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Diss Factsheets

Administrative data

Description of key information

The acute toxicity of ETBE is low. The oral and dermal LD50 values in rats and rabbits were >2000 mg/kg bw (both routes of exposure). In an inhalation study with rats, a LC50 value of > 5.88 mg/l was obtained. This result is confirmed by White et al (1995) (28 day inhalation study with rats, maximal concentration 16.8 mg/l, no mortality) and CIIT (1996a,b) (90 day inhalation studies with rats and mice, maximal concentration 21 mg/l, no mortality).
Limited human data showed that exposure to 25 and 50 ppm ETBE vapour for 2 hr was associated with slightly decreased lung function. However, the changes were mild in nature and minor in extent, and reflect normal variation that is of no clinical significance.

Key value for chemical safety assessment

Acute toxicity: via oral route

Endpoint conclusion
mg/kg bw

Acute toxicity: via inhalation route

Endpoint conclusion
mg/m³ air

Acute toxicity: via dermal route

Endpoint conclusion
mg/kg bw

Additional information

Three acute toxicity studies by oral route with rats with the same result were available for assessment, two of which have been conducted according to OECD Guideline 401 and under GLP (Institut Pasteur de Lille, 1992a; Pharmakon Europe, 1994a). As no data on the tested sample of ETBE is known regarding the first study, the latter study is considered the key study. ETBE was administered undiluted by gavage at a dose of 2.67 ml/kg, equivalent to 2003 mg/kg bw, to groups of 5 male and 5 female Sprague-Dawley rats. There were no deaths during the 14 days post-exposure period. The LD50 value for acute toxicity in rats was determined to be > 2003 mg/kg bw. The behaviour of animals was subdued 1-4 hr post-exposure. All animals were normal on day 2.

One acute toxicity study by inhalation with rats, performed according to OECD Guideline 403 and under GLP, was available for assessment (IIT Research Institute, 1989a). 5 male and 5 female SD rats were exposed to the vapours of ETBE (99% purity) by nose-only inhalation at the limit concentration of 5.88 mg/l. There were no deaths during the exposure period or during the 14 days observation period. The LC50 was determined to be > 5.88 mg/l. Clinical signs comprised redness around the nose/eyes and discoloured facial fur immediately after exposure (appearance of most animals was normal the following day). This result is confirmed by White et al (1995) (28 days inhalation study with rats, maximal concentration 16.8 mg/l, no mortality) and CIIT (1996a,b) (90 days inhalation studies with rats and mice, maximal concentration 21 mg/l, no mortality).

Two acute dermal toxicity studies are available both comparable to OECD guideline 402 and performed under GLP with the same result. The study report which contained the most details on the substance was considered the key study (IIT Research Institute, 1989b). ETBE was applied at a dose level of 2000 mg/kg bw to the shaved dorsum of 5 male and 5 female White rabbits under occlusion for 24 hr. There were no deaths. The LD50 was determined to be > 2000 mg/kg bw. Dermal irritation (i. e., oedema and erythema) was observed following removal of the wrappings (all rabbits). Eschar formation was observed within 5 to 7 days after test article administration in most animals and was ultimately noted in all study animals. Complete recovery from all signs of dermal irritation was not evident at study termination. No other overt signs of toxicity were present.

Regarding the observed dermal irritation, results obtained from the available skin irritation studies are considered more relevant for purposes of hazard identification.

Human data (eight subjects) (Nihlen et al, 1998b) showed a small (3-4%) but significant (P<0.05) decrease in forced vital capacity (FVC) and vital capacity (VC) in subjects exposed to 25 or 50 ppm ETBE vapour compared to clean air exposures, however guidelines issued by the American Thoracic Society and others (Lebowitz et al., 1987; American Thoracic Society, 1995, 2005) indicate that short-term changes in lung function of <5% are likely to reflect normal variation and are therefore of no clinical significance. Significant reductions in other pulmonary function measures tested (i.e. FEV1, TLCO) were not observed. In conclusion, reports of slightly decreased lung function in this study were mild in nature and minor in extent, and likely to reflect normal variation rather than an effect of ETBE vapour on lung function.

American Thoracic Society (1995) Standardization of Spirometry: 1994 Update, American Journal of Respiratory and Critical Care Medicine, 152, 1107-1136

American Thoracic Society. (2005) Interpretative Strategies for Lung Function Testing in ATS/ERS Task Force: Standardization of Lung Function Testing (V. Brusasco, R. Crapo & G. Viegi (Eds.) European Respiratory Journal 26, 948-968.

Lebowitz, M.D., Quackenboss, J., Camilli, A.E., Bronnimann, D., Holbert, C.J., Boyer, B. (1987) The epidemiological importance of intraindividual changes in objective pulmonary responses. European Journal of Epidemiology, 3, 390-398.

Justification for classification or non-classification

In accordance to Directive 67/548/EEC and EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008, classification is not necessary for acute oral, dermal and inhalation toxicity based on the available data.