Safety evaluation of certain food additives - ipcs inchem

348 ALIPHATIC LINEAR ,-UNSATURATED ALDEHYDES
proliferation was not significantly increased over controls in the liver after exposure
to 100 mg/kg bw for 1 or 4 weeks (Stout et al., 2008).
This study indicates that 2-hexenal (No. 1353) can induce DNA adduct
formation and cell proliferation upon gavage administration, but only at the site of
contact and at doses inducing forestomach toxicity. DNA adduct formation following
gavage administration of 2-hexenal was also described in the previous evaluation
(Annex 1, reference 174). Based on these data and data on other 2-alkenals, the
Committee at the previous meeting concluded that
high cellular concentrations of 2-alkenals may deplete glutathione, leading to
oxidative stress and the formation of protein and DNA adducts. Under these
conditions, alkenals may also form endogenously from the increased lipid
peroxidation of membrane polyunsaturated fatty acids. To some extent, repair is
observed after cessation of exposure. At the concentrations of alkenals that are
present in the diet, there is no significant potential for oxidative stress or the
formation of DNA adducts.
In the absence of a study of long-term toxicity and carcinogenicity on 2hexenal,
but clear evidence of carcinogenic activity in the forestomach of rats and
mice following gavage administration of the structurally similar ,-unsaturated
aldehyde trans,trans-2,4-hexadienal (No. 1175), the Committee at the previous
meeting discussed the relevance of these findings for humans (Annex 1,
reference 174). It was concluded that
the appearance of forestomach lesions in the 2-year bioassays in rodents in which
trans,trans-2,4-hexadienal was administered at high concen-trations by gavage
has no relevance to humans, given that the results are attributable to the irritating
effect of high bolus doses of trans,trans-2,4-hexadienal delivered to the contact
site (forestomach) by gavage, and not the effects of systemic concentrations in
the whole animal. On bio-chemical grounds and in analogy to trans,trans-2,4hexadienal,
trans-2-hexenal (No. 1353), therefore, would also be expected not to
have any carcinogenic potential in humans.
(c) Genotoxicity
Only for 1 of the 22 substances in this group has a study of genotoxicity in
vitro been reported. For this substance, (E,Z)-methyl 2-nonenoate (No. 1813), there
was no evidence of mutagenicity in a standard and modified (preincubation method)
Ames assay when various strains of Salmonella typhimurium (TA98, TA100, TA102,
TA1535 and TA1537) were incubated with up to 5000 μg/plate, with or without
metabolic activation (Poth, 2003).
One additional study of genotoxicity in vitro has been reported for two
substances evaluated previously. Negative results were obtained in an SOS
chromotest when Escherichia coli strain PQ 37 was incubated with 2-hexenal
(No. 1353) or 2-heptenal (No. 1360) at concentrations up to 69 and 90 μg/plate,