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Genetic toxicity in vitro

Description of key information

No genetic toxicity study withbarium 4-dodecylphenolateis available, thus the genetic toxicity will be addressed with existing data on the individual moieties barium and dodecylphenolate.

Barium 4-dodecylphenolate is not expected to be genotoxic, since the two moieties barium and dodecylphenolate have not shown gene mutation potential in bacteria and mammalian cells.

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

Genetic toxicity in vivo

Description of key information

No genetic toxicity study withbarium 4-dodecylphenolateis available, thus the genetic toxicity will be addressed with existing data on the individual moieties barium and dodecylphenolate.

Barium 4-dodecylphenolate is not expected to be genotoxic, since the two moieties barium and dodecylphenolate have not shown gene mutation potential in mammalian cells.

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.

 

 

Dodecylphenolate

Based on the outcome of the models, phenol, dodecyl-, branched is not considered to cause gene mutation. The substance under concern is within the applicability domain of all independent prediction models within VEGA. The prediction is reliable to replace an Ames test to fulfill requirements for Regulation (EC) No 1907/2006 (REACH) Annex VII section 8.4.1.

In accordance with the SIDS Initial Assessment Profile (SIAP), “the mutagenic potential of tetrapropenyl phenol has also been determined in a CHO/HGPRT mammalian cell gene mutation assay similar to OECD Test Guideline 476 (Condray 1987). This study is considered to be reliable with restrictions (Klimisch Code = 2). The test material was evaluated in the presence and absence of an S-9 metabolic activation system. In this study, tetrapropenyl phenol was not mutagenic when tested in the CHO/HGPRT forward mutation assay at concentrations up to 20 µg/ml in the presence of metabolic activation system and up to 2 μg/ml in the absence of metabolic activation system, in preliminary and definitive assays.

 

Tetrapropenylphenol was evaluated in an In Vivo Rat Bone Marrow Chromosome Aberration Assay similar to OECD Test Guideline 475.This study is considered to be reliable with restrictions (Klimisch Code = 2) (Condray 1987).The test material was administered by oral gavage to rats at dose levels of 0, 500, 1500, and 5000 mg/kg. Six rats/sex from each group were sacrificed at 6, 12, 24, and 48 hours after treatment. The bone marrow cells were aspirated from each femur and processed for cytogenetic analysis.Slides from five rats of each sex (60 cells per animal) were examined for chromosomal aberrations for the 6-, 12, and 24-hour groups (since there was no evidence of mitotic delay, slides from the 48-hr group were not scored). Mortality was observed at the high dose, and reduced body weight gain was observed in the mid- and high-dose groups. No significant differences in mitotic index or chromosome number were seen when compared to the concurrent control group; and there was no evidence of test article induced chromosome damage as measured by increases in the frequency of chromosome aberrations or percent aberrant cells. In the cyclophosphamide-treated positive control group, a significant increase in the average number of aberrations, percent of cells with aberrations, and decreased mitotic index was observed, confirming the sensitivity of the assay. Under the conditions of this study, tetrapropenyl phenol is not clastogenic.”(SIAP, 2006)

 

 

References:

SIAP (2006): SIDS Initial Assessment Profile for Phenol, (tetrapropenyl) derivates; Tetrapropenyl phenol and Phenol, dodecyl-, branched; SIAM 22, 18-21 April 2006)

Barium 4-dodecylphenolate

Barium 4-dodecylphenolate is not expected to be genotoxic, since the two moieties barium and dodecylphenolate have not shown gene mutation potential in bacteria and mammalian cells. Further testing is not required. Thus, barium 4-dodecylphenolate is not to be classified according to regulation (EC) 1272/2008 as genetic toxicant. For further information on the toxicity of the individual constituents, please refer to the relevant sections in the IUCLID and CSR.

Justification for classification or non-classification

Barium 4-dodecylphenolate 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.