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Genetic toxicity in vitro

Description of key information

No genetic toxicity study with barium dibenzoate is available, thus the genetic toxicity will be addressed with existing data on the individual moieties barium and benzoate.

Barium dibenzoate is not expected to be genotoxic, since the two moieties barium and benzoate have not shown gene mutation potential in bacteria and mammalian cells as well as in in vivo clastogenicity tests.

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

Genetic toxicity in vivo

Description of key information

No genetic toxicity study with barium dibenzoate is available, thus the genetic toxicity will be addressed with existing data on the individual moieties barium and benzoate.

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

Additional information

Barium

None of the in vitro genotoxicity studies rated as reliable showed any effect in bacterial reverse mutation assays, in mammalian cell gene mutation tests (TK assay) or in mammalian cell chromosome aberration tests, thus the classification criteria according to regulation (EC) 1272/2008 as germ cell mutagen are not met.

 

in vitro clastogenicity

Based on the outcome of guideline-compliant studies 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).

Overall it can be concluded that barium dichloride does not induce chromosome aberrations in vitro in somatic mammalian cells. Therefore, the conduct of in vivo clastogenicity experiments is not required.

 

in vitro gene mutation

Anonymous (1994)

The authors state that barium dichloride induces gene mutations in cultured mouse lymphoma cells (L5178Y) in the presence of S9 in a statistical significant manner. However, the mutation frequency increased from 32 per 106

cells in the control culture to a maximum of 59 per 106 cells at 1000µg/mL (with a RTG of 10%). Being a statistical significant increase in mutation frequency, the biological significance however is considered questionable, since the highest MF is still well below the value recommended by the IWGT (Moore et al., 2003; Moore et al., 2006; Moore et al., 2007) of 154 per 106 cells. Furthermore, a comparison with historical data for the performing laboratory is not possible, since the data was not given in the study report.

Due to the questionable biological relevance, the statistical significant increase in mutation frequency in both barium dichloride cultures with metabolic activation is not considered as clear positive response. Therefore, it was decided to repeat the whole experiment under clearly defined conditions, which a highly pure test item under guideline and GLP compliant conditions.

 

Lloyd (2010)

It is 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).

Overall it can be concluded that barium dichloride does not induce gene mutations in vitro in bacteria and somatic mammalian cells. Therefore, the conduct of in vivo gene mutation experiments is not required.

 

 

References

Moore M et al. (2003)

Mouse lymphoma thimidine kinase gene mutation assay: International workshop on Genotoxicity tests workgroup report – Plymouth, UK 2002. Mutation Research (2003), 540, 127-140.

 

Moore M M, Honma M, Clements J, Bolcsfoldi G, Burlinson B et al. (2006)

Mouse lymphoma thymidine kinase gene mutation assay: follow up meeting of the International Workshop on Genotoxicity Testing – Aberdeen, Scotland, 2003 – Assay acceptance criteria, positive controls, and date evaluation. Environmental and Molecular Mutagenesis 2006, 47, 1-5.

 

Moore M M, Honma M, Clements J, Bolcsfoldi G, Burlinson B et al. (2007)

Mouse lymphoma thymidine kinase gene mutation assay: meeting of the International Workshop on Genotoxicity Testing, San Francisco, 2005, recommendations for 24-h treatment. Mutation Research 2007, 627, 36-40.

  

Benzoate

All available tests for gene mutations in bacteria did not show any effects of the test substance with or without metabolic activation. A poorly reported test in yeast (no metabolic activation) was positive, but the validity of this result could not be checked (Piper, 1999). No effects were reported after exposure of prophage containing E. coli strains (Rossmann, 1991) or in an SOS/umu test in S. typhimurium (Nakumara 1987). For cytogenetic effects, a chromosome aberration test was ambiguous without metabolic activation (Ishidate, 1983). Several other limited reported tests on sister chromatid exchange (without metabolic activation) were negative. The test substance was positive in a Comet assay (Esref, 2009), but it was clearly negative in an in vitro micronucleus test (with and without metabolic activation) (Nesslany, 1999).

 

Additional studies were identified but were not available for review. The available results confirm that the test substance does not induce gene mutations and is not likely to induce effects on the chromosomal level.

 

A battery of in vivo tests was conducted with the structurally related sodium benzoate and these all clearly indicated no cytogenetic effects. These studies are considered to fully address and over-ride the ambiguous results found in the in-vitro data set. The toxicokinetic evaluation on sodium benzoate concluded that the substance will not be taken up as the salt, but rather as the test substance entity (NOTOX 2010). Therefore, it can be concluded that the results for the test substance will not differ from those found in in vivo tests with sodium benzoate.

Based on the clear negative in-vivo results, it is concluded that the test substance does not induce genetic toxicity.

Barium dibenzoate

Barium dibenzoate is not expected to be genotoxic, since the two moieties barium and benzoate have not shown gene mutation potential in bacteria and mammalian cells as well as in in vitro clastogenicity. Further testing is not required. For further information on the toxicity of the individual assessment entities, please refer to the relevant sections in the IUCLID and CSR.

 

Justification for classification or non-classification

Barium dibenzoate is not to be classified according to regulation (EC) 1272/2008 as genetic toxicant, since all in vitro and in vivo studies with the respective moieties did not show any gene mutation potential.