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

Opinion of the Scientific Panel.

Flavouring Group Evaluation 21: Thiazoles, thiophene, thiazoline and thienyl derivatives from chemical group 29. Miscellaneous substances from chemical group 30. (Commission Regulation (EC) No 1565/2000 of 18 July 2000)

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

EFSA: Scientific opinion of the Scientific Panel.

Flavouring Group Evaluation 3, Revision 1 (FGE.03Rev1): Acetals of branched- and straight-chain aliphatic saturated primary alcohols and branched- and straight-chain saturated or unsaturated aldehydes, an ester of a hemiacetal and an orthoester of formic acid, from chemical groups 1, 2 & 4 (Commission Regulation (EC) No 1565/2000 of 18 July 2000)[1]

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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 Scientific Panel is asked to evaluate 58 flavouring substances in the Flavouring Group
Evaluation, Revision 1 (FGE.03Rev1), using the procedure as referred to in the Commission Regulation (EC) No 1565/2000. These 58 flavouring substances belong to chemical groups 1, 2 and 4 of
Annex I of the Commission Regulation (EC) No 1565/2000.

The present Flavouring Group Evaluation deals with 56 acetals of branched- and straight-chain aliphatic saturated primary alcohols and branched- and straight-chain saturated or unsaturated
aldehydes, one orthoester of formic acid and one ester of a hemiacetal.
Thirty-two of the 58 flavouring substances possess one or more chiral centres. For 30 of these substances the stereoisomeric composition has not been specified.

One of the 58 substances can exist as a geometrical isomer [FL-no: 06.063] and no indication has been given that one of the possible isomers has preponderance in the commercial flavouring
material. Fifty-seven of the flavouring substances are classified into structural class I and the orthoester [FL-no: 06.096] into structural class III.
Fifty-one of the substances in the present group of 58 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 Panel requires more precise data on use and use levels.
According to the default MSDI approach, the 57 flavouring substances have intakes in Europe from 0.001 to 14 microgram/capita/day, which are below the threshold of concern value for structural
class I of 1800 microgram/person/day. Likewise the estimated level of intake for the orthoester [FL-no: 06.096] of 0.013 microgram/capita/day is below the threshold of concern for structural
class III of 90 microgram/person/day.
Adequately reported genotoxicity studies are only available for one of the flavouring substances. These studies do not give rise to safety concern with respect to genotoxicity of the flavouring
substance in this Flavouring Group Evaluation. Consideration was given to methanol, formaldehyde, ethanol, and acetaldehyde that are potential hydrolysis products of several of the acetals in
the present Flavouring Group Evaluation. Because of the natural occurrence in food and the endogenous formation in humans of considerably larger amounts of these compounds, their formation from
hydrolysis of the acetals were not considered to be of safety concern with respect to genotoxicity at their estimated levels of intakes, based on the MSDI approach.
The 58 candidate substances are expected to be metabolised to innocuous products.
There are no toxicological studies available on the 58 flavouring substances or on structurally related acetals other than data on acute toxicity.
On the basis of the default MSDI approach the Panel concluded that the 56 acetals, the orthoester and the ester of a hemiacetal would not give rise to safety concerns at levels of intake
arising from their use as flavouring substances.
When the estimated intakes were based on the mTAMDI approach they ranged from 3 to 4900 microgram/person/day for the 57 substances from structural class I. For 15 of the substances the intakes
were above the threshold of concern for structural class I of 1800 microgram/person/day. For the one substance from structural class III [FL-no: 06.096] the mTAMDI is 1600 microgram/person/day,
which is above the threshold of concern for structural class III of 90 microgram/person/day.

Thus, for 16 of the 58 flavouring substances considered in this opinion, the intakes, estimated on the basis of the mTAMDI, exceed the relevant threshold for their structural class to which the
flavouring substance has been assigned. Therefore, for these 16 substances more reliable exposure data are required. On the basis of such additional data, these flavouring substances should be
reconsidered using the Procedure. Subsequently, additional data might become necessary.

In order to determine whether this evaluation could 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 41 of the 58 flavouring substances, except that information on
geometrical isomerism/chirality is missing for 31 substances. The specifications are not adequate for 17 substances [FL-no: 03.023, 06.041, 06.042, 06.043, 06.045, 06.046, 06.047, 06.063,
06.105, 06.106, 06.107, 06.109, 06.115, 06.123, 06.124, 06.128, 06.129].

Thus, the final evaluation of the materials of commerce cannot be performed for 34 substances ([FL-no: 03.023, 06.041, 06.042, 06.043, 06.044, 06.045, 06.046, 06.047, 06.048, 06.049, 06.050,
06.063, 06.079, 06.082, 06.083, 06.084, 06.085, 06.086, 06.091, 06.092, 06.105, 06.106, 06.107, 06.109, 06.111, 06.114, 06.115, 06.123, 06.124, 06.127, 06.128, 06.129, 06.130, 06.131], pending
further information. The remaining 24 substances [FL-no: 06.051, 06.052, 06.053, 06.054, 06.055, 06.057, 06.058, 06.059, 06.061, 06.062, 06.064, 06.065, 06.066, 06.067, 06.069, 06.070, 06.071,
06.073, 06.074, 06.075, 06.076, 06.096, 06.100 and 06.125] would present no safety concern at the levels of intake estimated on the basis of the MSDI approach.

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

Opinion of the Scientific Panel.

Request related to a 17th list of substances for food contact materials

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Within the general task of evaluating substances intended for use in materials in contact with food according to the Regulation (EC) No.1935/2004 of the European Parliament and of the Council
of 27 October 2004 on materials and articles intended to come into contact with foodstuffs, the AFC Panel evaluated the following substances:

Opinion

Summary

Scientific panel members – Fernando Aguilar, Herman Autrup, Sue Barlow, Laurence Castle, Riccardo Crebelli, Wolfgang Dekant, Karl-Heinz Engel, Nathalie Gontard, David Gott,
Sandro Grilli*, Rainer Gürtler, John Christian Larsen, Jean-Charles Leblanc, Catherine Leclercq, François Xavier Malcata, Wim Mennes, Maria Rosaria Milana, Iona Pratt, Ivonne
Rietjens, Paul Tobback, Fidel Toldrá.

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