2-ethylbutyric acid

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

The reproductive and developmental toxicity of 2-ethylbutyric acid has been evaluated as part of three studies. In female rats exposed to 2-ethylbutyric acid during gestation (day 6 and 15), maternal respiratory toxicity has been reported but no effect on motor function (Narotsky et al., 1991). The development of the litters in this study between postnatal day 1 - 6 revealed no significant effect on development. Similarly, Narotsky et al., (1994) demonstrated that gestating female rats treated at 150 and 200 mg/kg bw/day experienced no or a limited impact on reproductive performance and that the F1 generation was not significantly affected. Maternal respiratory toxicity (rales and dyspnea), reduced body weight gain, and death was observed in dams, however, contributing to a LOAEL (maternal toxicity) and NOAEL (developmental toxicity) of 150 and 200 mg/kg bw/day, respectively. As part of a combined 42-day repeated dose and developmental / reproductive toxicity experiment from the Ministry of Health, Labour and Welfare (MHLW), Government of Japan performed in line with OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test), 2 ethylbutyric acid was determined to have a NOAEL of 250 and 50 mg/kg bw/day for reproductive toxicity and developmental toxicity, respectively. As the latter experiment obtained from the MHLW is considered to be a key study (Klimisch score = 2), the NOAEL of 250 (highest dose tested) and 50 mg/kg bw/day derived for fertility and developmental toxicity, respectively, have been selected for the purpose of the endpoint conclusion.

Link to relevant study records

Reference

Reference 1

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2001

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

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)

GLP compliance:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Route of administration:

oral: gavage

Vehicle:

corn oil

Duration of treatment / exposure:

Males were dosed for a 42-day period that began 14 days before mating. Females were dosed 14 days prior to mating up until day 4 of lactation (i.e. during mating and pregnancy).

Frequency of treatment:

Once per day

Dose / conc.:

0 mg/kg bw/day (nominal)

Remarks:

Control

Dose / conc.:

10 mg/kg bw/day (nominal)

Dose / conc.:

50 mg/kg bw/day (nominal)

Dose / conc.:

250 mg/kg bw/day (nominal)

No. of animals per sex per dose:

13 males and 13 females per dose

Control animals:

yes, concurrent vehicle

Parental animals: Observations and examinations:

Body weight (gain), food consumption, haematological findings, and biochemical findings of males / females.

Oestrous cyclicity (parental animals):

Estrous cycle in females.

Postmortem examinations (parental animals):

Macroscopic findings, histopathological findings, and organ weight in males / females.

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Transient salivation was observed in one male and one female at 250 mg/kg bw/day.

Mortality:

no mortality observed

Description (incidence):

No deaths related to the substance.

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

No effect in females. Males exhibited decreased white blood cell count at ≥50 mg/kg bw/day and decreased platelet count at 250 mg/kg bw/day.

Clinical biochemistry findings:

not specified

Description (incidence and severity):

No affect on blood chemistry and biochemical findings in males, although females exhibted significantly different y-GTP, total bilirubin, and Ca at 50 mg/kg bw/day and y-GTP at 250 mg/kg bw/day.

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

No significant toxicological effects were found following necropsy.

Histopathological findings: neoplastic:

no effects observed

Description (incidence and severity):

No significant toxicological effects were found following necropsy.

Reproductive performance:

effects observed, treatment-related

Description (incidence and severity):

No adverse effects were observed on reproductive parameters, such as estrous cycle, copulation index, fertility index, precoital interval, gestation length, numbers of corpora lutea and implantations, gestation index, implantation index and delivery index. Birth index and live birth index was lower for the 250 mg/kg bw/day treatment group.

Key result

Dose descriptor:

NOAEL

Remarks:

Repeated dose toxicity

Effect level:

10 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male

Remarks on result:

other: Additional information not available

Key result

Dose descriptor:

NOAEL

Remarks:

Repeated dose toxicity

Effect level:

50 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

female

Remarks on result:

other: Additional information not available

Key result

Dose descriptor:

NOAEL

Remarks:

Reproductive toxicity

Effect level:

250 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

female

Remarks on result:

other: Additional information not available

Clinical signs:

no effects observed

Description (incidence and severity):

No treatment-related change in external appearance.

Mortality / viability:

mortality observed, treatment-related

Description (incidence and severity):

Number of live pups at 250 mg/kg bw/day was lower than control (0 mg/kg bw/day) and other treatment groups.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

No treatment-related change in body weight.

Gross pathological findings:

no effects observed

Description (incidence and severity):

No treatment-related change observed following necropsy.

Histopathological findings:

no effects observed

Description (incidence and severity):

No treatment-related change observed following necropsy.

Key result

Dose descriptor:

NOAEL

Remarks:

Developmental toxicity

Generation:

F1

Effect level:

50 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Remarks on result:

other: Additional information not available

Key result

Reproductive effects observed:

yes

Lowest effective dose / conc.:

250 mg/kg bw/day (nominal)

Treatment related:

yes

Relation to other toxic effects:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

Conclusions:

2-Ethylbutyric acid was determined to have a NOAEL for reproductive toxicity and developmental toxicity of 250 and 50 mg/kg bw/day, respectively. A NOAEL for repeated dose toxicity was concluded to be 10 mg/kg bw/day in males and 50 mg/kg bw/day in females. These results were the outcome of a combined repeated dose (42-day) and developmental / reproductive toxicity test in male and female rats.

Executive summary:

A combined experiment was undertaken to determine the repeated dose toxicity and developmental / reproductive toxicity of 2-ethylbutyric acid in male and female rats. Animals were administered the substance in a corn oil vehicle via oral gavage once per day for a total of 42 days at doses of 0 (control), 10, 50, or 250 mg/kg bw/day. The experiment was performed in line with Good Laboratory Practise (GLP) and OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test).

No mortality was recorded over the duration of the test that was related to 2-ethylbutyric acid. Transient salivation in males / females (250 mg/kg bw/day); decreased white blood cell count (50 mg/kg bw/day) and platelet count (250 mg/kg bw/day) in males; increased kidney weight in males / females (250 mg/kg bw/day); decreased live pups on day 0 and 4 of lactation (250 mg/kg bw/day); and decreased birth index and live birth index (250 mg/kg bw/day) was recorded. No significantly negative effects were observed in males and females relating to body weight gain; food intake; blood chemistry; necropsy; histopathology; and reproductive parameters (e.g. estrous cycle, copulation index). There were no treatment-related changes in body weight, external appearance, and necropsy findings in rat pups.

2-Ethylbutyric acid was determined to have a NOAEL of 250 and 50 mg/kg bw/day for reproductive toxicity and developmental toxicity, respectively. A NOAEL for repeated dose toxicity was concluded to be 10 mg/kg bw/day in males and 50 mg/kg bw/day in females.

Reference 2

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

1994

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: Insufficient information for an assessment of reliability.

Qualifier:

according to guideline

Guideline:

other: Chernoff-Kavlock Assay

GLP compliance:

not specified

Species:

rat

Strain:

Sprague-Dawley

Sex:

female

Route of administration:

oral: gavage

Vehicle:

corn oil

Duration of treatment / exposure:

Dams were treated during gestation days 6 to 15

Frequency of treatment:

Once per day

Dose / conc.:

0 mg/kg bw/day (nominal)

Remarks:

Control

Dose / conc.:

150 mg/kg bw/day (nominal)

Dose / conc.:

200 mg/kg bw/day (nominal)

Control animals:

yes

Parental animals: Observations and examinations:

Maternal body weight and clinical symptoms of toxicity

Litter observations:

Pup numbers, weight, and toxicity symptoms

Postmortem examinations (parental animals):

Number of implantations

Postmortem examinations (offspring):

Deceased pups were examined for soft-tissue alterations and externally malformed pups were examined for alterations to the skeletal and soft-tissue.

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Females exhibited rales and dyspnea (respiratory toxicity).

Mortality:

mortality observed, treatment-related

Description (incidence):

3 dams were found to be deceased following treatment of 150 mg/kg bw/day and 5 dams following 200 mg/kg bw/day.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Females exhibted reduced body weight gain.

Reproductive performance:

no effects observed

Description (incidence and severity):

Number of implantations not significantly affected, nor was perinatal loss relative to the control group.

Key result

Dose descriptor:

LOAEL

Effect level:

150 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

female

Mortality / viability:

no mortality observed

Description (incidence and severity):

Live pups on postnatal day 1 and 6 not significantly affected.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

Pup weight on day 1 and 6 not significantly affected.

Gross pathological findings:

no effects observed

Description (incidence and severity):

No malformations observed.

Key result

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

200 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

not specified

Conclusions:

An experiment was performed to evaluate the developmental / reproductive toxicity of 2-ethylbutyric acid and several additional aliphatic acids in female rats. Deaths were observed in dams at 150 and 200 mg/kg bw/day. Symptoms of maternal respiratory toxicity and decreased body weight gain were apparent in treated females but there did not appear to be a significant effect on reproductive performance or the F1 generation. The LOAEL for maternal toxicity was determined to be 150 mg/kg bw/day and the NOAEL for developmental toxicity concluded to be 200 mg/kg bw/day.

Reference 3

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

1991

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: Insufficient information for an assessment of reliability.

Principles of method if other than guideline:

Not available

GLP compliance:

not specified

Species:

rat

Strain:

Sprague-Dawley

Sex:

female

Route of administration:

oral: gavage

Vehicle:

corn oil

Duration of treatment / exposure:

Treatment occured on gestation day 6 and 15

Frequency of treatment:

Day 6 and 15 (twice)

Remarks:

Two dose levels (information not available)

Maternal respiratory toxicity was reported in treated dams; however, no motor depression was observed and development of the litters was not significantly affected.

Conclusions:

An experiment was performed to evaluate the developmental / reproductive toxicity of eleven aliphatic acids, including 2-ethylbutanoic acid. The registered substance was shown to induce maternal respiratory toxicity but have no or a limited effect on dam motor function and the development of the litters between postnatal day 1 - 6.

Effect on fertility: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

250 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Effects on developmental toxicity

Description of key information

In an experiment for developmental toxicity, the treatment of mice to 600 mg/kg 2-ethylbutyric acid on day 8 gestation resulted in a number of effects to fetal development, including fetal weight, exencephaly, live fetal number, and litter size. 600 mg/kg bw was the lowest effective dose, however, it should be noted that this was the only concentration tested in the study. The registered substance could be regarded as having the capacity to be toxic to development (teratogenicity).

A suitable dose descriptor was not available from this study and its reliability could not be suitably assessed due to a lack of available information (Klimisch score = 4). Subsequently, a NOAEL of 50 mg/kg bw/day for developmental toxicity obtained from a key study (Klimisch score = 2) that has been indicated under 'Toxicity to reproduction' was selected to represent the endpoint conclusion. See Effects on fertility: Description of key information.

Link to relevant study records

Reference

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

1986

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: Insufficient information for an assessment of reliability.

Principles of method if other than guideline:

Not available

GLP compliance:

not specified

Species:

other: Mouse

Strain:

NMRI

Route of administration:

subcutaneous

Vehicle:

water

Duration of treatment / exposure:

Injection on day 8 of gestation and examination on day 18 (10 day exposure period).

Frequency of treatment:

Single injection

Duration of test:

10 days

Dose / conc.:

0 mg/kg bw/day (nominal)

Remarks:

Control

Dose / conc.:

600 mg/kg bw/day (nominal)

Remarks:

As sodium salt

Control animals:

yes

Ovaries and uterine content:

Implantation sites

Fetal examinations:

Number of live fetuses, live fetus weight, examination for malformations, and mortality at birth.

Dead fetuses:

effects observed, treatment-related

Description (incidence and severity):

Number of live fetuses was reduced in the treated group.

Other effects:

no effects observed

Description (incidence and severity):

Embryolethality (%) was considered to be similar in control and exposed fetuses.

Remarks on result:

other: Not available

Fetal body weight changes:

effects observed, treatment-related

Description (incidence and severity):

Fetal weight was lower in the treated group.

Changes in litter size and weights:

effects observed, treatment-related

Description (incidence and severity):

Litters were smaller in the treated group.

External malformations:

effects observed, treatment-related

Description (incidence and severity):

Exencephaly (% of live fetuses) was higher in the treated group.

Remarks on result:

other: Not available

Key result

Developmental effects observed:

yes

Lowest effective dose / conc.:

600 mg/kg bw/day (nominal)

Treatment related:

not specified

Relation to maternal toxicity:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

Conclusions:

Exposure of female mice during day 8 of gestation to 600 mg/kg bw 2-ethylbutyric acid resulted in reduced live fetuses, fetal weight, and litter size and exencephaly in live fetuses. Embryolethality was considered to be similar in the control and treated group. 600 mg/kg bw can be regarded as the lowest effective dose, however, it should be noted that this was the only concentration tested in the study.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

50 mg/kg bw/day

Study duration:

subchronic

Species:

rat