2-propylvaleric acid

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Well-documented publication of experiments with test procedures in accordance with generally accepted scientific standards and described in sufficient details.

Data source

Reference

Reference Type:

publication

Title:

Valproic Acid Developmental Toxicity and Pharmacokinetics in the Rhesus Monkey: An Interspecies Comparison

Author:

A.G. Hendrickx, H. Nau, P. Binkerd, J.M. Rowland, J.R. Rowland, M.J. Cukierski, and M.A. Curieski

Year:

1988

Bibliographic source:

Teratology 38:329-345 (1988)

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

The present study was undertaken to
1) evaluate the teratogenic potential of VPA administered to rhesus monkeys during organogenesis,
2) determine the maternal disposition of VPA on the first and last days of treatment,
3) determine embryo concentrations of VPA during early organogenesis, and
4) correlate these teratogenic and pharmacokinetic findings in rhesus monkeys and compare them with similar data in other species.

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Valproic acid (VPA)

IUPAC Name:

Valproic acid (VPA)

Constituent 2

Reference substance name:

2-propylvaleric acid

EC Number:

202-777-3

EC Name:

2-propylvaleric acid

Cas Number:

99-66-1

Molecular formula:

C8H16O2

IUPAC Name:

2-propylpentanoic acid

Details on test material:

Valproic acid (VPA) was supplied by Sigma Chemical Co., St Louis, MO. The VPA was neutralized with an equimolar amount of aqueous sodium hydroxide. (See "any other information on material and method")

Test animals

Species:

monkey

Strain:

other: Macaca mulatta

Administration / exposure

Route of administration:

other: Nasogastric intubation

Vehicle:

other: aqueous sodium hydroxide

Analytical verification of doses or concentrations:

not specified

Details on mating procedure:

- Impregnation procedure: females mated with a fertile male on menstrual cycle days 11, 13, and 15 or 11 and 13.
- Mating occurred during a limited period of 2 hours per day with day 13 designated as day zero (0) of pregnancy.
- Proof of pregnancy: pregnancy was detected by radioreceptorassay or a radioimmunoassay (RIA) between gestational days (GD) 18 and 20.

Duration of treatment / exposure:

GD 21 - GD 50: 20, 75, 100, 150, 200 mg/kg/day doses.
GD 20- GD 23: 450 and 600 mg/kg/day dose.

Frequency of treatment:

daily

No. of animals per sex per dose:

1 female for 450 mg/kg/day,
3 females for each of the doses of 20, 75, 150 mg/kg/day,
6 females for 600 mg/kg/day,
7 females for 100 mg/kg/day,
10 females for 200 mg/kg/day.

Control animals:

yes, concurrent vehicle

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:yes. Remark: minimal effects and not dose-dependant

Effect levels (maternal animals)

Key result

Remarks on result:

not measured/tested

Maternal abnormalities

Key result

Abnormalities:

effects observed, non-treatment-related

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:yes

Effect levels (fetuses)

Key result

Remarks on result:

not measured/tested

Fetal abnormalities

Key result

Abnormalities:

effects observed, treatment-related

Localisation:

external: cranium

external: face

skeletal: skull

skeletal: rib

skeletal: vertebra

Overall developmental toxicity

Developmental effects observed:

not specified

Any other information on results incl. tables

The following important observations were made:

- Dose-dependent developmental toxicity (increased embryo/fetal mortality), intrauterine growth retardation, and craniofacial and skeletal defects.

- Biphasic plasma elimination curves for total and free VPA on the first and last days of treatment at both 100 and 200 mg/kg/day

- Dose-independent elimination kinetics at the plasma concentrations

- No significant change in pharmacokinetic parameters between the first and last days of treatment at either dose level.

- Placental transfer studies: apparently embryos were exposed to half the free VPA concentrations present in maternal plasma.

Applicant's summary and conclusion

Conclusions:

The authors point to the necessity of evaluating both teratogenic and pharmacokinetic endpoints to explain species differences and the limitations of estimating human developmental hazards from experimental data.
In the conditions of the study, embryotoxic and teratogenic effects were observed. Craniofacial and skeletal defects were the most significant findings in this study.