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Key value for chemical safety assessment

Genetic toxicity in vitro

Description of key information

No evidence of mutagenicity was seen in an Ames test performed with barium fluoride. As barium fluoride will dissociate under physiological conditions to form barium and fluoride ions, the available data on barium chloride and sodium fluoride were used to conclude on the mutagenic potential of barium fluoride.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (negative)

Genetic toxicity in vivo

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

The genotoxic potential of barium fluoride was assessed in a "Weight-of-Evidence" approach in accordance with section 1.2 of REACH Annex XI. Under physiological conditions barium fluoride will dissociate into barium and fluoride ions. Therefore the genotoxicity of barium fluoride may reasonably be considered to be determined by the availability of Ba2+ cations and F- anions.

In vitro gene mutation study in bacteria

Barium fluoride was examined for mutagenic activity in the Ames test (OECD guideline 471 and GLP compliant) using Salmonella typhimurium strains TA 1535, TA 1537, TA 98, TA 100 and the tryptophan-requiring Escherichia coli strain WP2 uvrA, in the absence and presence of metabolic activation (CiTox, 2017).The test item concentrations in the Initial Mutation Test and in the Confirmatory Mutation Test (5 strains) were 5000, 1581, 500, 158.1, 50, 15.81 and 5 (Confirmatory only) μg/plate. The mean values of revertant colonies of the solvent control plates were within the historical control range, the reference mutagens showed the expected increase in the number of revertant colonies, the viability of the bacterial cells was checked by a plating experiment in each test. At least five analyzable concentrations were presented in all strains of the main tests. The tests were considered to be valid. Barium fluoride did not induce a dose-related increase in the number of revertant (His+) colonies in each of the four tester strains (TA 1535, TA1537, TA98 and TA100) and in the number of revertant (Trp+) colonies in tester strain WP2uvrA both in the absence and presence of S9-metabolic activation. Based on the results of this study it is concluded that barium fluoride is not mutagenic in the Salmonella typhimurium and in the Escherichia coli reverse mutation assay.

The absence of mutagenic potential in bacteria was confirmed in the available Ames test for barium chloride and sodium fluoride in which no evidence of mutagenicity was seen.

In vitro gene mutation study in mammalian cells

No in vitro gene mutation study in mammalian cells is available for barium fluoride. Comprehensive data on gene mutation in mammalian cells are available for barium chloride and sodium fluoride. As a first surrogate for bioavailability, the water solubility of a test substance may be used. Both barium chloride and sodium fluoride are highly water soluble with ca. 375 g/L and 40 g/L, respectively at neutral pH, whereas barium fluoride has a solubility of 1.6 g/L. Hence, any read across from barium chloride and sodium fluoride to BaF2 is inherently conservative.

Barium

In a study according to OECD guideline 476 and in compliance with GLP, barium chloride dihydrate was examined for its potential to induce gene mutations at the TK-locus of cultured mouse lymphoma L5178Y cells (Lloyd, 2010). It was concluded that barium dichloride did not induce gene mutations in the TK locus of L5178Y mouse lymphoma cells when tested up to toxic and/or precipitating concentrations in two independent experiments in the absence and presence of a rat liver metabolic activation system (S9 mix).

Fluoride

The mutagenic activity of sodium fluoride was tested in a mammalian cell mutagenicity study under neutral and acidic conditions in the V79/HGPRT system (Slamenova 1996). Sodium fluoride was found to be cytotoxic at neutral pH, and highly cytotoxic in acidic conditions. Sodium fluoride treatment did not result in any mutagenic activity, and incubation of cells at reduced pH reduced the level of spontaneous mutations. The authors suggest that an acid environment which supports formation of hydrogen fluoride increases toxic but not mutagenic potencies of sodium fluoride.

A positive result with sodium fluoride is however reported in a mouse lynmphoma assay (NTP, 1990).

In vitro clastogenicity

For barium fluoride, no information is available on the potential to induce chromosome aberrations (clastogenicity). Therefore the available data on barium chloride and sodium fluoride are used to assess the potential to induce chromosome aberations. As a first surrogate for bioavailability, the water solubility of a test substance may be used. Both barium chloride and sodium fluoride are highly water soluble with ca. 375 g/L and 40 g/L, respectively at neutral pH, whereas barium fluoride has a solubility of 1.6 g/L. Hence, any read across from barium chloride and sodium fluoride to BaF2 is inherently conservative.

Barium

Based on the outcome of a guideline-compliant study barium dichloride does not induce chromosome aberrations in mammalian cells, when tested up to toxic and/or precipitating concentrations in two independent experiments in the absence and presence of a rat liver metabolic activation system (S9 mix).

Fluoride

The results of the chromosome aberration test were inconclusive (NTP 1990). The two laboratories used to test the effects of sodium fluoride on CHO cells showed conflicting results; one reported a negative result and one reported a positive result for both induction of sister chromatid exchanges and chromosomal aberrations

Conclusion

No evidence of mutagenicity was seen in an Ames test performed with barium fluoride. As barium fluoride will dissociate under physiological conditions to form barium and fluoride ions, the available data on barium chloride and sodium fluoride were assessed in a WoE approach to conclude on the mutagenic potential of barium fluoride. The results of the studies with barium chloride do not show any potential for mutagenicity. Although sodium fluoride shows a positive response in some in-vitro assays, fluoride is commonly known as non-genotoxic (ATSDR, 2003). In addition, the EU RAR concludes that fluoride does not interact directly with DNA and is not genotoxic when administered via an appropriate route (i.e. by oral or inhalation exposure)

Refs.

- ATSDR 2003. Toxicological profile for fluorides, hydrogen fluoride and fluorine. U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service Agency for Toxic Substances and Disease Registry. September 2003.

- EU RAR Hydrogen Fluoride. EU RAR Hydrogen Fluoride, Volume 8, 2001.

Justification for classification or non-classification

Based on the available data , barium fluoride should not be considered to have a mutagenic potential, and hence no classification or labelling is required according to regulation (EC) 1272/2008.

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