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Diss Factsheets

Administrative data

Key value for chemical safety assessment

Genetic toxicity in vitro

Description of key information

- AMES (OECD 471, GLP): negative (BASF1989; 40M0482/884148)

- HPRT test in CHO cells (OECD 476, GLP): negative (BASF2016; 50M0080/13M357)

- MNT in V79 cells (OECD 487, GLP): negative (BASF2017; 33M0080/13M358)

Additional information

Mutagenicity in bacteria

In the chosen key study for mutagenicity in bacteria acc. to OECD 471 and GLP, i.e. an AMES test, tetrahydro-2-isobutyl-4-methyl-2H-pyran was tested in a plate in a plate incorporation and preincubation test using the strains S. typhimurium TA 1535, TA 1537, TA 98, TA 100 and E. coli WP2 up to a max. concentration of 5000 µg/plate with and without the addition of liver S9 mix from Aroclor 1254 induced rats (BASF1989; 40M0482/884148). 

No increase in the number of his+ or trp+ revertants was observed up to cytotoxic concentrations of tetrahydro-2-isobutyl-4-methyl-2H-pyran either without S-9 mix or after the addition of a metabolizing system. According to these results, tetrahydro-2-isobutyl-4-methyl-2H-pyran is determined as non-mutagenic in the Ames test under the experimental conditions chosen. 

 

Mutagenicity in mammalian cells

In the key study for mutagenicity in mammalian cells acc. to OECD 476 and GLP, tetrahydro-2-isobutyl-4-methyl-2H-pyran was assessed for its potential to induce gene mutations at the hypoxanthine-guanine phosphoribosyl transferase (HPRT) locus in Chinese hamster ovary (CHO) cells in vitro (BASF2016; 50M0080/13M357). Two independent experiments were carried out, both with and without the addition of liver S9 mix from phenobarbital- and β-naphthoflavone induced rats (exogenous metabolic activation). According to initial range-finding cytotoxicity tests for the determination of the experimental doses and taking into account the cytotoxicity actually found in the main experiments, test concentrations were selected.

At least the highest concentrations evaluated for gene mutations (400 µg/ml) were clearly cytotoxic in the absence and the presence of metabolic activation. Tetrahydro-2-isobutyl-4-methyl-2H-pyran did not cause any relevant increase in the mutant frequencies either without S9 mix or after the addition of a metabolizing system in all valid experiments performed independently of each other. Thus, under the experimental conditions of this study, tetrahydro-2-isobutyl-4-methyl-2H-pyran is not mutagenic in the HPRT locus assay under in vitro conditions in CHO cells in the absence and the presence of metabolic activation.

 

Clastogenicity/Aneugenicity in mammalian cells

In the key study for cytogenicity in mammalian cells acc. to OECD 487 and GLP was assessed for its potential to induce micronuclei in V79 cells in vitro (BASF2017; 33M0080/13M358). Three independent experiments were carried out with and without the addition of liver S9 mix from induced rats (exogenous metabolic activation). According to an initial range-finding cytotoxicity test for the determination of the experimental doses and taking into account the cytotoxicity actually found in the main experiment, adequate test concentrations were selected. A sample of at least 1000 cells for each culture was analyzed for micronuclei, i.e. 2000 cells for each test group.

Cytotoxicity indicated by clearly reduced cell count (indicated by relative population doubling) or proliferation index (CBPI) was observed at least at the highest applied concentration of tetrahydro-2-isobutyl-4-methyl-2H-pyran in all experimental parts of this study. No biologically relevant increase in the number of micronucleated cells was observed either without S9 mix or after the addition of a metabolizing system. A dose-related increase in micronucleus rates with statistical significance and containing a single outlier value above the 95% control limit of our historical negative control data was observed in the 2nd experiment in the presence of metabolic activation. This finding was not confirmed in a repeat experiment and was considered biologically irrelevant. On the basis of the results of the present study, tetrahydro-2-isobutyl-4-methyl-2H-pyran did not cause any biologically relevant increase in the number of cells containing micronuclei.

Thus, under the experimental conditions described, tetrahydro-2-isobutyl-4-methyl-2H-pyran is considered not to have a chromosome-damaging (clastogenic) effect nor to induce numerical chromosomal aberrations (aneugenic activity) under in vitro conditions in V79 cells in the absence and the presence of metabolic activation.

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.