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Mutagenicity in bacteria

In the chosen key study, i.e. an AMES test acc. to OECD 471 and GLP, strains TA 1535, TA 1537, TA 98, TA 100 and TA 102 of Salmonella typhimurium were exposed alpha-Bisabolol nat. (standard plate test) at concentrations of 1.5 µg - 1500 µg/plate in the presence and of 0.5 - 500 µg/plate in the absence of Aroclor induced rat liver S-9 mix (Symrise 2001; AM01202N). The test substance was bacteriotoxic towards the strains TA1535, TA1537, TA98, and TA100 at 150 µg/plate and towards the strain TA102 at 500 µg/plate. In the presence of S9-mix the test substance was bacteriotoxic towards the strains TA1535, TA1537, and TA100 at 500 µg/plate and towards the strains TA98 and TA102 at 1500μg/plate. In the concentration range investigated, the test item did not induce a significant increase in the mutation frequency of the tester strains in the presence and absence of a metabolic activation system. According to the results of the present study, alpha-Bisabolol nat. is not mutagenic in the Ames test under the experimental conditions chosen here.

In a supporting study, i.e. an AMES test
 acc. to OECD 471 and GLP, strains TA 1535, TA 100, TA 1537 and TA 98 of Salmonella typhimurium were exposed to (+/-) alpha-Bisabolol at concentrations of 20.0 µg - 5000 µg/plate (Standard plate test) and 2.5 µg - 1500 µg/plate (preincubation test) with and without metabolic activation (Aroclor induced rat liver S-9 mix; BASF 1996; 40M0144/954069). An increase in the number of his+ revertants was not observed both in the standard plate test and in the preincubation test either without S-9 mix or after the addition of a metabolizing system. A bacteriotoxic effect was observed depending on the strain and test conditions. According to the results of the present study, the test substance is not mutagenic in the Ames test under the experimental conditions chosen here. 

In a supporting study, i.e. an AMES II test (liquid fluctuation test – microtiter version) based on Gee, P. et al. (Mut. Res., 412, 115 – 130; 1998), the Salmonella typhimurium strain TA 98 and a TA Mix (Mixed strains TA 7001 - TA 7006) were exposed to the stereoisomer (-) alpha-Bisabolol (nat. roh), i.e. a main component of the registered substance racemic alpha-Bisabolol, at concentrations of 1.25 µg - 5000 µg/plate with and without metabolic activation (Aroclor induced rat liver S-9 mix; BASF 2001; 44M0588/004135). A bacteriotoxic effect (decrease in the number of positive wells / clearing of the background lawn) was observed only with S-9 mix from about 100 µg/mL onward. An increase in the number of positive wells (his+ revertants) was not observed either without S-9 mix or after the addition of a metabolizing system. According to the results of the present study, Bisabolol nat. roh is not mutagenic in the Ames II assay under the experimental conditions chosen here.

In an AMES test, reported in literature, the (-)-alpha-Bisabolol was found to be non mutagenic in Samonella typ. tester strains TA 100, TA 98, TA 97a, TA 1535 (Gomes-Carneiro 2005).
Overall, racemic (+/-) alpha-Bisabolol is considered to be non-mutagenic in bacteria.
 

Mutagenicity in mammalian cells
In the key study chosen, a mammalian cell gene mutation assay according to OECD guideline 476 and GLP was performed to investigate the potential of
(+/-)-alpha-Bisabolol (Dragosantol 100) to induce mutations at the mouse lymphoma thymidine kinase locus using the cell line L5178Y (Symrise 2008; 1155305). The first main experiment was performed with and without liver microsomal activation and a treatment period of 4 h. The second experiment was performed with a treatment period of 24 hours in the absence of metabolic activation and 4 hours in the presence of metabolic activation. No substantial and reproducible dose dependent increase in mutant colony numbers was observed in both main experiments. No relevant shift of the ratio of small versus large colonies was observed up to the maximal concentration of the test item. Appropriate positive controls showed a distinct increase in induced mutant colonies, indicating that the tests were sensitive and valid. In conclusion it can be stated that during the mutagenicity test described and under the experimental conditions reported (+/-)-alpha-Bisabolol (Dragosantol 100) not induce mutations in the mouse lymphoma thymidine kinase locus assay using the cell line L5178Y in the absence and presence of metabolic activation. Therefore, (+/-)-alpha-Bisabolol (Dragosantol 100) is considered to be non-mutagenic in this mouse lymphoma assay.

Chromosome aberration in mammalian cells
In the chosen key study,
(+/-)-alpha-Bisabolol was assessed for its potential to induce structural chromosomal aberrations in V79 cells in vitro both in the presence and in the absence of a metabolizing system according to OECD-guideline 473 and GLP (BASF 1996; 32M0144/954094). The test substance did not cause any increase in the number of structurally aberrant metaphases incl. and excl. gaps at both sampling times either without S-9 mix or after adding a metabolizing system in two experiments performed independently of each other. No increase in the frequency of cells containing numerical aberrations was demonstrated either. Thus, under the experimental conditions chosen here the conclusion is drawn that (+/-)-alpha-Bisabolol is not a chromosome-damaging (clastogenic) agent under in vitro conditions using V79 cells.





Short description of key information:
Mutagenicity in bateria (Ames, OECD 471, GLP): negative (Symrise 2001; AM01202N)
Mutagenicity in mammalian cells (MLA, OECD 476, GLP): negative (Symrise 2008; 1155305)
Chromosome aberration in mammalian cells (CA, OECD 473, GLP): negative (BASF 1996; 32M0144/954094)

Endpoint Conclusion:

Justification for classification or non-classification

The present data on genetic toxicity do not fulfill the criteria laid down in 67/548/EEC and regulation (EU) 1272/2008 and therefore, a non-classification is warranted.

 

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