Diethyl ether

Endpoint summary

Description of key information

An oral NOAEL of 500 mg/kg bw/day was reported for a 90-day rat study (US EPA). No other oral data are available. No dermal data are available.

 

The key inhalation study is considered to be a new study, requested by ECHA to be performed as subchronic inhalation study according to OECD 413 under GLP. In this study the NOAEL was reported as 1’500 ppm (high dose group in this study, i.e. ~ 4’500 mg/m³) in absence of any adverse effects observed.

 

This finding was supported by other studies of a structural similar substance di-isopropyl ether, mainly the study by Dalbey and Feuston (1996) in which a NOAEC of 3300 ppm (13800 mg/m³) was derived for subchronic (90-day). Further supportive inhalation effect levels include the following:

NOAEC = 10000 ppm, rat, 35d (Stevens)

NOEC = 2000 ppm, rat, 44d (Chenoweth)

NOEC = 1000 ppm, guinea pig, 20d (Stevens)

NOAEC = 2000 ppm, guinea pig, 43d (Chenoweth)

NOEC = 1000 ppm, mouse, 20d (Stevens)

NOEC = 2000 ppm, rabbit, 43d (Chenoweth)

NOEC = 20000 ppm, rat, 90d (Reuzel, 1981) (read across from dimethyl ether)

NOAEC = 20000 ppm, rat, 30 weeks (Collins, 1978) (read across from dimethyl ether)

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Dose descriptor:

NOAEL

500 mg/kg bw/day

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

4 500 mg/m³

Study duration:

subchronic

Experimental exposure time per week (hours/week):

30

Species:

rat

Additional information

Read-across

The registered substance, and the two read-across substances, DME and DIPE, all belong to the class of aliphatic ethers, each possessing two aliphatic alkyl groups connected by a single oxygen atom. Transition from DME to DEE and DIPE occurs with elongation of the aliphatic alkyl groups. DME possesses two methyl (C1) groups, DEE two ethyl (C2) groups and DIPE two isopropyl (C3) groups. These three mono-functional substances are considered to be members of a homologous series of aliphatic ethers, within which in general the properties of the individual homologues are expected to vary in a predictable manner, and in particular, the properties of DEE are expected to lie between those of the smaller DME and the larger DIPE. This expectation is supported by the known physicochemical properties.

Considering their structural similarities in sharing a common functional group, and given that their physicochemical properties follow a pattern, DME, DEE and DIPE can be considered as a “group”. As such, DME and DIPE are expected to be appropriate surrogates for DEE.

Oral

Subchronic:

The results of a U.S. EPA funded 90 day oral-gavage rat study are available in the secondary literature (U.S. EPA, 1987), which set a NOEL at 500 mg/kg bw/d. This value is carried forward for the purposes of risk assessment and classification and labelling, by the oral route.

Dermal

No repeated dose toxicity information is available for the dermal route. Due to the high vapour pressure, inhalation is considered to be the major route of exposure. Any dermal exposure to the pure substance is likely to be brief due to the rapid vaporisation.

Inhalation

Due to the high vapour pressure, inhalation is considered to be the most relevant route of exposure.

Subacute:

Two studies which examined subacute repeated dose toxicity in several species are available. Due to their non-standard nature they are not considered to be individually reliable, however, a weight-of-evidence approach is possible. Both studies were significantly longer than 28 days and one (Stevens, 1975) was conducted with continuous exposure.

From the study by Stevens, a NOAEC could be assigned to 10000 ppm for continuous exposure of 35 days in the rat. However, significant interspecies variation in toxicity was observed, with both guinea pigs and mice demonstrating gross hepatic enlargement and mortality at 10000 ppm. No effects were observed at 1000 ppm. Similarly, Chenoweth (1970) indicated no observed effects for three species (rat, mouse, rabbit) at 2000 ppm for 44-day exposure (7h/d, 5d/wk; the only dosed concentration).

Subchronic:

Dimethyl ether data and diisopropyl ether data for subchronic toxicity are included as read-across from analogous substances which are expected to have a similar toxicity profile (see read across comment above).

The registered substance, and the two read-across substances, DME and DIPE, all belong to the class of aliphatic ethers, each possessing two aliphatic alkyl groups connected by a single oxygen atom. Transition from DME to DEE and DIPE occurs with elongation of the aliphatic alkyl groups. DME possesses two methyl (C1) groups, DEE two ethyl (C2) groups and DIPE two isopropyl (C3) groups. These three mono-functional substances are considered to be members of a homologous series of aliphatic ethers, within which in general the properties of the individual homologues are expected to vary in a predictable manner, and in particular, the properties of DEE are expected to lie between those of the smaller DME and the larger DIPE. This expectation is supported by the known physicochemical properties.

Considering their structural similarities in sharing a common functional group, and given that their physicochemical properties follow a pattern, DME, DEE and DIPE can be considered as a “group”. As such, DME and DIPE are expected to be appropriate surrogates for DEE.

Reliable rat inhalation studies with dimethyl ether are available in the published literature (Reuzel, 1981 and Collins, 1978). In the study by Reuzel no changes were observed, compared to the control group, in appearance, condition, behaviour, body weight, food intake or efficiency, hematology or biochemical parameters, urine composition, organ weights, and gross pathology or histopathology. A NOEC of 20000 ppm was identified.

The subchronic (30 weeks) inhalation study in rats by Collins is not strictly comparable due to the longer exposure period. The study identified reduction in male liver weights at the highest dose, 20000 ppm, but no histopathological changes. Both sexes showed changes in serum chemistry at the highest dose of dimethyl ether. From this study a NOAEC of 20000 ppm was identified.

The 90-day study by Dalbey and Feuston (1996) examined repeated dose toxicity in rats exposed to diisopropyl ether at concentrations of 480, 3300, or 7100 ppm (equivalent to 2000, 13800, or 29700 mg/m ³, respectively). Mild hypertrophy was observed at the high-dose (7100 ppm) in combination with 39% (male) and 18% (female) increased absolute liver weight. The high dose of 7100 ppm was considered to be the LOAEC effect level.

At the mid-dose, no histopathological changes were observed. Absolute liver weight gain was 26% in males and 6% in females. Sorbitol dehydrogenase dropped from 11(5) or 16(7) IU/L in controls to 9(3) IU/L. Given the absolute liver weight gain was seen only in males, and was unaccompanied by other effects, the mid-dose of 3300 ppm (13800 mg/m³) is considered for the purposes of read-across to diethyl ether to be a suitable NOAEC.

Chronic:

No chronic studies on diethyl ether are available.

Assessment

Subchronic and chronic studies with diethyl ether are not available. Based on the available data, it is considered that the NOAEC of 3300 ppm (13800 mg/m³) for diisopropyl ether (Dalbey and Feuston, 1996) be carried forward for risk assessment for diethyl ether by the inhalation route. This is because this value is the more conservative of the 3 NO(A)EC values that have been identified in subchronic studies conducted with the read across substances dimethyl ether and diisopropyl ether.

Justification for classification or non-classification

The submission substance did not exhibit significant toxic effects arising from a repeated exposure. As a result, the substance does not meet the criteria for classification according to Regulation (EC) No 1272/2008, Annex I section 3.9.