3-methylbutyl butyrate

Endpoint summary

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 isoamyl 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 158.24 g/mol) the No Observed Adverse Effect Levels (NOAELs) of the test item isoamyl butyrate for general toxicity effects and reproduction/developmental toxicity was 734.85 mg/kg/day. Using this read across approach, the target substance has not to be 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

Reference 1

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

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

Adequacy of study:

key study

Justification for type of information:

The read-across justification is included as an attachment in IUCLID section 13.

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

reference to same study

Key result

Dose descriptor:

NOAEL

Effect level:

> 800 mg/kg bw/day (nominal)

Based on:

other: 3-methylbutyl isovalerate

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 3-methylbutyl isovalerate as a read across substance on systemic toxicity and reproductive/development 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 source substance-related adverse systemic toxicity effects or reproduction/development effects up to 800 mg/kg bw/day. Therefore, the No-Observed-Adverse-Effect Levels (NOAELs) for general toxicity effects and reproduction/developmental toxicity are considered to be at least 800 mg/kg bw/day.
In consideration of the molecular weight of both source and target substances (172.27 and 158.24 g/mol) the No Observed Adverse Effect Levels (NOAELs) of the test item for general toxicity effects and reproduction/developmental toxicity was 734.85 mg/kg/day.

Executive summary:

The potential toxicity on systemic toxicity and reproductive/development toxicity was assessed from the source substance 3-methylbutyl isovalerate (see read-across justification).

 

This study was conducted to evaluate the potential toxicities of 3-methylbutyl isovalerate as a read across substance regarding general systemic effects and reproductive/developmental toxicity. The source substance 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 source substance but were not mated. Afterwards, they were assigned to 2 weeks of recovery period after the completion of source substance 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 the source substance administration and these findings was uncertain; however, they were not considered to have toxicological relevance since no source substance-related adverse effects in other parameters at 800 mg/kg were observed during the study.

 

No source substance-related change was observed up to 250 mg/kg. At 800 mg/kg, source substance-related salivation was observed in both sexes but was not considered to have toxicological relevance. No source substance-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 source substance-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.

 

Source substance-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 source substance-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.

 

In consideration of the molecular weight of both source and target substances (172.27 and 158.24 g/mol) the No Observed Adverse Effect Levels (NOAELs) of the test item for general toxicity effects and reproduction/developmental toxicity was 734.85 mg/kg/day.

Reference 2

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 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

734.85 mg/kg bw/day

Study duration:

subchronic

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

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

Combined repeated-dose toxicity study, key study (read-across)

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). The 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. In consideration of the molecular weight of both source and target substances (172.27 and 158.24 g/mol) the No Observed Adverse Effect Levels (NOAELs) of the test item for general toxicity effects and reproduction/developmental toxicity was 734.85 mg/kg/day.

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; therefore, the test substance is not classificable as STOT RE according to CLP (Regulation EC No 1272/2008), as amended for the fifteenth time in Regulation (EU) 2020/182.