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Key value for chemical safety assessment

Additional information

In Vitro

Tetrahydrofuran has been tested for mutagenicity in the Ames assay and in the CHO/HPRT assay and for chomosomal aberrations in Chinese hamster ovary cells (CHO-W-B1). In a key study, tetrahydrofuran was negative for mutagenicity when tested in Salmonella sp. stains TA97, TA98, TA100, TA1535 and TA1537 up to a limiting plate incorporation level of 10,000 micrograms/plate, either with or without metabolic activation. In an additional study, tetrahydrofuran was negative when tested in Salmonella sp. strains TA100, TA1537, and TA98 when tested up to a limiting plate incorporation level of 10,000 micrograms/plate, either with or without metabolic activation. In this latter study, addition of the glutathione depletor 1,1,1 -trichloropropene (TCPO; 0.3 microlilters/plate) did not cause an increase in revertant colonies/plate. Tetrahydrofuran was negative as a mutagen when tested in the CHO/HPRT assay, either in the presence or absence of S9 activation. Tetrahydrofuran was tested for the induction of chromosomal aberrations in cultured Chinese hamster ovary cells. In this study, concentrations of tetrahydrofuran up to 5,000 micrograms/mL did not produce cytogenicity, either with or without metabolic activation. Tetrahydrofuran was also tested for the potential to cause sister chromatid exchanges in Chinese hamster ovary cells. In this study, THF was negative up to 5,000 micrograms/mL, either with or without metabolic activation.

Two published studies indicate the potential for oxidized tetrahydrofuran to react in vitro with a modified nucleoside base, nucleoside bases and with calf thymus DNA. In a study reported by Loureiro et al. (2005), tetrahydrofuran forms three adducts with 1,N2 -etheno-deoxyguanosine, itself formed from unsaturated aldehydes as a result of lipid peroxidation of cell membranes. The relevance of this to in vivo systems cannot be determined from this study. In a second study reported by Hermida et al. (2006), tetrahydrofuran is shown to form adducts with individual nucleoside bases as well as with calf thymus DNA. Although the relevance of such adducts to the toxicity of tetrahydrofuran was not established in this latter study, the authors propose that such adducts may contribute to the toxicological effects of tetrahydrofuran exposure. In both the Loureiro et al. (2005) and Hermida et al. (2006) reports, stable adducts were obtained only after reduction with sodium borohydride. Given the lack of evidence concerning the in vivo stability of such adducts, it is not possible to draw any definitive conclusions regarding the potential health effectrs of such adducts. Addequate in vivo genotoxicity information is available for tetrahydrofuran suggesting that such adducts have little or no relevance to the health effects assessment for tetrahydrofuran.

In Vivo

Tetrahydrofuran has been tested for genetic toxicity in vivo in a mouse micronucleus test; in in vivo tests in male mice measuring sister chromatid exchanges (SCE) and chromosomal aberrations (CA) in bone marrow cells; and in a sex-linked recessive lethal (SLRL) test in Drosophila melanogaster. In the mouse micronucleus test, peripheral blood was obtained from mice treated by inhalation for 6 hours/day, 5 days/week for 14 weeks at concentrations up to 5000 ppm (see Section 7.5.3). With the exception of an equivocal response in male mice, represented as an increase in the frequency of micronucleated normochromatic cells (P = 0.074), tetrahydrofuran failed to produce a positive response. Tetrahydrofuran was negative for the induction of chromosomal aberrations or sister chromatid exchanges when tested in mice in vivo following single intraperitoneal injections of up to 2,000 mg/kg bwt. Tetrahydrofuran produced no response in the SLRL test in Drosophila melanogaster when fed at 10,000 or 125,000 ppm or when injected at 40,000 ppm.

Short description of key information:
The testing of tetrahydrofuran in a series of both in vitro and in vivo genetic toxicity tests has resulted in generally negative results.

Endpoint Conclusion: No adverse effect observed (negative)

Justification for classification or non-classification

THF was generally negative when tested for mutagenicity/cytogenicity in either in vitro or in vivo assays. Based on this evidence, THF would not be rated as a mutagen under either the EU DSD classification system (EU Directive 67/548/EEC) or the EU CLP classification system (EU Regulation 1272/2008).