Registration Dossier

Administrative data

Description of key information

Key value for chemical safety assessment

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Dose descriptor:
LOAEC
638 mg/m³

Additional information

In accordance with section 2 REACH Annex XI, studies via the oral and dermal route do not need to be conducted as the substance is a gas.

The toxicity of TFE following repeated exposure by inhahalation has been studied in the mouse, rat and hamster for durations up to 13 weeks. In the mouse, the most significant finding was renal tubular karyomegaly, the NOAEL being 625 (2555 mg/m3) in a 13 week study. The rat showed greater sensitivity to the kidney toxicity, with effects including proteinuria being seen at concentrations of >/= 312 ppm (1275 mg/m3) in a 13 week study (LOAEL). The effects were also more severe, with renal tubular degeneration, accompanied by increases in kidney weight at higher concentrations. Increases in liver weight were also seen in rats exposed to 5000ppm (20400 mg/m3) TFE for 13 weeks. A NOAEL of 203 ppm (830 mg/m3) for kidney effects was observed in the rat study.

In addition, both species showed a secondary hypoproliferative anaemia when exposed to TFE. The changes in the various indicies were minimal, but statistically significant at higher exposure concentration levels in the rat and were more pronounced in males than in females.

In contrast, no evidence of kidney toxicity or anaemia was seen in hamsters exposed to TFE at concentrations up to 1989 ppm (8130 mg/m3) in a 13 week study. There was equivocal evidence of testicular toxicity in male hamsters exposed by inhalation to 2500 ppm (10220 mg/m3) in a 28 day study. However, in a 13 week study in the same strain of hamster, an exposure-related focal hypocellularity of the germinal epithelium of the seminiferous tubule was observed in males exposed to TFE at concentrations of 1989 (8130 mg/m3). This observation was made against a background of variability in testes weight and overall testicular development in the different groups, including controls, making it difficult to make the overall interpretation of the significance of the data. Testicular atrophy was not seen in rats or mice.

Exposure of B6C3F1 mice, 6 h/d, 5 d/wk by inhalation to concentrations of TFE ranging from 312 ppm up to 1250 ppm (1275 to 5110 mg/m3) for 95 weeks caused reduced survival rates in all exposed groups but no clinical findings related to exposure to TFE. An increased incidence of angiectasis was observed in all exposed groups, accompanied by multifocal coagulative necrosis of the liver in all exposed groups of males and increased incidences of haematopoietic cell proliferation in the liver in females and the spleen of all exposed groups of both males and females. Increased incidences of renal tubular dilatation and karyomegaly were also observed in all exposed groups.

Exposure of F344 rats, 6 h/d, 5 d/wk by inhalation to concentrations of TFE, ranging from 156 ppm to 1250 ppm (638 to 5110 mg/m3) for 103 weeks caused reduced survival rates in all exposed groups. The only clinical finding related to exposure to TFE was opacity of the eyes in females exposed to 1250 ppm, due to the presence of cataracts. Increased incidences of renal tubule degeneration, located predominantly at the cortico-medullary junction were seen in all exposed groups and increased incidences of renal tubule hyperplasia were seen in males exposed to 625 ppm TFE and females exposed to 1250 ppm TFE. In addition, increased incidences of hepatic angiectasis were observed in all exposed groups of female rats.

Value used for CSA (route: inhalation):

LOAEC 638 mg/m3 air (156 ppm from the 2 -year study)

Justification for classification or non-classification

Based on the data from the 2 -year studies, classification for TFE is not warranted according to EU directive 67/548/EEC because significant nephrotoxicity was only seen in the rat following exposure to concentrations in excess of 0.25 mg/l, 6 hr/day for 2 years.

Classification in the STOT-RE is not warranted according to the EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation EC No. 1272/2008 because significant nephrotoxicity was only seen in the rat exposed to concentrations well in excess of 250 ppm, 6 hr/day for 90 days.