The European Food Safety Authority (EFSA) asked the Panel on Food Contact Materials, Enzymes,
Flavourings and Processing Aids (the Panel) to provide scientific advice to the Commission on the
implications for human health of chemically defined flavouring substances used in or on foodstuffs in
the Member States. In particular, the Panel was asked to evaluate flavouring substances using the
Procedure as referred to in the Commission Regulation (EC) No 1565/2000.
The present revision of FGE.220, FGE.220Rev1, concerns the evaluation of additional data submitted
by Industry in response to the requested genotoxicity data in FGE.220 on the representative substance
for subgroup 4.4b, 4-hydroxy-2,5-dimethylfuran-3(2H)-one [FL-no: 13.010].
Flavouring Group Evaluation 220 (FGE.220) concerns 10 substances, corresponding to subgroup 4.4
of FGE.19. The 10 substances are alpha,beta-unsaturated 3(2H)-furanones [FL-no: 13.010, 13.084,
13.085, 13.089, 13.099, 13.117, 13.119, 13.157, 13.175 and 13.176]. The substances were further
subdivided into two subgroups as five of the 10 substances can only exist as alpha,beta-unsaturated ketones (subgroup 4.4a) while in the other five substances the alpha,beta double bond can be involved
in keto-enol tautomerism (subgroup 4.4b).
For the substances in subgroup 4.4a [FL-no: 13.089, 13.117, 13.119, 13.157 and 13.175], the previous
conclusions of the Panel in FGE.220 were that the available data on genotoxicity were too limited to
evaluate these substances through the Procedure. Additional studies were needed as outlined in the
Genotoxicity Test Strategy for Substances belonging to Subgroups of FGE.19 (EFSA, 2008bb).
For the substances in subgroup 4.4b [FL-no: 13.010, 13.084, 13.085, 13.099 and 13.176], the Panel
had in FGE.220 expressed the view that evidence for genotoxicity was available both in vitro and in
vivo. Evidence from in vitro studies indicated that the genotoxicity of the candidate substances in this
subgroup may be caused by indirect (thresholded) mechanisms of action (in particular generation of
reactive oxygen species). The concern for carcinogenicity was alleviated, since one of the substances,
for which positive genotoxicity data in mice were obtained, was not carcinogenic in a valid chronic
assay in rats. Therefore, no further genotoxicity tests in somatic cells were required. However, some
evidence was also available that this substance might elicit genotoxic effects in germ cells, which
theoretically may result in reduced reproductive capacity or in inheritable genetic damage. Reduced
reproductive capacity and inheritable genetic damage are toxicological endpoints which differ from
carcinogenicity and therefore, the negative results for the carcinogenicity study could not be used to
overrule this concern. It is not clear if (and if so to what extent) the thresholded mechanism mentioned
above would be relevant for genotoxic effects in the germ cells. Therefore, the Panel conclusions of
the previous evaluation in FGE.220 were that these five substances could not be evaluated through the
The Panel recognised that the studies which provided indications for germ cell genotoxicity were of
limited validity. For this reason a robust GLP-controlled cytogenetic investigation in mouse
spermatocytes according to the OECD guideline 483 was requested.
In March 2009 the Flavouring Industry submitted new data in reply to the above requested data for
subgroup 4.4b of FGE.220. These data have now been examined by the Panel which has concluded the
following. The results of a valid rat fertility and dominant lethal study have shown that the
representative substance for subgroup 4.4b, 4-hydroxy-2,5-dimethylfuran-3(2H)-one [FL-no: 13.010],
is unable to induce adverse effects both on male rat reproductive capacity and dominant lethality. On
this basis, the Panel concludes that there is no concern for this substance to induce heritable genetic
damage or adverse effects on male reproductive capacity. Accordingly the substances in subgroup
4.4b of FGE.19 [FL-no: 13.010, 13.084, 13.085, 13.099 and 13.176] can be evaluated using the
Since no data were submitted to further evaluate the genotoxic potential of the substances in subgroup
4.4a, the Panel maintains its position that for this subgroup additional data on genotoxicity are needed.
© European Food Safety Authority, 2011