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Scientific Opinion on Flavouring Group Evaluation 8, Revision 3 (FGE.08Rev3): Aliphatic and alicyclic mono-, di-, tri-, and polysulphides with or without additional oxygenated functional groups from chemical groups 20 and 30

EFSA Journal 2011;9(5):1988 [131 pp.]. doi:10.2903/j.efsa.2011.1988
  EFSA Panel on Food Contact Materials, Enzymes, Flavourings and Processing Aids (CEF) Panel Members Arturo Anadon, Mona-Lise Binderup, Wilfried Bursch, Laurence Castle, Riccardo Crebelli, Karl-Heinz Engel, Roland Franz, Nathalie Gontard, Thomas Haertle, Trine Husøy, Klaus-Dieter Jany, Catherine Leclercq, Jean Claude Lhuguenot, Wim Mennes, Maria Rosaria Milana, Karla Pfaff, Kettil Svensson, Fidel Toldra, Rosemary Waring, Detlef Wölfle Acknowledgment The Panel wishes to thank the members of the Working Groups on Flavourings for the preparation of this Opinion: Ulla Beckman Sundh, Vibe Beltoft, Wilfried Bursch, Angelo Carere, Karl-Heinz Engel, Henrik Frandsen, Rainer Gürtler, Frances Hill, Trine Husøy, John Christian Larsen, Pia Lund, Wim Mennes, Gerard Mulder, Karin Nørby, Gerard Pascal, Iona Pratt, Gerrit Speijers, Harriet Wallin and EFSA’s staff member Kim Rygaard Nielsen for the preparatory work on this scientific Opinion. Contact cef-unit@efsa.europa.eu
Type: Opinion of the Scientific Committee/Scientific Panel On request from: European Commission Question number: EFSA-Q-2011-0038 , EFSA-Q-2011-0039 , EFSA-Q-2011-0040 Adopted: 04 February 2011 Published: 11 May 2011 Affiliation: European Food Safety Authority (EFSA), Parma, Italy
Abstract

The Panel on Food Contact Materials, Enzymes, Flavourings and Processing Aids of the European Food Safety Authority was requested to evaluate 70 flavouring substances in the Flavouring Group Evaluation 08, Revision 3, using the Procedure in Commission Regulation (EC) No 1565/2000. For the substances 2-methylpropane-2-thiol [FL-no: 12.174], methyl methanethiosulphonate [FL-no: 12.159], 2-methylbutane-2-thiol [FL-no: 12.172] and 2,4,4-trimethyl-1,3-oxathiane [FL-no: 16.057] there is an indication of a genotoxic potential in vitro. Therefore, in the absence of further genotoxicity data, the Panel concluded that the Procedure could not be applied to these four substances. For four substances, 3-mercaptooctanal [FL-no: 12.268], 3-mercaptodecanal [FL-no: 12.269], methanedithiol diacetate [FL-no: 12.271] and 3,5-dimethyl-1,2-dithiolane-4-one [FL-no: 12.295] no data on use as flavouring substances in Europe are available. Therefore, no intakes in Europe can be estimated and accordingly the Panel concluded that the Procedure could not be applied to these four substances either. The remaining 62 substances were evaluated through a stepwise approach that integrates information on structure-activity relationships, intake from current uses, toxicological threshold of concern, and available data on metabolism and toxicity. The Panel concluded that 48 substances do not give rise to safety concerns at their levels of dietary intake, estimated on the basis of the MSDI approach. For the remaining fourteen substances [FL-no: 12.120, 12.093, 12.094, 12.097, 12.100, 12.112, 12.116, 12.164, 12.167, 12.199, 15.007, 15.102 and 15.125 and 15.134] evaluated through the Procedure, no appropriate NOAEL was available and additional data are required. Besides the safety assessment of these flavouring substances, the specifications for the materials of commerce have also been considered and for eightteen substances information on specifications is lacking.

© European Food Safety Authority, 2011

Summary

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 requested to evaluate 70 flavouring substances in the Flavouring Group Evaluation 8, Revision 3 (FGE.08Rev3), using the Procedure as referred to in the Commission Regulation (EC) No 1565/2000. These 70 flavouring substances belong to chemical groups 20 and 30, Annex I of the Commission Regulation (EC) No 1565/2000.

The present Flavouring Group Evaluation (FGE) deals with 70 straight or branched chain or heterogeneous ring aliphatic hydrocarbons containing one or more sulphur atoms. The sulphur-containing functional groups are present as thiols, sulphides or sulphones. Based on their structures, the candidate substances can be subdivided into 11 subgroups.

Twenty-two of the 70 flavouring substances possess one or more chiral centres [FL-no: 12.104, 12.106, 12.120, 12.135, 12.177, 12.178, 12.180, 12.182, 12.214, 12.250, 12.266, 12.268, 12.269, 12.278, 12.295, 15.007, 15.047, 15.048, 15.083, 15.134, 16.057 and 16.114]. The stereoisomeric composition has not been specified sufficiently for nine of these 22 substances [FL-no: 12.120, 12.250, 12.266, 12.268, 12.269, 12.278, 15.007, 15.134 and 16.114]. Six of the 70 substances can exist as geometrical isomers [FL-no: 12.098, 12.163, 12.164, 12.298, 15.056 and 15.110]. Industry has informed that these substances occurs as mixtures of geometrical isomers, however, the composition of the mixtures have not been specified sufficiently, as the actual ratio has to be given.

Composition of mixtures should be clarified for [FL-no: 12.298 and 15.007].

Forty-four of the candidate substances belong to structural class I, 19 belong to structural class II and six belong to structural class III.

Forty-five of the flavouring substances in the present group have been reported to occur naturally in a wide range of food items.

According to the default MSDI approach, the 66 of the 70 flavouring substances for which Flavour Industry have submitted data, have intakes in Europe ranging from 0.0012 to 6.1 microgram/capita/day, which are below the threshold of concern value for structural class I (1800 microgram/person/day), structural class II (540 microgram/person/day) and structural class III (90 microgram/person/day) substances.

On the basis of the reported annual production volumes in Europe (MSDI approach), the combined intake of the 39 of 44 candidate substances belonging to class I for which data were submitted and the substance evaluated through the Procedure, the 17 of the 19 candidate substances belonging to class II for which data were submitted and the substance evaluated through the Procedure, and the six of seven candidate substances belonging to class III and evaluated through the Procedure, would result in total intakes of approximately 11, 6 and 16, respectively, which do not exceed the thresholds of concern. Based on reported production volumes, European per capita intakes (MSDI) could be estimated for 68 of the 127 supporting substances. The total combined intakes of the candidate and supporting substances (for which there are European intake data) are approximately 648, 115 and 16 microgram/capita/day for structural class I, II and III, respectively, which do not exceed the thresholds of concern for structural class I, II or III of 1800, 540 or 90 microgram/person/day, respectively.

Data on genotoxicity of the candidate substances are limited and the genotoxicity could not be adequately assessed. The data available, however, give rise to some concern of a genotoxic potential of two of the candidate substances 2-methylpropane-2-thiol [FL-no: 12.174] and methyl methanethiosulphonate [FL-no: 12.159]. The Panel, therefore, concluded that the Procedure could not be applied to these two substances, nor to the two to [FL-no: 12.174] structurally related candidate substances, 2-methylbutane-2-thiol [FL-no: 12.172] and 2,4,4-trimethyl-1,3-oxathiane [FL-no: 16.057] until adequate in vivo genotoxicity data become available. The Panel noted that in FGE.08 five of the supporting substances were tertiary thiols [FL-no: 12.038, 12.085, 12.137, 12.138 and 12.145] for which a concern for genotoxicity has been raised in FGE.08Rev1. These supporting substances have been evaluated by the JECFA at the 53rd meeting and are not scheduled for evaluation by EFSA. However, these substances should be considered by Panel based on the outcome of the evaluation of the two candidate substances being tertiary thiols [FL-no: 12.172 and 12.174].

The genotoxicity data available for the remaining candidate substances do not preclude their evaluation through the Procedure.

For three substances in structural class I, 3-mercaptooctanal, 3-mercaptodecanal, methanedithiol diacetate [FL-no: 12.268, 12.269 and 12.271] and for one substance, 3,5-dimethyl-1,2-dithiolane-4-one in structural class II [FL-no: 12.295] no data on use as flavouring substances in Europe are available, therefore no intakes can be estimated and accordingly these substances can not be evaluated through the procedure.

The candidate substances and supporting substances are expected to share common routes of absorption, distribution and metabolism, and exhibit similar toxicological properties. These metabolic pathways are unlikely to be saturated, given the low levels of exposure from their use as flavouring substances. However, due to the reactivity of the metabolites, the candidate substances cannot be predicted to be metabolised to innocuous products.

Except for subgroups II [FL-no: 12.120, 15.102 and 15.125], VI [FL-no: 12.093, 12.094, 12.097, 12.100, 12.112, 12.116, 12.164 and 12.167], IX [FL-no: 12.199] and XI [FL-no: 15.007] and one candidate substance in subgroup VII [FL-no: 15.134], adequate repeated-dose toxicity studies are available for supporting substances from the different subgroups, allowing derivation of adequate margins of safety by comparing the NOAEL values with the MSDI.

It is considered that on the basis of the default MSDI approach the 48 of the 62 candidate substances evaluated through the Procedure would not give rise to safety concerns at the estimated levels of intake arising from their use as flavouring substances. Additional toxicity data are required for the three candidate substances in subgroup II [FL-no: 12.120, 15.102 and 15.125], for the eight candidate substances in subgroup VI [FL-no: 12.093, 12.094, 12.097, 12.100, 12.112, 12.116, 12.164 and 12.167], for one candidate substance in subgroup VII [FL-no: 15.134], for the candidate substance in subgroup IX [FL-no: 12.199] and for the candidate substance in subgroup XI [FL-no: 15.007].

Additional in vivo data on genotoxicity are required for candidate substances 2-methylpropane-2-thiol [FL-no: 12.174], methyl methanethiosulphonate [FL-no: 12.159], 2-methylbutane-2-thiol [FL-no: 12.172] and 2,4,4-trimethyl-1,3-oxathiane [FL-no: 16.057].

When the estimated intakes were based on the mTAMDI they ranged from 28 to 8000 microgram/person/day for the 39 of the 44 candidate substances from structural class I for which intake data have been submitted and the substances have been evaluated through the Procedure. These intakes were below the threshold of concern for structural I of 1800 microgram/person/day, except for two candidate substances [FL-no: 12.250 and 12.282]. The estimated intakes for the 16 of the 19 candidate substances assigned to structural class II for which intake data have been submitted and the substances evaluated through the Procedure, based on the mTAMDI, ranged from 46 to 78 microgram/person/day, which are below the threshold of concern for structural class II of 540 microgram/person/day. The estimated intakes for the five candidate substances assigned to structural class III and evaluated through the Procedure, based on the mTAMDI, are in the range of 78 to 500 microgram/person/day. For one of the substances [FL-no: 15.081] the mTAMDI is below the threshold of concern of 90 microgram/person/day. The 54 candidate substances which have mTAMDI intake estimates below the threshold of concern for structural class I, II and III, are also expected to be metabolised to innocuous products.

For the six flavouring substances [FL-no: 12.120, 12.136, 12.250, 12.282, 15.134 and 16.114] evaluated through the Procedure, for which the intakes, estimated on the basis of the mTAMDI, exceed the relevant threshold for their structural class more reliable exposure data are required, as well as for the substances for which use levels have not been provided. On the basis of such additional data, these flavouring substances should be re-evaluated using the Procedure. Subsequently, additional toxicological data might become necessary.

In order to determine whether the conclusion for the 62 candidate substances evaluated through the Procedure can be applied to the material of commerce, it is necessary to consider the available specifications. Specifications including complete purity criteria and identity for the materials of commerce have been provided for 68 of the 70 candidate substances. For two substances [FL-no: 12.266 and 15.125] have specifications not been provided. Information on chirality has not been specified sufficiently for nine of the substances [FL-no: 12.120, 12.250, 12.266, 12.268, 12.269, 12.278, 15.007, 15.134 and 16.114] and composition of the mixture of the geometrical isomers is lacking for six of the substances [FL-no: 12.098, 12.163, 12.164, 12.298, 15.056 and 15.110], and composition of mixture should be clarified for [FL-no: 12.298 and 15.007]. For four substances is an identity test missing [FL-no: 12.268, 12.269, 12.271 and 12.282]. Additional toxicity data are required for the three candidate substances in subgroup II [FL-no: 12.120, 15.102 and 15.125], for the eight candidate substances in subgroup VI [FL-no: 12.093, 12.094, 12.097, 12.100, 12.112, 12.116, 12.164 and 12.167], for one candidate substance in subgroup VII [FL-no: 15.134], for the candidate substance in subgroup IX [FL-no: 12.199] and the candidate substance in subgroup XI [FL-no: 15.007].. Additional in vivo data on genotoxicity are required for candidate substances 2-methylpropane-2-thiol [FL-no: 12.174], methyl methanethiosulphonate [FL-no: 12.159], 2-methylbutane-2-thiol [FL-no: 12.172] and 2,4,4-trimethyl-1,3-oxathiane [FL-no: 16.057]. For four substances, 3-mercaptooctanal [FL-no: 12.268], 3-mercaptodecanal [FL-no: 12.269], methanedithiol diacetate [FL-no: 12.271] and 3,5-dimethyl-1,2-dithiolane-4-one [FL-no: 12.295] data on use as flavouring substances in Europe are required.

Thus, the final evaluation of the materials of commerce cannot be performed for 32 of the 70 substances [FL-no: 12.093, 12.094, 12.097, 12.098, 12.100, 12.112, 12.116, 12.120, 12.159, 12.163, 12.164, 12.167, 12.172, 12.174, 12.199, 12.250, 12.266, 12.268, 12.269, 12.271, 12.278, 12.282, 12.295, 12.298, 15.007, 15.056, 15.102, 15.110, 15.125, 15.134, 16.057 and 16.114], pending further information.

The remaining 38 flavouring substances evaluated through the Procedure [FL-no: 12.096, 12.099, 12.103, 12.104, 12.106, 12.111, 12.117, 12.124, 12.125, 12.127, 12.129, 12.135, 12.136, 12.151, 12.152, 12.158, 12.165, 12.166, 12.177, 12.178, 12.180, 12.181, 12.182, 12.183, 12.189, 12.191, 12.196, 12.200, 12.205, 12.214, 12.221, 12.277, 15.047, 15.048, 15.081, 15.083, 15.103 and 15.111] would present no safety concern at the levels of intake estimated on the basis of the MSDI approach.

Keywords

Flavourings, safety, aliphatic, alicyclic, monosulphides, disulphides, trisulphides, polysulphides, FGE.08