Furan

Carcinogenicity

Description of key information

In studies of up to 104 weeks oral gavage administration of Furan to rats or mice, there was clear evidence of carcinogenic activity in male and female F344/N rats based on increased incidences of cholangiocarcinoma and hepatocellular neoplasms of the liver and on increased incidences of mononuclear cell leukemia. There was clear evidence of carcinogenic activity of furan in male and female B6C3F1 mice based on increased incidences of hepatocellular neoplasms of
the liver and benign pheochromocytoma of the adrenal gland.
Nonneoplastic liver lesions associated with furan administration in rats and mice included biliary tract fibrosis, hyperplasia, inflammation, and proliferation,
as well as hepatocellular cytomegaly, degeneration, hyperplasia, necrosis, and vacuolization. In rats, increased severity of nephropathy with an associated
increased incidence in parathyroid hyperplasia was associated with exposure to furan.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion

Dose descriptor:

LOAEL

2 mg/kg bw/day

Justification for classification or non-classification

Based on the rat carcinogenicity study, furan is classified in Hazard Class Carc. 1B with hazard statement H350 "may cause cancer".

Additional information

In the key rat carcinogenicity study (NTP 1993), groups of 70 rats of each sex were administered 2, 4, or 8 mg furan per kg body weight in corn oil by garage 5 days per week for 2 years. After 9 and 15 months exposure, 10 rats per group were evaluated for the presence of treatment-associated lesions.

Mean body weights of male rats that received 8 mg/kg furan were lower than controls from approximately week 73 to the end of the study. Survival of male and female rats that received 8 mg/kg was lower than controls from approximately week 85 to the end of the studies as a result of moribund condition associated with liver and biliary tract neoplasms and mononuclear cell leukemia.

Cholangiocarcinoma of the liver occurred in all groups of dosed rats and was present in many rats of each sex at the 9- and 15-month interim evaluations. Hepatocellular adenomas or carcinomas (combined) were significantly increased in male rats after 2 years administration and hepatocellular adenomas were significantly increased in female rats; hepatocellular neoplasms were not observed at the 9- or 15-month interim evaluations. Increased incidences of numerous nonneoplastic liver lesions were present in rats administered furan. These lesions included biliary tract fibrosis, hyperplasia, chronic inflammation, and proliferation and hepatocyte cytomegaly, cytoplasmic vacuolization, degeneration, nodular hyperplasia, and necrosis.

The incidence of mononuclear cell leukemia was increased in male and female rats that received 4 or 8mg/kg furan.

The severity of nephropathy increased with dose and the incidence was significantly increased in all groups of dosed rats; this increased severity was accompanied by an associated increased incidence of parathyroid hyperplasia (renal secondary hyperparathyroidism).

In the mouse study (NTP 1993) groups of 50 mice of each sex received doses of 8 or 15 mg/kg furan 5 days per week for 2 years.

Incidences of hepatocellular adenomas and carcinomas were significantly increased in mice receiving furan. The incidence of numerous nonneoplastic hepatocellular lesions were also increased in dosed mice. These lesions included hepatocyte cytomegaly, degeneration, necrosis, multifocal hyperplasia, and cytoplasmic vacuolization and biliaty tract dilatation, fibrosis, hyperplasia, and inflammation. The incidences of benign pheochromocytoma and focal hyperplasia of the adrenal medulla were increased in low- and high-dose male and in high-dose female mice.

Various other studies (including Wislon et al, Elmore and Sirica, Sirica et al and Butterworth et al, all cited by IARC monograph vol 63), primarily concerned with identifying a potential mechanism, all confirm the carcinogenic potenatial of furan in rats and mice.

References

Butterworth, B.E., et al. (1992) Overexpression of mye independent of induced cell proliferation: a delayed response to 6 weeks furan administration (Abstract 637). Proc. Am. Assoc. Cancer Res., 33, 106 (as cited in IARC 1987)

Butterworth, B.E., et al. (1994) Expression of myc,fos, and Ha-ras in the livers of furan-treated F344 rats and B6C3F1 mice. MoL. Carcinog., 9,24-32 (as cited in IARC 1987)

Elmore, L. & Sirica, A.E. (1993) 'Intestinal-type' of adenocarcinoma preferentially induced in rightlcaudate liver lobes of rats treated with furan. Cancer Res., 53,254-259 (as cited in IARC 1987)

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

NTP (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., et al. (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., et al. (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, D.M., Goldsworthy, T.L., Popp, J.A. & Butterworth, B.E. (1992) Evaluation of genotoxicity, pathological lesions, and cell proliferation in livers of rats and mice treated with furan. Environ. moL. Mutag., 19,209-222 (as cited in IARC 1987)

Carcinogenicity: via oral route (target organ): cardiovascular / hematological: hematopoiesis; digestive: liver; glandular: adrenal gland