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Abstract The European Commission requested EFSA to update the scientific guidance for the preparation of applications for authorisation of novel foods, previously developed following the adoption of Regulation (EU) 2015/2283 on novel foods. This guidance document provides advice on the scientific information needed to be submitted by the applicant towards demonstrating the safety of the novel food. Requirements pertain to the description of the novel food, production process, compositional data, specifications, proposed uses and use levels and anticipated intake of the novel food. Furthermore, information needed in sections on the history of use of the novel food and/or its source, absorption, distribution, metabolism, excretion, toxicological information, nutritional information and allergenicity is also described. The applicant should integrate and interpret the data presented in the different sections to provide their overall considerations on how the information supports the safety of the novel food under the proposed conditions of use. Where potential health hazards have been identified, they are to be discussed in relation to the anticipated intake of the novel food and the proposed target populations. On the basis of the information provided, EFSA will assess the safety of the novel food under the proposed conditions of use.

The European Union (EU) is committed to transitioning toward a circular economy model, with food waste being one of the areas to be targeted. To close the loop of food waste generated during food processing and discarded at the retail or consumption phases, research and innovation parties proposed to valorize agro-food by-products to produce novel foods and food improvement agents (food additives, food enzymes, and food flavorings). In the EU, the authorization of such novel foods and food improvement agents is governed by different regulatory frameworks. A centralized safety assessment by the European Food Safety Authority (EFSA) is the prerequisite for their authorization through the so-called Union Lists. Up to December 2023, EFSA published 45 scientific opinions on the safety of novel foods, food enzymes, and food additives derived from by-products of plant and animal origin. The current study illustrates examples of these by-products for the production of novel foods or food improvement agents and the data requirements behind their respective safety assessments conducted by EFSA. In this review, applications on novel foods, food enzymes, and food additives received by EFSA were screened and analyzed to find the common scientific requirements and differences in terms of the safety evaluation of such products. Various by-products (i.e., corncobs, coffee husks, spent grains of barley and rice, grape pomace, pumpkin peels, bovine whey, eggshells, shrimp heads, and animal organs or tissues) were described in the applications as being processed (extraction, physical treatments, and chemical and enzymatic reactions) to obtain novel foods and food improvement agents. The heterogeneity and complexity of these products emphasize the challenge of their safety assessment, depending on the characteristics of each product. However, as this study shows, the scientific requirements underpinning their safety do not differ substantially in the different regulated product areas considered, with similar information needed to assess their safety in terms of identity, production process, compositional characterization, proposed/intended uses and exposure assessment, toxicological information, and allergenicity data. Additional nutritional information and data on the history of use are required in the case of novel foods.

Abstract The European Commission has determined that cannabidiol (CBD) can be considered as a novel food (NF), and currently, 19 applications are under assessment at EFSA. While assessing these, it has become clear that there are knowledge gaps that need to be addressed before a conclusion on the safety of CBD can be reached. Consequently, EFSA has issued this statement, summarising the state of knowledge on the safety of CBD consumption and highlighting areas where more data are needed. Literature searches for both animal and human studies have been conducted to identify safety concerns. Many human studies have been carried out with Epidyolex®, a CBD drug authorised to treat refractory epilepsies. In the context of medical conditions, adverse effects are tolerated if the benefit outweighs the adverse effect. This is, however, not acceptable when considering CBD as a NF. Furthermore, most of the human data referred to in the CBD applications investigated the efficacy of Epidyolex (or CBD) at therapeutic doses. No NOAEL could be identified from these studies. Given the complexity and importance of CBD receptors and pathways, interactions need to be taken into account when considering CBD as a NF. The effects on drug metabolism need to be clarified. Toxicokinetics in different matrices, the half‐life and accumulation need to be examined. The effect of CBD on liver, gastrointestinal tract, endocrine system, nervous system and on psychological function needs to be clarified. Studies in animals show significant reproductive toxicity, and the extent to which this occurs in humans generally and in women of child‐bearing age specifically needs to be assessed. Considering the significant uncertainties and data gaps, the Panel concludes that the safety of CBD as a NF cannot currently be established.

Abstract Following a request from the European Commission, the EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA) was asked to deliver an opinion on iron hydroxide adipate tartrate as a novel food (NF) pursuant to Regulation (EU) 2015/2283 and as a source of iron in the context of Directive 2002/46/EC. The NF is intended to be used in food supplements up to a maximum dose of 100 mg per day, corresponding to a maximum daily intake of iron of 36 mg. The target population proposed by the applicant is the general population above 3 years of age. The NF which is the subject of the application is an engineered nanomaterial having primary particles, of almost spherical morphology, with a diameter typically smaller than 5 nm. The studies provided for absorption, distribution, metabolism and excretion (ADME) and bioavailability indicate that iron, once taken up into the epithelial cells of the gut, is subject to the same mechanisms of regulation and absorption as that of other forms of iron. Further studies provided in the context of the toxicological assessment indicate that the NF does not lead to iron bioaccumulation in tissues and organs at the doses tested. The Panel notes that the NF contains nickel at concentrations that may increase the risk of flare‐up reactions in nickel‐sensitised young individuals up to 10 years of age. In the 90‐day toxicity study, findings related to haematology, clinical biochemistry and organ weights were observed and the Panel defined a no observed adverse effect level (NOAEL) of 231 mg/kg body weight (bw) per day, that is, the mid‐dose used in the study. The Panel considers that the NF is a source from which iron is bioavailable and it is safe under the proposed conditions of use.

Abstract Following a request from the European Commission, the EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA) was asked to deliver an opinion on selenite triglycerides as a novel food (NF) pursuant to Regulation (EU) 2015/2283, their safety when added for nutritional purposes to food supplements as a source of selenium and the bioavailability of selenium from this source, in the context of Directive 2002/46/EC. The proposed NF is the first lipophilic organic form of selenium so far described in the literature. It is composed by a mixture of individual Se‐containing lipids which do not occur in nature. The Panel considers that the information provided on the composition of the NF does not allow a complete characterisation of the product. From the data provided to characterise the absorption, distribution, metabolism and excretion of the NF, it cannot be established in which chemical form Se is systemically available and if it can enter the functional Se body pool to fulfil Se physiological functions. The Panel considers that, since it is not demonstrated that the NF is converted to a known form of Se following ingestion and absorption, the NF is to be treated as a xenobiotic with unknown properties in the body. From a subchronic toxicity study in rats, the Panel derives a lowest observed adverse effect level (LOAEL) for general toxicity of 2 mg Se/kg body weight (bw) per day based on findings indicating liver as a target organ, as it has been shown for other studies on dietary Se. The Panel concludes that the NF is absorbed and provides Se, but in an unknown form of which the bioavailability has not been determined. The Panel also concludes that the safety of the NF under the intended conditions of use cannot be established.

Abstract Following a request from the European Commission, the EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA) was asked to deliver a scientific opinion on the extension of use of calcium l‐methylfolate to be used as a source of folate added for nutritional purposes to infant and follow‐on formula, baby food and processed cereal‐based food pursuant to Regulation (EU) 609/2013. In 2004, EFSA assessed the use of calcium l‐methylfolate as a source of folate in foods for particular nutritional uses, food supplements and foods intended for the general population. The new alternative synthetic step proposed to produce the nutrient source, using platinum as a catalyst, did not raise any safety concern and the production process was found to consistently yield a product in line with the proposed specifications. Based on the studies assessed in the previous evaluation, it was concluded that calcium l‐methylfolate is non‐genotoxic and that subchronic and embryotoxicity/teratogenicity studies in rats did not reveal any adverse effects up to the highest doses tested. The Panel considered that no additional toxicological studies are required on the nutrient source. The intervention study in healthy infants provided by the applicant did not indicate differences in growth and tolerance parameters in infants who consumed either an infant formula supplemented with calcium l‐methylfolate or with folic acid, and did not raise concerns regarding safety or tolerability of the infant formula with the proposed nutrient source. The study also provided further supporting evidence for the bioavailability of calcium l‐methylfolate. The Panel considers that calcium l‐methylfolate is a source from which folate is bioavailable and concludes that calcium l‐methylfolate is safe under the proposed uses and use levels for infants and young children.

Abstract Following a request from the European Commission, the EFSA Panel on Nutrition, Novel Foods and Allergens (NDA) was asked to deliver an opinion on nicotinamide riboside chloride as a novel food (NF) pursuant to Regulation (EU) 2015/2283, including an evaluation of the safety of its use in food supplements as a source of niacin, and the bioavailability of nicotinamide from this source, in the context of Directive 2002/46/EC. The NF, a synthetic form of nicotinamide riboside, is proposed to be used in food supplements for the healthy adult population at levels up to 300 mg/day. The production process, composition, specifications, batch‐to‐batch variability and stability of the NF do not raise safety concerns. Animal and human data indicate that the NF contributes to the nicotinamide body pool. There are no concerns regarding genotoxicity. Human studies do not raise safety concerns. The proposed maximum use level corresponds to an amount of nicotinamide, which is sixfold lower than the tolerable upper intake level (UL) set for adults, excluding pregnant and lactating women. The margin of exposure (MoE) of 70 derived from repeated dose toxicity studies with rats and dogs is considered sufficient for the adult population, excluding pregnant and lactating women. Regarding these two population groups, the MoE of 76 derived from a developmental toxicity study in rats is considered insufficient in the absence of data which could justify accepting a MoE lower than 100. The Panel concludes that the NF is safe under the proposed conditions of use for the healthy adult population, excluding pregnant and lactating women, and that an intake of the NF up to 230 mg/day is safe for pregnant and lactating women. The Panel also concludes that the NF is a source from which nicotinamide, a form of niacin, is bioavailable.

Abstract In 2018, the EFSA NDA Panel adopted the Scientific Opinion on the safety of d‐ribose as a novel food pursuant to Regulation (EU) 2015/2283 when used in a variety of food, concluding that d‐ribose is safe for the general population at intake levels up to 36 mg/kg body weight (bw) per day, but that its safety at the intended uses and use levels as proposed by the applicant could not be established. Following a request from the European Commission, the EFSA NDA Panel was asked to carry out a supplementary safety assessment for d‐ribose by considering the new proposed uses and use levels submitted by the applicant. In order to address the present mandate, an intake assessment was carried out based on individual data from the EFSA Comprehensive European Food Consumption Database. Intakes were estimated for all age groups of the general population. The resulting ranges for the mean and high‐level estimated intakes of d‐ribose for all the population groups, including the target population groups, did not exceed the acceptable level of intake for the general population previously defined, i.e. 36 mg/kg bw per day, except for one survey on adolescents where the mean and 95th percentile of the intake estimates were 8.6 and 39.4 mg/kg bw per day, respectively. The Panel concludes that the novel food, d‐ribose, is safe under the new proposed conditions of use.

Abstract The present scientific opinion deals with the assessment of the bioavailability of magnesium, from the proposed nutrient source, magnesium citrate malate (MgCM), when added for nutritional purposes to food supplements. MgCM is a mixed salt consisting of magnesium cations and citrate and malate anions, and with a magnesium content of 12–15%. MgCM is proposed to be used in food supplements that are intended to provide up to 300–540 mg/day magnesium. The data provided demonstrate that the production process results in batches of MgCM that comply with the product specifications and that the product is stable throughout its proposed shelf life. The human studies provided demonstrate that magnesium from MgCM is bioavailable. However, the extent of its bioavailability per se or compared to other magnesium sources cannot be established due to the lack of an appropriate magnesium source as a comparator in the studies provided or relevant kinetic data for magnesium. One publication provided in the dossier reported that supplementation with MgCM decreases calcium absorption, but this finding was not supported by publications on different magnesium salts and therefore the Panel could not draw conclusions from this finding. The Panel concludes that MgCM is a source from which magnesium is bioavailable, but the extent of its bioavailability cannot be established. The Panel notes that at the proposed maximum use levels of MgCM, the existing tolerable upper intake level for magnesium in nutritional supplements, water, or added to food and beverages (250 mg/day) is exceeded.

Abstract The present opinion deals with the evaluation of the proposed increase of the currently authorised maximum amounts of ferric sodium ethylenediaminetetraacetic acid (EDTA) as a novel food ingredient used as a source of iron, and its extension of use in processed cereal‐based foods and baby foods. The applicant also provided information on two forms of ferric sodium EDTA, one previously assessed by EFSA and a new one of finer consistency. To support the proposed changes to the uses of ferric sodium EDTA, the applicant proposed a revision of the current acceptable daily intake (ADI) for EDTA, derived from that set for the food additive calcium disodium EDTA (E 385). The Panel confirmed that ferric sodium EDTA is a source from which iron is bioavailable. In assessing the safety of the proposed revision to the existing specifications for the novel food ingredient ferric sodium EDTA, the Panel noted that this would not discriminate between the previously evaluated substance and the one of finer consistency. In particular, the Panel noted that particle size was not one of the proposed parameters for the revised specifications. The Panel noted that it was not possible to determine whether particles of ferric sodium EDTA in the nano range were present in the product with finer consistency in the solid form. The toxicological data submitted did not add any new relevant information to the database on which the current ADI for EDTA is based. Consequently, the Panel concluded that there was no sound scientific justification to increase the ADI for EDTA and hence increase the use levels of ferric sodium EDTA or introduce additional uses as proposed by the applicant. The Panel recommended that additional toxicological data should be provided to address the shortcomings in the available toxicity database prior to the re‐evaluation of calcium disodium EDTA (E 385).

Abstract Following a request from the European Commission, the EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA) was asked to deliver an opinion on D‐ribose as a novel food (NF) pursuant to Regulation (EU) 2015/2283. The applicant intends to market the NF as ingredient in a variety of foods, food supplements and in certain foods for specific groups. The NF is produced by fermentation using a transketolase‐deficient strain of Bacillus subtilis and marketed as Bioenergy Ribose™. The information provided on the batch‐to‐batch variability, specifications, stability, production process and history of the organism used as a source of the NF is sufficient and does not raise safety concerns. The Panel considers that the effects observed in a subchronic toxicity study in rats could be the consequence of nutritional imbalances, but toxicological effects could not be ruled out; from this study, the Panel derived a No observed adverse effect level (NOAEL) of 3.6 g/kg body weight (bw) per day. From the human studies indicating a potential decrease in glucose levels and/or the occurrence of transient symptomatic hypoglycaemia at intakes of 10 g of d‐ribose, the Panel defined 70 mg/kg bw per day as the NOAEL with respect to hypoglycaemia that can be considered applicable for adults. For children, the Panel acknowledges the lack of human data directly relevant for this population group. Based on the NOAEL derived from the subchronic toxicity study in rats, an acceptable level of intake of 36 mg/kg bw per day was defined that would also take into account the potentially increased sensitivity of certain population groups to hypoglycaemia. The Panel concludes that the NF is safe for the general population at intake levels up to 36 mg/kg bw per day and considers that the safety of the NF at the intended uses and use levels as proposed by the applicant has not been established.

Abstract To meet the general requirement for transparency in EFSA's work, all its scientific assessments must consider uncertainty. Assessments must say clearly and unambiguously what sources of uncertainty have been identified and what is their impact on the assessment conclusion. This applies to all EFSA's areas, all types of scientific assessment and all types of uncertainty affecting assessment. This current Opinion describes the principles and methods supporting a concise Guidance Document on Uncertainty in EFSA's Scientific Assessment, published separately. These documents do not prescribe specific methods for uncertainty analysis but rather provide a flexible framework within which different methods may be selected, according to the needs of each assessment. Assessors should systematically identify sources of uncertainty, checking each part of their assessment to minimise the risk of overlooking important uncertainties. Uncertainty may be expressed qualitatively or quantitatively. It is neither necessary nor possible to quantify separately every source of uncertainty affecting an assessment. However, assessors should express in quantitative terms the combined effect of as many as possible of identified sources of uncertainty. The guidance describes practical approaches. Uncertainty analysis should be conducted in a flexible, iterative manner, starting at a level appropriate to the assessment and refining the analysis as far as is needed or possible within the time available. The methods and results of the uncertainty analysis should be reported fully and transparently. Every EFSA Panel and Unit applied the draft Guidance to at least one assessment in their work area during a trial period of one year. Experience gained in this period resulted in improved guidance. The Scientific Committee considers that uncertainty analysis will be unconditional for EFSA Panels and staff and must be embedded into scientific assessment in all areas of EFSA's work.

Abstract Methodologies for integrating (weighing) evidence and assessing uncertainties are of utmost importance to ensure that scientific assessments are transparent, robust and fit for purpose to support decision‐makers. One of the key challenges remains the development of harmonised methodologies for both weighing scientific evidence and assessing uncertainties in the food safety area mainly because of the multidisciplinary and complex nature of the topics involved. The breakout session ‘Weighing evidence and assessing uncertainties’ was held at the EFSA 2nd Scientific Conference ‘Shaping the Future of Food Safety, Together’. This paper aims at summarising the contributions of this breakout session and formulates recommendations to further support the development of harmonised methodologies and practical applications for weighing evidence and analysing uncertainty in key areas of food safety, including chemical risk assessment, microbiological risk assessment and environmental risk assessment.

Abstract The EFSA 2nd Scientific Conference ‘Shaping the Future of Food Safety, Together’ gathered an international audience composed of scientists, risk assessors, risk managers, as well as non‐governmental organisations and industry representatives. This article summarises the final plenary session where a panel was asked to draw out overall impressions and conclusions for the EFSA to take away for its strategic planning into the future. The main conclusions of the conference are presented under five major themes. With new methodologies, technologies, big data and the increased societal demand for enhanced engagement in the risk assessment process, there is a clear need to maintain levels of expertise from traditional areas and to consider the inclusion of new areas and sources of expertise to perform scientific assessments. Academia, industry, research and regulatory science should work together to achieve this goal. As science progresses at pace, the continued development of assessment methodologies to deal with increasingly complex assessment questions is necessary, as is the need for applied research to underpin the support to policy development that EFSA provides. Greater collaboration is needed to reach agreement on best methods and practices for scientific assessment not just internationally, but also, equally importantly, across legislative areas and scientific disciplines, and in consultation with society at large. The communication of complex science, including important concepts such as uncertainty and risk perception, is not a trivial task, and must be integrated into the scientific process. As such, the relationship between risk assessment and risk management must continue to mature, remaining close, yet independent.