Safety evaluation of certain food additives - ipcs inchem

500 FURAN-SUBSTITUTED ALIPHATIC HYDROCARBONS
Furan has been studied in standard 2-year bioassays (National Toxicology
Program, 1991). Groups of Fischer 344 rats (70 per sex) were administered 2, 4 or
8 mg furan/kg bw by gavage in corn oil 5 days per week for 2 years. After treatment
for 9 and 15 months, 10 rats from each group were evaluated for the presence of
treatment-associated lesions. The strongest treatment-related effects were
observed in the liver. In all treated groups, cholangiocarcinoma of the liver was
observed and was present in many rats of each sex at the 9- and 15-month interim
evaluations. Incidences of hepatocellular adenomas or carcinomas (combined)
were significantly increased in male rats after 2 years of furan exposure, and
hepatocellular adenomas were significantly increased in female rats. Nonneoplastic
liver lesions, including biliary tract fibrosis, hyperplasia, chronic
inflammation, proliferation and hepatocyte cytomegaly, cytoplasmic vacuolization,
degeneration, nodular hyperplasia and necrosis were abundant in all rats
administered furan. Incidences of mononuclear cell leukaemia were increased in
male and female rats that received 4 or 8 mg furan/kg bw, and the incidence in the
8 mg/kg bw groups of each sex exceeded the historical control ranges for corn oil
gavage studies.
In 2-year bioassays in mice, groups of 50 B6C3F1 mice of each sex received
doses of 8 or 15 mg furan/kg bw 5 days per week for 2 years (National Toxicology
Program, 1991). As with the rat studies, the strongest treatment-related effects were
observed in the liver. The incidences of hepatocellular adenomas and carcinomas
were significantly increased in mice receiving treatment. The incidences of
numerous non-neoplastic hepatocellular lesions were increased in dosed mice.
These lesions included hepatocyte cytomegaly, degeneration, necrosis, multifocal
hyperplasia, cytoplasmic vacuolization and biliary tract dilatation, fibrosis,
hyperplasia and inflammation.
Under the conditions of these 2-year gavage studies, the National Toxicology
Program (NTP) concluded that there was clear evidence of carcinogenic
activity of furan in male and female Fischer 344/N rats based on increased
incidences of cholangiocarcinoma and hepatocellular neoplasms of the liver and on
increased incidences of mononuclear cell leukaemia. There was also 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
phaeochromocytomas of the adrenal gland.
The furan hepatocarcinogenicity demonstrated in the NTP 2-year bioassays
has been studied and interpreted as proceeding through a mechanism that is
secondary to the potent hepatotoxicity of furan. Furan has limited metabolic options
available and is primarily transformed via cytochrome P450 catalysis to a reactive
metabolite, cis-2-butene-1,4-dial. The high concentrations of furan that were
administered in the 2-year bioassays led to high levels of cis-2-butene-1,4-dial, and
this enedialdehyde reacts in a non-enzymatic reaction with cellular proteins and with
glutathione, leading to uncoupling of hepatic oxidative phosphorylation, necrosis
and apoptosis, which ultimately result in hepatocarcinogenicity (Burka et al., 1991;
Fransson-Steen et al., 1997; Mugford et al., 1997; Peterson et al., 2006). While this
enedialdehyde metabolite has been demonstrated to form DNA adducts in vitro,
DNA adducts have not been found in vivo in studies with male Fischer 344 rats