Diethyl ether

Endpoint summary

Description of key information

Skin irritation:

In a GLP study conducted according to OECD test guideline 404, diethyl ether was found to be not irritating to the skin of albino rabbits (Colas, 2010). Data from a GLP in vitro skin irritation test conducted according to an OECD draft guideline (Paulus, 2010) and from non-validated in vivo studies supports the lack of irritation potential of diethyl ether on the skin.

Eye irritation:

In a GLP in vitro Hen's Egg Test-Chorioallantoic Membrane (HET-CAM) test, diethyl ether was reported to possess severe irritation potential (Paulus, 2010). In a GLP in vitro Bovine Corneal Opacity and Permeability (BCOP) test, diethyl ether was reported to not cause serious eye damage (Remmele, 2010). In an in vivo eye irritation study on diethyl ether, which was conducted in accordance with OECD Guideline for the Testing of Chemicals No. 405 and in compliance with GLP, diethyl ether did not induce significant or irreversible damage to the rabbit eye (Mallaun, 2010).

Key value for chemical safety assessment

Skin irritation / corrosion

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Eye irritation

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Additional information

Skin Irritation:

In a GLP study conducted according to OECD test guideline 404, diethyl ether was found to be not irritating to the skin of albino rabbits (Colas, 2010). Supportive of this finding are the results of a GLP in vitro study conducted according to an OECD draft guideline [Draft Proposal for a New Guideline, In Vitro Skin Irritation: Reconstructed Human Epidermis (RhE) Test Method, Version 7.6, 9 September 2009)] in which diethyl ether was found to be not irritating. Positive and negative controls produced anticipated results and the study was considered valid.

Additional information from non-validated in vivo studies supports the conclusion that diethyl ether is not irritating to the skin (Smyth et al., 1962; Futamura et al., 2009). Conversely, a ToxTree QSAR prediction of irritation was found and was supported by a similar prediction for an analogous substance (di-n-butyl ether). Due to the high volatility of the substance, the method of application (open, occlusive, etc.) is likely to be highly significant in determining the results. The weight of evidence suggests that diethyl ether is not irritating to the skin.

Eye Irritation:

The available information indicates that eye irritation effects may be expected with the substance. A GLP in vitro HET-CAM test (Paulus, 2010) found diethyl ether to be severely irritating and evidence from in vivo studies supports the irritating potential of diethyl ether on the eye (Smyth et al., 1962; Hopkins et al., 1976; Sugai et al., 1990). A Toxtree QSAR prediction was inconclusive. 

Another in vitro eye irritation study on diethyl ether was identified, which was performed according to OECD Guideline for the Testing of Chemicals No. 437 and in compliance with GLP (Remmele, 2010). In this study, 3 bovine corneas were washed with Eagle’s minimum essential medium (EMEM) then exposed to 750 µL of diethyl ether for 10 minutes. Corneas were washed 3 times with EMEM (containing phenol red) and once with EMEM (without phenol red) and then incubated for another 2 hours. Observations of opacity and permeability were taken. Highly de-ionized water and 1% (w/v) sodium hydroxide solution were used as the negative and positive controls, respectively. An in vitro irritancy score (IVIS) was assessed. Both the negative and positive control results were within the historical control data range. A mean IVIS of 38.6 was reported for diethyl ether. Based on the observed results and applying the evaluation criteria, diethyl ether does not cause serious eye damage in the Bovine Corneal Opacity and Permeability Test (BCOP test) under the test conditions. The test method does not yet allow for the evaluation of eye irritation. The result does not exclude an irritation potential of the test substance.

For final decision upon the classification with regard to eye irritation, results from an in vivo study were needed and therefore, an in vivo eye irritation study on diethyl ether was conducted in accordance with OECD Guideline for the Testing of Chemicals No. 405 and in compliance with GLP (Mallaun, 2010). The study was considered without deviations and was reliable and selected as the key study. The individual mean scores for corneal opacity and iris light reflex were 0.00 for all three animals. The individual mean scores for the conjunctivae were 0.67, 0.33 and 0.00 for reddening and 0.00 for chemosis for all three animals. Mild to moderate, early-onset and transient ocular changes, such as reddening of the conjunctivae and sclerae, ocular discharge and chemosis were reported. These effects were reversible and were no longer evident 72 hours after treatment, the end of the observation period for all animals. No abnormal findings were observed in the cornea or for the iris light reflex of any animals at any of the examinations. No corrosion was observed at any of the measuring intervals. No staining of the treated eyes by the test item was observed and no clinical signs were observed. According to CLP classification (EC 1272/2008), diethyl ether is not classified with respect to eye irritation in rabbits.

Other studies on the in vivo eye irritation potential of diethyl ether in rabbits include studies by Sugai et al. (1990), Hopkins et al. (1976), and Smyth et al. (1962). These studies were not considered as key studies due to the lack of detailed methods or results. Irritating effects were reported in these studies, however, the degree of irritation is unknown due to the lack of details. It was not possible to assess the validity of these results and two of the studies (Hopkins et al., 1976; Sugai et al., 1990) were considered unreliable. 

Justification for classification or non-classification

 Skin Corrosion / Irritation: According to the in vitro EpiSkin results, the submission substance is non-corrosive and non-irritating. According to the Guidance on the Application of the CLP Criteria (ECHA Reference ECHA-09-G-02-EN), the EpiSkin method is valid for the classification of substances for skin irritancy according to CLP criteria. As a result, the substance does not meet the criteria for classification according to Regulation (EC) No 1272/2008, Annex I section 3.2.

 

Serious Eye Damage / Eye Irritation: According to the Guidance on the Application of the CLP Criteria (ECHA Reference ECHA-09-G-02-EN), a positive result in the HET-CAM or the BCOP is classified as serious eye damage Category 1, while negative results in the HET-CAM and the BCOP must be followed by further testing. In a follow-up in vivo study, diethyl ether did not induce significant or irreversible damage to the rabbit eye. As a result, diethyl ether does not have to be classified with respect to eye irritation in rabbits according to Regulation (EC) No 1272/2008, Annex I section 3.2.