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Toxicological information

Toxicity to reproduction

Currently viewing:

Administrative data

Endpoint:
one-generation reproductive toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1976
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1999
Report date:
1999

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 415 [One-Generation Reproduction Toxicity Study (before 9 October 2017)]
Deviations:
yes
GLP compliance:
no

Test material

Constituent 1
Reference substance name:
valproic acid
IUPAC Name:
valproic acid
Details on test material:
Name of Active Ingredient: Valproic Acid

Test animals

Species:
rat
Strain:
other: CD albino
Sex:
male/female

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on mating procedure:
Proof of pregnancy: sperm in vaginal smear referred to as day 0 of gestation
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
Males: 60 days prior to mating through day 20 of mating period
Females: 14 days prior to mating to day 21 post partum
Frequency of treatment:
Daily
Details on study schedule:
One half of the females from each group were sacrificed on day 13 of gestation for evaluation. The others were allowed to deliver spontaneously

Day of sacrifice of females: day 13 of gestation (n = 10) and 21 days post-partum (n = 10)
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day
Dose / conc.:
65 mg/kg bw/day
Dose / conc.:
150 mg/kg bw/day
Dose / conc.:
350 mg/kg bw/day
No. of animals per sex per dose:
10 animals/sex/dose
Control animals:
yes, concurrent vehicle

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
not specified
Mortality:
not specified
Body weight and weight changes:
not specified
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
not specified
Reproductive function: sperm measures:
not specified
Reproductive performance:
effects observed, treatment-related
Description (incidence and severity):
Dose-related delay in parturition

Effect levels (P0)

Key result
Dose descriptor:
other:
Remarks on result:
not measured/tested

Target system / organ toxicity (P0)

Key result
Critical effects observed:
not specified

Results: F1 generation

General toxicity (F1)

Clinical signs:
not specified
Dermal irritation (if dermal study):
not specified
Mortality / viability:
mortality observed, treatment-related
Description (incidence and severity):
At 350 mg/kg/d, reduction of number neonates per litter and prematurely death of neonates
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Slight reduction of body weight gain of neonates at 65 and 150 mg/kg/d
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Histopathological findings:
not specified

Developmental neurotoxicity (F1)

Behaviour (functional findings):
not specified

Developmental immunotoxicity (F1)

Developmental immunotoxicity:
not specified

Effect levels (F1)

Key result
Dose descriptor:
other:
Remarks on result:
not measured/tested

Target system / organ toxicity (F1)

Key result
Critical effects observed:
not specified

Overall reproductive toxicity

Key result
Reproductive effects observed:
no

Any other information on results incl. tables

The reproductive capacity of males and females of either group was not altered by valproic acid administration.

The main observations were as follows:

- at 65 and 150 mg/kg/day: the bodyweight gain of neonates was very slightly lower than that of contro

ls,

- at 150 and 350 mg/kg/day: reduction in the number of implantation sites. This decrease was due to

high pre-implantation loss,

- at 350 mg/kg/day :

. reduction of the mean number of neonates per lifter,

. all neonates issued from dams of this group died very shortly after birth.

 

Dosage (mg/Kg/day expressed in valproic acid)

0

65

150

350

parents

Females with sperm

/10

/10

/10

/10

Pregnant females

8

8

10

9

Female with delivery

8

8

10

9

Mean duration of gestation (days)

22

22

22

23

Litter means

Live births

10.9

12.3

12.6

9.3

Stillbirths

0

0

0

0.4

Survivors days 4 pp

7.4

9.5

8

0

Weight at birth (g)

6.5

6.4

6.3

6.0

Applicant's summary and conclusion

Conclusions:
The results of these studies show the toxic effect of valproic acid at 350 mg/kg/day with reduced number of pregnant females and delayed parturition. The loss of approximately 30% of neonates very shortly after birth, indicates the existence of pre- and peri-natal toxicity. Moreover, the low survival index and marked retardation of body weight gain in neonates can be attributed to post-natal toxicity.