[[(2-ethylhexyl)oxy]methyl]oxirane

Endpoint summary

Description of key information

Based on the study results with of oxirane, 2-((C12-14-alkyloxy)methyl)derivs), the no-observed-effect level (NOEL) of systemic toxicity was 100 mg/kg bw/day in a sub-chronic repeated dose study by dermal application. There was no exposure-related mortality and no effects on body weight, weight gain or food consumption. Haematology, clinical chemistry, and urinalyses results also failed to reveal any differences between control and test animals. There were no gross or histopathological alterations attributed to test item. As justified, this information can be read-across to 2-ethylhexyl glycidyl ether, considering the similarities and similar properties of the two substances.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: dermal

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

test procedure in accordance with national standard methods with acceptable restrictions

Remarks:

A deduction from Klimisch 1 (reliable without restrictions) to Klimisch 2 (reliable with restrictions) was made to appreciate read-across uncertainties.

Justification for type of information:

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
The source substance oxirane, 2-((C12-14-alkyloxy)methyl)derivs (EC 271-846-8, C12-14GE) used for read-across and the target substance [[(2-ethylhexyl)oxy]methyl]oxirane (EC 219-553-6, EHGE) do share a common functional group (glycidylether) and both are manufactured by reacting an alcohol with epichlorohydrine to an alkyl glycidylether under alkalinic conditions (see also see attached file "Comparison_EHGE_C12_14GE_20221024_Final.pdf").

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
Data derived with the source substance oxirane, 2-((C12-14-alkyloxy)methyl)derivs (EC 271-846-8, C12-14GE) are used for read-across to the target substance [[(2-ethylhexyl)oxy]methyl]oxirane (EC 219-553-6, EHGE) as outlined and justified in the attached file "Comparison_EHGE_C12_14GE_20221024_Final.pdf", although having some limitations.

3. ANALOGUE APPROACH JUSTIFICATION
Please see attached file "Comparison_EHGE_C12_14GE_20221024_Final.pdf"

4. DATA MATRIX
Please see attached file "Comparison_EHGE_C12_14GE_20221024_Final.pdf"

Reason / purpose for cross-reference:

read-across source

Dose descriptor:

NOEL

Effect level:

1 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: See 'Remark'

Dose descriptor:

NOEL

Remarks:

systemic toxicity

Effect level:

100 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

dermal irritation

Critical effects observed:

not specified

Conclusions:

Based on the study results with of oxirane, 2-((C12-14-alkyloxy)methyl)derivs), the no-observed-effect level (NOEL) of systemic toxicity was 100 mg/kg bw/day in a sub-chronic repeated dose study by dermal application. As justified, this information can be read-across to 2-ethylhexyl glycidyl ether, considering the similarities and similar properties of the two substances.

Executive summary:

The repeated dose study was conducted to evaluate the sub-chronic dermal toxicity potential of test substance in Fischer 344 rats following a 5 days per week dosing regimen for approximately 13 weeks.

A range finding study was conducted in which two rats/sex/dose level were dosed dermally with 0, 10, 100, or 1000 mg/kg bw/day test substance in acetone, 5 days/week for up to a total of 10 applications. In-life observations and dermal scoring indicated an ungroomed appearance in high-dose group rats; erythema, edema, scaling/fissuring and scabs in high and middle-dose group rats and slight scaling in low dose group rats. Four doses of 1000 mg/kg bw/day exceeded the maximum-tolerated dose as defined by loss of integrity of the epidermis. Grossly, the skin of high-dose rats appeared scaly, thickened and was ulcerated. Microscopically, the response consisted of epidermal hyperplasia with hyperkeratosis and parakeratosis along with hyperplasia of the sebaceous glands with ulceration, inflammation and edema. The epidermal response was similar at 100 mg/kg bw/day, however the epidermis remained intact. Treatment-related effects in low dose rats were limited to slight scaling at the dermal test site.

Based on the results of the range finding study, non-occluded dermal doses of 0, 1, 10, and 100 mg AGE/kg bw/day in acetone were administered to ten rats/sex/dose level 5 days/week for 13 weeks. Standard toxicologic parameters were evaluated. Treatment-related gross and histopathologic lesions were limited to the skin of high-dose rats. Applications of 100 mg/kg/day reached the maximum-tolerated dose defined by the USEPA (1988) with a definitive, uniform reaction at the dermal treatment site consisting of epidermal hyperplasia, hyperkeratosis, sebaceous gland hyperplasia and a mild inflammatory response. The response was similar after 2 or 13 weeks, although the response was equivocally of greater severity after 2 weeks. Crusts, underlain by intact hyperplastic epidermis, were present after 2 weeks but not after 13 weeks. The no-observed effect level for systemic toxicity was 100 mg/kg bw/day.

Considering the similarities and similar properties of the substance with 2-ethylhexyl glycidyl ether, it is justified, to read-across this information to the target substance 2-ethylhexyl glycidyl ether.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

100 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Repeated dose toxicity: dermal - local effects

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: dermal

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

test procedure in accordance with national standard methods with acceptable restrictions

Remarks:

A deduction from Klimisch 1 (reliable without restrictions) to Klimisch 2 (reliable with restrictions) was made to appreciate read-across uncertainties.

Justification for type of information:

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
The source substance oxirane, 2-((C12-14-alkyloxy)methyl)derivs (EC 271-846-8, C12-14GE) used for read-across and the target substance [[(2-ethylhexyl)oxy]methyl]oxirane (EC 219-553-6, EHGE) do share a common functional group (glycidylether) and both are manufactured by reacting an alcohol with epichlorohydrine to an alkyl glycidylether under alkalinic conditions (see also see attached file "Comparison_EHGE_C12_14GE_20221024_Final.pdf").

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
Data derived with the source substance oxirane, 2-((C12-14-alkyloxy)methyl)derivs (EC 271-846-8, C12-14GE) are used for read-across to the target substance [[(2-ethylhexyl)oxy]methyl]oxirane (EC 219-553-6, EHGE) as outlined and justified in the attached file "Comparison_EHGE_C12_14GE_20221024_Final.pdf", although having some limitations.

3. ANALOGUE APPROACH JUSTIFICATION
Please see attached file "Comparison_EHGE_C12_14GE_20221024_Final.pdf"

4. DATA MATRIX
Please see attached file "Comparison_EHGE_C12_14GE_20221024_Final.pdf"

Reason / purpose for cross-reference:

read-across source

Dose descriptor:

NOEL

Effect level:

1 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: See 'Remark'

Dose descriptor:

NOEL

Remarks:

systemic toxicity

Effect level:

100 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

dermal irritation

Critical effects observed:

not specified

Conclusions:

Based on the study results with of oxirane, 2-((C12-14-alkyloxy)methyl)derivs), the no-observed-effect level (NOEL) of systemic toxicity was 100 mg/kg bw/day in a sub-chronic repeated dose study by dermal application. As justified, this information can be read-across to 2-ethylhexyl glycidyl ether, considering the similarities and similar properties of the two substances.

Executive summary:

The repeated dose study was conducted to evaluate the sub-chronic dermal toxicity potential of test substance in Fischer 344 rats following a 5 days per week dosing regimen for approximately 13 weeks.

A range finding study was conducted in which two rats/sex/dose level were dosed dermally with 0, 10, 100, or 1000 mg/kg bw/day test substance in acetone, 5 days/week for up to a total of 10 applications. In-life observations and dermal scoring indicated an ungroomed appearance in high-dose group rats; erythema, edema, scaling/fissuring and scabs in high and middle-dose group rats and slight scaling in low dose group rats. Four doses of 1000 mg/kg bw/day exceeded the maximum-tolerated dose as defined by loss of integrity of the epidermis. Grossly, the skin of high-dose rats appeared scaly, thickened and was ulcerated. Microscopically, the response consisted of epidermal hyperplasia with hyperkeratosis and parakeratosis along with hyperplasia of the sebaceous glands with ulceration, inflammation and edema. The epidermal response was similar at 100 mg/kg bw/day, however the epidermis remained intact. Treatment-related effects in low dose rats were limited to slight scaling at the dermal test site.

Based on the results of the range finding study, non-occluded dermal doses of 0, 1, 10, and 100 mg AGE/kg bw/day in acetone were administered to ten rats/sex/dose level 5 days/week for 13 weeks. Standard toxicologic parameters were evaluated. Treatment-related gross and histopathologic lesions were limited to the skin of high-dose rats. Applications of 100 mg/kg/day reached the maximum-tolerated dose defined by the USEPA (1988) with a definitive, uniform reaction at the dermal treatment site consisting of epidermal hyperplasia, hyperkeratosis, sebaceous gland hyperplasia and a mild inflammatory response. The response was similar after 2 or 13 weeks, although the response was equivocally of greater severity after 2 weeks. Crusts, underlain by intact hyperplastic epidermis, were present after 2 weeks but not after 13 weeks. The no-observed effect level for systemic toxicity was 100 mg/kg bw/day.

Considering the similarities and similar properties of the substance with 2-ethylhexyl glycidyl ether, it is justified, to read-across this information to the target substance 2-ethylhexyl glycidyl ether.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Study duration:

subchronic

Species:

rat

Additional information

According to Regulation (EC) 1907/2006, repeated dose toxicity test only need to be performed via the most likely exposure route for human. Since the most likely route is considered to be via dermal, the test via oral can be waived.

This repeated dose study was conducted to evaluate the subchronic dermal toxicity potential of test substance in Fischer 344 rats following a 5 days per week dosing regimen for approximately 13 weeks.

A range finding study was conducted in which two rats/sex/dose level were dosed dermally with 0, 10, 100, or 1000 mg/kg/day of test substance, 5 days/week for up to a total of 10 applications. In-life observations and dermal scoring indicated an ungroomed appearance in high-dose group rats; erythema, edema, scaling/fissuring and scabs in high and middle-dose group rats and slight scaling in low dose group rats. Four doses of 1000 mg/kg/day exceeded the maximum-tolerated dose as defined by loss of integrity of the epidermis. Grossly, the skin of high-dose rats appeared scaly, thickened and was ulcerated. Microscopically, the response consisted of epidermal hyperplasia with hyperkeratosis and parakeratosis along with hyperplasia of the sebaceous glands with ulceration, inflammation and edema. The epidermal response was similar at 100 mg/kg/day, however the epidermis remained intact. Treatment-related effects in low dose rats were limited to slight scaling at the dermal test site.

Based on the results of the range finding study, non-occluded dermal doses of 0, 1, 10, or 100 mg/kg/day of test substance in acetone were administered to ten rats/sex/dose level 5 days/week for 13 weeks. Standard toxicologic parameters were evaluated. There were no treatment-related changes in clinical or ophthalmologic observations, body weights, feed consumption or clinical pathology during the thirteen-week study. Treatment-related gross and histopathologic lesions were limited to the skin of high-dose rats. Applications of 100 mg/kg/day reached the maximum-tolerated dose defined by the USEPA (1988) with a definitive, uniform reaction at the dermal treatment site consisting of epidermal hyperplasia, hyperkeratosis, sebaceous gland hyperplasia and a mild inflammatory response. The response was similar after 2 or 13 weeks, although the response was equivocally of greater severity after 2 weeks. Crusts, underlain by intact hyperplastic epidermis, were present after 2 weeks but not after 13 weeks. The no-observed effect level for systemic toxicity was considered to be greater than 100 mg/kg/day.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Since the most likely route is considered to be via dermal, the test via oral can be waived.

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
Since the most likely route is considered to be via dermal, the test via inhalation can be waived.

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:
Since the most likely route is considered to be via dermal, the test via inhalation can be waived.

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:
Guideline test with GLP was used for read-across.

Justification for classification or non-classification

The health effects of test substance have been evaluated in a number of repeated-dose toxicity studies conducted in rats and no evidence of systemic toxicity has been seen at any concentration. The only treatment-related effects noted in these studies were changes to the dermal treatment site following repeated exposures, which were considered to be a local adaptive response and showed no dose relationship. Therefore, test substance can be classified as category 2 for dermal repeated-toxicity under CLP (Regulation EC No.1272/2008).