Flavouring group evaluation 419 (FGE.419): 2-methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one.

The EFSA Panel on Food Additives and Flavourings (FAF) was requested to evaluate the safety of 2-methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one [FL-no: 16.134] as a new flavouring substance, in accordance with Regulation (EC) No 1331/2008. The substance has not been reported to occur naturally and is chemically synthesised. In food, it is intended to be used as a flavouring substance only in chewing gum. The chronic dietary exposure to [FL-no: 16.134] was estimated to be 45 µg/person per day for a 60-kg adult and 28.4 µg/person per day for a 15-kg 3-year-old child. [FL-no: 16.134] did not show genotoxicity in a bacterial reverse mutation test and an in vitro mammalian cell micronucleus assay. Based on the submitted toxicokinetic and metabolism data, it can be predicted that the flavouring substance is metabolised to innocuous products only. The Panel derived a lower confidence limit of the benchmark dose (BMDL) of 0.71 mg/kg bw per day for a 20% increase in the relative thyroid (including parathyroid) weight observed in a 90-day toxicity study in rats. Based on this BMDL, adequate margins of exposure of 887 and 374 could be calculated for adults and children, respectively. The Panel concluded that there is no safety concern for [FL-no: 16.134], when used as a flavouring substance at the estimated level of dietary exposure, based on the intended use and use levels as specified in Appendix B. The Panel further concluded that the combined exposure to [FL-no: 16.134] from its use as a food flavouring substance and from its presence in toothpaste and mouthwash is also not of safety concern.

Flavouring Group Evaluation 413 (FGE.413): Naringenin.

The EFSA Panel on Food Additives and Flavourings (FAF) was requested to evaluate the safety of naringenin [FL-no: 16.132] as a new flavouring substance, in accordance with Regulation (EC) No 1331/2008. No other substances with sufficient structural similarity have been identified in existing FGEs that could be used to support a read-across approach. The information provided on the manufacturing process, the composition and the stability of [FL-no: 16.132] was considered sufficient. From studies carried out with naringenin, the Panel concluded that there is no concern with respect to genotoxicity. The use of naringenin as a flavouring substance at added portions exposure technique (APET) exposure levels is unlikely to pose a risk for drug interaction. For the toxicological evaluation of naringenin, the Panel requested an extended one-generation toxicity study on naringenin, in line with the requirements of the Procedure and to investigate the consequence of a possible endocrine-disrupting activity. The Panel considered that changes in thymus weight, litter size, post-implantation loss and a consistent reduced pup weight in the high-dose F2 generation could not be dismissed and selected therefore, the mid-dose of 1320 mg/kg body weight (bw) per day for the parental males as the no observed adverse effect level (NOAEL) of the study. The exposure estimates for [FL-no: 16.132] (31,500 and 50,000 µg/person per day for children and adults, respectively) were above the threshold of toxicological of concern (TTC) for its structural class (III). Using the NOAEL of 1320 mg/kg bw per day at step A4 of the procedure, margins of exposure (MoE) of 1590 and 630 could be calculated for adults and children, respectively. Based on the calculated MoEs, the Panel concluded that the use of naringenin as a flavouring substance does not raise a safety concern.

Flavouring Group Evaluation 21 Revision 6 (FGE.21Rev6): thiazoles, thiophenes, thiazoline and thienyl derivatives from chemical groups 29 and 30.

The Panel on Food additives and Flavourings (FAF) was requested to evaluate the flavouring substances 2,4-dimethyl-3-thiazoline [FL-no: 15.060] and 2-isobutyl-3-thiazoline [FL-no: 15.119] in Flavouring Group Evaluation 21 revision 6 (FGE.21Rev6). FGE.21Rev6 deals with 41 flavouring substances of which 39 have been already evaluated to be of no safety concern when based on the MSDI approach. For [FL-no: 15.060 and 15.119], a concern for genotoxicity was raised in FGE.21. Genotoxicity data have been submitted for the supporting substance 4,5-dimethyl-2-isobutyl-3-thiazoline [FL-no: 15.032] evaluated in FGE.76Rev2. The concerns for gene mutations and clastogenicity are ruled out for [FL-no: 15.032] and for the structurally related substances [FL-no: 15.060 and 15.119], but not for aneugenicity. Therefore, the aneugenic potential of [FL-no: 15.060 and 15.119] should be investigated in studies with the individual substances. For [FL-no: 15.054, 15.055, 15.057, 15.079 and 15.135], (more reliable) information on uses and use levels is needed to (re)calculate the mTAMDIs in order to finalise their evaluation. Provided that information is submitted for [FL-no: 15.060 and 15.119] with respect to potential aneugenicity, that would allow evaluation of these substances through the Procedure, also for these two substances, more reliable data on uses and use levels would be required. Upon submission of such data, additional data on toxicity may become necessary for all seven substances. For [FL-no: 15.054, 15.057, 15.079 and 15.135], information on the actual percentages of stereoisomers in the material of commerce based on analytical data should be provided.

Protocol for designing INVITES-IN, a tool for assessing the internal validity of in vitro studies.

This protocol describes the design and development of a tool for evaluation of the internal validity of in vitro studies, which is needed to include the data as evidence in systematic reviews and chemical risk assessments. The tool will be designed specifically to be applied to cell culture studies, including, but not restricted to, studies meeting the new approach methodology (NAM) definition. The tool is called INVITES-IN (IN VITro Experimental Studies INternal validity). In this protocol, three of the four studies that will be performed to create the release version of INVITES-IN are described. In the first study, evaluation of existing assessment tools will be combined with focus group discussions to identify how characteristics of the design or conduct of an in vitro study can affect its internal validity. Bias domains and items considered to be of relevance for in vitro studies will be identified. In the second study, group agreement on internal validity domains and items of importance for in vitro studies will be identified via a modified Delphi methodology. In the third study, the draft version of the tool will be created, based on the data on relevance and importance of bias domains and items collected in Studies 1 and 2. A separate protocol will be prepared for the fourth study, which includes the user testing and validation of the tool, and collection of users' experience.

Scientific opinion on Flavouring group evaluation 216 revision 2 (FGE.216Rev2): consideration of the genotoxicity potential of α,ß-unsaturated 2-phenyl-2-alkenals from subgroup 3.3 of FGE.19.

The EFSA Panel on Food Additives and Flavourings (FAF) was requested to evaluate the genotoxic potential of five flavouring substances from subgroup 3.3 of FGE.19, in the Flavouring Group Evaluation 216 (FGE.216). In FGE.216 and in FGE.216Rev1, the CEF Panel requested additional genotoxicity data on 2-phenylcrotonaldehyde [FL-no: 05.062], the representative for these five substances. New experimental data on [FL-no: 05.062] were provided and are evaluated in the present revision of FGE.216 (FGE.216Rev2). Based on the new data, the Panel concluded that, for all the five substances, the concerns for gene mutations and clastogenicity are ruled out by the negative results observed in an in vivo gene mutation assay and in an in vivo comet assay, respectively. In vitro, [FL-no: 05.062] induced micronuclei through an aneugenic mode of action. The available in vivo micronucleus studies were inconclusive and cannot be used to rule out potential aneugenicity of [FL-no: 05.062] in vivo. Therefore, the Panel compared the lowest concentration resulting in aneugenicity in vitro with the use levels reported for this substance. Based on this comparison, the Panel concluded that the use of the flavouring substance [FL-no: 05.062] at the reported use levels in several food categories would raise a concern for aneugenicity. Based on structural similarity, for the remaining four substances in this FGE [FL-no: 05.099, 05.100, 05.175 and 05.222], an aneugenic potential may also be anticipated. For these four substances, individual data are needed to establish whether they have aneugenic potential. Accordingly, it is currently not appropriate to assess any of these five substances through the Procedure for the evaluation of flavouring substances.

Scientific opinion on flavouring group evaluation 415 (FGE.415): (E)-3-benzo[1,3]dioxol-5-yl-N,N-diphenyl-2-propenamide.

The EFSA Panel on Food Additives and Flavourings (FAF) was requested to evaluate the safety of the substance (E)-3-benzo[1,3]dioxol-5-yl-N,N-diphenyl-2-propenamide [FL-no: 16.135] as a new flavouring substance, in accordance with Regulation (EC) No 1331/2008. The substance has not been reported to occur naturally and it is chemically synthesised. It is intended to be used as a flavouring substance in specific categories of food, but not intended to be used in beverages. The chronic dietary exposure to [FL-no: 16.135] estimated using the added portions exposure technique (APET), is calculated to be 780 µg/person per day for a 60-kg adult and 480 µg/person per day for a 15-kg 3-year-old child. [FL-no: 16.135] did not show genotoxic effects in bacterial mutagenicity and mammalian cell micronucleus assays in vitro. Developmental toxicity was not observed in a study in rats at the dose levels up to 1,000 mg/kg body weight (bw) per day. The Panel derived a BMDL of 101 mg/kg bw per day from a 90-day toxicity study. Based on this BMDL, adequate margins of exposure of 7,800 and 3,200 could be calculated for adults and children, respectively. The Panel concluded that there is no safety concern for [FL-no: 16.135], when used as a flavouring substance at the estimated level of dietary exposure calculated using the APET approach, based on the intended uses and use levels as specified in Appendix B. The Panel further concluded that the combined exposure to [FL-no: 16.135] from its use as a food flavouring substance and from its presence in toothpaste is also not of safety concern.

Scientific opinion on Prosmoke BW 01.

The EFSA Panel on Food Additives and Flavourings (FAF) was requested to evaluate the safety of Prosmoke BW 01 as a new smoke flavouring primary product, in accordance with Regulation (EC) No 2065/2003. Prosmoke BW01 is produced by pyrolysis of beechwood (Fagus sylvatica L.) sawdust. Its water content is estimated at 56 wt%, the total identified volatile fraction accounts for 28 wt% of the primary product, corresponding to 64% of the solvent-free mass, while the unidentified fraction amounts to 16 wt% of the primary product. Analytical data provided for three batches demonstrated that their batch-to-batch-variability was sufficiently low. However, for the batch used for the toxicological studies, there were substantial deviations in the concentration of nearly all the constituents compared to the other three batches. The dietary exposure of Prosmoke BW 01 was estimated to be between 6.2 and 9.2 mg/kg body weight (bw) per day, respectively, using SMK-EPIC and SMK-TAMDI. Using the FAIM tool, the 95th percentile exposure estimates ranged from 3.2 mg/kg bw per day for the elderly to 17.9 mg/kg bw per day for children. The Panel noted that furan-2(5H)-one is present in all batches of the primary product at an average concentration of 0.88 wt%. This substance was evaluated by the FAF Panel as genotoxic in vivo after oral exposure. The Panel considered that the (geno)toxicity studies available on the whole mixture were not adequate to support the safety assessment, due to limitations in these studies and because they were performed with a batch which may not be representative for the material of commerce. Considering that the exposure estimates for furan-2(5H)-one are above the TTC value of 0.0025 µg/kg bw per day (or 0.15 µg/person per day) for DNA-reactive mutagens and/or carcinogens, the Panel concluded that Prosmoke BW 01 raises a concern with respect to genotoxicity.

Scientific Opinion on Flavouring Group Evaluation 63, Revision 4 (FGE.63Rev4): consideration of aliphatic secondary saturated and unsaturated alcohols, ketones and related esters evaluated by JECFA (59th and 69th meetings) structurally related to flavouring substances evaluated by EFSA in FGE.07Rev6.

The EFSA Panel on Food Additives and Flavourings was requested to evaluate 43 flavouring substances assigned to the Flavouring Group Evaluation 63 (FGE.63), using the Procedure as outlined in the Commission Regulation (EC) No 1565/2000. Twenty-nine substances have already been considered in FGE.63 and its revisions ([FL-no: 02.023, 02.099, 02.104, 02.136, 02.155, 02.252, 07.015, 07.069, 07.081, 07.099, 07.100, 07.101, 07.102, 07.114, 07.123, 07.151, 07.190, 07.240, 07.247, 07.249, 07.256, 09.281, 09.282, 09.657, 09.658, 09.923, 09.924, 09.925 and 09.936]). The remaining 14 flavouring substances have been cleared with respect to genotoxicity in FGE.204Rev1 ([FL-no: 02.102, 02.193, 07.044, 07.048, 07.082, 07.104, 07.105, 07.106, 07.107, 07.121, 07.139, 07.177, 07.188 and 07.244]) and they are considered in this revision 4 of FGE.63. The substances were evaluated through a stepwise approach that integrates information on the structure-activity relationships, intake from current uses, toxicological threshold of concern (TTC) and available data on metabolism and toxicity. The Panel concluded that none of these 43 substances gives rise to safety concerns at their levels of dietary intake, when estimated on the basis of the 'Maximised Survey-derived Daily Intake' (MSDI) approach. Besides the safety assessment of the flavouring substances, the specifications for the materials of commerce have also been considered and found adequate for 43 flavouring substances. However, for 14 of these flavouring substances in the present revision and for 10 of the substances in the previous revision (FGE.63Rev3), the 'modified Theoretical Added Maximum Daily Intakes' (mTAMDIs) values are equal to or above the TTCs for their structural classes (I and II). For 15 substances previously evaluated in FGE.63Rev3, use levels are still needed to calculate the mTAMDI estimates. Therefore, in total for 39 flavouring substances, more data on uses and use levels should be provided to finalise their safety evaluations.

Scientific Opinion on Flavouring Group Evaluation 7, Revision 6 (FGE.07Rev6): saturated and unsaturated aliphatic secondary alcohols, ketones and esters of secondary alcohols and saturated linear or branched-chain carboxylic acids from chemical group 5.

The EFSA Panel on Food Additives and Flavourings was requested to evaluate 55 flavouring substances assigned to the Flavouring Group Evaluation 07 (FGE.07), using the Procedure as outlined in the Commission Regulation (EC) No 1565/2000. Fifty-three substances have already been considered in FGE.07 and its revisions. This revision 6 includes two additional substances which have been cleared with respect to genotoxicity in FGE.201Rev2 (4-methyl-3-hepten-5-one [FL-no: 07.261]) and FGE.204Rev1 (non-2-en-4-one, [FL-no: 07.187]). The substances were evaluated through a stepwise approach that integrates information on the structure-activity relationships, intake from current uses, toxicological threshold of concern (TTC) and available data on metabolism and toxicity. The Panel concluded that none of the 55 substances gives rise to safety concerns at their levels of dietary intake, when estimated on the basis of the 'Maximised Survey-derived Daily Intake' (MSDI) approach. Besides the safety assessment of the flavouring substances, the specifications for the materials of commerce have also been considered and found adequate. Normal and maximum use levels were available for all flavouring substances. For 52 substances, including the newly included substances [FL-no: 07.187 and 07.261], their 'modified Theoretical Added Maximum Daily Intakes' (mTAMDIs) estimates were above the TTC for their structural classes (I and II). Therefore, for these 52 flavouring substances, more detailed data on uses and use levels should be provided to finalise their safety evaluations.

Scientific Opinion on Flavouring Group Evaluation 67, Revision 3 (FGE.67Rev3): consideration of 23 furan-substituted compounds evaluated by JECFA at the 55th, 65th, 69th and 86th meetings.

The Panel on Food Additives and Flavourings (FAF) was requested to consider the JECFA evaluations of 25 flavouring substances assigned to the Flavouring Group Evaluation 67 (FGE.67Rev3), using the Procedure as outlined in the Commission Regulation (EC) No 1565/2000. Eleven substances have already been considered in FGE.67 and its revisions (FGE.67Rev1 and FGE.67Rev2). During the current assessment, two substances were no longer supported by industry, therefore 12 candidate substances are evaluated in FGE.67Rev3. New genotoxicity and toxicity data are available for 2-pentylfuran [FL-no: 13.059] and 2-acetylfuran [FL-no: 13.054], which are representative substances of subgroup IV [FL-no: 13.069, 13.106, 13.148] and VI-B [FL-no: 13.045, 13.070, 13.083, 13.101, 13.105, 13.138, 13.163], respectively. Based on these data, the Panel concluded that the concern for genotoxicity is ruled out for both [FL-no: 13.054] and [FL-no: 13.059] and consequently for the substances that they represent. Since the candidate substances cannot be anticipated to be metabolised to innocuous products only, they were evaluated along the B-side of the Procedure. The Panel derived a NOAEL of 22.6 mg/kg bw per day and a BMDL of 8.51 mg/kg bw per day, for 2-acetylfuran and 2-pentylfuran, respectively. For all 12 substances sufficient margins of safety were calculated when based on the MSDI approach. Adequate specifications for the materials of commerce are available for all 23 flavouring substances. The Panel agrees with JECFA conclusions, for all 23 substances, 'No safety concern at estimated levels of intake as flavouring substances' based on the MSDI approach. For 18 substances [FL-no: 13.021, 13.022, 13.023, 13.024, 13.031, 13.045, 13.047, 13.054, 13.059, 13.074, 13.083, 13.101, 13.105, 13.106, 13.138, 13.148, 13.163 and 13.190], the mTAMDI intake estimates are above the threshold of toxicological concern (TTC) for their structural classes and more reliable data on uses and use levels are required to finalise their evaluation.

Scientific Opinion on Flavouring Group Evaluation 13 Revision 3 (FGE.13Rev3): furfuryl and furan derivatives with and without additional side-chain substituents and heteroatoms from chemical group 14.

The Panel on Food additives and Flavourings of the EFSA was requested to update Flavouring Group Evaluation 13 using the Procedure as outlined in Commission Regulation (EC) No 1565/2000, to include an evaluation of the flavouring substances 2-ethyl-5-methylfuran [FL-no: 13.125] and 2-octylfuran [FL-no: 13.162]. FGE.13 revision 3 (FGE.13Rev3) deals with 26 flavourings substances of which 24 have been already evaluated to be of no safety concern. For [FL-no: 13.125] and [FL-no: 13.162], a concern for genotoxicity was raised in FGE.13Rev1. This concern could be ruled out based on new genotoxicity data on supporting substances in FGE.67Rev3. Subsequently, [FL-no: 13.125 and 13.162] were evaluated, through a stepwise approach that integrates intake from current uses, toxicological threshold of concern (TTC), and available data on metabolism and toxicity, along the B-side of the Procedure, making use of a BMDL of 8.51 mg/kg body weight (bw) per day. The Panel derived this BMDL from an oral subchronic toxicity study with the supporting substance 2-pentylfuran [FL-no: 13.059]. Using this BMDL, for [FL-no: 13.125 and 13.162], adequate margins of safety were calculated based on the MSDI approach. The Panel concluded that the 26 candidate substances in FGE.13Rev3 do not give rise to safety concerns at their levels of dietary intake, when estimated on the basis of the MSDI approach. Adequate specifications for the materials of commerce have been provided for all 26 substances. Data on uses and use levels are needed for [FL-no: 13.130]. For 21 flavouring substances [FL-no: 13.011, 13.102, 13.108, 13.113, 13.114, 13.122, 13.125, 13.127, 13.129, 13.132, 13.133, 13.135, 13.136, 13.139, 13.141, 13.143, 13.146, 13.149, 13.162, 13.178 and 13.185], the mTAMDI intake estimates are above the TTC for their structural class and more reliable data on uses and use levels are required to finalise their evaluation.

Scientific Opinion on Flavouring Group Evaluation 69, Revision 1 (FGE.69Rev1): consideration of aromatic substituted secondary alcohols, ketones and related esters evaluated by JECFA (57th meeting), structurally related to aromatic ketones from chemical group 21 evaluated by EFSA in FGE.16Rev2.

The EFSA Panel on Food Additives and Flavourings was requested to evaluate 35 flavouring substances attributed to the Flavouring Group Evaluation 69 (FGE.69), using the Procedure as outlined in the Commission Regulation (EC) No 1565/2000. Thirty-two substances have already been considered in FGE.69 [FL-no: 02.033, 02.034, 02.036, 02.064, 02.065, 02.080, 07.004, 07.013, 07.022, 07.023, 07.025, 07.026, 07.028, 07.029, 07.032, 07.038, 07.040, 07.042, 07.070, 07.079, 07.086, 07.087, 09.144, 09.178, 09.179, 09.189, 09.200, 09.231, 09.249, 09.476, 09.486 and 09.501]. The remaining three substances [FL-no: 02.066, 07.024 and 07.027] have been cleared with respect to genotoxicity in FGE.215Rev1 and are considered in this revision FGE.69Rev1. The substances were evaluated through a stepwise approach, namely the Procedure, that integrates information on the structure-activity relationships, intake from current uses, Threshold of Toxicological Concern (TTC) and available data on metabolism and toxicity. The Panel considered that for 33 flavouring substances evaluated through the Procedure the specifications are adequate and the Panel agrees with JECFA conclusions 'No safety concern at estimated levels of intake as flavouring substances' when based on the MSDI approach. For two flavouring substances [FL-no: 07.038 and 07.042], there is insufficient information on their chemical identity to reach a final conclusion. For six substances [FL-no: 02.066, 07.013, 07.024, 07.028, 07.032 and 07.086], there is no concern when the exposure was estimated based on the 'modified Theoretical Added Maximum Daily Intake' (mTAMDI) approach. For 28 substances, use levels are needed to calculate the mTAMDI estimates in order to identify those flavouring substances that need more refined exposure assessment and to finalise the evaluation accordingly. For one substance [FL-no: 07.027], more reliable data on uses and use levels are required in order to finalise the safety evaluation.

Scientific Opinion on Flavouring Group Evaluation 72, Revision 2 (FGE.72Rev2): consideration of aliphatic, branched-chain saturated and unsaturated alcohols, aldehydes, acids and related esters evaluated by JECFA (61st, 68th and 69th meetings) and structurally related to flavouring substances in FGE.05Rev3.

The EFSA Panel on Food Additives and Flavourings was requested to evaluate 31 flavouring substances assigned to the Flavouring Group Evaluation 72 (FGE.72), using the Procedure as outlined in the Commission Regulation (EC) No 1565/2000. Twenty-three substances have already been considered in FGE.72 and FGE.72Rev1 ([FL-no: 02.011, 02.012, 02.027, 02.029, 02.058, 02.076, 02.109, 05.020, 05.021, 05.124, 05.148, 05.169, 08.036, 08.044, 08.047, 08.055, 08.064, 08.070, 08.079, 09.273, 09.408, 09.931 and 16.001]). The remaining eight flavouring substances have been cleared with respect to genotoxicity in FGE.200Rev1 ([FL-no: 05.114]) and FGE.201Rev2 ([FL-no: 02.174, 05.033, 05.090, 05.095, 05.105, 05.107 and 05.126]) and they are considered in this revision 2 of FGE.72. The substances were evaluated through a stepwise approach that integrates information on the structure-activity relationships, intake from current uses, toxicological threshold of concern (TTC), and available data on metabolism and toxicity. The Panel concluded that none of these 31 substances gives rise to safety concerns at their levels of dietary intake, estimated on the basis of the 'Maximised Survey-derived Daily Intake' (MSDI) approach. Besides the safety assessment of the flavouring substances, the specifications for the materials of commerce have also been considered and found adequate for all 31 flavouring substances. For 21 substances, evaluated through the Procedure in the previous revision (FGE.72Rev1), no normal and maximum use levels are available. For four substances, the modified Theoretical Added Maximum Daily Intake (mTAMDI) intake estimates are equal to ([FL-no: 05.090]) or above ([FL-no: 05.107, 05.105, 05.033]) the TTC for their structural class. Therefore, for these 25 substances more detailed data on uses and use levels should be provided in order to refine their exposure assessments and to finalise their safety evaluations.

Scientific Opinion on Flavouring Group Evaluation 91, Revision 3 (FGE.91Rev3): consideration of aliphatic, aromatic and α,ß-unsaturated sulfides and thiols evaluated by JECFA (53rd, 61st, 68th and 76th meetings), structurally related to substances in FGE.08Rev5.

The EFSA Panel on Food Additives and Flavourings was requested to evaluate 49 flavouring substances assigned to the Flavouring Group Evaluation 91 (FGE.91), using the Procedure as outlined in the Commission Regulation (EC) No 1565/2000. Forty-four substances have been considered in FGE.91 and its revisions (FGE.91Rev1 and FEG.91Rev2). With regard to the remaining five flavouring substances considered in this revision 3 of FGE.91: two ([FL-no: 12.065 and 12.079]) have been cleared with respect to genotoxicity in FGE.201Rev2; two ([FL-no: 12.169 and 12.241]) were originally allocated to FGE.74Rev4 and one ([FL-no: 12.304]) to FGE.08Rev5. The Panel considered the flavouring substance [FL-no: 12.169] representative for the tertiary monothiols [FL-no: 12.038, 12.085, 12.137, 12.138, 12.145, 12.252, 12.259, 12.241 and 12.304]. The substances were evaluated through a stepwise approach that integrates information on the structure-activity relationships, intake from current uses, toxicological threshold of concern (TTC), and available data on metabolism and toxicity. The Panel concluded that none of these 49 substances gives rise to safety concerns at their levels of dietary intake, estimated on the basis of the 'Maximised Survey-derived Daily Intake' (MSDI) approach. The specifications for the materials of commerce have also been considered and found adequate for all 49 flavouring substances. For five substances [FL-no: 12.077, 12.162, 12.265, 12.267 and 17.036], evaluated through the Procedure in FGE.91Rev2, no normal and maximum use levels are available. For 10 substances [FL-no: 12.065, 12.038, 12.079, 12.108, 12.139, 12.264, 12.274, 12.252, 12.284 and 12.304], the modified Theoretical Added Maximum Daily Intake (mTAMDI) intake estimates are above the TTC for their structural class. Therefore, for these 15 substances, more detailed data on uses and use levels should be provided in order to refine their exposure assessments and to finalise their safety evaluations.

Scientific Opinion on Flavouring Group Evaluation 61 Revision 2 (FGE.61Rev2): consideration of aliphatic acetals evaluated by JECFA (57th, 63rd and 68th meetings) structurally related to acetals evaluated by EFSA in FGE.03Rev2.

The EFSA Panel on Food Additives and Flavourings was requested to evaluate 12 flavouring substances attributed to the Flavouring Group Evaluation 61 (FGE.61), using the Procedure as outlined in the Commission Regulation (EC) No 1565/2000. Nine substances have already been considered in FGE.61 and FGE.61Rev1 [FL-no: 06.001, 06.004, 06.005, 06.008, 06.009, 06.015, 06.028, 06.037, 06.081]. The remaining three substances [FL-no: 06.025, 06.031 and 06.072] have been cleared with respect to genotoxicity in FGE.200Rev1 and are considered in this revision 2 of FGE.61. The substances were evaluated through a stepwise approach that integrates information on the structure-activity relationships, intake from current uses, toxicological threshold of concern (TTC), and available data on metabolism and toxicity. The Panel concluded that none of the 12 substances gives rise to safety concerns at their levels of dietary intake, estimated on the basis of the 'Maximised Survey-derived Daily Intake' (MSDI) approach. Besides the safety assessment of the flavouring substances, the specifications for the materials of commerce have also been considered and found adequate. For nine flavouring substances [FL-no: 06.001, 06.004, 06.005, 06.008, 06.009, 06.015, 06.028, 06.037 and 06.081], use levels are still needed to calculate the modified Theoretical Added Maximum Daily Intake (mTAMDI) values in order to identify those flavouring substances that need more refined exposure assessment and to finalise the evaluation accordingly.

Scientific Opinion on Flavouring Group Evaluation 71 Revision 1 (FGE.71Rev1): consideration of aliphatic, linear, α,ß-unsaturated alcohols, aldehydes, carboxylic acids, and related esters evaluated by JECFA (63rd and 69th meeting) structurally related to flavouring substances evaluated in FGE.05Rev3.

The EFSA Panel on Food Additives and Flavourings was requested to evaluate 39 flavouring substances assigned to the Flavouring Group Evaluation 71 (FGE.71), using the Procedure in Commission Regulation (EC) No 1565/2000. Nine substances have already been considered in FGE.71 [FL-no: 08.054, 08.073, 08.123, 09.037, 09.156, 09.157, 05.158, 09.235, 09.239]. The remaining 30 substances [FL-no: 02.020, 02.050, 02.090, 02.112, 02.137, 02.156, 02.210, 05.037, 05.060, 05.070, 05.073, 05.076, 05.078, 05.102, 05.109, 05.150, 05.171, 05.179, 09.276, 09.277, 09.303, 09.385, 09.394, 09.395, 09.396, 09.397, 09.398, 09.399, 09.678 and 09.841] have been cleared with respect to genotoxicity in FGE.200Rev1 and they are considered in this revision. The substances were evaluated through a stepwise approach that integrates information on the structure-activity relationships, intake from current uses, toxicological threshold of concern (TTC), and available data on metabolism and toxicity. The Panel concluded that none of the 39 substances gives rise to safety concerns at their levels of dietary intake, estimated on the basis of the 'Maximised Survey-derived Daily Intake' (MSDI) approach. Besides the safety assessment of the flavouring substances, the specifications for the materials of commerce have also been considered and found adequate, except for [FL-no: 08.073 and 09.235]. For these two substances, data on the composition of the stereoisomeric mixture should be requested. Normal and maximum use levels should be provided for nine flavouring substances [FL-no: 08.054, 08.073, 08.123, 09.037, 09.156, 09.157, 05.158, 09.235, 09.239]. For two flavouring substances [FL-no: 02.020 and 05.076], the 'modified Theoretical Added Maximum Daily Intake' (mTAMDI) estimates are above the TTC for their structural class I. Therefore, additional information on uses and use levels should be provided for these eleven substances in order to finalise their evaluation.

Scientific Opinion on Flavouring Group Evaluation 217 Revision 2 (FGE.217Rev2), consideration of genotoxic potential for α,ß-unsaturated ketones and precursors from chemical subgroup 4.1 of FGE.19: lactones.

The Panel on Food Additives and Flavourings of the European Food Safety Authority was requested to evaluate the genotoxic potential of 12 flavouring substances from subgroup 4.1 of FGE.19 in the Flavouring Group Evaluation 217 (FGE.217). Based on experimental data, in previous versions of this FGE (FGE.217 and FGE217Rev1), for 6-methylcoumarin [FL-no: 13.012] and 5-ethyl-3-hydroxy-4-methylfuran-2(5H)-one [FL-no: 10.023] the concern for genotoxicity was ruled out. 6-Methylcoumarin was evaluated using the Procedure in FGE.80Rev1. For 5-ethyl-3-hydroxy-4-methylfuran-2(5H)-one [FL-no: 10.023] and the structurally related substance 3-hydroxy-4,5-dimethylfuran-2(5H)-one [FL-no: 10.030], no further EFSA considerations were needed because these substances were evaluated by JECFA before 2000. Also based on experimental data, in FGE217Rev1, the concern for genotoxicity could not be ruled out for furan-2(5H)-one [FL-no: 10.066] and 3,4-dimethyl-5-pentylidenefuran-2(5H)-one [FL-no: 10.042], which later substance represents the following flavourings: [FL-no: 10.034, 10.036, 10.043, 10.046, 10.054, 10.057, 10.060 and 10.170]. In the current revision of this FGE (FGE217Rev2), based on the results of additional genotoxicity studies, the FAF Panel concluded that [FL-no: 10.066] is genotoxic in vivo. Therefore, furan-2(5H)-one [FL-no: 10.066] cannot be evaluated according to the Procedure. For [FL-no: 10.042] in order to rule out a concern for clastogenicity at site of first contact, the FAF Panel requests results from an in vivo comet assay in duodenum. In addition, [FL-no: 10.042] has also been identified as an aneugenic substance in vitro. Until the concern for clastogenicity at site of first contact for [FL-no: 10.042] and the concern for aneugenicity can be ruled out, this substance and [FL-no: 10.034, 10.036, 10.043, 10.046, 10.054, 10.057, 10.060 and 10.170] cannot be evaluated through the Procedure.

Scientific Opinion on Flavouring Group Evaluation 208 Revision 3 (FGE.208Rev3): consideration of genotoxicity data on alicyclic aldehydes with α,ß-unsaturation in ring/side-chain and precursors from chemical subgroup 2.2 of FGE.19.

The EFSA Panel on Food Additives and Flavourings was requested to evaluate the genotoxic potential of flavouring substances from subgroup 2.2 of FGE.19 in the Flavouring Group Evaluation 208 Revision 3 (FGE.208Rev3). In FGE.208Rev1, the Panel on Food Contact Materials, Enzymes, Flavourings and Processing Aids (CEF) evaluated genotoxicity studies on the representative substance p-mentha-1,8-dien-7-al [FL-no: 05.117], which was found to be genotoxic in vivo. The Panel concluded that there was a potential safety concern for the nine substances in this FGE that were all represented by [FL-no: 05.177]. Consequently, substance [FL-no: 05.117], as well as four substances ([FL-no: 05.121, 09.272, 09.899 and 09.900]), no longer supported by industry were deleted from the Union List. In FGE.208Rev2, the Panel assessed genotoxicity studies submitted on five flavouring substances [FL-no: 02.060, 02.091, 05.106, 09.278 and 09.302] and concluded that the concern for genotoxicity could be ruled out for these substances, except from myrtenal [FL-no: 05.106] for which the available data were considered equivocal. Thus, industry provided additional genotoxicity studies (a bacterial reverse mutation assay and a combined in vivo bone marrow erythrocytes micronucleus test and Comet assay in liver and duodenum) for this substance which were evaluated in the present opinion, FGE.208Rev3. Based on these new data, the Panel concluded that the concern for genotoxicity could be ruled out for myrtenal [FL-no: 05.106]. Subsequently, this substance can be evaluated through the Procedure.

Scientific Opinion on Flavouring Group Evaluation 215 Revision 1 (FGE.215Rev1): seven α,ß-unsaturated cinnamyl ketones from subgroup 3.2 of FGE.19.

The Panel on Food Additives and Flavourings of the European Food Safety Authority was requested to evaluate the genotoxic potential of flavouring substances from subgroup 3.2 of FGE.19 in the Flavouring Group Evaluation 215, Revision 1 (FGE.215Rev1). In FGE.215, the Panel on Food Contact Materials, Enzymes, Flavourings and Processing Aids concluded that the concern for genotoxicity could not be ruled out and requested in vivo data for the two representative substances 4-phenylbut-3-en-2-one [FL-no: 07.024] and 1-(4-methoxyphenyl)pent-1-en-3-one [FL-no: 07.030]. The Flavour Industry has provided additional genotoxicity studies for both representative substances [FL-no: 07.024] and [FL-no: 07.030]. Based on these new data, the Panel concluded that the concern for genotoxicity is ruled out for the representative substance [FL-no: 07.024] and for the structurally related substances 4-phenylbut-3-en-2-ol [FL-no: 02.066] and 3-methyl-4-phenylbut-3-en-2-one [FL-no: 07.027] which can accordingly be evaluated through the Procedure in FGE.69. For the representative substance 1-(4-methoxyphenyl)pent-1-en-3-one [FL-no: 07.030], the Panel concluded that [FL-no: 07.030] is aneugenic in vitro. For such substances, there is currently no agreed follow-up strategy to finalise their safety assessment. The Panel is aware that the EFSA Scientific Committee is going to address this issue and a statement clarifying the assessment of in vitro aneugenic substances is under preparation. The Panel concluded therefore that, for the time being, the representative substance 1-(4-methoxyphenyl)pent-1-en-3-one [FL-no: 07.030] and the structurally related substances vanillylidene acetone [FL-no: 07.046] and 1-(4-methoxyphenyl)-4-methylpent-1-en-3-one [FL-no: 07.049] cannot be evaluated through the Procedure. The Panel further concluded that 4-(2,3,6-trimethylphenyl)but-3-en-2-one [FL-no: 07.206] is to be considered as a stand-alone substance due to the presence of the methyl groups, therefore, in vitro genotoxicity data were requested for [FL-no: 07.206]. Industry communicated that the evaluation of [FL-no: 07.206] is not supported any longer, therefore additional data were not submitted.