Octanal

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

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

Reliability:

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

Reference Type:

publication

Title:

Developmental Toxicity and Structure-Activity Relationships of Aliphatic Acids, including Dose-Response Assessment of Valproic Acid in Mice and Rats

Author:

Narotsky MG, Francis EZ and Kavlock RJ

Year:

1993

Bibliographic source:

Fundamental and Applied Toxicology 22, 251-265 (1994)

Materials and methods

Test guideline

Qualifier:

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:

no

Test material

Test material information

Constituent 1

Reference substance name:

Octanoic acid

EC Number:

204-677-5

EC Name:

Octanoic acid

Cas Number:

124-07-2

Molecular formula:

C8H16O2

IUPAC Name:

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

Species:

rat

Strain:

Sprague-Dawley

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- 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

ENVIRONMENTAL CONDITIONS
- 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

Vehicle:

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:

daily

Duration of test:

dams were terminated on postnatal day 6

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 1125 and 1500 mg/kg bw/day
Basis:
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:

yes

Examinations

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: through out exposure period

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


POST-MORTEM EXAMINATIONS: Yes
- 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

Statistics:

Student's t-test

Indices:

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)

1

Dose descriptor:

LOAEL

Effect level:

1 125 mg/kg bw/day (actual dose received)

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

2

Dose descriptor:

NOAEL

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:

NOAEL

Effect level:

1 500 mg/kg bw/day (actual dose received)

Based on:

test mat.

Basis for effect level:

other: developmental toxicity

Fetal abnormalities

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

Conclusions:

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.