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Administrative data

Key value for chemical safety assessment

Additional information

Bacterial gene mutation

In the bacterial gene mutation tests, the substance tested negative. The study by De Flora (1981) was limited in that no strain sensitive to DNA cross-linking was used. While the study by Waskell (1978) corroborates the work of De Flora, only the strains TA98 and TA100 were used.

 

Micronucleus study

In an in vitro micronucleus assay, diethyl ether was tested at concentrations ranging from 2.5 to 5.0 µL/mL in human peripheral blood lymphocytes both in the absence and presence of S9 metabolic activation (Hofman-Huther, 2010). According to the study authors, diethyl ether did not cause an increase in the number of micronuclei either in the absence of presence of S9 metabolic activation in the 4 hour (i.e., short-term) but an increase in the number of micronuclei was noted in the 44 hour (i.e., long-term) study. It is possible that the positive result was driven, at least in part, by the low number of micronuclei noted in the control cultures. Additionally, the micronucleus frequency at 4.0 and 4.5 µL/mL are within the historical range of 0.4 to 2.3% (i.e., 2.2 % at 4.0 µL/mL and 2.3% at 4.5 µL/mL); the micronucleus frequency of 2.5% at a dose level of 5.0 µL/mL is slightly above the historical range. Due to the possible skewing of statistics induced by the control values, the results of Experiment II may be equivocal or weakly positive.

 

Gene mutation study in mammalian cells

Diethyl ether, when tested at concentrations ranging from 0.156 to 5 µL/mL in mouse lymphoma L5178Y cells both in the absence and presence of S9 metabolic activation, did not produce an increase in the mutant frequency (Kraft, 2010). Incubation with positive control substances in the presence or absence of metabolic activation resulted in anticipated increases in the mutation frequencies.

 

Non-standard studies

The bacterial DNA-repair studies carried out by De Flora (1984) indicated no toxic effects to either repair deficient or proficient strains up to the maximum concentration tested. Similarly, the sister chromatid exchange study by Shite (1979) indicated no cause for concern. It should be noted that the interpretation of such studies is ambiguous with regards to potential mutagenicity.

 

Aqueous extracts tested positive in the Ames test using strains TA100 and TA102 by Chen (1993). These extracts were found to contain peroxides which were isolated and also tested positive in the same test, and negative with the strain TA1535. While the formation of potentially mutagenic peroxides is of concern, it is considered to only be of relevance in the case of preservative-free diethyl ether. In this case the explosive nature of these peroxides is of concern, and has resulted in well established measures to mitigate their formation (exclusion of air and light) and the need for regular testing. Positive Ames test results found by Chen were in extracts which tested strongly positive with standard commercial peroxide testing strips. These results are not considered relevant to the genotoxicity of pure diethyl ether.

Micronucleus (in vivo)

In an in vivo micronucleus assay, diethyl ether was administered via intraperitoneal injection to male and female NMRI mice at doses of 0 (control), 400, 1,000, or 2,000 mg/kg body weight (Donath, 2010). Cotton seed oil was used as the vehicle and cyclophosphamide was administered via intraperitoneal injection as the positive control. The administration of diethyl ether, at a dose of 2,000 mg/kg body weight, resulted in ataxia and constricted abdomen in 5 males and 5 females; however, the test article did not cause an increase in the number of micronuclei at any dose level. A significant increase in the number of micronuclei was noted in mice who received cyclophosphamide. 

Short description of key information:

bacterial gene mutation: negative (De Flora)

bacterial gene mutation: negative (Waskell)

bacterial DNA-repair: ambiguous (De Flora)

mammalian gene mutation: negative (Kraft)

mammalian cytogenicity: equivocal (Hofman-Huther)

sister chromatid exchange: negative (Shite)

mammalian cytogenicity: negative (BSL2010)

Endpoint Conclusion: No adverse effect observed (negative)

Justification for classification or non-classification

The submission substance produced negative results in both in vitro and in vivo genetic toxicity studies. As a result, the substance does not meet the criteria for classification according to Regulation (EC) No 1272/2008, Annex I section 3.5.