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Diss Factsheets

Administrative data

Description of key information

2-Ethylbutyric acid was shown to have a No Observed Adverse Effect Level (NOAEL) of 300 mg/kg bw/day in rats as part of a 14-day repeated dose toxicity (oral) experiment. A combined repeated dose and reproductive / developmental toxicity experiment was performed for 2-ethylbutyric acid over a 42-day period, in which there was a reported decrease in white blood cells at 50 mg/kg bw/day and in platelet count at 250 mg/kg bw/day in male rats. Following necropsy, kidney weight was reported to be significantly higher at 250 mg/kg bw/day in male and female rats. The NOAEL was subsequently considered to be 10 mg/kg bw/day in males and 50 mg/kg bw/day in females. The results of this experiment have been selected for the purpose of the endpoint conclusion given that they are more conservative and they have been obtained in a key study (Klimisch score = 2).

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Referenceopen allclose all

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
1978
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:
male
Route of administration:
oral: feed
Duration of treatment / exposure:
14 days
Control animals:
yes, concurrent no treatment
Key result
Dose descriptor:
NOAEL
Effect level:
300 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Conclusions:
In a 14-day repeated dose experiment for oral toxicity, 2-ethylbutyric acid was determined to have a No Observed Adverse Effect Level (NOAEL) of 300 mg/kg bw/day. The Lowest Observed Adverse Effect Level (LOAEL) could not be calculated.
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.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
10 mg/kg bw/day
Study duration:
subchronic
Species:
rat

Additional information

Justification for classification or non-classification