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Key value for chemical safety assessment

Additional information

In VitroTesting:

Several investigators have evaluated the potential of sodium fluoride to induce gene mutations in bacteria. Sodium fluoride did not induce gene mutations in Salmonella typhimuriumstrains TA97a, TA98, TA100, TA102, TA1535, TA1537, and Saccharomyces cerevisiae strain D4. All strains were tested with or without Aroclor 1254-induced male Sprague-Dawley or Syrian hamster liver S9.

Equivocal results have been reported for the potential of sodium fluoride to cause gene mutation in mammalian cells. Sodium fluoride has been shown to increase the frequency of mutations at the thymidine kinase locus in cultured mouse lymphoma cells and human lymphoblastoid cells. Some studies showed a preferential increase in the frequency of small mutant colonies which indicative of chromosomal damage rather than point mutations. Sodium fluoride did not increase the frequency of mutations at the hypoxanthine-guanine phosphoribosyl transferase locus in rat liver epithelial cells, Chinese hamster ovary cells or Chinese hamster lung cells exposed under neutral conditions.

Some in vitro cytogenetic assays, have reported sodium fluoride to be clastogenic. After exposure to sodium fluoride, the frequency of chromosomal aberrations (compared to unexposed controls) was increased in Chinese hamster ovary cells, rat vertebral body-derived cells, rat bone marrow cells, human peripheral blood lymphocytes, and human and chimpanzee lymphoid cells. The chromosomal aberrations induced by sodium fluoride were primarily breaks/deletions and gaps, with very few exchanges. In other studies, no significant increase in chromosomal aberrations were observed in human fibroblasts, Chinese hamster ovary cells, or human diploid lung cells exposed to sodium fluoride at concentrations at or below 10 mg/L. In some studies that found no increase in the frequency of chromosomal aberrations in human lymphocytes exposed to fluoride, the results were likely due to a number of variables related to the methodology used to assess clastogenic activity (i.e., the method of classifying chromosomal aberrations, phase of the cell cycle during which the cells were exposed, and the concentration of fluoride).

 No increase in sister chromatid exchange (SCE) was reported in human peripheral blood lymphocytes, Chinese hamster ovary cells or rat bone marrow cells following exposure to sodium fluoride. In contrast to these negative results, increased sister chromatid exchange was observed in Chinese hamster ovary cells after sodium fluoride exposure. The inconsistency in results observed for the induction of sister chromatid exchange after sodium fluoride exposure may be, at least in part, due to the differences in harvest times used to accommodate cell cycle delay.

Some studies have indicated that sodium fluoride increases unscheduled DNA synthesis but a study by Skare, et al., (1986) suggests that these positive results might be due to an artifact caused by autoradiographic measurements of UDS, possibly by formation of precipitable complexes of magnesium, fluoride and [3H]thymidine triphosphate. Modifications of the UDS/autoradiography protocol to include more extensive washing resulted in no UDS response.

In Vivo Testing:

Negative results have been reported in most in vivo studies of sodium fluoride conducted by the most relevant route of exposure, oral (either acutely or chronically).

Micronucleus: Sodium fluoride did not induce micronucleated polychromatic erythrocytes in male rats dosed at 1000 mg/kg (MTD over 24 hours). Sodium fluoride administered in the drinking water (up to 400 ppm fluoride) for six weeks did not cause increases in micronuclei in peripheral erythrocytes or chromosome aberrations in bone marrow cells in male B6C3F1 mice. Chronic treatment of B6C3F1 mice with sodium fluoride[ to 75 ppm (0.3 to 23 mg/kg/day)] for 21 weeks did not significantly increase the frequency of micronucleated polychromatic erythrocytes.

DNA repair: Single oral doses of sodium fluoride up to 84 mg/kg body weight and repeated oral doses of sodium fluoride up to 42 mg/kg body weight for 5 consecutive days to adult male Sprague-Dawley rats did not induce DNA-strand breaks in testicular cells. Sodium fluoride in the drinking water (100 ppm) administered to Wistar female rats caused dental fluorosis, but it did not induce DNA damage in cells of the peripheral blood, oral mucosa or brain.

SCE: Sodium fluoride given to Chinese hamsters either orally (up to 130 mg/kg body weight) or in the drinking water (up to 75 ppm) did not induce increased frequencies of sister chromatid exchanges in bone marrow cells. No significant differences in the frequencies of baseline SCEs, mitomycin C-induced SCEs, baseline chromosomal aberrations, or cell replication rates were found between Swiss-Webster mice raised for 7 generations on a high fluoride diet (50 ppm fluoride, as NaF) and Swiss-Webster mice raised for 7 generations on a low fluoride diet (<0.5 ppm, as NaF).

In humans, no clastogenic effects were induced in the peripheral blood lymphocytes of five osteoporotic patients that had been treated with sodium fluoride at a dose range of 50 to 75 mg/day (equivalent to 22.6 to 33.9 mg fluoride/day) for 15 - 49 months. In addition, long-term exposure (35 years) to fluoride in drinking water of human populations with either normal or inadequate nutrition, even at elevated levels of approximately 4.8 ppm, did not significantly increase the frequency of sister chromatid exchanges.

Short description of key information:
Both postive and negative results have been reported in in vitro genotoxicity studies, the in vivo studies indicate no genotoxicity when evaluated in reliable studies conducted following administration by an appropriate route of exposure. Fluoride salts are not expected to be genotoxic.

Endpoint Conclusion: No adverse effect observed (negative)

Justification for classification or non-classification

While both positive and negative results have been reported in vitro, the reliable in-vivo studies indicate that fluoride salts do not interact directly with DNA and are not genotoxic when administered by an appropriate route of exposure. No classification is proposed.