Furan

Endpoint summary

Additional information

In vitro

Bacterial mutagenicity

Furan has been tested in a reliable study using S. typhimurium TA 1535, TA 1537, TA 98 and TA 100 and a method similar to OECD TG 471. No increase in the number of revertants was observed with and without activation; solvent and positive controls gave expected results. (Mortelmans et al (1986); NTP (1993)). Other results are reported: a positive result (described by the authors as weakly positive) was recorded in an assay using S. typhimurium TA 98 and TA 100: increases in mutant frequency were seen in strain TA 100 with and without metabolic activation (Lee et al (1994)). A negative result was reported in a study using S typhimurium strains TA 98 and TA 100 (Shinohara (1986)). In a non-standard study, evidence of possible mutagenicity was observed in an E. coli bacteriophage T7 (Ronto et al (1992)). Negative results are reported for mutagenicity to S. typhimurium TA 100 and TA 102 (Dillon et al 1992 cited in IARC)

The furan metabolite cis-2-butene-1,4-dial was studied in S. typhimurium strains TA 97, TA 98, TA 100, TA 102 and TA 104 using a liquid incubation method. A positive response was observed in the absence of metabolic activation in strain TA 104 at non-toxic concentrations, but not at non-toxic concentrations in the other strains tested (Peterson LA et al (2000)).

Cytogenicity studies

Furan has been tested in CHO cells in a study that is similar to OECD 473. An increase in the number of cells with aberrations was observed in the presence and absence of metabolic activation (McGregor 1988 as cited in NTP 1993). The response was observed at concentrations of 100-500 µg/l without metabolic activation, and at 500-1000 µg/l with metabolic activation (not tested with metabolic activation). A further study on induction of chromosome aberrations in CHO cells found an effect in the presence but not in the absence of metabolic activation (Stich et al 1981 as cited in Jecfa 2011). A study on the in vitro induction of micronuclei in human lymphocyte cultures reported negative results in either the presence or absence of metabolic activation. (Durling Svensson & Abramsson-Zetterberg 2007 as cited in Jecfa 2011). This result is in agreement with that reported for induction of micronuclei in L5178Y cells in the absence of metabolic activation (Jecfa 2011 citing Kellert et al 2008b). The furan metabolite, BDA, is reported as negative for induction of micronuclei in mouse lymphoma l5178Y cells (Jecfa 2011 citing Kellert et al 2008b).

Mutagenicity to mammalian cells

An increase in mutant frequency without metabolic activation was recorded in a study that tested furan for mutagenicity to L5178Y cells (not tested with metabolic activation) (McGregor 1988 as cited in NTP 1993). The furan metabolite cis-2-butene-1,4-dial was positive only at a very narrow range of concentrations when tested in V79 and L5178Y cells for mutagenicity but positive for induction of small colonies in TK cells in a study which concluded that furan was negative for these endpoints (Furan RA, University of Wuerzberg (2010)). Mutagenic effects were not observed when furan was tested at 0.225-3.1 mmol/l, without metabolic activation L5178Y cells, but the metabolite BDA was positive when tested in these cells (Kellert et al 2008b as cited in Jecfa 2011). The furan metabolite cis-2-butene-1,4-dial was positive only at a very narrow range of concentrations when tested in V79 and L5178Y cells for mutagenicity but positive for induction of small colonies in TK cells in a study which concluded that furan was negative for these endpoints (Furan RA, University of Wuerzberg (2010)).

Other in vitro/non-mammalian endpoints

Results are also reported for sister chromatid exchange (NTP (1993)): positive at moderate doses without S9, positive only at high doses in the presence of metabolic activation. In another sister chromatid exchange assay, a substance induced increase in SCEs was observed in the presence but not the absence of metabolic activation (Stich et al 1981 as cited in Jecfa 2011).

DNA repair in primary rat hepatocytes and primary mouse hepatocytes has been investigated: results were negative (Wilson et al 1992 as cited in Jecfa 2011). No substance-induced DNA strand breaks were reported in mouse lymphoma L5178 tk+/- cells treated with furan, but when the potential metabolite BDA was tested, a positive result was obtained (Kellert et al 2008b as cited in Jecfa 2011).

No effects were seen in Drosophila melanogaster after exposure to furan in feed (10 000 ppm) or by abdominal injection (25 000) (NTP 1993 and NTP 2012).

In vivo

Significant increases in chromosome aberrations were observed in mouse bone marrow cells after ip administration of furan; the effect was observed only after extended harvest time at highest dose tested (250 mg/kg bw) (NTP (1993)). A negative result is reported for a chromosome aberration study in rat bone marrow cells exposed to 0.1-2.0 mg/kg bw furan for 5 days or 4 weeks (Mosesso 2009 as cited in Jecfa 2011). No increase in sister chromatid exchange was observed in mouse bone marrow cells after ip administration of furan NTP (1993)). The sampling time were 23 h for mice treated with 87.5-350 mg/kg bw furan, and 42 h for animals treated with 25-100 mg/kg bw furan. No increase in SCEs was observed in rat bone marrow cells exposed to 0.1-2.0 mg/kg bw/day furan for 5 days or 4 weeks (Mosesso 2009 as cited in Jecfa 2011). No damage to DNA in rat hepatocytes or mouse bone marrow was observed following exposure to furan (Wilson et al as cited by NTP 2012 and NTP 1993). Induction of micronuclei has been studied in rats after dosing with furan at 2, 4, 8 and 75 mg/kg bw per day (oral gavage) for four weeks, and at single doses of 15, 100 and 250 mg/kg bw (oral gavage). A statistically-significant increase in the incidence of micronuclei was observed in the repeated-dose groups at doses of 4 mg/kg bw/day and above. A dose-related trend of increase in micronuclei was observed in the acute study, but the increase was not statistically significant (Leopardi et al 2010 as cited in Jecfa 2011).

References

IARC (1987) IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Suppl. 7, Overall Evaluations of Carcinogenicity: An Updating of IARC Monographs Volumes 1-42, Lyon, p. 59

Jecfa (2011), Safety evalutation of certain contaminants in food. WHO FOOD ADDITIVE SERIES: 63, World Health Organization Geneva, Food and Agriculture Organization of the United Nations Rome.

Durling LJK, Svensson K, Abramsson-Zetterberg L (2007). Furan is not genotoxic in the micronucleus assay in vivo or in vitro. Toxicology Letters, 169(1):43–50. (as cited in Jecfa 2011)

Dekant W. (2010) Furan RA - Role of genetic and non-genetic mechanisms in furan risk, University of Wuerzberg, Germany

McGregor, D.B., et al. (1988). Responses of the L5178Y tk+/tk- mouse lymphoma cell forward mutation assay: III. 72 coded chemicals. Environ. Mol Mutagen. 12, 85 -154. (as cited in NTP 1993)

NTP. (1993). NTP Technical Report on the Toxicology and Carcinogenesis Studies of Furan in F344/N Rats and B6C3F Mice. National Toxicology Program P.O. Box 12233 Research Triangle Park, NC 27709

Stich HF et al. (1981). Clastogenicity of furans found in food. Cancer Letters, 13(2):89–95. USFDA (2004). Determination of furan in foods [method dated 7 May 2004; modified 2 June 2005 and 27 October 2006]. Silver Spring, MD, United States Department of Health and Human Services, Food and Drug Administration (http://www.fda.gov/Food/FoodSafety/FoodContaminantsAdulteration/ChemicalContaminants/Furan/ucm078400.htm). USFDA (2009). Exploratory data on furan in food: individual food products. Silver Spring, (as cited in Jecfa 2010)

Wilson DM et al. (1992). Evaluation of genotoxicity, pathological lesions and cell proliferation in livers of rats and mice treated with furan. Environmental and Molecular Mutagenesis, 19(3):209–222 (as cited in Jecfa 2011)

Kellert M et al. (2008b). Tests for genotoxicity and mutagenicity of furan and its metabolite cis-2-butene-1,4-dial in L5178Y tk+/- mouse lymphoma cells. Mutation Research, 657:127–132 (as cited in Jecfa 2011)

Leopardi P et al. (2010). Assessment of in vivo genotoxicity of the rodent carcinogen furan: evaluation of DNA damage and induction of micronuclei in mouse splenocytes. Mutagenesis, 25(1):57–62 (as cited in Jecfa 2011)

Short description of key information:
In vitro
Gene mutation (Bacterial reverse mutation assay/Ames: negative with and without metabolic activation in S. typhimurium TA 1535, TA 1537, TA 98 and TA 100 (similar to OECD TG 471) (Mortelmans et al (1986)).
Gene mutation (Bacterial reverse mutation assay/Ames: the furan metabolite cis-2-butene-1,4-dial was positive without metabolic activation in S. typhimurium TA 97, TA 98, TA 100, TA 102 and TA 104 (similar to OECD TG 471) (Peterson LA et al (2000)).
Cytogenicity in mammalian cells: positive with and without metabolic activation in CHO cells (similar to OECD 473) (NTP (1993) citing McGregor 1988).
Mutagenicity in mammalian cells: positive without metabolic activation in L5178Y mouse lymphoma cells (similar to OECD TG 476) (NTP (1993) citing McGregor 1988).

In vivo
Micronucleus assay in mouse (ip administration): positive after extended harvest at highest dose tested (250 mg/kg bw) (similar to OECD 474) (NTP (1993)).

Endpoint Conclusion: Adverse effect observed (positive)

Justification for classification or non-classification

Furan is classified as Mutagenic Category 2 according to Regulation (EC)1272/2008.