3-methylbutyl isovalerate

Endpoint summary

Description of key information

In the key Combined Repeated Dose Toxicity 28-day / Reproduction/Developmental Toxicity Screening Test in rats (OECD 422), the No Observed Adverse Effect Level (NOAEL) for the test item was 800 mg/kg bw/day (top dose).

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 for cross-reference:

reference to same study

Qualifier:

according to guideline

Guideline:

OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Limit test:

no

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 toxocity. 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.

In reproductive/developmental observations, no test item-related changes were observed in estrus cycle, precoital time, fertility data, reproductive and littering findings, F1 pups clinical signs, body weight, anogenital distance, nipple retention and external examination.

Test item-related increase in T4 was observed in adult males (1.24-fold of control) at 800 mg/kg and in pups (up to 1.22-fold of control) 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 conclusion, no test item-related adverse effects in general effects and reproduction/development were observed up to 800 mg/kg. Therefore, the No-Observed-Adverse-Effect Levels (NOAELs) for general toxicity and reproduction/developmental toxicity are considered to be at least 800 mg/kg/day.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

800 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

The key study was 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

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

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

In the key study, a test item-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).

Justification for classification or non-classification

No adverse effects were observed in the Combined Repeated Dose Toxicity 28-day / Reproduction/Developmental Toxicity Screening Test in rats or supporting study (dose range finder study); therefore, the test substance is not classificable as STOT RE according to CLP (Regulation EC No 1272/2008).