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Carcinogenicity

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Description of key information

- Carcinogenicity, oral:     NOAEL  = 10 mg/kg bw/day for the mouse, 120 daily exposures no guideline followed; study: Eschenbrenner & Miller + weight of evidence from Della Porta (1960), Page (1976) and Weisburger (1977)

- Carcinogenicity, dermal:      no study available

- Carcinogenicity, inhalation:      NOAEC = 32 mg/m³ air (= 5 ppm) for the rat and the mouse, 2 y (OECD TG 453); study: Nagano 2007 B), based on increase of hepatocarcinoma incidences at higher level exposures.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
10 mg/kg bw/day

Carcinogenicity: via inhalation route

Endpoint conclusion
Dose descriptor:
NOAEC
32 mg/m³

Additional information

For this endpoint, several studies are available by the oral and inhalation route. Since the most relevant route of exposure for human is inhalation, the key parameter was assessed mainly for inhalation. Nevertheless, the studies by oral exposure support the results found by inhalation: the liver was the main target organ for both routes of exposure. Cytotoxicity seems to be an important factor in the generation of pre-neoplastic lesions. Taking into account that no genotoxicity has been observed with CTC in vivo, a threshold for carcinogenicity is postulated for CTC.

 

Carcinogenicity, inhalation:

In a combined 2-year combined carcinogenicity/repeated dose study in the rat and the mouse by Nagano et al (2007 B), animals were exposed for 6 h/d, 5 d/week during 104 weeks. The study was performed in compliance with OECD TG 453 and GLP. In both species, at 160 and 800 mg/m³ (25 and 125 ppm), a marked to severe liver toxicity and an increase in incidences for liver carcinomas were determined. At 32 mg/m³ (5 ppm) the number of carcinomas in both species was not raised and only minor toxic effects were apparent. In the female mice group at 32 mg/m³ (5 ppm), an increased number of hepatocellular adenomas was reported at 32 mg/m³ (5 ppm) but only with a low statistical significance (p ≤ .05); in the medium and high dose groups, hepatocellular carcinomas were observed (both in mice and in rats). Therefore a NOAEL of 5 ppm (v/v) (= 32 mg/m³) in both species after chronic exposure to CTC via the inhalation route can be derived from this study. This NOAEL is in accordance with the opinion of the SCOEL in the "Recommendation of the Scientific Expert Group on Occupational Exposure Limits for Carbon Tetrachloride" (SEG/SUM/31, 2009). In conclusion the NOAEC of 32 mg/m³ (= 5 ppm) in rats for the carcinogenic potential of CTC and the corresponding LOAEC of 64 mg/m³ (10 ppm) is considered applicable for the risk assessment.

 

Carcinogenicity, oral:

Tumorigenic responses of rats, mice and hamsters have been observed after oral administration of CTC. The liver was the main target for appearance of tumours. In the Eschenbrenner study (1946), the NOAEL was 10 mg/kg bw /day in mice (non-guideline protocol). In another study by oral route in rats, the LOAEL was 25 mg/kg bw/d, based on a dose-dependent increase of carcinogenic effects at the double dose (78 weeks exposure). In Syrian hamsters, the LOAEL was found to be 25 mg/kg bw/d after 78 weeks exposure by oral route (Della Porta, 1960).

 

Carcinogenicity, dermal:

No study is available for this route.

 

General conclusion on carcinogenicity

Studies in humans were inadequate to show an association between exposure to carbon tetrachloride and carcinogenicity. None of the human epidemiology studies reported associations to cancer of the liver, which is the main site of carcinogenicity in animal studies. In conclusion, as reported by IARC, there is inadequate evidence in humans for the carcinogenicity of carbon tetrachloride, but there is sufficient evidence in experimental animals for the carcinogenicity of carbon tetrachloride.

Carcinogenicity: via oral route (target organ): digestive: liver

Carcinogenicity: via inhalation route (target organ): digestive: liver

Carcinogenicity: via dermal route (target organ): digestive: liver

Justification for classification or non-classification

Carcinogenicity, oral, dermal and inhalation:

Appropriate studies in animals clearly shown that CTC is carcinogenic in animals (in different species). In humans, there are no studies indicating that CTC is carcinogenic. Based on the results of the above mentioned studies on the carcinogenic potential of CTC via the oral and the inhalation route and based on considerations on the potential toxic mode of action of CTC after application via the dermal route the following classification is considered appropriate:

Category 2 (Suspected human carcinogens) according to EU Regulation (EC) N0. 1272/2008 (CLP)

Category 3 according to EU directive 67/578/EEC.

A threshold approach for the risk assessment of the carcinogenicity of CTC is considered appropriate, considering the data on genotoxicity.