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Description of key information

In a combined repeated dose toxicity 28-day / Reproduction/Developmental Toxicity Screening Test in rats (OECD 422), the No Observed Adverse Effect Level (NOAEL) for 3 -methylbutyl isovalerate as a Read-across substance was 800 mg/kg bw/day (top dose).

In consideration of the molecular weight of both source and target substances (172.27 and 130.19 g/mol) the No Observed Adverse Effect Levels (NOAELs) for general toxicity effects and reproduction/developmental toxicity was 604.6 mg/kg/day.

Using this read across approach, the target substance is not classified for long term toxicity endpoints according to CLP.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2016-08-04 to 2017-02-15
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Reason / purpose:
reference to same study
Related information:
Composition 1
Reference:
Composition 0
Qualifier:
according to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Limit test:
no
Test material information:
Composition 1
Key result
Dose descriptor:
NOAEL
Effect level:
> 800 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No treatment-related effects of toxicological significance were observed.
Key result
Critical effects observed:
no
Conclusions:
This study was conducted to evaluate the potential toxicity of the test substance on systemic toxicity when administered via oral gavage to Sprague-Dawley rats at dose levels of 0, 75, 250 and 800 mg/kg bw/day. There were no test item-related adverse systemic toxicity effects up to 800 mg/kg bw/day. Therefore, the No-Observed-Adverse-Effect Levels (NOAELs) for general toxicity is considered to be at least 800 mg/kg bw/day
Executive summary:

This study was conducted to evaluate the potential toxicities of the test item regarding general systemic effects and reproductive/developmental toxicity. The test item was administered by oral gavage to Sprague-Dawley rats (12 animals per sex per group) at dose levels of 0, 75, 250 and 800 mg/kg with a dose volume of 2 mL/kg. Males and females were dosed for two weeks prior to mating and continued through the day before sacrifice in males (total 50 days), and continued through the lactation day (LD) 13 in females. Additional animals in the recovery groups 0 and 800 mg/kg (6 animals per sex per group) received the test item but were not mated. Afterwards, they were assigned to 2 weeks of recovery period after the completion of test item administration. General systemic observations including mortality, general clinical signs, body weights, body weight gain, food consumption, functional behavior examination, motor activity examination, macroscopic findings, hematology, coagulation, clinical chemistry, organ weights and microscopic findings were measured and evaluated. In addition, reproductive/developmental observations including estrus cycle, precoital time, fertility data, reproductive and littering findings, F1 pups clinical signs, body weight, anogenital distance, nipple retention and external examination were measured. Thyroid hormone (T4) level in blood was also analysed for adult males and pups at sacrifice.

 

No deaths or moribund animals occurred in any group throughout the study. One female of which all pups were found dead and which showed prolonged parturition, irregular respiration and skin paleness at 800 mg/kg was sacrificed unscheduled on gestation day (GD) 24.The relationship of test item administration and these findings was uncertain; however, they were not considered to have toxicological relevance since no test item-related adverse effects in other parameters at 800 mg/kg were observed during the study.

 

No test item-related change was observed up to 250 mg/kg. At 800 mg/kg, test item-related salivation was observed in both sexes but was not considered to have toxicological relevance. No test item-related change was observed in body weight, body weight gain, food consumption, functional behavior examination, motor activity examination, macroscopic findings, hematology, coagulation, clinical chemistry, organ weights and microscopic findings.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
604.6 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
The key study was a read across from a good quality study, conducted using OECD Guideline 422 and complies with GLP and was therefore assigned 1 (reliable without restrictions).

Repeated dose toxicity: inhalation - systemic effects

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Reference
Endpoint:
short-term repeated dose toxicity: inhalation
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: inhalation
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: dermal
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Test material information:
Composition 1
Endpoint conclusion
Endpoint conclusion:
no study available

Mode of Action Analysis / Human Relevance Framework

Additional information

The No Observed Adverse Effect Levels (NOAELs) for general toxicity effects and reproduction/developmental of the target substance was predicted from the source substance (see read across justification).

In the key study, a source substance-related increase in thyroid hormone (T4) was observed in adult males at 800 mg/kg and in pups at 250 and 800 mg/kg. However, it was not considered to have toxicological relevance since there were no correlated changes in other parameters including microscopic findings of thyroids (with parathyroids).

In consideration of the molecular weight of both source and target substances (172.27 and 130.19 g/mol) the No Observed Adverse Effect Levels (NOAELs) for general toxicity effects and reproduction/developmental toxicity was 604.6 mg/kg/day.

A supporting 90-day repeat oral dose limit test was conducted with the test item in rats at up to 12.5 mg/kg/d in 1980. There was an increase in adrenal and thyroid weights (both absolute and relative) in both sexes. However there was no corresponding histopathology accompanying these changes suggestive of an adverse effect. As a result, the NOAEL from this study was at least 12.5 mg/kg/d.

This study was conducted according to the currently available protocols available at the time but is limited in its usefulness for characterizing the hazards of ethyl isovalerate. The supporting study was tested at low levels in a limit-test protocol and does not meet the current expectations for documentation. As a result, read-across was chosen as the preferred approach to complete the characterization of the repeat-dose hazards of the target substance.

Justification for classification or non-classification

No adverse effects were observed in the key combined repeated dose with the reproduction/developmental toxicity screening test (OECD 422) in rats for isoamyl isovalerate as a read-across substance; therefore, using a read across approach the test substance is not classificable as STOT RE according to CLP (Regulation EC No 1272/2008).