Furan

Endpoint summary

Description of key information

In rat and mouse studies up to 13-weeks duration, the liver was identified as the main target organ in both species. Also in rats, the kidneys, thymus, testes and ovaries were also affected.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Dose descriptor:

LOAEL

4 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Additional information

Repeated-dose studies clearly identify the liver as the target organ of furan toxicity by the oral route in the mouse and rat (NTP, 1993). The rat was notably more sensitive than the mouse to the toxicity of furan in terms of time to onset of liver changes and severity and incidence of lesions at a particular dose. Typically, the lesions in the rat were characterized by hyperplasia and cholangiofibrosis of the biliary tract, and cytomegaly, degeneration and necrosis of hepatocytes. These lesions occurred at doses that were less than those associated with increased liver weights. Nodular hyperplasia was also observed in the rat. Although furan induced the same types of hepatocelluar lesions in both species, the most prominent lesions in the rat affected the biliary tract, whereas in mice, hepatocytes and the biliary tract were equally affected by furan administration. Also, at the higher doses in the rat, renal tubular lesions were noted, as well as atrophy of the thymus, testes and ovaries; none of these effects were noted in the mouse.

Various other studies, many investigating the potential underlying mechanism, all confirm the liver as a target organ for furan in both rats and and mice (including Sirica et al as cited in IARC monograph vol 63, Gill et al and Wilson et al as cited in Jecfa 2011, Hickling at al and Fransson-Steen et al as cited in HSDB).

References

Fransson-Steen R et al (1997) Furan-induced liver cell proliferation and apoptosis in female B6C3F1 mice. Toxicology.1997 Mar 28;118(2-3):195-204 (as cited in HSBD 2011)

Gill S et al. (2009). Subchronic oral toxicity “90-day study” to determine effects of furan in Fischer 344 rats. In: Investigations on toxicity of furan—a preliminary report. Ottawa, Ontario, Health Canada, Food Directorate, pp. 5–41. (as cited in Jecfa 2011)

Hickling KC et al (2010) Evidence of oxidative stress and associated DNA damage, increased proliferative drive, and altered gene expression in rat liver produced by the cholangiocarcinogenic agent furan. Toxicologic Pathol 38 (2) : 230 -43 (as cited in HSBD 2011)

Hickling KC et al (2010) Induction and progression of cholangiofibrosis in rat liver injured by oral administration of furan. Toxicologic Pathol 38 (2) : 213 -29 (as cited in HSBD 2011)

HSDB (2011) Hazardous Substances Data Bank. Databank Number 89, last revised 16 June 2011.http://toxnet.nlm.nih.gov/cgi-bin/sis/search/f?./temp/~lMMQU6:1

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.

National Toxicology Program (1993), Toxicology and Carcinogenesis Studies of Furan (CAS No. 110-00-9) in F344 Rats and B6C3F1 Mice (Gavage Studies). NTP Technical Report Series no. 402. Research Triangle Park, NC: National Toxicology Program. 286 pp. http://ntp.niehs.nih.gov/ntp/htdocs/LT_rpts/tr402.pdf. Southern Research Institute, Birmingham, AL.

Sirica, A.E., Cole, S.L. & Williams, T. (1994a) A unique rat model of bile ductular hyperplasia in which liver is almost totally replaced with well-differentiated bile ductules. Am. 1. Pathol., 144, 1257-1268 (as cited in IARC 1987)

Sirica, A.E., Gainey, T.W. & Mumaw, V.R. (l994b) Ductular hepatocytes. Evidence for a bile ductular cell origin in furan-treated rats. Am. 1. Pathol., 145,375-383 (as cited in IARC 1987)

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. Yaylayan VA (2006). (as cited in Jefca 2011)

Repeated dose toxicity: via oral route - systemic effects (target organ) cardiovascular / hematological: thymus; digestive: liver; urogenital: kidneys; urogenital: ovaries; urogenital: testes

Justification for classification or non-classification

Based on the rat 13 -week oral study in which the liver was identified as a target organ (along with the thymus, testes and ovaries), and supported by the mouse 13 -week oral study in which the liver was also a target organ, furan is classified in Hazard Class STOR RE 2 with the Hazard Statement "may cause damage to the liver through prolonged or repeated exposure".