Tetrahydro-3-methylfuran

Endpoint summary

Additional information

In Vitro

No in vitro o genetic toxicity studies/data are available for Tetrahydro-3-methylfuran (3-methyl-THF). However, the in vitro genetic toxicity of 3-methyl-THF can be adequately characterized by read-across to a closely related substance, Tetrahydrofuran (THF, CAS# 109-99-9). THF 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, THF 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, THF 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. THF was negative as a mutagen when tested in the CHO/HPRT assay, either in the presence or absence of S9 activation. THF 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. THF 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 THF 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), THF 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), THF 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 THF 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 effects of such adducts. Adequate in vivo genotoxicity information is available for THF suggesting that such adducts have little or no relevance to the health effects assessment for tetrahydrofuran. Based on the negative mutagenicity data for THF and the absence of reliable data to the contrary, it can be concluded 3 -methyl-THF would not be mutagenic in vitro.

In Vivo

No in vivo genetic toxicity studies/data are available for Tetrahydro-3-methylfuran (3-methyl-THF). However, the in vivo genetic toxicity of 3-methyl-THF can be adequately characterized by read-across to a closely related substance, Tetrahydrofuran (THF, CAS# 109-99-9). THF 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 inDrosophila 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), THF failed to produce a positive response. THF was negative for the induction of chromosomal aberrations or sister chromatid exchanges when tested in micein vivofollowing single intraperitoneal injections of up to 2,000 mg/kg bwt. THF 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. Based on the negative mutagicity data for THF and the absence of reliable data to the contrary, it can be concluded 3-methyl-THF would not be mutagenic in vivo.

Short description of key information:
No in vitro or in vivo genetic toxicity studies/data are available for Tetrahydro-3-methylfuran (3-methyl-THF). However, the in vitro and in vivo genetic toxicity of 3-methyl-THF can be adequately characterized by read-across to a closely related substance, Tetrahydrofuran (THF, CAS# 109-99-9). The testing of THF 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

There are no genetic toxicity data on tetrahydro-3 -methylfuran (3 -methyl-THF). However, based on the absence of mutagenicity in all in vitro and in vivo tests on bacterial and mammalian cells for a close structurally related analogue, tetrahydrofuran (THF, CAS# 109 -99 -9), 3 -methyl-THF does not meet the criteria for classification as R46 (May cause heritable genetic damage) or R68 (Possible risk of irreversible effects) under the EU DSD classification criteria (EU Directive 67/548/EEC) or as a Germ Cell Mutagen (Cat. 1 or 2) under the EU CLP classification criteria (Regulation (EC) 1272/2008).