Vanadate(1-), oxo[phosphato(3-)-.kappa.O]-, hydrogen, hydrate (2:2:1)

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

no data available

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Well documented. Purity of the test substance not stated.

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

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:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Trisodium tetraoxovanadate

EC Number:

237-287-9

EC Name:

Trisodium tetraoxovanadate

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
No further details are given.

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.
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

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
0 mg/kg body weight
Basis:
nominal conc.

Doses / concentrations 2

Remarks:

Doses / Concentrations:
7.5 mg/kg body weight
Basis:
nominal conc.

Doses / concentrations 3

Remarks:

Doses / Concentrations:
15 mg/kg body weight
Basis:
nominal conc.

Doses / concentrations 4

Remarks:

Doses / Concentrations:
30 mg/kg body weight
Basis:
nominal conc.

Doses / concentrations 5

Remarks:

Doses / Concentrations:
60 mg/kg body weight
Basis:
nominal conc.

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.
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

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

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:

NOAEL

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:

NOAEL

Effect level:

15 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: fetotoxicity

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

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.