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Toxicological information

Developmental toxicity / teratogenicity

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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:
no data available
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Remarks:
only summary results but no details or individual data presented

Data source

Reference
Reference Type:
publication
Title:
Developmental toxicity evaluation of orthovanadate in the mouse
Author:
Sanchez, D. et al.
Year:
1991
Bibliographic source:
Biol. Trace Element Res. 30, 219-226

Materials and methods

Test guideline
Qualifier:
no guideline 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:
no
Limit test:
no

Test material

Constituent 1
Reference substance name:
Trisodium tetraoxovanadate
EC Number:
237-287-9
EC Name:
Trisodium tetraoxovanadate
Cas Number:
13721-39-6
IUPAC Name:
trisodium tetraoxovanadate(3-)
Constituent 2
Reference substance name:
sodium orthovanadate
IUPAC Name:
sodium orthovanadate
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

Species:
mouse
Strain:
Swiss
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- 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

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-23
- Humidity (%): 45 +/- 5
- Photoperiod: 12 hours dark/light cycle

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
- 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.
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
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (nominal)
Dose / conc.:
7.5 mg/kg bw/day (nominal)
Dose / conc.:
15 mg/kg bw/day (nominal)
Dose / conc.:
30 mg/kg bw/day (nominal)
Dose / conc.:
60 mg/kg bw/day (nominal)
No. of animals per sex per dose:
14-20 dams per dose group
Control animals:
yes
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).

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: No data

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: general appearance of pregnant mice were monitored daily.

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

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

WATER CONSUMPTION: No data

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 18 with an overdose of ether.
- All dams were evaluated for body weight, liver and kidney weights.
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
Statistics:
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.
Indices:
no details given
Historical control data:
no data

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
not specified
Dermal irritation (if dermal study):
not specified
Mortality:
mortality observed, treatment-related
Description (incidence):
- 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.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
- Maternal weight gain was significantly reduced below control values in the 30 mg/kg/day dose group on gestational days 6-15.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
- Food consumption exhibited a significant decrease in the 15 and 30 mg/kg/day dose groups on gestational days 0-18.
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:
effects observed, treatment-related
Description (incidence and severity):
- There was an increase in relative kidney weight at 30 mg/kg/day, which were statistically significant versus controls.
Gross pathological findings:
not specified
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Details on results:
Maternal toxic effects:yes

Details on maternal toxic effects:
Doses of 30 and 60 mg/kg/day of sodium orthovanadate resulted in maternal toxicity.
- Exposure to 7.5 or 15 mg/kg/day of the test substance did not result in any maternal death.
- 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.

Maternal developmental toxicity

Number of abortions:
not specified
Pre- and post-implantation loss:
not specified
Total litter losses by resorption:
not specified
Early or late resorptions:
not specified
Dead fetuses:
no effects observed
Changes in pregnancy duration:
not specified
Changes in number of pregnant:
not specified
Other effects:
no effects observed
Details on maternal toxic effects:
- 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, fetal body weights and the number of stunted fetuses.

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
7.5 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
body weight and weight gain
food consumption and compound intake
mortality

Maternal abnormalities

Abnormalities:
not specified

Results (fetuses)

Fetal body weight changes:
not specified
Reduction in number of live offspring:
not specified
Changes in sex ratio:
not specified
Changes in litter size and weights:
not specified
Changes in postnatal survival:
not specified
External malformations:
no effects observed
Skeletal malformations:
effects observed, treatment-related
Description (incidence and severity):
- 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 were sen at 30 mg/kg bw/d.
Visceral malformations:
no effects observed
Other effects:
not specified
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 at 30 mg/kg bw/d.
- 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:
NOAEL
Effect level:
15 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
not specified
Basis for effect level:
skeletal malformations

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
At 30 and 60 mg sodium orthovandate/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.

Although this publication shows some deficiencies with respect to reporting of methods and results it was conducted in a suficient number of female mice and can be regarded as relevant and approriate.