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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:
other: Report is reliable with restriction, and regarded as sufficient for evaluation of the embryo-/foetotoxic and teratogenic potential of sodium selenite.
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
publication
Title:
Effects of sodium selenite on methylmercury embryotoxicity and teratogenicity in mice.
Author:
Nobunaga T, Satoh H, Suzuki T.
Year:
1979
Bibliographic source:
Toxicol.Appl. Pharmacol.47, 79-88

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Female mice were given drinking water containing sodium selenite (3 ppm and 6 ppm selenium) at two different dose levels for approximately 1 month before gestation and thereafter up to day 18 of gestation. Examinations were undertaken to evaluate effects of the test item on female fertility and embryo-/foetotoxicity and teratogenicity.
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): sodium selenite, pentahydrate
- Molecular formula (if other than submission substance): Na2SeO3 * 5H20
- Molecular weight (if other than submission substance): 263.01 g/mol
- Substance type: technical product
- Physical state: solid
No further details are given.

Test animals

Species:
mouse
Strain:
other: IVCS
Details on test animals and environmental conditions:
TEST ANIMALS
- Age at study initiation: 60 days
- Housing: housed 4 or 5 per cage during the precoital period and 1 to 2 per cage during gestation, in plastic cages with wood chips for bedding.
- Diet: ad libitum; food was a dough made from a commercial-chow for mice.
- Water: ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23-26
- Photoperiod: 14 hours light/ 10 hours dark cycle

No further details are given.

Administration / exposure

Route of administration:
oral: drinking water
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
- The test substance was dissolved in water to obtain a 0.03% solution.

DIET PREPARATION
- The diet-chow used did not contain any measurable amounts of selenium when measured by the Watkinson's method (sensitivity: 0.13 nmol/g).


Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
no data
Details on mating procedure:
After 30 days, as mice came into pro-oestrus, they were individually mated overnight with a healthy non-treated male mouse of the same strain. If female mice did not mate during the first overnight trial, they were separated from the males and maintained on experimental feed until next pro-oestrus. Mating trials were terminated on Day 56 after the start of the experiment.

- Impregnation procedure: cohoused
- M/F ratio per cage: 1/1
- Length of cohabitation: overnight
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: vaginal plug referred to as day 0 of pregnancy
Duration of treatment / exposure:
30 days prior to gestation until GD 18
Frequency of treatment:
daily, continuously in drinking water
Duration of test:
until day 18 of gestation
No. of animals per sex per dose:
3 groups including one control group:
- Low dose group: 14 animals
- High dose group: 10 animals
- Control group: 14 animals
Control animals:
yes
Details on study design:
- Dose selection rationale: in previous studies concentrations of selenium around 25-38 nmol/mL (2-3 ppm as selenium) induced mild or severe toxic effects in long-term experiments (Schroeder and Mitchener, 1971 a, b; Palmer and Olson 1974).

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: No data

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes
- Time schedule for examinations: every third day in the precoital experimental period.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- The amount of food consumed in each cage was determined by measuring the decrease in weight of preweighed feed.
- The loss of weight of feed due to water evaporation was calculated as 8% per day.

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: water consumption was determined by measuring the decrease in volume of premeasured water in feeding bottles.

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 18
- Organs examined: uterus

OTHER:
- Oestrus cycles of mice were determined by vaginal smears which were sampled with physiological saline, dried on glass slides, and stained with Giemsa solution were examined microscopically every morning.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No data
- Number of corpora lutea: No data
- Number of total implantations: Yes
- Number of surviving foetuses, dead foetuses, dead embryos, resorptions and implantation sites
- Litter size was defined as the number of surviving foetuses per dam.
Fetal examinations:
The surviving foetuses were killed by ether or decapitation and examined under a dissecting microscope for gross abnormalities. After dissection of internal organs and tissues, the foetuses were prepared for skeletal examinations by the method of Dawson (1926).

- External examinations: Yes
- Soft tissue examinations: Yes
- Skeletal examinations: Yes
- Head examinations: No data
Statistics:
t-test
Indices:
no data
Historical control data:
no data

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:no effects

Details on maternal toxic effects:
WATER CONSUMPTION
- Water consumption was statistically significantly decreased in comparison to control during the precoital period, but not from GD 3-18.

FOOD CONSUMPTION
- No effects on food consumption were observed in comparison to the control group.

BODY WEIGHTS
- No effects on body weight were observed during the precoital or gestation period.

OTHERS
- Oestrus cycle length was increased by about 11.8% in comparison to control in the high dose group (6 ppm), but not in the low dose group (3 ppm).
- Conception rates were 90, 86 and 100% in the control low and high dose groups, respectively.
- The average time until conception showed no significant differences from control.

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
3 ppm (nominal)
Based on:
element
Basis for effect level:
other: significant decrease in foetal body weights
Remarks on result:
not measured/tested

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Details on embryotoxic / teratogenic effects:
EMBRYO-/FETOTOXICITY
- There were no effects on the number of implantation sites, resorptions, total implants per mother, litters, dead embryos and foetuses in comparison to the control group.
- The number of surviving foetuses and percentage in relation to total implants were not significantly lower than control.
- Foetal body weight was statistically significantly lower in high dose animals (6 ppm), but not in the low dose (3 ppm) compared to controls.

TERATOGENICITY
- The incidence of gross malformations and skeletal anomalies was not affected by treatment.

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
3 ppm (nominal)
Based on:
element
Basis for effect level:
other: fetotoxicity

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

No information on test compound intake is available. Therefore, the dose levels in mg/kg bw/d are calculated base on an average water consumption for a 25 g mouse of 5 ml per day. Thus, the dose levels of 0.6 and 1.2 mg/kg bw/d for Na2SeO3 x 5 H2O are calculated for the 3 and 6 ppm dietary levels.

Calculation of NOAEL for ZnSeO3 based on molecular weights:

molar weight ZnSeO3: 192.3672 g/mol

molar weight Na2SeO3 x 5H2O: 263.01 g/mol

--> 0.6 mg Na2SeO3 x 5H2O = 0.44 mg ZnSeO3 --> NOAEL (mice, oral) ZnSeO3 = 0.44 mg/kg bw/d

Calculation of NOAEL for selenium based on molecular weights:

molar weight Na2SeO3 x 5H2O: 263.01 g/mol

molar weight Se: 78.96 g/mol

--> 0.6 mg Na2SeO3 x 5H2O = 0.18 mg Se --> NOAEL (mice, oral) = 0.18 mg Se/kg bw/d

Applicant's summary and conclusion

Conclusions:
Treatment of female mice with sodium selenite (pentahydrate) in drinking water (3 and 6 ppm Se) for 30 days before gestation and following mating until day 18 of gestation did not cause maternal toxicity, but oestrus cycle length was increased in comparison to control in the high dose group (6 ppm). Beside a statistically significant decrease in foetal body weights in high dose animals (6 ppm), no further signs of embryo-/foetotoxicity or teratogenicity were observed. Thus, the lower dose level of 3 ppm represents a NOAEL. This corresponds to 0.6 mg/kg bw/d Na2SeO3 x5 H2O and can be recalculated to 0.44 mg/kg bw/d ZnSeO3.