Tetrahydrothiophene 1,1-dioxide

Endpoint summary

Key value for chemical safety assessment

Genetic toxicity in vitro

Description of key information

Sulfolane has been examined for genotoxicity in a range of recognized core in vitro assay types and has shown negative results. There are no chemically reactive functional groups in the molecule, and it would not be expected to undergo significant metabolism to any reactive species. The available studies on metabolism support this view (Anderson, et. al., 1976; Roberts and Warwick, 1961). The substance carries no alerts for possible genotoxic activity based on established Structure Activity Relationship (SAR) principles (Tennant and Ashby, 1991).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (negative)

Genetic toxicity in vivo

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

In vitro

In a study conducted according to the OECD TG 471 (Hatano Research Institute, 1996a), sulfolane did not induce reverse gene mutations in Salmonella typhimurium or E. coli strains in the presence or absence of metabolic activation when tested up to 5,000 μg/plate. Sulfolane was also not mutagenic to Salmonella typhimurium strains with and without metabolic activation when tested at concentrations of 642, 1926, 5778, 17333 and 52000 μg/plate (Hazleton, 1982b).

In a mouse lymphoma assay (Cortina, 1983), the effects of exposure to sulfolane on induction of forward mutations at the thymidine kinase locus were investigated in cultured L5178Y mouse lymphoma cells in the absence and presence of S9 metabolic activation. Sulfolane was considered by the report author to be mutagenic in both the absence and presence of metabolic activation, but the increase in mutant frequency was not dose-dependent and was accompanied by reduced cell viability which was also not dose-dependent. When assessed by the criteria in the draft new OECD Test Guideline: "In vitro mammalian cell gene mutation assays using the thymidine kinase gene", the mutant frequency does not exceed the solvent controls by the global evaluation factor (relevant for the plate method) of 90 x 10⁻⁶. Therefore it is considered the test substance is negative for mutagenicity under the conditions of the test.

Tetrahydrothiophene 1,1-dioxide has been tested for mutagenicity in mouse lymphoma L5178Y cells according to OECD TG 490, and in compliance with GLP (RTC, 2018). No test-substance induced increase in the number of mutations was observed when tested up to limit concentration in the presence and absence of metabolic activation. The result of the first experiment, 3-hour exposure with and without metabolic activation, was confirmed in a second experiment, 24-hour exposure without metabolic activation. Appropriate solvent and positive controls were included and gave expected results. It is concluded that the test substance is negative for mutagenicity to mammalian cells under the conditions of the study.

Sulfolane, at concentrations up to 5 mg/ml did not result in a consistent increase in the rate of mitotic gene conversion in S. cerevisiae either in the absence or presence of metabolic activation (Shell, 1982). No increased chromosomal aberrations were observed in CHL/IU cells when treated with sulfolane in the absence or presence of metabolic activation (Hatano Research Institute, 1996b). Increased chromosomal damage was not observed in cultured rat liver (RL4) cells when treated with sulfolane (up to 1,000 μg/ml) in the absence of metabolic activation (Shell, 1982).

Sulfolane was considered negative when tested for the induction of sister chromatid exchanges in cultured Chinese hamster ovary (CHO) cells in the presence and absence of metabolic activation (Hazleton, 1983b).

In Vivo

No in vivo genotoxicity studies have been conducted on sulfolane.

However, sulfolane has been tested in a range of recognized core in vitro assay types and has shown negative results for genotoxicity. In vitro bacterial gene mutation studies using S. typhimurium and E. coli have shown no mutagenic activity when sulfolane was tested in the presence and absence of S9 metabolic activation.

Summary, genetic toxicity

In an in vitro cytogenetic assay in mammalian cells (CHL), sulfolane was negative when tested in both the presence and absence of S9 metabolic activation. Sulfolane was considered negative when tested for the induction of sister chromatid exchanges in cultured Chinese hamster ovary (CHO) cells in the presence and absence of metabolic activation. In a mouse lymphoma assay, sulfolane was considered by the study author to be mutagenic in both the absence and presence of metabolic activation. The findings were confounded, however, by reduced cell viability at all dose levels. No dose-response was observed, and the results are considered negative according to current criteria. A recent mouse lymphoma assay, conducted according to OECD 490, concluded that sulfolane did not induce mutation at the TK locus of L5178Y mouse lymphoma cells in vitro in the absence or presence of S9 metabolic activation, under the conditions of the assay.There are no functional groups in the molecule, and it would not be expected to undergo significant metabolism to any reactive species. It carries no alerts for possible genotoxic activity based on established Structure Activity Relationship (SAR) principles (Tennant and Ashby, 1991).

Andersen, M.E., Jones, R.A., Kurlansik, L., Mehl, R.G., and Jenkins, L.J., Jr. (1976) Sulfolane-induced convulsions in rodents. Res. Commun. Chem. Pathol. Pharmacol. 15: 571-580.

Roberts, J.J., and Warwick, G.P. (1961) The mode of action of alkylating agents – III The formation of 3-hydroxytetrahydrothiophene-1;1-dioxide from 1:4-dimethylsulphonyloxybutane (Myleran), S-β-L-alanyltetrahydrothiophenium mesylate, tetrahydrothiophene and tetrahydrothiophene-1:1-dioxide in the rat, rabbit and mouse. Biochem. Pharmacol. 6: 217-227.

Tennant and Ashby, 1991: Ashby, J. and Tennant, R. W. Definitive relationships among chemical structure, carcinogenicity and mutagenicity for 301 chemicals tested by the U.S. NTP. Mutation Research, 257, (1991) 229-306.

Justification for classification or non-classification

Sulfolane has been examined for genotoxicity in a range of recognized core in vitro assay types and has shown negative results. Therefore, sulfolane does not warrant classification as a mutagen under CLP.