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Diss Factsheets

Administrative data

developmental toxicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
not stated - published information 15 July 1993
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The structure-activity relationship assessment does not contain many of the guideline requirements for determination of developmental toxicity

Data source

Reference Type:
Developmental Toxicity and Structure-Activity Relationships of Aliphatic Acids, including Dose-Response Assessment of Valproic Acid in Mice and Rats
Narotsky MG, Francis EZ and Kavlock RJ
Bibliographic source:
Fundamental and Applied Toxicology 22, 251-265 (1994)

Materials and methods

Test guideline
no guideline followed
Principles of method if other than guideline:
The teratogenic anticonvulsant valproic acid (VPA; 2-propylpentanoic acid) and related chemicals including octanoic acid were screened for developmental toxicity using the Chernoff/Kavlock assay. Test agents, in corn oil, were administered by gavage to Sprague-Dawley rats once daily during organogenesis. The dams were allowed to deliver and the pups were examined postnatally
GLP compliance:
not specified
Limit test:

Test material

Constituent 1
Chemical structure
Reference substance name:
Octanoic acid
EC Number:
EC Name:
Octanoic acid
Cas Number:
Molecular formula:
octanoic acid
Test material form:
not specified
Details on test material:
- Name of test material (as cited in study report): octanoic acid

- Analytical purity: 99.5%

Test animals

Details on test animals or test system and environmental conditions:
- Source:Charles River Laboratories
- Age at study initiation: timed-pregnant - no further details for age/weight
- Weight at study initiation: no data

- Housing:
- Diet (e.g. ad libitum): Purina Lab chow No. 5001 or Wayne Lab Blox
- Water (e.g. ad libitum): tap water ad libitum
- Acclimation period: no data

- Temperature (°C): 22.2±1.1
- Humidity (%): 50±10%
- Air changes (per hr): not stated
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: To: no information

Administration / exposure

Route of administration:
oral: gavage
unchanged (no vehicle)
Details on exposure:
Dose volume of 2 ml/ kg bw/day

Animals were treated by gavage once daily on gestation day 6 to 15. The doses were based on individual bodyweight recorded on gestation day 6.
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No information
Details on mating procedure:
- Impregnation procedure: purchased timed pregnant
Duration of treatment / exposure:
Treated from gestation day 6-15
Frequency of treatment:
Duration of test:
dams were terminated on postnatal day 6
Doses / concentrations
Doses / Concentrations:
0, 1125 and 1500 mg/kg bw/day
actual ingested
No. of animals per sex per dose:
For octanoic acid there were 15 control dams, 11 low dose and 9 high dose dams on study
Control animals:


Maternal examinations:
- Time schedule: through out exposure period

- Time schedule for examinations: GD 6, 8, 10, 13, 16 and 20

- Sacrifice on postnatal day 6, (gestation day 22 was defined as postnatal day 1)
- Organs examined: uterus for evidence of implantations

Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No data
- Number of corpora lutea: No data
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes

Number of implants, number of live pups, perinatal loss % and pup weights on postnatal days 1 and 6 are the only parameters reported
Fetal examinations:
- External examinations: Yes: all per litter on postnatal days 1, 3 and 6
- Soft tissue examinations: Yes: all externally malformed pups
- Skeletal examinations: Yes: on postnatal day 6 for two survivors per litter, one per sex where possible.
- Head examinations: No data
Student's t-test
No further information
Historical control data:
No information presented in publication

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes. Remark: Clinical signs - rales and dyspnoea commonly observed respiratory effects of treatment. Bodyweight loss particularly for decedents. Early, dose related, mortality.

Details on maternal toxic effects:
Chernoff/lKavlock Assays
Maternal data. Maternal toxicity was demonstrated for all compounds by weight loss or reduced weight gain, especially early in the treatment period and by clinical signs of respiratory effects including rales and dyspnoea. Vocalization and nasal breathing sounds, associated with nasal congestion, were also frequently observed.
Maternal mortality was observed for all compounds, including octanoic acid. Mortality was higher than expected on the basis of preliminary data with nongravid rats. Most deaths were attributed to the respiratory effects of treatment. Necropsy findings of foam or semi-solid material in the trachea were associated with rales, and gas in the gastrointestinal tract was associated with dyspnea. Several deaths, noted in the assay for octanoic acid (and other congeners - 2MP, VPA. 2EH, 2MO, 3MH, and 5MH) occurred shortly after dosing. The dose-related pattern of mortality suggested that they may have been treatment-related.
Transient motor depression, manifested by ataxia and/or decreased motoractivity generally within 4 hr after dosing, was pronounced in rats treated Not apparent for octanoic acid treated rats.

Effect levels (maternal animals)

open allclose all
Dose descriptor:
Effect level:
1 125 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
Effect level:
1 500 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
Effects of treatment with VPA were not replicated in the study with octanoic acid.

Effect levels (fetuses)

Key result
Dose descriptor:
Effect level:
1 500 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: developmental toxicity

Fetal abnormalities

not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

The Chernoff/Kavlock assays revealed

valproic acid (VPA)

-like developmental toxicity (delayed parturition, decreased progeny viability, and/or lumbar ribs) and some congeners, but no effects for octanoic acid.

Although perinatal mortality was noted for octanoic acid, despite the maternally lethal doses administered, these compounds clearly did not induce the developmental effects seen with

valproic acid (VPA)

. The frequency and severity of the maternal toxicity (respiratory effects) seen in the screening assays were sometimes greater than anticipated based on preliminary studies with non-pregnant rats, suggesting that pregnant rats may be more susceptible. The respiratory effects may be attributable to gastro-oesophageal reflux and subsequent aspiration of the dosing solution following gavage administration. Airway constriction and pulmonary edema may be related to irritation caused by aspirated test material.

Applicant's summary and conclusion

Maternal toxicity was evident for octanoic acid at both dose levels, 1500 and 1125 mg/kg bw/d but no signs of embryotoxicity were observed in rats or mice. No NOAEL was established but the maternal NOAEL is less than 1125 mg/kg bw/day.
Executive summary:

In this developmental toxicity study performed using the read-across substance octanoic acid, mated female rats were gavaged on Days 6 -15 of gestation at dose levels of 1125 or 1500 mg/kg bw/d. Maternal toxicity was apparent at both dose levels but no evidence of developmental toxicity was apparent. Specifically, octanoic acid did not demonstrate the embryotoxicity associated with the structurally related substance valproic acid.