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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Significant methodological deficiencies - purity of the test substances were not stated Deficiencies: - number of pregnant females was too low - information on gravid uterus weight (including cervix), number of corpora lutea, number of dead foetuses, foetal sex as well as on external, skeletal and soft alterations of foetuses were missing - clinical observation and macroscopic examination of dams were missing - intervals of recording body weight and food consumption were not stated - individual animal data was not given
Data waiving:
other justification
Justification for data waiving:
other:

Data source

Reference
Reference Type:
publication
Title:
Placental transfer of fluoride and tin in rats given various fluoride and tin salts
Author:
Theuer, R.C. et al.
Year:
1971
Bibliographic source:
J. Nutr., 101: 525-532.

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Pregnant Sprague-Dawley rats were fed a diet containing tin fluoride from day 0 of pregnancy until gestation day 20. Body weight of dams, food/water intake, number of implantation sites, number of resorption, number of live foetuses, number of litters, placental weight, foetal weight as well as tin levels in foetuses and placentas were recorded.
GLP compliance:
not specified
Remarks:
GLP was not compulsory at time of study conduct
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
other: solid
Details on test material:
- Name of test material (as cited in study report): stannous fluoride (obtained from Ozark-Mahoning, Tulsa, Okla.)
- Molecular formula: SnF2

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
TEST ANIMALS - Sprague-Dawley derived rats
- Source: Laboratory Supply Co., Indianapolis, Ind.
- Age at the start of gestation: 15 to 19 weeks
- Weight at the start of gestation: 252 to 285 g
- Housing: housed individually in screened-bottom galvanized cages
- Diet (ad libitum): low fluoride basal diet (≤2 ppm fluoride; tin was not detectable (i.e., <0.5 ppm))
- Water (ad libitum)
- Acclimation period: 12 weeks before mating weanlings were acclimatised

Administration / exposure

Route of administration:
oral: feed
Vehicle:
other: hydrolysed corn starch
Details on exposure:
DIET PREPARATION
The tin-containing salt was ground in a mortar and pestle and triturated in partially hydrolysed corn starch to insure adequate distribution in the diets. The salt was blended with about 50 times its weight of this starch, and micropulverised.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
After formulation, the diet was analysed for tin. Tin levels in diet were determined by emission spectroscopy (Gibb, 1942)*. The lower limit of detection of the method was 0.5 ppm tin in the diet.
*Reference:
- Gibb, T. R. P. 1942 Optical methods of chemical analysis. McGraw-Hill Book Co., New York, pp. 49 - 52.
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused: female rats in groups were caged with proven breeder males from the same supplier. The impregnated females were returned to individual cages.
- M/F ratio per cage: 2 males / 12 females
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
Duration of treatment / exposure:
20 days
Frequency of treatment:
ad libitum
Duration of test:
20 days
Doses / concentrations
Remarks:
Doses / Concentrations:
158, 310, and 625 ppm tin
Basis:
analytical conc.
No. of animals per sex per dose:
not clearly stated, but at least 9 to 10 females with live foetuses
Control animals:
yes, plain diet
Details on study design:
no data

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: No data
DETAILED CLINICAL OBSERVATIONS: No data
BODY WEIGHT: Yes, weight gain was obtained

FOOD CONSUMPTION AND COMPOUND INTAKE: Yes
- Food intake: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data

WATER CONSUMPTION AND COMPOUND INTAKE: Yes
- Time schedule for examinations: twice weekly; water bottles were changed and intake calculated from the difference between initial and final weight of each bottle.

POST-MORTEM EXAMINATIONS: No data

Females were sacrificed on gestation day 20.
Ovaries and uterine content:
Examinations included:
- Gravid uterus weight: No data
- Number of corpora lutea: No data
- Number of implantation sites: Yes
- Number of resorptions: Yes
- Number of live foetuses
- Number of litters
- Placentas were removed, weighed and frozen individually on dry ice. They were stored prior to analysis for tin.

Tin levels in placentas were determined by emission spectroscopy (Gibb, 1942)*. The lower limit of detection of the method was 0.05 ppm tin in the placentas.
*Reference:
- Gibb, T. R. P. 1942 Optical methods of chemical analysis. McGraw-Hill Book Co., New York, pp. 49 - 52.
Fetal examinations:
The foetuses were removed, weighed and frozen individually on dry ice. They were stored prior to analysis for tin.
Tin levels in foetuses were determined by emission spectroscopy (Gibb, 1942)*. The lower limit of detection of the method was 0.05 ppm tin in the foetuses.

- External examinations: Yes, foetal weight
- Soft tissue examinations: No data
- Skeletal examinations: No data
- Head examinations: No data

*Reference:
- Gibb, T. R. P. 1942 Optical methods of chemical analysis. McGraw-Hill Book Co., New York, pp. 49 - 52.
Statistics:
Statistically significant effects of test salts and test salt level were determined by two-way analysis of variance of the values for the animals in relevant groups. Duncan's multiple range test was used to determine statistically significant differences between individual means at the 95% confidence level (Steel and Torrie, 1960)*.

*Reference:
- Steel, R. G. D., and J. H. Torrie 1960 Principles and Procedures of Statistics. McGraw-Hill Book Co., New York.
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:
REPRODUCTIVE PERFORMANCE
- reproductive performance of the animals fed the diet was excellent.
- average number of viable foetuses per litter (ranges): SnF2: 11 to 12; control (plain diet): 12
- average placental weight showed little variation (ranges): SnF2: 0.47 to 0.52 g); control (plain diet): 0.48 g
- a few other pregnant female rats were allowed to give birth to young; parturition occurred most frequently 23 days after detection of sperm in the vagina.
- foetal resorptions: SnFl2: 0 of 30 litters; control (plain diet): 0 of 9).

WATER INTAKE, FOOD INTAKE, AND WEIGHT GAIN DURING GESTATION
- analysis of 7-day food intake showed that the level of test salt had a significant effect (P<0.05).
- weight gain during the first week of pregnancy was significantly affected by test salt level (P<<0.01).
- rats fed the highest levels of stannous fluoride gained significantly (P<0.05) less weight than rats fed the lowest level of this salt.
- total net weight gain was highly significantly related both to salt level (p<<0.01).
- rats fed the highest level of the test salt containing fluoride had a significantly (p<0.05) reduced net weight gain during pregnancy compared to the lowest level of the test salt.
- net weight gain of the rats fed the highest level of stannous fluoride was significantly (p<0.05) lower than that of the rats in other group.

- placental level of tin bore little relationship to the tin level in the diet.
- placenta contained relatively little tin whether the diet contained detectable tin or not.

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
FOETAL TIN LEVELS
- foetal tin values were higher when the females were fed test salts containing tin.
- no consistent stepwise increase in foetal tin as dietary tin increased.
- statistical analysis of the foetal tin levels of groups fed 125, 250, or 500 ppm tin, indicated a significant (p<0.05) effect of dietary tin level on foetal tin level.
- average foetal weight for each group (ranges): SnF2: 3.4 to 3.9 g/pup; control (plain diet): 3.7

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
> 625 ppm (analytical)
Based on:
element
Remarks:
tin (test salt: SnF2)
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:
According to the authors, there was no effect on the numbers of litters, resorptions, live foetuses per litter, mean placental and foetal weights if tin fluoride was administered.