Food additives, flavourings, processing aids and materials in contact with food (AFC)

The Scientific Panel on Food Additives, Flavourings, Processing Aids and Materials in Contact with Food (the Panel) is asked to advise 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 is asked to evaluate 54 flavouring substances in the Flavouring Group Evaluation 21 (FGE.21), using the procedure as referred to in the Commission Regulation (EC) No
1565/2000. These 54 flavouring substances belong to chemical groups 29 and 30 of Annex I of the Commission Regulation (EC) No 1565/2000.

The present Flavouring Group Evaluation deals with 54 candidate substances from chemical groups 29 and 30, falling into the main chemical groups of thiazoles (S- and N- containing), thiazoline
(S- and N- containing) and thienyl derivatives (S-containing), and thiophene itself (S-containing).
The 54 substances in this group are divided into ten subgroups based on the nature of the ring (aromatic (clustered in subgroups A-Ia,b,c to A-III) vs. non-aromatic (clustered in subgroups B-I
to B-V)), type and number of ring heteroatoms (sulphur or sulphur with nitrogen), and the degree of saturation in the non-aromatic rings.
Five of the 54 flavouring substances possess a chiral centre and three flavouring substances possess three chiral centres. For these eight substances the stereoisomeric composition has not been
specified.
Forty-five of the flavouring substances are classified into structural class II and nine into structural class III.
Forty-two of the substances have been reported to occur naturally in a wide range of food items.
In its evaluation, the Panel as a default used the Maximised Survey-derived Daily Intakes (MSDIs) approach to estimate the per capita intakes of the flavouring substances in Europe. However,
when the Panel examined the information provided by the European Flavouring Industry on the use levels in various foods, it appeared obvious that the MSDI approach in a number of cases would
grossly underestimate the intake by regular consumers of products flavoured at the use level reported by the Industry, especially in those cases where the annual production values were reported
to be small. In consequence, the Panel had reservations about the data on use and use levels provided and the intake estimates obtained by the MSDI approach.
In the absence of more precise information that would enable the Panel to make a more realistic estimate of the intakes of the flavouring substances, the Panel has decided also to perform an
estimate of the daily intakes per person using a modified Theoretical Added Maximum Daily Intake (mTAMDI) approach based on the normal use levels reported by Industry. In those cases where the
mTAMDI approach indicated that the intake of a flavouring substance might exceed its corresponding threshold of concern, the Panel decided not to carry out a formal safety assessment using the
Procedure. In these cases the Scientific Panel requires more precise data on use and use levels.
According to the default MSDI approach, the 54 flavouring substances in this group have intakes in Europe from 0.0012 to 2.2 microgram/capita/day, which are well below the threshold of concern
value for structural class II (540 microgram/person/day) and structural class III (90 microgram/person/day) substances.

The data available for 2-methylthiazolidine [FL-no: 15.090] and 2-propylthiazolidine [FL-no: 15.099] (subgroup B-III: thiazolidines) raise the possibility of a genotoxic potential in vitro.
Therefore, the Panel decided that the Procedure should neither be applied to these two flavouring substances nor to the three structurally related substances 2-methyl-2-thiazoline [FL-no:
15.086], 2,4-dimethyl-3-thiazoline [FL-no: 15.060] and 2-isobutyl-3-thiazoline [FL-no: 15.119] (subgroup B-II: thiazolines) until adequate in vivo genotoxicity data become available.
The metabolic data on the flavouring substances in the present flavouring group evaluation were insufficient to allow conclusions about their metabolic fate, and accordingly the 49 flavouring
substances evaluated using the Procedure cannot be anticipated to be metabolised to innocuous products. However, the Panel concluded that the evidence of binding to macromolecules from possible
formation of electrophilic metabolites, (e.g. by either ring scission or S-oxidation), was not sufficiently strong to preclude the application of the Procedure.
Toxicological data both on the flavouring substances and on structurally related substances were limited and did not include any information about their chronic or reproductive toxicity, or
their carcinogenicity. Valid toxicological data providing a NOAEL which, when compared to the intake from use as flavouring substances, indicate an adequate margin of safety were only available
for 26 flavouring substances in subgroup A-Ic (thiophenes with thiol-containing ring substituents) and subgroup A-II (thiazoles).

For the remaining 23 flavouring substances belonging to the subgroups A-Ia (thiophene), A-Ib (thiophenes with non-thiol-containing ring substituents), A-III (benzothiazoles), B-I
(dihydrothiophenes), B-IV (dithiazines) and B-V (dihydrothiazines) the Panel considered that there were insufficient data available to provide a margin of safety from their use as flavouring
substances and that additional toxicity data are needed.
When the estimated intakes were based on the mTAMDI approach they ranged from 74 to 210 microgram/capita/day for the 45 flavouring substances from structural class II. Thus, the intakes are
below the threshold of concern for structural class II of 540 microgram/person/day. For the nine flavouring substances from structural class III the estimated intakes based on the mTAMDI
approach ranged from 74 to 150 microgram/capita/day. The intakes for four of these nine flavouring substances are above the threshold of concern for structural class III of 90
microgram/person/day.
Thus, for four of the 49 flavouring substances considered in this opinion the intakes, estimated on the basis of the mTAMDI, exceed the relevant threshold for the structural class to which the
flavouring substances have been assigned. Therefore, for these flavouring substances more reliable exposure data are required. On the basis of such additional data, these flavouring substances
should be reconsidered along the steps of the procedure. Following this procedure additional toxicological data might become necessary.

In order to determine whether the conclusion for the 49 flavouring substances which have been evaluated using the Procedure can be applied to the materials of commerce, it is necessary to
consider the available specifications.
Adequate specifications including complete purity criteria and identity tests for the materials of commerce have been provided for all 49 flavouring substances, except that information on
chirality is missing for eight substances. Thus, the final evaluation of the materials of commerce cannot be performed for these eight substances [FL-no: 15.042, 15.054, 15.055, 15.060, 15.077,
15.090, 15.099 and 15.119], pending further information.
In conclusion, for 23 flavouring substances [FL-no: 15.037, 15.040, 15.042, 15.043, 15.045, 15.054, 15.055, 15.064, 15.070, 15.072, 15.074, 15.076, 15.077, 15.088, 15.091, 15.092, 15.093,
15.094, 15.096, 15.097, 15.106, 15.107 and 15.114] the Panel considered that additional toxicity data are needed and for eight substances [FL-no: 15.042, 15.054, 15.055, 15.060, 15.077, 15.090,
15.099 and 15.119] information on chirality is missing. For the remaining 26 flavouring substances the Panel considered there were valid toxicological data providing adequate margins of safety
compared to the intakes from use as flavouring substances. Therefore, the following 26 flavouring substances evaluated using the Procedure would present no safety concern at their estimated
levels of intake estimated on the basis of the MSDI approach: [FL-no: 15.038, 15.039, 15.044, 15.050, 15.051, 15.052, 15.058, 15.061, 15.062, 15.063, 15.067, 15.068, 15.069, 15.071, 15.078,
15.080, 15.082, 15.084, 15.085, 15.087, 15.089, 15.098, 15.108, 15.115, 15.116 and 15.118].

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