Hexafluoropropene

Carcinogenicity

Justification for classification or non-classification

“A substance that has not been tested for carcinogenicity may in certain instances be classified in Category 1A, Category 1B or Category 2 based on tumour data from a structural analogue together with substantial support from consideration of other important factors….” “The specific category depends on the category of the known carcinogen and the degree of confidence in the robustness of the read‐across prediction. The category will not be higher than the chemical used to read‐across from, but normally may be the same. However, a lower category may be applied if the read‐across highlights a possible carcinogenic hazard, and thus supports a classification, but there is uncertainty as to the robustness of the read‐across prediction or there is evidence, for instance from mechanistic or other studies, that the chemical may be of lower concern for carcinogenicity. “Read across information so far is limited to the presumed GSH metabolite which theoretically may induce kidney tumours. Therefore, there is some uncertainty in the prediction of HFP as a suspected carcinogen. No mechanistic argument can be used for a read across to the other tumours observed with TFE. The higher systemic toxicity of HFP in comparison to TFE would in principle preclude exposure to HFP at similar high concentrations in a chronic toxicity study due to excessive toxicity. Significantly, the existing subacute and subchronic studies of HFP in rats and mice (90 day studies) did not show any additional histopathological tumour‐precursor lesions and in particular no neoplasia or preneoplastic changes in any of the tissues analysed. Therefore, according to the criteria in section 3.6.2 using both a strength and weight of evidence approach, these considerations would strongly support the classification of HFP as a Cat. 2 carcinogen according to EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008 on a strictly precautionary basis.

Additional information

Hexafluoropropene has been shown to produce kidney damage in laboratory animals exposed via repeated inhalation. Based on in vitro and in vivo toxicokinetic data, it is speculated that intrarenal conjugation of hexafluoropropene with glutathione (GSH) may be an important step in the bioactivation of hexafluoropropene. S‐hexafluoropropyl‐glutathione (HFPG) formed in the kidney could be processed by gamma‐glutamyltranspeptidase and dipeptidases to the corresponding cysteine S‐conjugate, which is metabolized by renal cysteine conjugate b‐lyase, to give an electrophilic intermediate, most likely a thionoacyl fluoride.

Suspicion that HFP might be carcinogenic is limited to a potential kidney tumour formation by a non‐genotoxic mechanism. It is concluded from 10 existing genotoxicity studies with HFP that from a weight‐of‐evidence approach there is no concern of a genotoxic mode of action with HFP.

Carcinogenicity testing of HFP will consume large numbers of laboratory animals, but will not drive improved safety for workers, given the current stringent workplace exposure limit in mind and the proposed Cat 2 cancer classification. Additional animal testing with HFP seems to be in conflict with the stated aim of REACH to avoid unnecessary animal testing and should be a “last resort” to obtain data