Ethyl 3-(2,4-dimethyl-1,3-dioxolan-2-yl)propanoate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

NOAEL (parental, reproductive) ≥ 1000 mg/kg bw (actual dose received)

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

The toxic potential of the substance to the reproductive parameters was evaluated in a Combined Repeated Dose Toxicity Study with the Reproduction/ Developmental Toxicity Screening Test according to the OECD Guideline 422 and EPA OPPTS 870.3650 and in GLP compliance. The test substance was administered by daily oral gavage to 10 male and 10 female Wistar Han rats at dose levels of 100, 300 and 1000 mg/kg. An additional group of 10 male and 10 female rats served as the control (0 mg/kg). Males were exposed for 2 weeks prior to mating, during mating, and up to termination (for 29 days). The females were exposed for 2 weeks prior to mating, during mating, during post-coitum, and at least 4 days of lactation (for 44-50 days).

Generally, sporadic, statistically significant changes were noted in some parameters in the study, but none of these were considered as toxicologically significant. No parental toxicity was observed up to the highest dose level tested (1000 mg/kg). No toxicologically significant changes were noted in any of the parental parameters investigated in this study (i.e. clinical appearance, functional observations, body weight, food consumption, clinical laboratory investigations, macroscopic examination, organ weights, and microscopic examination).

No treatment-related changes were noted in any of the reproductive parameters investigated in this study (i.e. mating, fertility and conception indices, precoital time, and numbers of corpora lutea and implantation sites).

As for Annex IX of REACH Regulation (EC) 1907/2006, an extended one-generation reproductive toxicity study is required if the available repeated dose toxicity studies indicate adverse effects on reproductive organs or tissues or reveal other concerns in relation with reproductive toxicity. The screening for reproductive/developmental toxicity study performed according to the OECD 422 does not indicate adverse effects on reproductive organs and does not reveal any concern in relation with reproductive toxicity. Therefore, the extended one-generation reproductive toxicity study does not need to be performed.

NOAEL (parental, reproductive) ≥ 1000 mg/kg bw/day

Effects on developmental toxicity

Description of key information

NOAEL (parental, developmental) ≥ 1000 mg/kg bw (actual dose received)

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Species:

rat

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

The toxic potential of the substance to the developmental parameters was evaluated in a Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test according to the OECD Guideline 422 and EPA OPPTS 870.3650 and in GLP compliance. The test substance was administered by daily oral gavage to 10 male and 10 female Wistar Han rats at dose levels of 100, 300 and 1000 mg/kg. An additional group of 10 male and 10 female rats served as the control (0 mg/kg). Males were exposed for 2 weeks prior to mating, during mating, and up to termination (for 29 days). The females were exposed for 2 weeks prior to mating, during mating, during post-coitum, and at least 4 days of lactation (for 44-50 days).

Generally, sporadic, statistically significant changes were noted in some parameters in the study, but none of these were considered as toxicologically significant. No parental toxicity was observed up to the highest dose level tested (1000 mg/kg). No toxicologically significant changes were noted in any of the parental parameters investigated in this study (i.e. clinical appearance, functional observations, body weight, food consumption, clinical laboratory investigations, macroscopic examination, organ weights, and microscopic examination).

No treatment-related changes were noted in any of the developmental parameters investigated in this study (i.e. gestation index and duration, parturition, maternal care and early postnatal pup development consisting of mortality, clinical signs, body weight and macroscopy).

No parental toxicity or developmental toxicity was noted up to the highest tested dose (1000 mg/kg).

 

As for Annex IX of REACH Regulation (EC) 1907/2006, an extended one-generation reproductive toxicity study is required if the available repeated dose toxicity studies indicate adverse effects on reproductive organs or tissues or reveal other concerns in relation with reproductive toxicity. The screening for reproductive/developmental toxicity study performed according to the OECD 422 does not indicate adverse effects on reproductive organs and does not reveal any concern in relation with reproductive toxicity. Therefore, the extended one-generation reproductive toxicity study does not need to be performed.

 

The developmental toxicity potential of the test substance has been evaluated in a read-across approach considering the developmental toxicity of similar substances of the test substance (Similar Substances 02, 03, 04 and 05). A detailed evaluation of the developmental toxicity of the similar substances is attached to the Toxicity to Reproduction endpoint summary. The justification for the Read Across is given in Section 13 of IUCLID.

 

The available OECD Guideline 422 study on the test item is not a subchronic toxicity study as would have been required according to Annex IX of REACH Regulation. However, in combination with the rest of the available data on the similar substances, the NOAEL identified can be used as the key value for the chemical safety assessment of the TS.

 

NOAEL (parental, developmental) ≥ 1000 mg/kg bw (actual dose received).

Justification for classification or non-classification

No significantly adverse effects were observed during the screening test for reproductive and developmental toxicity up to the highest tested concentration and in combination with the rest of the available data on the similar substances used for the read-across approach (see attached document) and the read-across justification in section 13 of Iuclid). For this reason, the NOAEL (parental/developmental) was determined as ≥ 1000 mg/kg bw.

 

According to the CLP Regulation (EC) No. 1272/2008, the following categories for reproductive toxicants are available:

- Category 1: Known or presumed human reproductive toxicant - Substances are classified in Category 1 for reproductive toxicity when they are known to have produced an adverse effect on sexual function and fertility, or on development in humans or when there is evidence from animal studies, possibly supplemented with other information, to provide a strong presumption that the substance has the capacity to interfere with reproduction in humans. The classification of a substance is further distinguished on the basis of whether the evidence for classification is primarily from human data (Category 1A) or from animal data (Category 1B).

- Category 1A: Known human reproductive toxicant - The classification of a substance in this Category 1A is largely based on evidence from humans.

- Category 1B: Presumed human reproductive toxicant - The classification of a substance in this Category 1B is largely based on data from animal studies. Such data shall provide clear evidence of an adverse effect on sexual function and fertility or on development in the absence of other toxic effects, or if occurring together with other toxic effects the adverse effect on reproduction is considered not to be a secondary nonspecific consequence of other toxic effects. However, when there is mechanistic information that raises doubt about the relevance of the effect for humans, classification in Category 2 may be more appropriate.

- Category 2: Suspected human reproductive toxicant - Substances are classified in Category 2 for reproductive toxicity when there is some evidence from humans or experimental animals, possibly supplemented with other information, of an adverse effect on sexual function and fertility, or on development, and where the evidence is not sufficiently convincing to place the substance in Category 1. If deficiencies in the study make the quality of evidence less convincing, Category 2 could be the more appropriate classification. Such effects shall have been observed in the absence of other toxic effects, or if occurring together with other toxic effects the adverse effect on reproduction is considered not to be a secondary non-specific consequence of the other toxic effects.

 

The substance is not classified as a Reproductive toxicant since no adverse effects on sexual function, fertility or on development occurred during the subacute exposure of the rats to the substance, as also supported by the rest of the available data on the similar substances used for the read-across approach.