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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:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: NTP study: abstract available

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
Unnamed
Year:
1994
Reference Type:
publication
Title:
Developmental Toxicity Evaluation of Sodium Fluoride Administered to Rats and Rabbits in Drinking Water
Author:
Heindel JJ, Bates HK, Price CJ, Marr MC, Myers CB & Schwetz BA
Year:
1996
Bibliographic source:
Fundamental and Applied Toxicology, Volume 30, Number 2, April 1996 , pp. 162-177(16)

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
other: NTP protocol
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Principles of method if other than guideline:
Developmental toxicity study
GLP compliance:
not specified
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Sodium fluoride
EC Number:
231-667-8
EC Name:
Sodium fluoride
Cas Number:
7681-49-4
Molecular formula:
FNa
IUPAC Name:
sodium fluoride
Details on test material:
Sodium fluoride.

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
Sprague-Dawley CD rats were fed standard laboratory chow ad libitum. Water (control and treated) was provided ad libitum.

Administration / exposure

Route of administration:
oral: drinking water
Vehicle:
water
Details on exposure:
Sodium fluoride was administered to rats in the drinking water, provided ad libitum.
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
The method detection limit was used to determine the level of NaF present in the control water, and this value was used to calculate the drinking water doses. The amount of F present in the standard diet was also determined.
Details on mating procedure:
No further information is available; assumed pregnant females were dosed
Duration of treatment / exposure:
Treatment from gestation day 6 to gestation day 15.
Frequency of treatment:
Daily
Duration of test:
Animals were treated on Day6-15 of gestation and sacrific
Doses / concentrationsopen allclose all
Dose / conc.:
0 ppm
Remarks:
nominal in water
Dose / conc.:
50 ppm
Remarks:
nominal in water
Dose / conc.:
150 ppm
Remarks:
nominal in water
Dose / conc.:
300 ppm
Remarks:
nominal in water
No. of animals per sex per dose:
26 female rats per dose group
Control animals:
yes, concurrent vehicle
Details on study design:
No further information

Examinations

Maternal examinations:
Animals were observed daily for clinical signs of toxicity. Food and water intakes and body weights were recorded on gestation days 0, 2, 4, 6, 8, 10, 12, 14, 16, 18 and 20. All animals were sacrificed on gestation day 20 and examined for maternal body and organ weights, implant status, foetal weight, sex and morphological development. An additional 10 mated animals per groups were subjected to the same experimental regimen but sacrificed on gestation day 16 for blood collection for determination of serum fluoride concentration.
Ovaries and uterine content:
Uterine contents were examined - implant status, foetal weight, sex and morphological development were recorded.
Fetal examinations:
Foetuses were examined for external, visceral or skeletal malformations, in addition to foetal body weights and sex.
Statistics:
No further information
Indices:
No further information
Historical control data:
No further information

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
No maternal lethality occurred at any dose. Maternal wight gain was significantly reduced at 300ppm during the first 2 days of exposure (gestation days 6-8), and a trend toward decreased weight gain was noted for the treatment period as a whole. Maternal food intake was significantly decreased (compared to controls) in the 300ppm group between gestation days 8-10. Water consumption was significantly decreased during exposure in the 300ppm group. No other differences were noted. At necropsy there were no effects on kidney or liver weights.

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Remarks:
maternal toxicity
Effect level:
150 ppm (nominal)
Basis for effect level:
other: maternal toxicity

Results (fetuses)

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

Details on embryotoxic / teratogenic effects:
NaF exposure did not significantly affect the frequency of post-implantation loss, mean fetal body weight per litter, or external, visceral, or skeletal malformations.

Effect levels (fetuses)

Dose descriptor:
NOAEL
Remarks:
development
Effect level:
300 ppm (nominal)
Based on:
other: Sodium fluoride
Sex:
female
Basis for effect level:
other: developmental toxicity

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

Control water fluoride levels were <0.6 ppm NaF.

Food contained an average of 12.4 ppm F (11.6 -13.4 ppm F).

The calculated doses from drinking water were 7, 18 and 27 mg NaF/kg bw/d (3, 8 and 12 mg F/kg bw/d) for the low, intermediate and high-dose groups respectively. Intake from food added approximately 2 mg NaF/kg bw/d (1 mg F/kg bw/d) to the intake for each group.

Determination of serum fluoride levels in the 10 animals per group terminated on 16 revealed mean levels of 0.007 ± 0.002, 0.035 ± 0.040, 0.039 ± 0.039, and 0.187 ± 0.076F at the end of the exposure period.

Applicant's summary and conclusion

Conclusions:
Sodium fluoride in drinking water was not maternally toxic up to doses of 300ppm, although decreased water consumption was seen as a result of poor palatability at this dose. There was no evidence of developmental toxicity in this study.
Executive summary:

Pregnant Sprague-Dawley CD rats were exposed to sodium fluoride in their drinking water at concentrations of 0, 50, 150 or 300 ppm daily between gestation days 6 and 15. Maternal weight gain was significantly reduced at 300 ppm during the first two days of exposure (days 6 to 16). Maternal water consumption (grams/kg/day) during exposure was significantly decreased in the animals exposed to 300ppm NaF. Post-exposure water consumption was normal in these animals indicating the probability of decreased palatability of the 300ppm solution. Necropsy of the maternal animals revealed no effects on kidney or liver weights. NaF exposure did not significantly affect the frequency of post-implantation loss, mean fetal body weight per litter, or external, visceral, or skeletal malformations.

This study established a NOAEL for maternal toxicity of 150 ppm (18 mg NaF/kg bw/d) and a NOAEL of 300 ppm for developmental toxicity (27 mg NaF/kg bw/d) administered in drinking water to pregnant CD rats during organogenesis.