Registration Dossier

Toxicological information

Developmental toxicity / teratogenicity

Currently viewing:

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:
no data available
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Well documented. Purity of the test substance not stated.

Data source

Reference Type:
Developmental toxicity evaluation of orthovanadate in the mouse
Sanchez, D.; et al.
Bibliographic source:
Biol. Trace Element Res. 30, 219-226

Materials and methods

Test guideline
other: no information available, if a guideline was followed
Principles of method if other than guideline:
Evaluation of the effects of vanadate (V5+) when administered once daily by gavage as sodium orthovanadate to mice throughout organogenesis.
GLP compliance:
Limit test:

Test material

Test material form:
other: solid
Details on test material:
- Name of test material (as cited in study report): Sodium orthovanadate
- Molecular formula (if other than submission substance): Na3VO4
- Physical state: solid
No further details are given.

Test animals

Details on test animals and environmental conditions:
- Source: Animals were obtained from Letica (Barcelona, Spain).
- Weight at study initiation: 26-29g
- Housing: mice were housed in solid-bottom plastic cages with stainless steel wire lids.
- Diet: ad libitum, standard laboratory chow
- Water: ad libitum
- Acclimation period: 1 week

- Temperature (°C): 21-23
- Humidity (%): 45 +/- 5
- Photoperiod: 12 hours dark/light cycle
No further details are given.

Administration / exposure

Route of administration:
oral: gavage
Details on exposure:
- The test substance was dissolved in deionised water.

Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No details are given.
Details on mating procedure:
After acclimatisation, females were mated overnight with adult males of the same strain. The morning on which a copulation plug was detected was considered as day 0 of gestation. At this time, animals were randomly assigned to either the control or the vanadate-treated group.
No further details are given.
Duration of treatment / exposure:
10 days
Frequency of treatment:
once daily on days 6-15 of pregnancy
Duration of test:
till day 18 of pregnancy
No. of animals per sex per dose:
14-20 dams per dose group
Control animals:
Details on study design:
- Dose selection rationale: The choice of the dosage levels was based on data from a previous study on the developmental toxicity of vanadyl sulfate in mice (Paternein, J.L.; et al. 1990).


Maternal examinations:

- Time schedule: general appearance of pregnant mice were monitored daily.

- Time schedule for examinations: body weight of pregnant mice were monitored daily.

- Time schedule for examinations: Food consumption of pregnant mice were monitored daily.


- Sacrifice on gestation day 18 with an overdose of ether.
- All dams were evaluated for body weight, liver and kidney weights.
No further details are given.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: No data
- Number of implantations: Yes
- Number of resorptions: Yes
- Number of dead and live fetuses: Yes
Fetal examinations:
- External examinations: all live fetuses were dissected from the uterus and evaluated for body weight, sex and external abnormalities.
- Soft tissue examinations: 1/3 of the fetuses from each litter were placed in Bouin's fluid to be examined for soft tissue abnormalities.
- Skeletal examinations: 2/3 of the fetuses from each litter were cleared and stained with alizarin red S before examination for skeletal malformations and variations.
- Head examinations: No data
Homogeneity of variance was analysed by Barlett's test. If variances were homogenous, a one-way analysis of variance (ANOVA) was used to test all dose groups simultaneously. The Kruskal-Wallis test was used when variances were not homogenous. Differences between control and orthovanadate-treated groups were analysed by Student's t-test. Incidence data were analysed using the chi-square test. The level of significance for all analyses was p<0.05.
no details given
Historical control data:
no data

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
Doses of 30 and 60 mg/kg/day of sodium orthovanadate resulted in maternal toxicity.
- In the high dose group, 17 dams (from 19 pregnant females dosed) died during the treatment period. Consequently, the two remaining dams were not included in the teratological evaluation of orthovanadate.
- At 30 mg/kg/day, 4 dams (from 18 pregnant females does) were found dead during the study.
- Exposure to 7.5 or 15 mg/kg/day of the test substance did not result in any maternal death.
- Maternal weight gain was significantly reduced below control values in the 30 mg/kg/day dose group on gestational days 6-15, whereas food consumption exhibited a significant decrease in the 15 and 30 mg/kg/day dose groups on gestational days 0-18.
- At scheduled termination on gestation day 18, there were no significant decreases in body weight, gravid uterine weight, corrected body weight and change in corrected body weight.
- There was a decrease in absolute and relative liver weight in the 15 mg/kg/days dose group and an increase in relative kidney weight at 30 mg/kg/day, which were statistically significant versus controls. However, the decreases in liver weight were not dose-related and therefore they were not attributed to treatment.
- Evaluation of gestational parameters for the mice indicated no treatment-related effects on number of total implantations per litter, number of live and dead/resorbed fetuses per litter, sex ratio, featl body weights and the number of stunted fetuses.

Effect levels (maternal animals)

Dose descriptor:
Effect level:
7.5 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes. Remark: skeletal anormalities

Details on embryotoxic / teratogenic effects:
- Sodium orthovanadate did not induce significant incidence of gross and visceral malformations or variations in mouse fetuses.
- Treatment-related changes were found during the examination of the incidence and type of skeletal anormalies: significant decreases in the number of ossified sacrococcygeal vertrebrae, as well as the number of ossified forelimb and hindlimb proximal phalanges
- No significant increases in the number of fetuses with reduced ossification of occipital and parietal bones or sternebrae were observed.

Effect levels (fetuses)

Dose descriptor:
Effect level:
15 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: fetotoxicity

Fetal abnormalities

not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion

At 30 and 60 mg/kg body weight, deaths occurred among the dams (4/18 and 17/19). Body weight gain was significantly reduced (approximately 20%) at 15 mg/kg b.w. No differences were reported in final body weight, gravid uterine weight, or corrected body weight.
NOAEL for maternal toxicity: 7.5. mg/kg. b.w./day.
NOAEL for foetotoxicity 15 mg/kg b.w./day.
Executive summary:

Sodium orthovanadate in deionised water was administered once daily by gavage on gestational days 6 -15 to mice at doses of 0, 7.5, 15, 30 and 60 mg/kg body weight/day. Dams were killed on day 18 of pregnancy, and fetuses were examined for external, visceral and skeletal defects. Maternal toxicity was observed at the highest doses levels, as evidenced by a significant number of deaths (60 and 30 mg/kg body weight/day) and reduced weight gain and food consumption (30 and 15 mg/kg body weight/day). Embryolethality and teratogenicity were not observed at maternally toxic doses and below, but fetal toxicity was evidenced by a significant delay in the ossification process of some skeletal districts at 30 mg/kg body weight/day. The NOAEL for maternal toxicity was 7.5 mg/kg body weight/day and 15 mg/kg body weight/day represented a NOAEL for developmental toxicity in mice under the conditions of this study.