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Description of key information

Key value for chemical safety assessment

Carcinogenicity: via inhalation route

Endpoint conclusion
Dose descriptor:
638 mg/m³

Justification for classification or non-classification

The positive results in two animal species in the carcinogenesis study indicate that TFE should be classified as a Category 2 Carcinogen under the EU Dangerous Substances Directive 67/548/EEC. The findings of the retrospective cohort mortality could neither conclusively confirm or refute the hypothesis that TFE poses a carcinogenic risk to human beings and, as such, do not impact on the assessment of the carcinogenic hazard of TFE. As TFE is a gas, ingestion and skin absorption are not likely routes of exposure. Therefore it is judged that the appropriate classification is Carcinogen Category 2; R49 - May cause cancer by inhalation.

Classification as a Category 1B Carcinogen, with the Hazard Statement H350: May cause cancer by inhalation, is also appropriate according to the EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation EC No. 1272/2008.

Additional information

TFE causes toxic effects in various organs and is carcinogenic in both the rat and the mouse after lifetime exposure.

The survival rates of all groups of mice exposed to TFE were reduced compared to controls, although there were no significant reductions in the mean body weights of survivors at the end of the study. In the liver, multifocal coagulative necrosis was observed in all groups of exposed males, whilst haematopoietic cell proliferation was observed in all groups of exposed females. Angiectasis was also observed in all groups of exposed males and females. In addition, increase incidences of renal tubular dilatation and karyomegaly, principally in the inner cortex, were also observed. No NOAEL can be established in the mouse on the basis of the information currently available.

Exposure of mice to TFE caused increased incidences of haemangiosarcoma of the liver and histiocytic sarcoma (all organs) in all groups of exposed males and females at the end of the study. Increased incidences of haemangiosarcoma were also apparent in groups of both males and females exposed to the highest concentrations of TFE for 15 months. Increased incidences of hepatocellular tumours were also observed in all treated groups of males and females.

In the rat, there was increased mortality following exposure to 625 ppm TFE (2555 mg/m3) and in all groups of females (upto 1250 ppm; 5110 mg/m3) when exposed for their lifetime. The primary target organs for toxicity in the rat were the liver and the kidney. Increased absolute and relative kidney weights and exesses of renal tubular adenoma, or adenoma and carcinoma combined, were reported. In addition, increases in absolute and relative liver weight were observed in both sexes, along with increased incidences of clear cell and mixed cell foci and hepatic angiectasis in all exposed groups. TFE caused an increase in the incidence of hepatocellular adenoma and/or carcinoma combined in both males and females, along with an increased incidence of haemangiosarcoma in the liver in females exposed to a high concentration of TFE.

No NOAEL for liver effects could be determined in male or female rats or for renal effects in male rats following life-time exposure to TFE. Therefore, 156 ppm (638 mg/m3) was a LOAEL for renal tubular degeneration in the rat and, since tumours were also observed at this level, for carcinogenic effects.

The pattern of findings in a large multi-centre retrospective mortality study substantially narrows the range of uncertainty on the possible cancer risk entailed by exposure to TFE during its synthesis and polymerization. The findings could neither conclusively confirm nor refute the hypothesis that TFE poses a carcinogenic risk to human beings. However, if a cancer hazard exists, then the risk is small, even in workers with relatively high exposure.