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Toxicological information

Toxicity to reproduction

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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
Cross-reference
Reason / purpose for cross-reference:
reference to same study
Reference
Endpoint:
short-term repeated dose toxicity: oral
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
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
Observations and examinations performed and frequency:
Body weight (gain), food consumption, haematological findings, and biochemical findings of males / females. Estrous cycle in females.
Sacrifice and pathology:
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:
effects observed, treatment-related
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
Description (incidence and severity):
At 250 mg/kg bw/day, male rats experienced increased relative kidney weight and females experienced increased absolute and relative kidney weight.
Gross pathological findings:
no effects observed
Description (incidence and severity):
No significant effects were found following necropsy.
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.
Other effects:
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
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
50 mg/kg bw/day (nominal)
System:
haematopoietic
Organ:
blood
leucocyte development
Treatment related:
yes
Dose response relationship:
not specified
Relevant for humans:
not specified
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
250 mg/kg bw/day (nominal)
System:
haematopoietic
Organ:
blood
platelet formation
Treatment related:
yes
Dose response relationship:
not specified
Relevant for humans:
not specified
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
250 mg/kg bw/day (nominal)
System:
urinary
Organ:
kidney
Treatment related:
yes
Dose response relationship:
not specified
Relevant for humans:
not specified

F1 Generation

No treatment-related change in external appearance. Number of live pups at 250 mg/kg bw/day was lower than control (0 mg/kg bw/day) and other treatment groups. No treatment-related change in body weight.

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.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2002
Report date:
2001

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
GLP compliance:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
2-ethylbutyric acid
EC Number:
201-796-4
EC Name:
2-ethylbutyric acid
Cas Number:
88-09-5
Molecular formula:
C6H12O2
IUPAC Name:
2-ethylbutyric acid
Test material form:
not specified

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female

Administration / exposure

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
Doses / concentrationsopen allclose all
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

Examinations

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.

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

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 function / performance (P0)

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.

Effect levels (P0)

open allclose all
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

Results: F1 generation

General toxicity (F1)

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.

Effect levels (F1)

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

Overall reproductive toxicity

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

Applicant's summary and conclusion

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.

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