Safety evaluation of certain food additives - ipcs inchem

FURAN-SUBSTITUTED ALIPHATIC HYDROCARBONS 525
3. COMMENTS
As stated above, the main concern with this group arises primarily from the
carcinogenicity of furan itself, which is believed to involve a reactive genotoxic
metabolite formed by epoxidation and opening of the furan ring. Furan is not a
member of this group of flavouring agents, but all the members of the group contain
a furan ring with either one or two substituents of varying complexity. In some
flavouring agents, a substituent is present on one side of the furan ring only,
whereas in others, substituents are present on both sides. The presence of an
extended side-chain attached to the furan ring would reduce the potential for
epoxidation of the double bond and provide a site for detoxication via metabolism
and elimination. The flavouring agent that has the simplest structure and would be
predicted to have the greatest potential for ring oxidation is 2-methylfuran (No.
1487); there is evidence from studies in vitro and in vivo that this compound
undergoes bioactivation to a reactive ring-opened metabolite that binds covalently
to both protein and DNA. Data are not available on the influence of the nature and
position of the ring substitution on potential for metabolic activation and adduct
formation. After administration of a single dose, 2-methylfuran produced liver toxicity
in rats from 50 mg/kg bw, but hepatotoxicity has not been reported for other
members of this group in more extensive studies.
Testing for genotoxicity has been performed on eight members of this group
of flavouring agents. The results of the studies of genotoxicity/mutagenicity in vitro
that were already available to the Committee at its previous meeting were both
positive and negative, with most positive results reported for chromosomal
aberration. These, however, were less frequent in the presence of metabolic
activation, indicating possible metabolic detoxication rather than bioactivation. 2-
Methylfuran (No. 1487), for example, produced chromosomal aberrations in vitro,
but the clastogenic activity was lower in the presence of a metabolizing system. The
limited data available on genotoxicity in vivo showed no evidence of chromosomal
aberration in mouse bone marrow or spermatocytes for 2-methylfuran. 2-Furyl
methyl ketone (No. 1503) also induced no chromosomal aberrations in mouse
spermatocytes, but a weak, transient increase in chromosomal aberrations was
observed in mouse bone marrow, associated with mitodepression. O-Ethyl-S-(2furylmethyl)thiocarbonate
(No. 1526) appeared not to induce micronucleus
formation in mouse bone marrow.
The new data on 2-furyl methyl ketone (No. 1503) available to the Committee
at its present meeting were a study on UDS in cultured hepatocytes in vitro, a study
on UDS in rat liver in vivo/in vitro and a test for SCEs in mouse bone marrow in vivo.
2-Furyl methyl ketone did not induce UDS either in vitro or in vivo/in vitro. However,
it did induce SCEs, confirming the concern for clastogenicity as expressed by the
Committee at its previous meeting. The Committee at its present meeting therefore
considered that the new data available did not resolve the concerns expressed
previously.