Vanadium, oxalate complexes

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Study period:

no data available

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Well reported study. The relevance of the study is limited since all developmental effects were associated by pronounced maternal toxicity. Purity of the test substance not stated.

Data source

Reference

Reference Type:

publication

Title:

Developmental toxicity of vanadium in mice after oral administration

Author:

Paternain, J.L.; et al.

Year:

1990

Bibliographic source:

J. App. Toxicol. 10, 181-6

Materials and methods

Test guideline

Guideline:

other: no information available if a guideline was followed

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

284-652-7

IUPAC Name:

284-652-7

Constituent 2

Reference substance name:

12439-96-2

Cas Number:

12439-96-2

IUPAC Name:

12439-96-2

Constituent 3

Reference substance name:

Vanadyl sulphate pentahydrate

IUPAC Name:

Vanadyl sulphate pentahydrate

Details on test material:

- Name of test material (as cited in study report): Vanadyl sulphate pentahydrate
- Molecular formula (if other than submission substance): VOSO4 * 5H2O
- 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: adult mice were obtained from Panlab (Barcelone, Spain).
- Weight at study initiation: 25-30 g
- Diet: ad libitum, commercial chow
- Water: ad libitum
- Acclimation period: 10 days

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: no data

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

No details are reported.

Details on mating procedure:

- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1/2; for mating, one male and two females were placed into a breeding cage.
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
No further details are given.

Duration of treatment / exposure:

on gestational days 6-15

Frequency of treatment:

once daily

Duration of test:

till day 18 of gestation

Doses / concentrations

Doses / concentrations 1

Remarks:

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

Doses / concentrations 2

Remarks:

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

Doses / concentrations 3

Remarks:

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

Doses / concentrations 4

Remarks:

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

No. of animals per sex per dose:

Three groups of 22 sperm-positive females were randomly assigned to each group.

Control animals:

yes

Details on study design:

- Dose selection rationale: the doses are approximately 1/12, 1/6 and 1/3 of the acute oral LD50 of VOSO4 * 5H2O for adult mice (LLobet, J.M.; Domingo, J.L., 1984).

Examinations

Maternal examinations:

CAGE SIDE OBSERVATIONS: No data

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: mice were observed daily for mortality and morbidity throughout the study.

BODY WEIGHT: Yes
- Time schedule for examinations: body weights were computed for the pre-treatment, treatment and post-treatment periods from daily records of these parameters.

FOOD CONSUMPTION: Yes
- Time schedule for examinations: food consumption was computed for the pre-treatment, treatment and post-treatment periods from daily records of these parameters.

WATER CONSUMPTION: No data

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 18 by over-exposure to ether.
- Organs examined: the uteri were excised and weighed.
- Dams were examined for visceral gross pathology.

OTHER: Yes
- Maternal liver, kidney, spleen and placenta were analysed for the concentration of vanadium. Vanadium concentrations were determined by atomic absorption spectrophotometry.

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: No data
- Number of implantations: Yes
- Number of resorptions: Yes
- Other: post-implantation losses were calculated for each litter as follows: (No. of implants - No. of live fetuses)/No. of implants x 100. The number of stunted fetuses (under 2/3 average body weight) was also recorded.

Fetal examinations:

The fetuses were taken by caesarean section.
- External examinations: fetuses were removed from their placentas and examined externally. Sex, weight and length were recorded.
- Soft tissue examinations: after the external observation was completed, approximately 1/3 of the remaining fetuses from each group were fixed in Bouin's solution and examined for soft tissue abnormalities.
- Skeletal examinations: remaining fetuses were fixed with Alizarin red solution and examined for skeletal abnormalities.
- Head examinations: No / No data
- Other: 3 fetuses from each dam were used for whole body analyses of vanadium.

Statistics:

Test groups were compared to the control group at a level of significance of P<0.05. Continuous data (e.g. maternal body weight, body weight gain, food consumption etc.) were analysed using one-way analysis of variance with significant F values analysed further using Student's t-test or the Mann-Whitney U test. Statistical comparison of the vanadium analyses were made by Student's t-test (one tailed), with a Bonferroni correction for multiple comparisons between treatment groups. A probability of P<0.05 was used as the criterion of statistical significance. Incidence data were compared using chi-square contingency tables (2x4). Each test group was compared to the control group when chi-square was significant.

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. Remark: body weight gain, organ weights, food consumption

Details on maternal toxic effects:
- No deaths or treatment-related clinical signs of toxicity were observed in the study. 2 animals died in the low-dose group, but these deaths appeared to be related of dosing accidents.
- There were no treatment-related gross necropsy findings.
- Mean body weight gain during the pre-treatment interval, days 0-6 of gestation, was comparable between treated and control groups. However, there were significant decreases in body weight gain during the exposure period in treated animals. The reduction in maternal weight gain during this period was dose-related and was observed at all dose levels. The body weight gain during the post-exposure interval indicated that the treated animals gained less weight than the controls, but these differences were not statistically significant.
- No significant differences occurred between vanadium-treated groups and the control group in food consumption during pregnancy. Although an apparent decrease in the mean food consumption was observed for the 75 and 150 mg/kg body weight/day groups from day 0 to day 18 of gestation, this decrease was not statistically significant.
- Maternal organ weights at termination, including absolute and corrected body weight, absolute liver weight, absolute kidney weight and placenta weight, were affected by treatment. Absolute maternal liver weight (g), but not relative liver weight (% body weight), was significantly decreased at 75 and 150 mg/kg body weight/day, whereas absolute maternal kidney weight was significantly decreased at 150 mg/kg/day.
- Gravid uterine weights were significantly lower at all dose levels relative to controls.
- There was no effect of vanadium on the number of total implantations, live and dead fetuses, late resorptions per litter, or on the percentage post-implantation losses or the sex ratio. The number of early resorptions per litter exhibited a dose-related increase for all vanadium-treated groups.
- Vanadium could not be detected in control mice. In contrast, it was detected in both maternal and fetal tissues of the treated animals. All these values were significant. However, a significant dose-related increase of vanadium concentrations was observed only in the dam kidney of treated animals.

Effect levels (maternal animals)

Dose descriptor:

LOAEL

Remarks:

(lowest dose level)

Effect level:

37.5 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: external defects, skeletal variations

Details on embryotoxic / teratogenic effects:
- Mean fetal body weights and mean fetal body lengths were significantly lower in the treated groups when compared to the control group.
- There was a significant incidence of stunted fetuses at the 75 mg/kg/day group (P<0.05) and at the 150 mg/kg/day group (P<0.001) relative to controls.
- Cleft palate and micrognathia were the most significant external malformations observed in the 150 mg/kg/day group.
- The total number of external defects was statistically significant for all vanadium-treated groups relative to controls.
- Hydrocephaly in fetuses from dams given 75 or 150 mg/kg/day of test substance was the only incidental abnormality observed after visceral examination.
- Increased incidence of skeletal variations was seen in all vanadium-treated groups. Decreased ossification of the supraoccipital bone and decreased ossification of the carpus and tarsus were the most common anormalies found. The increase in the total number of skeletal defects was significantly different from the controls in all the treated groups. In addition, this increase was dose-dependent.

Effect levels (fetuses)

1

Dose descriptor:

LOAEL

Remarks:

(lowest dose level)

Effect level:

37.5 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: embryotoxicity

2

Dose descriptor:

LOAEL

Remarks:

(lowest dose level)

Effect level:

37.5 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: fetotoxicity

3

Dose descriptor:

LOAEL

Remarks:

(lowest dose level)

Effect level:

37.5 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: teratogenicity

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

The present study involved oral administration of vanadyl sulphate pentahydrate to mice during organogenesis. Maternal toxicity in terms of decreased weight gain and reduction in body weight appeared to be produced in pregnant mice treated with vanadyl sulphate pentahydrate at doses of 37.5, 75 or 150 mg/kg/day. Embryo-/fetotoxicity was incidenced by an increased number of early resorptions and by lower fetal weights and lengths, as well as by increased incidence of poorly ossified skeletal elements at all dose levels. A significantly increased number of major malformations and minor anormalies indicated teratogenicity.
The NOEL for maternal toxicity, embryotoxicity, fetotoxicity and teratogenicity was <37.5 mg/kg/day of vanadyl sulphate pentahydrate, as signs of maternal and developmental toxicity were observed at this dose.

Executive summary:

Vanadium, as vanadyl sulphate pentahydrate, was evaluated for its embryotoxic, fetotoxic and teratogenic potential in Swiss mice. The compound was administered by gavage to pregnant mice at doses of 0, 37.5, 75 or 150 mg/kg body weight/day on days 6 -15 of pregnancy. On gestation day 18, all live fetuses were examined for external, visceral and skeletal malformations and variations.

Maternal toxicity was observed in all vanadium-treated animals, evidend by reduced weight gain, reduced body weight on gestation day 18 (corrected for gravid uterine weight) and decreased absolute liver and kidney weights at 75 and 150 mg/kg body weight/day. The number of total implants, live and dead fetuses, late resorptions, sex ratio and post-implantation losses were not significantly different between the vanadium-treated mice and the controls. However, there was a significant increase in the number of early resorptions per litter at all dose levels. Fetotoxicity was evidend by lower fetal weights and lengths and the presence of developmental variations. Malformation incidence also increased by administration of vanadium. Thus, the NOEL for maternal toxicity, embryo-/fetotoxicity and teratogenicity for vanadyl sulphate pentahydrate under these test conditions can be expected below 37.5 mg/kg body weight/day in Swiss mice.