Comorbidities in Dravet Syndrome and Lennox–Gastaut Syndrome

AbstractThis study aims to describe the main cognitive and behavioral comorbidities of Dravet syndrome (DS) and Lennox–Gastaut syndrome (LGS), their impact on the health-related quality of life (QOL) of patients and their caregivers, and provide a summary of the neuropsychological tools available for the evaluation of these comorbidities. The cognitive and behavioral comorbidities in patients with DS and LGS have a profound effect on the QOL of affected individuals and their caregivers and, as patients grow, tend to surpass the impact of the seizures. DS is a genetic condition associated with loss-of-function mutations in the SCNA1 sodium channel gene; LGS is an etiologically heterogeneous condition that is often secondary to structural brain abnormalities. The first seizures associated with DS typically present in the first year of life, and developmental delay becomes progressively evident thereafter. LGS usually starts between the ages of 3 and 8 years, with cognitive impairment becoming clinically evident in most patients within 5 years from the onset. In both DS and LGS, cognitive impairment is generally moderate to severe and is often accompanied by behavioral problems such as hyperactivity and inattention. In addition to optimal seizure control, regular assessment and active management of cognitive and behavioral comorbidities are required to meet the complex needs of patients with DS or LGS

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 mu g/person per day for a 60-kg adult and 480 mu g/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. (C) 2022 Wiley-VCH Verlag GmbH & Co. KgaA on behalf of the European Food Safety Authority

Scientific opinion on the renewal of the authorisation of Zesti Smoke Code 10 (SF‐002) as a smoke flavouring Primary Product

The EFSA Panel on Food Additives and Flavourings (FAF) was requested to evaluate the safety of the smoke flavouring Primary Product Zesti Smoke Code 10 (SF-002), for which a renewal application was submitted in accordance with Article 12(1) of Regulation (EC) No 2065/2003. This opinion refers to the assessment of data submitted on chemical characterisation, dietary exposure and genotoxicity of the Primary Product. Zesti Smoke Code 10 is obtained by pyrolysis of hickory and oak woods. Given the limitations of the quantification approach employed by the applicant, the Panel could not judge whether the applied methods meet the legal quality criterion that at least 80% of the volatile fraction shall be identified and quantified. At the maximum proposed use levels, dietary exposure estimates calculated with DietEx ranged from 0.02 to 4.6 mg/kg body weight (bw) per day at the mean and from no dietary exposure to 13.0 mg/kg bw per day at the 95th percentile. The Panel concluded that four components in the Primary Product raise a potential concern for genotoxicity. In addition, a potential concern for genotoxicity was identified for the unidentified part of the mixture. The Primary Product contains furan-2(5H)-one and benzene-1,2-diol, for which a concern for genotoxicity was identified in vivo upon oral administration. Considering that the exposure estimates for these two components are above the threshold of toxicological concern (TTC) of 0.0025 μg/kg bw per day for DNA-reactive mutagens and/or carcinogens, the Panel concluded that the Primary Product raises concern with respect to genotoxicity

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

Scientific opinion on the renewal of the authorisation of SmokEz Enviro‐23 (SF‐006) as a smoke flavouring Primary Product

The EFSA Panel on Food Additives and Flavourings (FAF) was requested to evaluate the safety of the smoke flavouring Primary Product SmokEz Enviro-23 (SF-006), for which a renewal application was submitted in accordance with Article 12(1) of Regulation (EC) No 2065/2003. This opinion refers to the assessment of data submitted on chemical characterisation, dietary exposure and genotoxicity of the Primary Product. SmokEz Enviro-23 is obtained by pyrolysis of oak, maple, hickory, ash, birch, beech and cherry woods. Given the limitations of the quantification approach employed by the applicant, the Panel could not judge whether the applied methods meet the legal quality criterion that at least 80% of the volatile fraction shall be identified and quantified. At the maximum proposed use levels, dietary exposure estimates calculated with DietEx ranged from 0.01 to 3.2 mg/kg body weight (bw) per day at the mean and from no dietary exposure to 9.5 mg/kg bw per day at the 95th percentile. The Panel concluded that four components in the Primary Product raise a potential concern for genotoxicity. In addition, a potential concern for genotoxicity was identified for the unidentified part of the mixture. The Primary Product contains furan-2(5H)-one and benzene-1,2-diol, for which a concern for genotoxicity was identified in vivo upon oral administration. Considering that the exposure estimates for these two components are above the threshold of toxicological concern (TTC) of 0.0025 μg/kg bw per day for DNA-reactive mutagens and/or carcinogens, the Panel concluded that the Primary Product raises concern with respect to genotoxicity

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 mu g/kg bw per day (or 0.15 mu g/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 67, Revision 3 (FGE.67Rev3) : consideration of 23 furan-substituted compounds evaluated by JECFA at the 55th, 65th, 69th and 86th meetings

Publisher PD

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

Acknowledgements: The Panel wishes to thank the following hearing expert for the support provided to this scientific output: Karin Nørby.Publisher PD

Scientific opinion on the renewal of the authorisation of proFagus Smoke R709 (SF‐008) as a smoke flavouring Primary Product

The EFSA Panel on Food Additives and Flavourings (FAF) was requested to evaluate the safety of the smoke flavouring Primary Product proFagus Smoke R709 (SF-008), for which a renewal application was submitted in accordance with Article 12(1) of Regulation (EC) No 2065/2003. This opinion refers to the assessment of data submitted on chemical characterisation, dietary exposure and genotoxicity of the Primary Product. ProFagus Smoke R709 is obtained by pyrolysis of beech and oak wood as main source materials. The panel concluded that the compositional data provided on the Primary Product are adequate. At the maximum proposed use levels, dietary exposure estimates calculated with DietEx ranged from 0.8 to 12.2 mg/kg body weight (bw) per day at the mean and from 2.3 to 51.4 mg/kg bw per day at the 95th percentile. The Panel concluded that three components in the Primary Product raise a potential concern for genotoxicity. In addition, a potential concern for genotoxicity was identified for the unidentified part of the mixture. The Primary Product contains furan-2(5H)-one, for which a concern for genotoxicity was identified in vivo upon oral administration. Considering that the exposure estimates for this component are above the TTC of 0.0025 μg/kg bw per day for DNA-reactive mutagens and/or carcinogens, the panel concluded that the Primary Product raises concern with respect to genotoxicity

Scientific opinion on the renewal of the authorisation of SmokEz C‐10 (SF‐005) as a smoke flavouring Primary Product

The EFSA Panel on Food Additives and Flavourings (FAF) was requested to evaluate the safety of the smoke flavouring Primary Product SmoKEz C-10 (SF-005), for which a renewal application was submitted in accordance with Article 12(1) of Regulation (EC) No 2065/2003. This opinion refers to the assessment of data submitted on chemical characterisation, dietary exposure and genotoxicity of the Primary Product. SmoKEz C-10 is obtained by pyrolysis of maple, oak, hickory, ash, birch, beech and cherry woods. Given the limitations of the quantification approach employed by the applicant, the Panel could not judge whether the applied methods meet the legal quality criterion that at least 80% of the volatile fraction shall be identified and quantified. At the maximum proposed use levels, dietary exposure estimates calculated with DietEx ranged from 0.01 to 5.1 mg/kg body weight (bw) per day at the mean and from no dietary exposure to 18.1 mg/kg bw per day at the 95th percentile. The Panel concluded that five components in the Primary Product raise a potential concern for genotoxicity. In addition, a potential concern for genotoxicity was identified for the unidentified part of the mixture. The Primary Product contains furan-2(5H)-one and benzene-1,2-diol, for which a concern for genotoxicity was identified in vivo upon oral administration. Considering that the exposure estimates for these two components are above the threshold of toxicological concern (TTC) of 0.0025 μg/kg bw per day for DNA-reactive mutagens and/or carcinogens, the Panel concluded that the Primary Product raises concern with respect to genotoxicity