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Abstract The present opinion is the follow‐up of the conclusions and recommendations of the Scientific Opinion on the re‐evaluation of silicon dioxide (E 551) as a food additive relevant to the safety assessment for all age groups. In addition, the risk assessment of silicon dioxide (E 551) for its use in food for infants below 16 weeks of age is performed. Based on the newly available information on the characterisation of the SAS used as E 551 and following the principles of the 2021 EFSA Guidance on Particle‐TR, the conventional safety assessment has been complemented with nano‐specific considerations. Given the uncertainties resulting from the limitations of the database and in the absence of genotoxicity concern, the Panel considered that it is not appropriate to derive an acceptable daily intake (ADI) but applied the margin of exposure (MOE) approach for the risk assessment. The Panel concluded that the MOE should be at least 36 for not raising a safety concern. The calculated MOEs considering the dietary exposure estimates for all population groups using the refined non‐brand loyal scenario, estimated at the time of the 2018 re‐evaluation, were all above 36. The Panel concluded that E 551 does not raise a safety concern in all population groups at the reported uses and use levels. The use of E 551 in food for infants below 16 weeks of age in FC 13.1.1 and FC 13.1.5.1 does not raise a safety concern at the current exposure levels. The Panel also concluded that the technical data provided support an amendment of the specifications for E 551 laid down in Commission Regulation (EU) No 231/2012. The paucity of toxicological studies with proper dispersion protocol (with the exception of the genotoxicity studies) creates uncertainty in the present assessment of the potential toxicological effects related to the exposure to E 551 nanosize aggregates.

Abstract The present opinion deals with the re‐evaluation of shellac (E 904) when used as a food additive and with the new application on the extension of use of shellac (E 904) in dietary foods for special medical purposes. The Panel derived an acceptable daily intake (ADI) of 4 mg/kg body weight (bw) per day for wax‐free shellac (E 904) produced by physical decolouring, based on a NOAEL of 400 mg/kg bw per day and applying an uncertainty factor of 100. The Panel concluded that the ADI of 4 mg/kg bw per day should be considered temporary for wax‐free shellac (E 904) produced by chemical bleaching, while new data are generated on the identity and levels of the organochlorine impurities in E 904. This ADI is not applicable for wax‐containing shellac as a food additive. For several age groups, the ADI was exceeded at the 95th percentile in the non‐brand‐loyal exposure assessment scenario and maximum level exposure assessment scenario. Considering the low exceedance and the fact that both the exposure estimation and the toxicological evaluation of shellac were conservative, the panel concluded that the calculated exceedance of the ADI does not indicate a safety concern. The Panel recommended to the European Commission separating specifications for E 904 depending on the manufacturing process, chemical bleaching and physical decolouring, because they result in different impurities; revising the definition of the food additive to include a description of each manufacturing process; deleting information on wax‐containing shellac from the EU specifications; revising the acid value for wax‐free shellac produced by chemical bleaching; lowering the maximum limit for lead; to consider introducing limits for other toxic elements potentially present in shellac; including a maximum limit for chloroform and total inorganic chloride in the EU specification for shellac produced by chemical bleaching.

Abstract Dengue fever is a source of substantial health burden in Vietnam. Given the well‐established influence of temperature and precipitation on vector biology and disease transmission, predictions of meteorological variables, such as those issued by ECMWF as a world‐leading provider of global ensemble forecasts, are likely to be valuable model inputs to a future dengue early warning system. In the absence of established verification at municipal and regional scales, this study assesses the skill of rainy season (May–October) ensemble precipitation and 2‐m temperature retrospective forecasts over North and South Vietnam initialized for dates during the period 2001–2020, evaluated against the ERA5 reanalysis for the same period. Forecasts are found to be significantly skilful compared with both climatology and persistence for lead times up to 10 days, including for cumulative precipitation values considered against independent rain gauge data. Rank histograms demonstrate that ensembles generally avoid excessive bias and consistently positive CRPSS values indicate substantial skill for temperature and cumulative precipitation forecasts for all spatial scales considered, despite differences in rainy season characteristics between North and South Vietnam. This forecast reliability demonstrates that meteorological input data based on ECMWF ensemble forecasts would add appreciably more value to the development of a future dengue early warning system compared to reference forecasts like climatology or persistence. These results raise hope for further exploration of predictive skill for relevant meteorological variables, particularly focused on their downscaling to produce district‐level epidemiological forecasts for urban areas where dengue is most prevalent.

Abstract The EFSA Panel on Food Additive and Flavourings (FAF Panel) provides a scientific opinion on the safety of soy leghemoglobin from genetically modified Komagataella phaffii as a food additive in accordance with Regulation (EC) No 1331/2008. The proposed food additive, LegH Prep, is intended to be used as a colour in meat analogue products. The yeast Komagataella phaffii strain MXY0541 has been genetically modified to produce soy leghemoglobin; the safety of the genetic modification is under assessment by the EFSA GMO Panel (EFSA‐GMO‐NL‐2019‐162). The amount of haem iron provided by soy leghemoglobin from its proposed uses in meat analogue products is comparable to that provided by similar amounts of different types of meat. The exposure to iron from the proposed food additive, both at the mean and 95th percentile exposure, will be below the ‘safe levels of intake’ established by the NDA Panel for all population groups. Considering that the components of the proposed food additive will be digested to small peptide, amino acids and haem B; the recipient (non GM) strain qualifies for qualified presumption of safety status; no genotoxicity concern has been identified and no adverse effects have been identified at the highest dose tested in the available toxicological studies, the Panel concluded that there was no need to set a numerical acceptable daily intake (ADI) and that the food additive does not raise a safety concern at the proposed use in food category 12.9 and maximum use level. The Panel concluded that the use of soy leghemoglobin from genetically modified Komagataella phaffii MXY0541 as a new food additive does not raise a safety concern at the proposed use and use level. This safety evaluation of the proposed food additive remains provisional subject to the ongoing safety assessment of the genetic modification of the production strain by the GMO Panel (EFSA‐GMO‐NL‐2019‐162).

Abstract 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.

Abstract Guar gum (E 412) was re‐evaluated in 2017 by the former EFSA Panel on Food Additives and Nutrient sources added to Food (ANS). As a follow‐up to this assessment, the Panel on Food Additives and Flavourings (FAF) was requested to assess the safety of guar gum (E 412) for its uses as food additive in food for infants below 16 weeks of age belonging to food categories 13.1.1 (Infant formulae) and 13.1.5.1 (Dietary foods for infants for special medical purposes and special formulae for infants). In addition, the FAF Panel was requested to address the issues already identified during the re‐evaluation of the food additive when used in food for the general population. The process involved the publication of a call for data to allow the interested business operators to provide the requested information to complete the risk assessment. In the response to EFSA requests, one IBO stated that E 412 is not used in food categories 13.1.1 and 13.1.5.1, but it is present in products under food category 13.1.5.2. The Panel concluded that the submitted data are not sufficient to support the safe use of guar gum (E 412) in food for infants (below and above 16 weeks of age) and young children under FC 13.1.1, 13.1.5.1 and 13.1.5.2. Additionally, the Panel concluded that the technical data provided by the IBO support further amendments of the specifications for E 412 laid down in Commission Regulation (EU) No 231/2012.

Abstract 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.

Abstract Background While many women with rheumatoid arthritis (RA) improve during pregnancy and others worsen, there are no biomarkers to predict this improvement or worsening. In our unique RA pregnancy cohort that includes a pre-pregnancy baseline, we have examined pre-pregnancy gene co-expression networks to identify differences between women with RA who subsequently improve during pregnancy and those who worsen. Methods Blood samples were collected before pregnancy (T0) from 19 women with RA and 13 healthy women enrolled in our prospective pregnancy cohort. RA improvement/worsening between T0 and 3rd trimester was assessed by changes in the Clinical Disease Activity Index (CDAI). Pre-pregnancy expression profiles were examined by RNA sequencing and differential gene expression analysis. Weighted gene co-expression network analysis (WGCNA) was used to identify co-expression modules correlated with the improvement/worsening of RA during pregnancy and to assess their functional relevance. Results Of the 19 women with RA, 14 improved during pregnancy (RAimproved) while 5 worsened (RAworsened). At the T0 baseline, however, the mean CDAI was similar between the two groups. WGCNA identified one co-expression module related to B cell function that was significantly correlated with the worsening of RA during pregnancy and was significantly enriched in genes differentially expressed between the RAimproved and RAworsened groups. A neutrophil-related expression signature was also identified in the RAimproved group at the T0 baseline. Conclusion The pre-pregnancy gene expression signatures identified represent potential biomarkers to predict the subsequent improvement/worsening of RA during pregnancy, which has important implications for the personalized treatment of RA during pregnancy.

Abstract Quillaia extract (E 999) was re‐evaluated in 2019 by the EFSA Panel on Food Additives and Flavourings (FAF). EFSA derived an acceptable daily intake (ADI) of 3 mg saponins/kg bw per day for E 999. Following a European Commission call for data to submit data to fill the data gaps, the present follow‐up opinion assesses data provided by interested business operators (IBOs) to support an amendment of the EU specifications for E 999. Additionally, this opinion deals with the assessment of the proposed extension of use for E 999 in food supplements supplied in a solid and liquid form, excluding food supplements for infants and young children and, as a carrier in botanical nutrients. The Panel concluded that the proposed extension of use, if authorised, could result in an exceedance of the ADI at the maximum of the ranges of the mean for children, adolescents and the elderly, and for all populations at the 95th percentile. An additional proposed extension of use for E 999 to be used as a carrier for glazing agents on entire fresh fruits and vegetables has been received. Since no information on the proposed use levels of E 999 on a saponins content basis has been provided by this applicant, the Panel was not able to evaluate the safety of this extension of use. Considering the technical data submitted, the Panel recommended some modifications of the existing EU specifications for E 999, mainly to lower the limits for lead, mercury and arsenic and to include a maximum limit for cadmium and for calcium oxalate. The Panel also recommended that the limits would be expressed on a saponins basis. The Panel proposed to revise the definition of E 999 to better describe the composition in a qualitative way.

Abstract The EFSA Panel on Food Additive and Flavourings (FAF Panel) provides a scientific opinion on the safety of a new process to produce steviol glycosides by fermentation of simple sugars using a genetically modified strain of Yarrowia lipolytica (named Y. lipolytica VRM). The manufacturing process may result in impurities different from those that may be present in the other steviol glycosides E 960a‐d, therefore the Panel concluded that separate specifications are required for the food additive produced as described in the current application. Viable cells and DNA from the production strain are not present in the final product. The Panel considered that the demonstration of the absence of kaurenoic acid in the proposed food additive, using a method with a limit of detection (LOD) of 0.3 mg/kg, is adequate to dispel the concerns for potential genotoxicity. Given that all steviol glycosides follow the same metabolic pathways, the Panel considered that the current steviol glycosides would fall within the same group of substances. Therefore, the Panel considered that the already existing data on rebaudioside M and structurally related steviol glycosides are sufficient, and a similar metabolic fate and toxicity is expected for the food additive. The results from the bacterial reverse mutation assay and the in vitro micronucleus assay were negative and indicated absence of genotoxicity from the food additive. The existing acceptable daily intake (ADI) of 4 mg/kg body weight (bw) per day, expressed as steviol equivalents, was considered to be applicable to the proposed food additive. The Panel concluded that there is no safety concern for steviol glycosides, predominantly Rebaudioside M, produced by fermentation using Y. lipolytica VRM, to be used as a food additive at the proposed uses and use levels.

Abstract The EFSA Panel on Food Additives and Flavourings (FAF) was requested to evaluate the safety of synthesised DNA oligonucleotides as a new food additive, in accordance with Regulation (EC) No 1331/2008. Considering that the additional information requested by the Panel during the risk assessment was not provided by the applicant, the assessment was concluded on the basis of the sole information available in the application. The proposed food additive consists of purified synthetic DNA sequences intended to be used for traceability purposes, alone or combined with carriers. Information provided by the applicant on the identity, characterisation and production process of the proposed food additive was considered insufficient. The Panel considered that the product specifications as proposed by the applicant do not adequately define and characterise the proposed food additive. The applicant proposed for the food additive the maximum use levels of 0.001 mg/kg for a variety of food categories. The food additive was also proposed as a Group I additive at a specific maximum level of quantum satis. The applicant did not provide exposure estimates according to the EFSA ANS Panel guidance (2012). No biological or toxicological data were provided by the applicant for the proposed food additive. Considering the inadequate information available and the uncertainty introduced by the proposal at quantum satis, along with the insufficient specifications, the Panel could not conclude on the safety of the food additive as proposed and described by the applicant.

Abstract This opinion addresses the re‐evaluation of erythritol (E 968) as food additive and an application for its exemption from the laxative warning label requirement as established under Regulation (EU) No 1169/2011. Erythritol is a polyol obtained by fermentation with Moniliella pollinis BC or Moniliella megachiliensis KW3‐6, followed by purifications and drying. Erythritol is readily and dose‐dependently absorbed in humans and can be metabolised to erythronate to a small extent. Erythritol is then excreted unchanged in the urine. It does not raise concerns regarding genotoxicity. The dataset evaluated consisted of human interventional studies. The Panel considered that erythritol has the potential to cause diarrhoea in humans, which was considered adverse because its potential association with electrolyte and water imbalance. The lower bound of the range of no observed adverse effect levels (NOAELs) for diarrhoea of 0.5 g/kg body weight (bw) was identified as reference point. The Panel considered appropriate to set a numerical acceptable daily intake (ADI) at the level of the reference point. An ADI of 0.5 g/kg bw per day was considered by the Panel to be protective for the immediate laxative effect as well as potential chronic effects, secondary to diarrhoea. The highest mean and 95th percentile chronic exposure was in children (742 mg/kg bw per day) and adolescents (1532 mg/kg bw per day). Acute exposure was maximally 3531 mg/kg bw per meal for children at the 99th percentile. Overall, the Panel considered both dietary exposure assessments an overestimation. The Panel concluded that the exposure estimates for both acute and chronic dietary exposure to erythritol (E 968) were above the ADI, indicating that individuals with high intake may be at risk of experiencing adverse effects after single and repeated exposure. Concerning the new application, the Panel concluded that the available data do not support the proposal for exemption.

Installing heat pumps instead of traditional gas boilers for heating purposes could lead to a drastic reduction in the consumption of natural gas in Germany, according to numerical simulations that combine gas and electricity markets

After decades of presuming that climate adaptation is a private good benefitting only those receiving resources to reduce individual climate risks, respondents in a survey experiment among the climate-vulnerable in Bangladesh chose less-particularistic adaptation projects than “electoral connection” disaster relief theories predict and more “short-sighted” projects than international diplomats anticipate. This article reports on the experiment, which asked a representative national sample of Bangladeshis whether they favor spending funds on short-term particularistic solutions (disaster relief stockpiles), medium-term inclusionary and non-excludable solutions (ocean embankments), or long-term, public goods solutions (the development of flood-resistant rice seeds). More respondents chose “middle ground” embankment spending, and a statistically significant change in respondent propensities was tied to their lived experience with climate vulnerability rather than electoral incentives. The logic of their choices contradicts existing explanations, implying that a reconsideration of vulnerable community preferences, and how to address them, may be needed.

Abstract 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.

Abstract 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.

Abstract The EFSA Panel on Food Additives and Flavourings (FAF) was requested to evaluate the safety of the smoke flavouring Primary Product Smoke Concentrate 809045 (SF‐003), 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. Product Smoke Concentrate 809045 is obtained by pyrolysis of beech wood. 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 0.1 to 1.5 mg/kg body weight (bw) per day at the mean and from 0.2 to 5.2 mg/kg bw per day at the 95th percentile. The Panel concluded that eleven 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.

Abstract The EFSA Panel on Food Additives and Flavourings (FAF) was requested to evaluate the safety of the smoke flavouring Primary Product proFagus Smoke R714 (SF‐001), 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 R714 is obtained by pyrolysis of beech and oak woods as main source materials. Based on the compositional data, the Panel noted that the identified and quantified proportion of the solvent‐free fraction amounts to 39 weight (wt)%, thus the applied method does not meet the legal quality criterion that at least 50% of the solvent‐free fraction shall be identified and quantified. At the maximum proposed use levels, dietary exposure estimates calculated with DietEx ranged from 0.7 to 10.9 mg/kg body weight (bw) per day at the mean and from 2.2 to 42.5 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 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.

Abstract The EFSA Panel on Food Additives and Flavourings (FAF) was requested to evaluate the safety of the smoke flavouring Primary Product Fumokomp (SF‐009), for which a renewal application was submitted in accordance with Article 12(1) of Regulation (EC) No 2065/2003 (in the renewal application the Primary Product is reported as ‘Fumokomp Conc.’). This opinion refers to an assessment of data submitted on chemical characterisation, dietary exposure and genotoxicity of the Primary Product. Fumokomp Conc. is produced by pyrolysis of beech and hornbeam woods. Gas chromatography–mass spectrometry (GC–MS) was applied for both identification and quantification of the volatile constituents of the Primary Product. Given the limitations of the method, the Panel cannot judge with confidence whether the applied method meets the legal quality criterion that at least 80% of the volatile fraction shall be identified and quantified. Moreover, the Panel concluded that the absence of furan‐2(5H)‐one from the Primary Product was not convincingly demonstrated. At the maximum proposed use levels, dietary exposure estimates calculated with FAIM ranged from 0.04 to 0.9 mg/kg body weight (bw) per day at the mean and from 0.1 to 1.5 mg/kg bw per day at the 95th percentile. The information available on the 32 identified components of the Primary Product, although limited, did not indicate a concern for genotoxicity for any of these substances. However, whole mixture testing in an in vitro mouse lymphoma assay gave positive results which would require an adequate in vivo follow‐up study. In addition, the potential for aneugenicity of the Primary Product has not been adequately investigated. Accordingly, the potential safety concern for genotoxicity of the Primary Product cannot be ruled out.

Abstract 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.

Abstract The EFSA Panel on Food Additives and Flavourings (FAF) was requested to evaluate the safety of the smoke flavouring Primary Product Scansmoke SEF7525 (SF‐004), 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. Scansmoke SEF7525 is obtained from a tar produced from a mixture of red oak, white oak, maple, beech and hickory. Based on the compositional data, the Panel noted that the identified and quantified proportion of the solvent‐free fraction amounts to 32.6 weight (wt)%, thus the applied method does not meet the legal quality criterion that at least 50% of the solvent‐free fraction shall be identified and quantified. At the maximum proposed use levels, dietary exposure estimates calculated with Food Additive Intake Model (FAIM) ranged from 0.6 to 3.8 mg/kg body weight (bw) per day at the mean and from 1.1 to 10.1 mg/kg bw per day at the 95th percentile. Based on the available information on genotoxicity on 44 identified components, the Panel concluded that two substances in the Primary Product, styrene and benzofuran, raise a potential concern for genotoxicity. In addition, a potential concern for genotoxicity was identified for the unidentified part of the mixture. Considering that the exposure estimates for styrene and benzofuran are above the threshold of toxicological concern (TTC) value of 0.0025 kg/kg bw per day for DNA‐reactive mutagens and/or carcinogens and since further data are needed to clarify their potential genotoxicity, the Panel concluded that the potential safety concern for genotoxicity of the Primary Product cannot be ruled out.

Summary: The combination of pamapimod and pioglitazone (KIN001) has a synergetic antiviral, anti-inflammatory, and antifibrotic activity, which may prevent evolution toward COVID-19-associated severe respiratory failure. In a randomized, placebo-controlled, double-blind, phase 2, multicenter trial, 128 non-critically ill hospitalized patients with confirmed COVID-19 were treated with KIN001 or a placebo for 28 days. The proportion of patients alive and free of oxygen or respiratory support at the end of the therapy was lower than anticipated but not different in the two groups (KIN001 n = 19, 29%, placebo n = 21, 33%). 85 participants had at least one adverse event, with no difference in the number and distribution of events between the two groups. The clinical trial was stopped for futility, mainly due to a lower-than-expected incidence of the primary endpoint. KIN001 was safe and well-tolerated but had no significant effect on clinical outcome.

Abstract Glycerol esters of wood rosin (GEWR) (E 445) were re‐evaluated in 2018. On the toxicity database and given the absence of reproductive and developmental toxicity data, the acceptable daily intake (ADI) of 12.5 mg/kg body weight (bw) per day for GEWR (E 445) established by the Scientific Committee on Food (SCF) in 1994 was considered temporary. The conclusions of the assessment were restricted to GEWR derived from Pinus palustris and Pinus elliottii and with a chemical composition in compliance with GEWR used in the toxicological testing. Following a European Commission call for data to submit data to fill the data gaps, the present follow‐up opinion assesses data provided by interested business operators (IBOs). Considering the technical data submitted by IBOs, the EFSA Panel on Food Additives and Flavourings (FAF Panel) recommended some modifications of the existing EU specifications for E 445, mainly a revision of the definition of the food additive and lowering the limits for toxic elements. Considering the available toxicological database evaluated during the re‐evaluation of E 445 by the ANS Panel in 2018, and the toxicological studies submitted by the IBOs, the Panel established an ADI of 10 mg/kg bw per day based on the no observed adverse effect level (NOAEL) of 976 mg/kg bw per day from the newly available dietary reproduction/developmental toxicity screening study in rats and applying an uncertainty factor of 100. Since GEWR from P. palustris and P. elliottii were tested in the toxicity studies considered to establish the ADI and in the absence of detailed information on the chemical composition (major constituents) in GEWR generated from other Pinus species, thus not allowing read across, the ADI is restricted to the GEWR (E 445) manufactured from P. palustris and P. elliottii. The Panel concluded that there was no safety concern for the use of GEWR (E 445), at either the maximum permitted levels or at the reported uses and use levels.

Abstract Calcium carbonate (E 170) was re‐evaluated in 2011 by the former EFSA Panel on Food Additives and Nutrient sources added to Food (ANS). As a follow‐up to this assessment, the Panel on Food Additives and Flavourings (FAF) was requested to assess the safety of calcium carbonate (E 170) for its uses as a food additive in food for infants below 16 weeks of age belonging to food category 13.1.5.1 (Dietary foods for infants for special medical purposes and special formulae for infants) and as carry over in line with Annex III, Part 5 Section B to Regulation (EC) No 1333/2008. In addition, the FAF Panel was requested to address the issues already identified during the re‐evaluation of the food additive when used in food for the general population. The process involved the publication of a call for data to allow the interested business operators (IBOs) to provide the requested information to complete the risk assessment. The Panel concluded that there is no need for a numerical acceptable daily intake (ADI) for calcium carbonate and that, in principle, there are no safety concern with respect to the exposure to calcium carbonate per se at the currently reported uses and use levels in all age groups of the population, including infants below 16 weeks of age. With respect to the calcium intake resulting from the use of E 170 in food for the general population and infants

Abstract Indigo carmine (E 312) was re‐evaluated in 2014 by the EFSA Panel on Food Additives and Nutrient sources added to Food (ANS). The ANS Panel confirmed the acceptable daily intake (ADI) of 5 mg/kg body weight (bw) per day for indigo carmine allocated by JECFA (1975). The ANS Panel indicated that the ADI was applicable to a material with a purity of 93% pure colouring and manufactured using processes resulting in comparable residuals as material used in the Borzelleca et al. studies (1985, 1986) and Borzelleca and Hogan (1985) which were the basis for deriving the ADI. The ANS Panel considered that any extension of the ADI to indigo carmine of lower purity and/or manufactured using a different process would require new data to address the adverse effects on the testes observed in the Dixit and Goyal (2013) study. Following a European Commission call for data to submit data to fill the data gaps, an IBO submitted technical and toxicological data. Considering the technical data, the EFSA Panel on Food Additives and Flavourings (FAF Panel) recommended some modifications of the existing EU specifications for E 132, mainly to lower the limits for toxic elements. Considering the toxicological data, an IBO has submitted a 56‐day dietary study to address the adverse effects on testes using a material with 88% purity. The results of this study submitted did not confirm the severe adverse effects observed in the Dixit and Goyal study. Considering all the available information, the Panel confirmed the ADI of 5 mg/kg bw per day for indigo carmine (E 132) disodium salts, meeting the proposed revisions of the specifications (85% minimum for the colouring matter). The Panel concluded that there is no safety concern for the use of indigo carmine (E 132) disodium salts at the reported use levels and submitted analytical data.

Abstract Xanthan gum (E 415) was re‐evaluated in 2017 by the former EFSA Panel on Food Additives and Nutrient sources added to Food. As a follow‐up to that assessment, the Panel on Food Additives and Flavourings (FAF) was requested to assess the safety of xanthan gum (E 415) for its uses as a food additive in food for infants below 16 weeks of age belonging to food category (FC) 13.1.5.1 (Dietary foods for infants for special medical purposes and special formulae for infants). In addition, the FAF Panel was requested to address the issues already identified during the re‐evaluation of the food additive when used in food for the general population. The process involved the publication of a call for data to allow the interested business operators to provide the requested information to complete the risk assessment. The Panel concluded that the technical data provided by the interested business operators support an amendment of the specifications for E 415 laid down in Commission Regulation (EU) No 231/2012. Due to the low validity of the available clinical studies, the Panel concluded that a reference point could not be derived from them but the results of the available studies on neonatal piglets could serve to derive a reference point. The Panel calculated the margin of exposure for infants below 16 weeks of age consuming food for special medical purposes (FC 13.1.5.1) for the highest xanthan gum exposure and concluded that there are no safety concerns for the use of xanthan gum (E 415) as a food additive in FC 13.1.5.1.

Abstract The Panel on Food Additives and Flavourings of the European Food Safety Authority was requested to evaluate the genotoxic potential of four flavouring substances [FL‐no: 10.023, 10.030, 10.057 and 13.012] from subgroup 4.1 of FGE.19. For three of these substances [FL‐no: 10.023, 10.030 and 13.012], the concern for genotoxicity has been ruled out in previous revisions of Flavouring Group Evaluation 217 (FGE.217). However, in FGE.217Rev2, a concern for genotoxicity could not be ruled out for 3a,4,5,7a‐tetrahydro‐3,6‐dimethylbenzofuran‐2(3H)‐one [FL‐no: 10.057]. After publication of FGE.217Rev2, industry provided additional genotoxicity studies for [FL‐no: 10.057], which are evaluated in the present opinion FGE.217Rev3. The flavouring substance [FL‐no: 10.057] did not induce gene mutations or numerical or structural chromosomal aberrations in vitro. Based on these data, the Panel concluded that the concern for genotoxicity is ruled out for [FL‐no: 10.057]. Consequently, it can be evaluated through the Procedure.

Abstract Sucrose esters of fatty acids (E 473) was re‐evaluated in 2004 by the former EFSA Panel on Food Additives, Flavourings, Processing Aids and Materials in Contact with Food (AFC Panel). In addition, the former EFSA Panel on Food Additives and Nutrient Sources added to Food (ANS Panel) issued scientific opinions on the safety of sucrose esters of fatty acids (E 473) in 2010, 2012 and 2018. As a follow‐up to these assessments, the Panel on Food Additives and Flavourings (FAF) was requested to assess the safety of sucrose esters of fatty acids (E 473) for its uses as food additive in food for infants below 16 weeks of age. In addition, the FAF Panel was requested to address the issues already identified by the EFSA AFC and ANS Panels when used in food for the general population. The process involved the publication of calls for data to allow the interested business operators to provide the requested information to complete the risk assessment. The Panel concluded that the technical data provided by the interested business operators support an amendment of the specifications for sucrose esters of fatty acids (E 473) laid down in Commission Regulation (EU) No 231/2012. According to the available information, E 473 is not used in food categories (FCs) 13.1.1 and 13.1.5.1, including all types of food for infants below 16 weeks of age, and in FC 13.1.5.2. As a consequence, an assessment of the safety for the uses of E 473 as food additive in these FCs and age group was not performed. When the updated exposure estimates considering the provided use levels for some food categories are taken into account the estimates of exposure to sucrose esters of fatty acids (E 473) exceeded the group acceptable daily intake (ADI) of 40 mg/kg body weight (bw) per day for many population groups.

Abstract The Panel on Food Additives and Flavourings (FAF) was requested to consider the JECFA evaluations of 28 flavouring substances in the Flavouring Group Evaluation 76 (FGE.76Rev2). Twenty‐one of these substances have been considered in FGE.76Rev1. Seven substances could not be evaluated, because of concerns with respect to genotoxicity. New genotoxicity data have been provided for 4‐methyl‐5‐vinylthiazole [FL‐no: 15.018] and 4,5‐dimethyl‐2‐isobutyl‐3‐thiazoline [FL‐no: 15.032], which are representative substances of [FL‐no: 15.005] and [FL‐no: 15.029, 15.030, 15.130 and 15.131], respectively. The Panel concluded that the concern for genotoxicity is ruled out for [FL‐no: 15.018 and 15.005]. The concerns for gene mutations and clastogenicity are ruled out for [FL‐no: 15.032, 15.029, 15.030, 15.130 and 15.131]. In vitro, [FL‐no: 15.032] induced micronuclei through an aneugenic mode of action. The available in vivo micronucleus study was not adequate to rule out the concern for potential aneugenicity in vivo. The Panel compared the lowest concentration resulting in aneugenicity in vitro with the use levels reported for [FL‐no: 15.032]. Based on this comparison, the Panel concluded that the use of [FL‐no: 15.032] at the maximum reported use levels does not raise a concern for aneugenicity. Based on structural similarity, for the remaining four substances [FL‐no: 15.029, 15.030, 15.130 and 15.131], an aneugenic potential may also be anticipated. Individual genotoxicity data are needed to establish whether they have aneugenic potential. The Panel agrees with JECFA conclusions for 24 flavouring substances ‘No safety concern at estimated levels of intake as flavouring substances’ when based on the MSDI approach. For six substances, more reliable information on uses and use levels are needed to refine the mTAMDI estimates. For 15 substances, use levels are needed to calculate the mTAMDIs. For [FL‐no: 15.109 and 15.113], information on the actual stereochemical composition is inadequate and the conclusion reached for the named substances cannot be applied to the materials of commerce.

Abstract Locust bean gum (E 410) was re‐evaluated in 2017 by the former EFSA Panel on Food Additives and Nutrient sources added to Food (ANS). As a follow‐up to that assessment, the Panel on Food Additives and Flavourings (FAF) was requested to assess the safety of locust bean gum (E 410) for its uses as a food additive in food for infants below 16 weeks of age belonging to food category 13.1.5.1 (Dietary foods for infants for special medical purposes and special formulae for infants). In addition, the FAF Panel was requested to address the issues already identified during the re‐evaluation of the food additive when used in food for the general population, including the safety assessment for FC 13.1.5.1 and 13.1.5.2 (Dietary foods for babies and young children for special medical purposes as defined in directive 1999/21/EC). The process involved the publication of a call for data. Based on the received data, the Panel concluded that the technical data provided by the interested business operators support an amendment of the specifications for locust bean gum (E 410) laid down in Commission Regulation (EU) No 231/2012. The Panel identified a reference point of 1,400 mg/kg bw per day based on reduced blood zinc levels in a piglet study. It applied the margin of exposure (MoE) for the safety assessment of locust bean gum (E 410) when used as a food additive in FC 13.1.5.1 and 13.1.5.2. The Panel concluded that a MoE above 1 would not raise a safety concern. A MoE above 1 was obtained for some of the scenarios and exposure levels for infants. For toddlers (consumers only of food for special medical purposes), the MoE was above 1 for all exposure levels.

Abstract 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.

Abstract Sodium carboxy methyl cellulose (E 466) was re‐evaluated in 2018 by the former EFSA Panel on Food Additives and Nutrient sources added to Food (ANS). As a follow‐up to this assessment, the Panel on Food Additives and Flavourings (FAF) was requested to assess the safety of E 466 for its uses as a food additive in food for infants below 16 weeks of age belonging to food categories (FC) 13.1.5.1 (Dietary foods for infants for special medical purposes and special formulae for infants) in line with Regulation (EC) No 1333/2008. In addition, the FAF Panel was requested to address the issues already identified during the re‐evaluation of the food additive when used in food for the general population, including the safety assessment for FC 13.1.5.1 and 13.1.5.2 (Dietary foods for babies and young children for special medical purposes as defined in directive 1999/21/EC). The process involved the publication of a call for data. Based on the received data, the Panel concluded that the technical data provided by the interested business operator support an amendment of the specifications for sodium carboxy methyl cellulose (E 466) laid down in Commission Regulation (EU) No 231/2012. The interested business operators declared that E 466 is not used in food for infants below 16 weeks of age and in FC 13.1.5.1. Due to the lack of data, an assessment has not been performed for this FC and age group. The interested business operators did not provide biological and toxicological data to support the uses of E 466 in FC 13.1.5.2. Due to the almost unchanged database compared to the situation before the call for data, the FAF Panel confirmed the previous EFSA ANS Panel conclusion according to which the available data did not allow for an adequate assessment of the safety of use of sodium carboxy methyl cellulose (E 466) in infants and young children consuming foods belonging to the FC 13.1.5.2. ©2022 European Food Safety Authority. EFSA Journal published by John Wiley and Sons Ltd on behalf of European Food Safety Authority.

Abstract Following a request from the European Commission, EFSA developed a new scientific guidance to assist applicants in the preparation of applications for the authorisation of flavourings to be used in or on foods. This guidance applies to applications for a new authorisation as well as for a modification of an existing authorisation of a food flavouring, submitted under Regulation (EC) No 1331/2008. It defines the scientific data required for the evaluation of those food flavourings for which an evaluation and approval is required according to Article 9 of Regulation (EC) No 1334/2008. This applies to flavouring substances, flavouring preparations, thermal process flavourings, flavour precursors, other flavourings and source materials, as defined in Article 3 of Regulation (EC) No 1334/2008. Information to be provided in all applications relates to: (a) the characterisation of the food flavouring, including the description of its identity, manufacturing process, chemical composition, specifications, stability and reaction and fate in foods; (b) the proposed uses and use levels and the assessment of the dietary exposure and (c) the safety data, including information on the genotoxic potential of the food flavouring, toxicological data other than genotoxicity and information on the safety for the environment. For the toxicological studies, a tiered approach is applied, for which the testing requirements, key issues and triggers are described. Applicants should generate the data requested in each section to support the safety assessment of the food flavouring. Based on the submitted data, EFSA will assess the safety of the food flavouring and conclude whether or not it presents risks to human health and to the environment, if applicable, under the proposed conditions of use.

Abstract The present opinion deals with the re‐evaluation of neohesperidine dihydrochalcone (E 959) when used as a food additive. It is obtained by catalytic hydrogenation of a flavanone – neohesperidine – which is naturally occurring and thus isolated by alcohol extraction in bitter oranges (Citrus aurantium). Based on in vivo data in rat, neohesperidine dihydrochalcone is likely to be absorbed, also in humans, and to become systemically available. It does not raise a concern regarding genotoxicity. The toxicity data set consisted of studies on subchronic and prenatal developmental toxicity. No human studies were available. The data set was considered sufficient to derive a new acceptable daily intake (ADI). Based on the weight of evidence (WoE) analysis, the Panel considered unlikely that neohesperidine dihydrochalcone would lead to adverse effects on health in animals in the dose ranges tested. The Panel also considered that a carcinogenicity study was not warranted and that the lack of human data did not affect the overall confidence in the body of evidence. The Panel derived an ADI of 20 mg/kg bodyweight (bw) per day based on a no observed adverse effect level (NOAEL) of 4,000 mg/kg bw per day from a 13‐week study in rat, applying the standard default factors of 100 for inter‐ and intraspecies differences and of 2 for extrapolation from subchronic to chronic exposure. For the refined brand‐loyal exposure assessment scenario, considered to be the most appropriate for the risk assessment, the exposure estimates at the mean ranged from

Abstract Sulfur dioxide–sulfites (E 220–228) were re‐evaluated in 2016, resulting in the setting of a temporary ADI of 0.7 mg SO2 equivalents/kg bw per day. Following a European Commission call for data, the present follow‐up opinion assesses data provided by interested business operators (IBOs) and additional evidence identified in the publicly available literature. No new biological or toxicological data addressing the data gaps described in the re‐evaluation were submitted by IBOs. Taking into account data identified from the literature search, the Panel concluded that there was no substantial reduction in the uncertainties previously identified in the re‐evaluation. Therefore, the Panel considered that the available toxicity database was inadequate to derive an ADI and withdrew the current temporary group acceptable daily intake (ADI). A margin of exposure (MOE) approach was considered appropriate to assess the risk for these food additives. A lower confidence limit of the benchmark dose of 38 mg SO2 equivalents/kg bw per day, which is lower than the previous reference point of 70 mg SO2 equivalents/kg bw per day, was estimated based on prolonged visual evoked potential latency. An assessment factor of 80 was applied for the assessment of the MoE. At the estimated dietary exposures, when using a refined exposure scenario (Data set D), MOEs at the maximum of 95th percentile ranges were below 80 for all population groups except for adolescents. The dietary exposures estimated using the maximum permitted levels would result in MOEs below 80 in all population groups at the maximum of the ranges of the mean, and for most of the population groups at both minimum and maximum of the ranges at the 95th percentile. The Panel concluded that this raises a safety concern for both dietary exposure scenarios. The Panel also performed a risk assessment for toxic elements present in sulfur dioxide–sulfites (E 220–228), based on data submitted by IBOs, and concluded that the maximum limits in the EU specifications for arsenic, lead and mercury should be lowered and a maximum limit for cadmium should be introduced.

Abstract The Scientific Committee (SC) reconfirms that the benchmark dose (BMD) approach is a scientifically more advanced method compared to the no‐observed‐adverse‐effect‐level (NOAEL) approach for deriving a Reference Point (RP). The major change compared to the previous Guidance (EFSA SC, 2017) concerns the Section 2.5, in which a change from the frequentist to the Bayesian paradigm is recommended. In the former, uncertainty about the unknown parameters is measured by confidence and significance levels, interpreted and calibrated under hypothetical repetition, while probability distributions are attached to the unknown parameters in the Bayesian approach, and the notion of probability is extended to reflect uncertainty of knowledge. In addition, the Bayesian approach can mimic a learning process and reflects the accumulation of knowledge over time. Model averaging is again recommended as the preferred method for estimating the BMD and calculating its credible interval. The set of default models to be used for BMD analysis has been reviewed and amended so that there is now a single set of models for quantal and continuous data. The flow chart guiding the reader step‐by‐step when performing a BMD analysis has also been updated, and a chapter comparing the frequentist to the Bayesian paradigm inserted. Also, when using Bayesian BMD modelling, the lower bound (BMDL) is to be considered as potential RP, and the upper bound (BMDU) is needed for establishing the BMDU/BMDL ratio reflecting the uncertainty in the BMD estimate. This updated guidance does not call for a general re‐evaluation of previous assessments where the NOAEL approach or the BMD approach as described in the 2009 or 2017 Guidance was used, in particular when the exposure is clearly lower (e.g. more than one order of magnitude) than the health‐based guidance value. Finally, the SC firmly reiterates to reconsider test guidelines given the wide application of the BMD approach.

Abstract 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.

Abstract The EFSA Panel on Food Additives and Flavourings (FAF) provides a scientific opinion on the safety of buffered vinegar as a new food additive. Buffered vinegar is a liquid or dried product prepared by adding sodium/potassium hydroxides (E 524 to E 525) and sodium/potassium carbonates (E 500 to E 501) to vinegar, compliant with European Standard EN 13188:2000 and exclusively obtained from an agricultural source origin (except wood/cellulose). The primary constituents of buffered vinegar are acetic acid and its salts. No biological or toxicological data obtained with the proposed food additive were submitted by the applicant as part of the dossier as, following oral ingestion, buffered vinegar dissociates into the acetic anion a natural constituent of the diet, and of the human body for which extensive data on their biological effects exist and for which EFSA in 2013 has previously concluded that the establishment of an acceptable daily intake (ADI) is not considered necessary. At the proposed maximum/typical use levels, the mean exposure to buffered vinegar from its use as a food additive expressed as acetic acid equivalents ranged from 8.9 mg/kg body weight (bw) per day in infants to 280.3 mg/kg bw per day in children. The 95th percentile of exposure to buffered vinegar ranged from 27.9 mg/kg bw per day in infants to 1,078 mg/kg bw per day in toddlers. The Panel concluded that there is no safety concern for the use of buffered vinegar as a food additive at the proposed maximum/typical use levels. The Panel could not conclude on the safety for the proposed uses at quantum satis as Group I food additive since the resulting exposure could not be estimated.

Abstract 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.

Abstract Glycerol (E 422) was re‐evaluated in 2017 by the former EFSA Panel on Food Additives and Nutrient sources added to Food (ANS). As a follow‐up to that assessment, in this opinion, the Panel on Food Additives and Flavourings (FAF) addresses the data gaps identified to support an amendment of the EU specifications for E 422 in Commission Regulation (EU) No 231/2012. The Panel performed a risk assessment of undesirable impurities present in E 422. The Panel concluded that the maximum limits in the EU specifications for the four toxic elements (arsenic, lead, mercury and cadmium) should be lowered based on actual levels in the commercial food additive E 422. The Panel recommended setting a numerical limit value for acrolein in the specifications for E 422. The potential exposure to free 3‐monochloropropanediol at the maximum limit of 0.1 mg/kg, as laid out in the specifications for E 422, does not give rise to a health concern. The Panel recommended to consider modifying the definition of E 422 in Commission Regulation (EU) No 231/2012 indicating that E 422 is obtained only from vegetable oils and fats and undergoes purification processes that involve distillation, and other clean up steps to obtain refined glycerol. Overall, the Panel concluded that the technical data provided support an amendment of the specifications for glycerol (E 422).

Abstract Background To evaluate our hypotheses that, when rheumatoid arthritis (RA) flares postpartum, gene expression patterns are altered compared to (a) healthy women, (b) RA women whose disease activity is low or in remission postpartum, and (c) pre-pregnancy expression profiles. Methods Twelve women with RA and five healthy women were included in this pilot study. RA disease activity and postpartum flare were assessed using the Clinical Disease Activity Index (CDAI). Total RNA from frozen whole blood was used for RNA sequencing. Differential gene expression within the same women (within-group) over time, i.e., postpartum vs. third trimester (T3) or pre-pregnancy (T0), were examined, using a significance threshold of q

Abstract Polyglycerol polyricinoleate (PGPR, E 476) was re‐evaluated in 2017 by the former EFSA Panel on Food Additives and Nutrient sources added to Food (ANS). As a follow‐up to this assessment, in this opinion, the Panel on Food Additives and Flavouring (FAF) addresses the data gaps identified to support an amendment of the EU specifications for E 476. Additionally, this opinion deals with the assessment of the proposed extension of use for E 476 in edible ices and a revision of the maximum permitted level in emulsified sauces. The Panel concluded that the proposed extension of use, if authorised, would not give rise to a safety concern. Additionally, the Panel performed a risk assessment of undesirable impurities potentially present in E 476. The Panel concluded that the maximum limits in the EU specifications for the four toxic elements (arsenic, lead, mercury, cadmium) should be lowered based on actual levels in the commercial food additive E 476. The Panel also concluded that maximum limits for glycidyl esters and 3‐monochloropropanediol should be included in the EU specifications for E 476. Alternatively, the Panel recommends an amendment of the definition of E 476 to include a requirement that the fats and oils used in the manufacturing of E 476 comply with the respective EU legislation regarding suitability for human consumption. Further, the Panel recommends a modification of the definition of E 476 indicating that polyglycerol used for the manufacturing of E 476 should be produced from glycerol meeting the specifications for E 422 (Commission Regulation (EU) No 231/2012). In this case, respective specification limits for epichlorohydrin, acrolein and butanetriol would not be needed for E 476. Finally, the Panel concluded that the proposed method based on the determination of ricinoleic acid is suitable for the determination of E 476 content in food.

Abstract Polyglycerol esters of fatty acids (PEFA, E 475) was re‐evaluated in 2017 by the former EFSA Panel on Food Additives and Nutrient sources added to Food (ANS). As a follow‐up to this assessment, in this opinion, the Panel on Food Additives and Flavouring (FAF) addresses the data gaps identified to support an amendment of the EU specifications for E 475. The Panel performed a risk assessment of undesirable impurities and constituents potentially present in E 475. The Panel concluded that the maximum limits in the EU specifications for the 4 toxic elements (arsenic, lead, mercury and cadmium) should be lowered based on actual levels in the commercial food additive E 475. The Panel also concluded that maximum limits for erucic acid, 3‐monochloropropanediol and glycidyl esters should be included in the EU specifications for E 475. Alternatively, the Panel recommends an amendment of the definition of E 475 to include a requirement that the fats and oils used in the manufacturing of E 475 comply with the respective EU legislation regarding suitability for human consumption. Further, the Panel concluded that there is no need for setting a specification limit for the content of trans‐fatty acids in E 475 as a limit is established in the Regulation (EU) No 2019/649, i.e. 2 g of trans‐fat per 100 g fat in food for the final consumer. Finally, the Panel recommends a modification of the definition of E 475 indicating that polyglycerol used for the manufacturing of E 475 should be produced from glycerol meeting the specifications for E 422 (Commission Regulation (EU) No 231/2012). In this case, respective specification limits for epichlorohydrin, acrolein and butanetriol would not be needed for E 475.

Abstract The EFSA Panel on Food Additives and Flavourings (FAF Panel) provides a scientific opinion on the safety of a proposed amendment of the specifications of enzymatically produced steviol glycosides (E 960c) with respect to the inclusion of rebaudioside D produced via enzyme‐catalysed bioconversion of purified stevia leaf extract. Rebaudioside D (95% on dry basis) is produced via enzymatic bioconversion of purified stevia leaf extract using uridine diphosphate (UDP)‐glucosyltransferase (UGT) and sucrose synthase enzymes produced by the genetically modified yeast K. phaffii UGT‐A, that facilitates the transfer of glucose to purified stevia leaf extract via glycosidic bonds. The same enzymes from K. phaffii UGT‐A may be used in the manufacturing process of the food additive, rebaudioside M produced via enzyme modification of steviol glycosides from stevia (E 960c(i)). The Panel considered that separate specifications would be needed for this food additive produced via the manufacturing process described in the current application, aligned with those already established for E 960c(i). The Panel concluded that there is no toxicological concern for Rebaudioside D produced via enzymatic bioconversion of purified stevia leaf extract using UDP‐glucosyltransferase and sucrose synthase produced by a genetically modified strain of the yeast K. phaffii. However, based on the available data, the Panel could not exclude the possibility that some residual amount of DNA coding for the kanamycin resistance gene could remain in the final product. Should this gene propagate in microbiota due to the presence of recombinant DNA in the final product, this would be of concern. Therefore, the Panel concluded that the safety of Rebaudioside D produced via this enzymatic bioconversion was not sufficiently demonstrated with the available data given that the absence of recombinant DNA was not shown.