Safety evaluation of certain food additives - ipcs inchem

520 FURAN-SUBSTITUTED ALIPHATIC HYDROCARBONS
2,5-dimethylfuran (No. 1488) and 2-furyl methyl ketone (No. 1503) at concentrations
of up to 55 000 μg/disc, alone and with metabolic activation (Shinohara et al., 1986).
2-Furyl methyl ketone tested negative at a concentration of 550 μg/disc, but was
reportedly positive at concentrations of 5500 μg/disc and greater alone and with
metabolic activation. Likewise, 2,5-dimethylfuran was negative at the lowest
concentration tested (i.e. 190 μg/disc) with metabolic activation, but tested positive
at every concentration tested in the absence of metabolic activation. In contrast,
2-methylfuran was negative with metabolic activation and induced significant
differences in the zones of inhibition only without metabolic activation. Additionally,
2-methylfuran and 2-acetylfuran were reported to cleave the double strand of
-phage DNA in the presence of Cu 2+ ; however, a negative control was not included,
and, therefore, the statistical significance of these results was not ascertained. Also,
it should be noted that potential concomitant cytotoxicity was not monitored in
this study.
The potential mammalian cell clastogenicities of 2-methylfuran (No. 1487),
2,5-dimethylfuran (No. 1488) and 2-furyl methyl ketone (No. 1503) were evaluated
in Chinese hamster ovary (CHO) cells, in which induction of chromosomal
aberrations was measured. Cells were exposed to substances from commercial
sources (purity not given) for 3 h, followed by 20 h of maintenance. In the absence
of exogenous metabolic activation, all three compounds produced increases in the
number of chromosomal aberrations, mainly chromatid exchanges; however, in the
presence of rat liver metabolic activation, only the clastogenicity of 2-furyl methyl
ketone was increased, whereas the clastogenic activities of 2-methylfuran and 2,5dimethylfuran
were reduced in comparison with test systems without metabolic
activation. Additionally, the authors noted that when NADP was eliminated from the
activation system, the reduction in the chromosomal aberrations observed for 2methylfuran
and 2,5-dimethylfuran and the increase in the clastogenic activity
observed with 2-furyl methyl ketone in the presence of the activation system were
abolished. This suggests that mixed-function oxidases are integral in the
metabolism of alkyl furan derivatives. It should be noted that the experiment with 2furyl
methyl ketone was performed at a limited number of concentrations (two), the
active one of which far exceeded (112.6 mmol/l = 13 220 μg/ml) standard
concentration limits for this assay and was toxic (Stich et al., 1981).
Beginning in the late 1980s, researchers began studying test conditions
(osmolality, ionic strength, low pH) that could cause an increase in clastogenic
activity (increased chromosomal aberrations and micronuclei) in the absence of any
chemical-induced effect on DNA (Zajac-Kaye & Ts’o, 1984; Brusick, 1986; Bradley
et al., 1987; Galloway et al., 1987; Seeberg et al., 1988; Morita et al., 1989; Scott
et al., 1991). More recent research indicates that extreme culture conditions (hypoand
hyperosmolality and high pH) induce apoptosis and necrosis, leading to DNA
fragmentation and producing false-positive responses in clastogenic assays
(Meintières & Marzin, 2004).
Apoptosis is a type of cell death that occurs under physiological conditions
or in response to external stimuli (e.g. DNA-damaging agents, growth factor
deprivation or receptor triggering). The mechanism of formation of apoptotic cells
includes activation of cysteine proteases (caspases), leading to increased