Safety evaluation of certain food additives - ipcs inchem

FURAN-SUBSTITUTED ALIPHATIC HYDROCARBONS 499
bonds in mixed disulfides may undergo reduction, releasing the thiol from the protein
(Brigelius, 1985; Sies et al., 1987; Cotgreave et al., 1989).
The remaining substance is a sulfide (No. 1525). Monosulfides are expected
to undergo oxidation, mainly to the corresponding sulfoxide and sulfone. Sulfoxides
and sulfones are physiologically stable and are excreted unchanged in the urine
(McBain & Menn, 1969; Nickson & Mitchell, 1994; Nickson et al., 1995; Nnane &
Damani, 1995).
(e) Furan metabolism and mechanism of action
The biotransformation processes that can act upon this group of furansubstituted
flavouring agents are, in large part, dependent on the presence or
absence of specific functional groups on the aliphatic side-chain. The substances
in this group are metabolized to polar products that are mainly conjugated and
then excreted in the urine. At higher dose levels, low relative molecular mass
alkyl furans (e.g. 2-methylfuran) can undergo ring oxidation to yield reactive
2-ene-1,4-dicarbonyl intermediates, which can, subsequently, be conjugated with
sulfhydryl trapping agents or react with protein and DNA. The most extreme
example of this is furan, which has limited metabolic options available and primarily
metabolizes via the ring oxidation mechanism to produce an enedialdehyde species
that is a potent hepatotoxin.
In standard Salmonella mutagenicity assays in vitro, furan did not induce
gene mutations in S. typhimurium strains TA98, TA100, TA1535 and TA1537, either
with or without S9 metabolic activation, at concentrations up to 3333 μg/plate
(Mortelmans et al., 1986). Furan was reported to give positive results in sister
chromatid exchanges and chromosomal aberration assays in Chinese hamster
ovary cells, with and without S9 (National Toxicology Program, 1991). Furan also
was reported to give positive results in trifluorothymidine resistance assays in
cultured mouse lymphoma L5178Y cells (McGregor et al., 1988). The average
mutation frequencies recorded in these experiments increased with increasing
concentrations of furan. However, furan cytotoxic effects, which were assessed by
measuring relative total growth in comparison with vehicle controls, were also
significant at the doses at which positive mouse lymphoma results were recorded.
In in vitro micronucleus assays in human lymphocytes, furan concentrations from 0
to 100 mmol/l either with or without rat liver S9 metabolic activation gave no increase
in the frequency of micronucleated cells (Durling et al., 2007).
In in vivo experiments, furan administered to male B6C3F1 mice by
intraperitoneal injection induced chromosomal aberrations but not sister chromatid
exchanges in bone marrow cells (National Toxicology Program, 1991). In germ cells
of male Drosophila melanogaster, furan did not produce sex-linked recessive
lethal mutations when administered either by feeding or by injection (Foureman et
al., 1994). In in vivo micronucleus experiments, furan was administered to male
BALB/c mice (intraperitoneally at 0–300 mg/kg bw or by subcutaneous injection at
0–275 mg/kg bw) and to male CBA mice (intraperitoneally at 0 and 225 mg/kg bw).
No increased level of micronucleated erythrocytes was detected in any of the
micronucleus assays (Durling et al., 2007).