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Developmental toxicity / teratogenicity

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developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: The study was conducted according to generally vaild procedures and accordinig to GLP guidelines. All parameters described are closely related or comparable to guideline methods.

Data source

Referenceopen allclose all

Reference Type:
Developmental toxicity evaluation of sodium fluoride administered to rats and rabbits in drinking water
Heindel, J.J. et al.
Bibliographic source:
Fundamental and Applied Toxicology 30: 162-177.
Reference Type:
study report

Materials and methods

Test guideline
equivalent or similar to guideline
EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
GLP compliance:
Limit test:

Test material

Constituent 1
Reference substance name:
Sodium fluoride
EC Number:
EC Name:
Sodium fluoride
Cas Number:
sodium fluoride
Details on test material:
- Name of test material (as cited in study report): sodium fluoride
- Analytical purity: >99%

Test animals

Details on test animals or test system and environmental conditions:
- Source: Charles River Laboratories, Inc., Raleigh, NC
- Weight at study initiation: mean body weights/group ranged from 248 to 253 g
- Fasting period before study: no
- Diet (e.g. ad libitum): ad libitium
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 7 days

- Temperature (°C): 22.2 (average)
- Humidity (%): 55% (average)
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: drinking water
Details on exposure:
Animals were exposed to 0, 50, 150 or 300 ppm sodium fluoride in drinking water
Analytical verification of doses or concentrations:
Details on analytical verification of doses or concentrations:
Preexposure analysis of drinking water solutions demontrated the concentrations of sodium fluoride to be within a range of 104-107% of target concentrations.
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1:1
- Length of cohabitation: overnight
- Any other deviations from standard protocol: The morning on which sperm were found in a vaginal lavage was designated as GD 0.
Duration of treatment / exposure:
Gestation days 6 through 15
Frequency of treatment:
ad libitum - drinking water
Duration of test:
Terminated on Gestation day 20
Doses / concentrations
Doses / Concentrations:
0, 50, 150 or 300 ppm sodium fluoride
nominal in water
No. of animals per sex per dose:
Control animals:
Details on study design:
- Dose selection rationale: The sodium fluoride concentrations tested were 50, 150 and 300 ppm which corresponded to approximately 7.5, 22.5, and 45 mg/kg/day based on an estimated water consumption of 150 mL/kg body weight/day. The LD50 for sodium fluoride in rats is at least 52 mg/kg/day or approximately 350 ppm if administered in drinking water. The concentrations were chosen after consideration of data from the NTP 14-day study in which female rats given 400 ppm sodium fluoride in drinking water showed decreasesd body weight and water consumption and clinical signs of toxicity (dehydration , lethargy, and hunched posture) while 800 ppm killed all the animals. The high dose (300 ppm) was chosen in an effort to induc e some maternal toxicity while avaoiding the potentially confounding effects of dehydration seen at the 400 ppm level in the 14-day study. The 300 ppm level was anticipated to be a nonlethal exposure based on the lack of lethality among rats exposed to 300 ppm sodium fluoride in the NTP 6-month drinking water studty and 50 ppm low level was expected to produce no maternal toxicity based on a lack of effects related to sodium fluoride consumption in the NTP 2-year toxicity study at exposures up to 100 ppm.


Maternal examinations:
- Time schedule: daily

- Time schedule: daily beginning on gestation day 6

- Time schedule for examinations: 0, 2, 4, 6, 8, 10, 12, 14, 16, 18 and 20

- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations:0, 2, 4, 6, 8, 10, 12, 14, 16, 18 and 20

- Sacrifice on gestation day # 20
- Organs examined: liver, kidney and uterus

Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Fetal examinations:
- External examinations: Yes: [all per litter]
- Soft tissue examinations: Yes: [all per litter]
- Skeletal examinations: Yes: [all per litter]
- Head examinations: Yes: [half per litter]
General linear model (GLM) procedures were applied for the analyses of varience (ANOVA) of maternal and fetal parameters. Prior to GLM-ANOVA analysis, an arcsine-square root transformation was performed on all litter-derived percentage data to normalize the means and Bartlett's test for homogeneity of variance was performed on all data to be analyzed by ANOVA. GLM-ANOVA anyalysis determined the significance of dose-response relationships and the significance of dose effects, replicate effects, and dose x replicate interactions. When ANOVA revealed a significant (p<0.05) dose effect, Dunnett's test and Williams' test were used to compare treated to control groups. One-tailed tests wre used for all pairwise comparisons except maternal body and organ weeights, food and water consuumption , fetal body weight, and percentage of males per litter. If a significant (p<0.05) dose x replicate interaction occurred, then the data for that endpoint were analyzed separately for dose effects witnin each replicate in the study, as well as for all replicates combined. Nominal scale measures were analyzed by a X2 test for independence and by a test for linear trend on proportions. When a X2 test showed significant experinent-wise differences, a one-tailed Fisher's exact test was used for pairwise comparisons of treatment and control groups.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
No animals died during the course of the study. No treatment-related clinical signs were observed in confirmed-pregnant animlsa during or after administration of sodium fluoride. Maternal body weight gain during the first 2 days of exposure (GD 6 to 8) was significantly reduced at 300 ppm relative to controls. Maternal water consumption of rats given 300 ppm sodium fluoride was significantly decreased for each period of observation from GD 6 to 15. Maternal food consumption was also decreased in the animals given 300 ppm sodium fluoride from GD 8 to 10, but did not differ from controls for any other period of measurement. Maternal liver and kidney weights on GD 20 were not differenct from control . Examination of uteri demonstrated that 100% (26/26), 96% (25/26), 89% (23/26), and 96% (25/26) of the mated animals in the control throught high-dose groups were pregnant.

Effect levels (maternal animals)

open allclose all
Dose descriptor:
Effect level:
ca. 150 ppm
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
Effect level:
ca. 300 ppm
Based on:
test mat.
Basis for effect level:
other: maternal toxicity

Results (fetuses)

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

Details on embryotoxic / teratogenic effects:
No embryotoxic or teratogenic effects related to exposure to sodium fluoride in drinking water was observed at any dose concentration.

Effect levels (fetuses)

Dose descriptor:
Effect level:
> 300 ppm
Based on:
test mat.
Basis for effect level:
other: developmental effects

Fetal abnormalities

not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion

Maternal exposure to sodium fluoride at conentrations up to 300 ppm (approximately 27 mg/kg/day) during organogenesis (gestation days 6 to 15) did not significantly affect the frequency of postimplantation loss, mean fetal body weight/litter, or external, visceral or skeletal malformations in the rat.