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Gene mutation in bacteria

In the key study, a bacterial reverse gene mutation assay according to GLP and OECD 471, the strains TA 98, TA 100, TA 1535 and TA 1537 of S. typhimurium and E.coli WP2 uvrA were exposed to the test item (analytical purity: 99.4%), using water as solvent. Test concentrations were 33; 100; 333; 1000; 2500 and 5000 μg/plate (Standard plate incubation test and Preincubation test, 20 minutes, 37 °C) in the presence and absence of mammalian metabolic activation (BASF, 40M0587/11M208, 2012). The positive control induced the appropriate responses in the corresponding strains. With the test substance there was no evidence of induced mutant colonies over the background. The study is classified as acceptable (reliability 1). Despite the requirements of OECD Guideline 471 (adopted 1997), 2-Aminoanthracene was the sole positive control in the presence of S9-Mix. Therefore, as recommended in OECD 471, metabolic activity of S9 was confirmed by using benzo(a)pyrene as a mutagen that requires metabolic activation by microsomal enzymes. A weak bacteriotoxic effect (slight decrease in the number of his+ revertants) was occasionally observed in the standard plate test and in the preincubation assay depending on the strain and test conditions from about 2 500 μg/plate onward. No test substance precipitation was found with and without metabolic activation.

According to the results of the study, the test substance is not mutagenic in the Ames test using Salmonella typhimurium strains TA98, TA100, TA 1535 and TA1537 and E.Coli WP2 uvrA in the absence and the presence of metabolic activation.

 

This result is supported by an Ames test II, using water as solvent in the Liquid fluctuation test (BASF, 44M0463/984178, 1999). Salmonella typhimurium strain TA98 was tested up to 1000 µg/mL and mixed strains (TA 7001 - TA 7006) up to 5000 µg/mL, both with and without metabolic activation. Neither genotoxicity nor cytotoxicity were observed. The positive controls yielded the expected results. According to the results of the supporting study, the test substance is not mutagenic in the bacterial reverse mutation assay under the experimental conditions chosen.

Gene mutation in mammalian cells

Gene mutation of 2-butyne-1,4-diol, ethoxylated (>1 < 4.5 mol EO) can be reliably evaluated by assessing (1) the mutagenic potency of the core molecule 2-butyne-1,4-diol (CasNo 110-65-6) and (2) of a structural analogue in which a similar (not cytogenic) core molecule is ethoxylated to the same degree (e.g. propylidynetrimethanol, >1<4.5 EO; CAS 50586-59-9). By this a reliable statement can be made regarding the mutagenic potency of 2-butyne-1,4-diol, ethoxylated (>1 < 4.5 mol EO) since it can experimentally be proven that both, the core molecule and the ethoxylated side groups, do not pose a mutagenic alert.

 

In an in vivo micronucleus test on mouse bone marrow cells, 1,4 -Butynediol did not induce mutagenicity at intraperitoneal doses of 17.5, 35, or 70 mg/kg in males and females (BASF, 1989).

Withpropylidynetrimethanol, >1<4.5 EO,a GLP conform in vitro mammalian cell gene mutation test according to OECD Guideline 476 was performed to investigate its potential to induce gene mutations at the thymidine kinase (TK) locus in mouse lymphoma L5178YTK+/-cells (BASF, 2008). The assay was performed using the microwell method in three independent experiments, using two parallel cultures each. In the first main experiment cells were exposed for 4 hours to the test item at concentrations of 84.4, 168.8, 337.5, 675, 1350 and 2700 µg/mL with and without metabolic activation. The second experiment was performed with a treatment time of 4 hours at concentrations of 450.0; 675.0; 900.0; 1 350.0; 1 800.0; 2 700.0 μg/mL with metabolic activation and a treatment time of 24 hours at concentrations of 84.4; 168.8; 337.5; 675.0; 1 350.0; 2 700.0 μg/mL without metabolic activation. In a third experiment mutagenicity was investigated at concentrations of 900.0; 1 350.0; 1 800.0; 2 700.0 μg/mL with metabolic activation and a 4-hour exposure period. The test substance did not cause any relevant increase in the number of mutant colonies either without metabolic activation or after the addition of a metabolizing system in all 3 experimental approaches. No cytotoxic effects indicated by reduced cloning efficiencies of below 20% of control or distinctly reduced relative suspension growth, were observed neither in the presence nor in the absence of metabolic activation. Therefore is was concluded, that under the experimental conditionspropylidynetrimethanol, >1<4.5 EOis not mutagenic in the mouse lymphoma assay with L5178Y TK +/- cells in the absence and the presence of metabolic activation.

Since both the core molecule 2-butyne-1,4-diol and an ethoxylated structural analog (propylidynetrimethanol, >1<4.5 EO) were tested negative for a mutagenic potential, a reliable statement can be made regarding the mutagenic potency of 2-butyne-1,4-diol, ethoxylated (>1 < 4.5 mol EO). Therefore2-butyne-1,4-diol, ethoxylated (>1 < 4.5 mol EO)is not considered to be mutagenic.

Cytogenicity in mammalian cells

The in vitro cytogenicityof 2-Butyne-1,4-diol, ethoxylated (>1 < 4.5 mol EO) in mammalian cells can be reliably evaluated by assessing (1) the core molecule2-butyne-1,4-diol (CasNo110-65-6)and (2) a molecule in which a similar (not cytogenic) core molecule is ethoxylated to the same degree (e.g. propylidynetrimethanol, >1<4.5 EO; CAS 50586-59-9). By this a statement can be made regarding the cytogenetic potency of 2-Butyne-1,4-diol, ethoxylated (>1 < 4.5 mol EO) since it can experimentally be proven that both, the core molecule and the ethoxylated side groups, do not pose a cytogenic potency.  

 

For2-butyne-1,4-diol a reliable in vitro chromosome aberration test was performed with chinese hamster lung fibroblasts (BG Chemie, 1989). With test concentrations of 10, 50, 100, 300, 850 µg/ml no induction of chromosomal aberrations was determined in absence and presence of metabolic activation. Therefore2-butyne-1,4-diolwas considered to be non-mutagenic in the in vitro chromosome aberration test with the test conditions chosen.

Forpropylidynetrimethanol, >1<4.5 EO an in vitro mammalian chromosome aberration test was performed in Chinese hamster lung fibroblasts (V79) (Bayer, 2010). The assay was performed according to GLP and the OECD test guideline 473 in two independent experiments at concentrations of 900, 1800, 3600 µg/mL with and without metabolic activation. No cytotoxicity was observed in the absence and presence of metabolic activation up to the highest concentration. No induction of structural chromosome aberrations was observed at the concentrations evaluated either with or without metabolic activation, whereas the appropriate mutagens (Mitomycin and Cyclophosphamide) used as positive controls produced valid responses. In conclusion, it can be stated that under the experimental conditions reported, the read across test item did not induce structural chromosomal aberrations in V79 cells of the Chinese hamster in vitro, when tested up to the highest concentration.

 

Since both the core molecule 2-butyne-1,4-diol and an ethoxylated structural analog (propylidynetrimethanol, >1<4.5 EO) were tested negative inchromosomal aberration assays, a reliable statement can be made regarding the cytogenic potency of 2-butyne-1,4-diol, ethoxylated (>1 < 4.5 mol EO). Therefore2-butyne-1,4-diol, ethoxylated (>1 < 4.5 mol EO)is considered to be non-clastogenic.

 

In vivo

No data were available for the assessment of genetic toxicity in vivo.


Short description of key information:
in vitro
Gene mutation in bacteria
(1) Ames test with S. typhimurium TA 1535, TA 1537, TA 98 and TA 100 as well as E.coli WP2 uvr A with and without metabolic activation: negative up to 5000 µg/plate, weak bacteriotoxic effect (Val 1, GLP, OECD 471, BASF 40M0587/11M208, 2012)
(2) Read across (CAS 1606-85-5) Ames test II (Liquid fluctuation test) with S. typhimurium TA 98 and Mixed strains (TA 7001 - TA 7006) with and without metabolic activation: negative up to 1000 µg/mL (TA98) and up to 5000 µg/mL (mixed strains), (Val 2, non-GLP, non-Guideline; BASF 44M0463/984178, 1999)

Gene mutation in mammalian cells
Read across (CAS 50586-59-9) Mammalian cell gene mutation assay with mouse lymphoma L5178Y cells with and without metabolic activation: negative up to 2700 µg/mL (Val 1, GLP, OECD 476; BASF 52M0775/074129, 2008).

Cytogenicity in mammalian cells
Read across (CAS 50586-59-9) in vitro mammalian chromosome aberration test using Chinese hamster lung fibroblasts (V79) with and without metabolic activation: negative up to 3600 µg/mL (Val 1, GLP, OECD 473; Bayer AT05831, 2010).

Conclusion: No genotox effects can be anticipated for 2-butyne-1,4-diol, ethoxylated (>1 < 4.5 mol EO).

Endpoint Conclusion: No adverse effect observed (negative)

Justification for classification or non-classification

Dangerous Substance Directive (67/548/EEC)

The available experimental test data for genetic mutagenicty are reliable and suitable for the purpose of classification under Directive 67/548/EEC. As a result the substance is not warranted to be classified for mutagenicity under Directive 67/548/EEC.

 

Classification, Labeling, and Packaging Regulation (EC) No. 1272/2008

The available experimental test data for genetic mutagenicity are reliable and suitable for the purpose of classification under Regulation (EC) No.1272/2008. As a result the substance is not warranted to be classified for mutagenicity, under Regulation (EC) No.1272/2008.