance at a repeated oral dose of 60 mg/kg/day for 104 weeks (Roe et al. 1979). The oral NOAEL for these effects was 17 mg/kg/day. Repeated dose inhalation exposure to chloroform vapours can induce increased incidence of renal adenomas and carcinomas in BDF1 mice (Yamamoto et al. 2002) at 147 mg/m3 or greater.The NOAEL value was considered 25 mg/m3. 

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion
Dose descriptor:
NOAEL
17 mg/kg bw/day

Carcinogenicity: via inhalation route

Endpoint conclusion
Dose descriptor:
NOAEC
25 mg/m³

Additional information

Oral exposure

Three chronic exposure studies were carried out with chloroform using the following strains of mice: C57BL, CBA, CF/1, ICI (Roe et al. 1979). The studies were carried out according to principles similar to those of the EU method B.32 with restrictions. Chloroform was administered orally by gavage in toothpaste or in arachis oil. Male ICI mice were most susceptible with regard to exposure to chloroform. Male ICI mice receiving chloroform at a dose of 60 mg/kg body weight/day in arachis oil exhibited a slight increase in moderate to severe fatty degeneration of the liver and a statistically significant increase in the incidence of kidney tumours (adenomas and carcinomas). Treatment with chloroform was associated with increased incidence of moderate to severe kidney lesions in CBA and CF/1 mice. The experimental NOAEL value established in the study was 17 mg/kg body weight/day.

A carcinogenicity study was carried out with male Osborne-Mendel rats receiving chloroform via drinking water during a period of 104 weeks (Jorgensen et al. 1985). The increased incidence of renal cell tumours was clearly dose-related. The occurrence of the renal tumours associated with chloroform treatment was likely to be of biological significance. At concentrations of 400 mg/L and above, the incidence of renal tumours exceeded that of both control groups. Thus, the NOAEL value for the increased incidence of renal tumours in male Osborne-Mendel rats was 200 mg/L.

The carcinogenicity of chloroform was also tested in female B6C3F1 mice being orally exposed to chloroform dissolved in drinking water at 0, 200, 400, 900, 1800 mg/L (corresponding to 0, 34, 65, 130, 263 mg/kg) during a period of 104 weeks (Jorgenson et al. 1985). No treatment-related increases in tumour incidence were observed in the female mice at any dose-level. The NOAEL for carcinogenicity in the study was 1800 mg chloroform/L drinking water.

Dermal exposure

The carcinogenicity via the dermal route has not been studied for chloroform. The inhalation NOAEC of 25 mg/m3 established for carcinogenicity will be used to derive the dermal threshold value and route-to-route extrapolation is performed. The absorption efficiencies for chloroform are given in the EU risk assessment (France 2007): 80 % via inhalation route and 10 % via dermal route. The inhalation volume of the testing animals (mouse: 0.41 m3/kg for the six hours, France 2007) is taken into account. There is no extrapolation from subchronic to chronic effects because comparable effect levels were seen at both exposure durations. The inhalation NOAEC can thus be corrected to produce a dermal NOAEL: 25 * 0.41 * 0.8 / 0.1 = 82 mg/kg bw/day (the NOAEL derived from the oral LOAEL is 150 mg/kg bw/day).

Inhalation exposure

A combined chronic toxicity/carcinogenicity study was carried out with chloroform in female and male BDF1 mice (Yamamoto et al. 2002) receiving repeated dose inhalation exposure to chloroform vapours at concentrations of 24, 147 and 441 mg/m3 for 104 weeks according to the method B.33 suggested by the European Commission. Adverse effects were mainly observed in the liver and kidneys of exposed animals. Inhalation exposure to chloroform of mice over a period of 2 years led to a significantly increased incidence of renal adenomas and carcinomas at exposure concentrations of 147 and 441 mg/m3. For the exposed mice, the histopathological changes in the kidneys including the cytoplasmic basophilia which occurred at 147 mg/m3 or greater, were employed as the biologically significant endpoint to deduce a NOAEL value of 25 mg/m3.

A combined chronic toxicity/carcinogenicity study was carried out with chloroform using female and male F-344 rats (Yamamoto et al. 2002) receiving inhalation exposure to chloroform vapours of 50, 147 and 441 mg/m3 during a period of 2 years. The study was in accordance with the method B.33 suggested by the European Commission with minor restrictions. The growth rate of female and male rats exposed to 147 mg/m3 chloroform vapour was suppressed over the controls. Nasal lesions were observed at exposure concentrations of 50 mg/m3 and above. The 2-year inhalation exposure to 50, 147 or 441 mg/m3 did not result in any significant increase in the incidence of liver and kidney tumours in both sexes. Exposure to chloroform at 147 or 441 mg/m3 induced nuclear enlargement of the proximal tubules and dilatation of the tubular lumen without development of renal tumours. No significantly increased incidence of histopathological lesions in the liver was found. The NOAEC value for the histopathological changes in the kidneys was found to be 50 mg/m3.


Carcinogenicity: via oral route (target organ): urogenital: kidneys

Carcinogenicity: via inhalation route (target organ): digestive: liver; urogenital: kidneys

Justification for classification or non-classification

On the basis of the available data the proposed GHS classification is Category 2 carcinogen, "Suspected human carcinogen", with the hazard statement: suspected of causing cancer. The substance is classified as carcinogen category 3 (R40) according to EU directive 67/548/EEC.