There is considerable interest in adverse outcome pathways (AOPs) as a means of organizing biological and toxicological information to assist in data interpretation and method development. While several chemical sectors have shown considerable progress in applying this approach, this has not been the case in the food sector. In the present study, safety evaluation reports of food additives listed in Annex II of Regulation (EC) No 1333/2008 of the European Union were screened to qualitatively and quantitatively characterize toxicity induced in laboratory animals. The resulting database was used to identify the critical adverse effects used for risk assessment and to investigate whether food additives share common AOPs. Analysis of the database revealed that often such scrutiny of AOPs was not possible or necessary. For 69% of the food additives, the report did not document any adverse effects in studies based on which the safety evaluation was performed. For the remaining 31% of the 326 investigated food additives, critical adverse effects and related points of departure for establishing health-based guidance values could be identified. These mainly involved effects on the liver, kidney, cardiovascular system, lymphatic system, central nervous system and reproductive system. AOPs are available for many of these apical endpoints, albeit to different degrees of maturity. For other adverse outcomes pertinent to food additives, including gastrointestinal irritation and corrosion, AOPs are lacking. Efforts should focus on developing AOPs for these particular endpoints. Keywords Food additives • Critical adverse effect • Adverse outcome pathway • Acceptable daily intake • 3Rs Abbreviations 3Rs Replacement, refinement, and reduction of animal tests ADI Acceptable daily intake AOP(s) Adverse outcome pathway(s) BMDL Benchmark dose lower confidence limit CAS Chemical abstracts service EDI Estimated daily intake

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Cleaning and disinfection are used in several steps of the food supply chain to prevent crosscontamination and microbial contamination of the end product. However, the use of cleaning and disinfection agents may result in chemical residues in food products. Therefore, the aim of this research was to gain insight into the active ingredients used as cleaning agents and disinfectants, their efficacy and whether potential residues may result in human health risks. During phase I of this research insights were gained on the active ingredients used in cleaning agents and disinfectants applied in poultry, eggs, leafy vegetables, and sprouts supply chains as example food chains, making use of a literature study, monitoring data, questionnaires and interviews. After this first phase, the second phase of this study focused on the poultry supply chain. An expert study, using questionnaires and interviews, was held in order to get more information on the use and the most important active ingredients for human health risks in cleaning agents. Furthermore, with a literature study, the efficacy of active ingredients (log reduction of pathogens), the possible by-products, and the toxicity of active ingredients was established for disinfectant. Phase I: LegislationOnly chemicals that are registered under Registration, Evaluation, Authorization and restriction of Chemicals (REACH) can be used in cleaning and disinfection products. The regulation of disinfectants within the European Union (EU) is more extensive compared to cleaning agents, as additional safety assessments are explicitly needed for the intended use of the disinfectants(Regulation (EU) No 528/2012 -Biocidal Products Regulation (BPR)). First, European Chemicals Agency (ECHA) performs a safety assessment on the level of solely the active ingredients. Secondly, another safety assessment has to be performed on the complete biocidal product under the responsibility of the Member States.In the Netherlands, the Board for the Authorisation of Plant Protection Products and Biocides (College voor de toelating van gewasbeschermingsmiddelen en biociden -Ctgb) is responsible for the authorisation of disinfectants. The Ctgb evaluates whether the intended use of the product is safe for humans, animals and the environment. Phase I: Cleaning and disinfection in poultry, egg, leafy vegetables and sprouts chainsA literature study, questionnaires and interviews, as well as the Ctgb database were used to establish a long-list of cleaning agents consisting of 37 active ingredients and of disinfection agents consisting of 42 active ingredients possible used for cleaning and disinfection in the Netherlands in poultry, egg, leafy vegetables and sprouts chains. Although a prioritisation of active ingredients in cleaning agents on risk of possible residues in food products was not possible, a long-list of disinfection agents was prioritised into a so-called intermediate list of 18 active ingredients. Disinfectants that were authorised by Ctgb but for which human health risks could not be exclu...

In the last decade, adverse outcome pathways have been introduced in the fields of toxicology and risk assessment of chemicals as pragmatic tools with broad application potential. While their use in the pharmaceutical and cosmetics sectors has been well documented, their application in the food area remains largely unexplored. In this respect, an expert group of the International Life Sciences Institute Europe has recently explored the use of adverse outcome pathways in the safety evaluation of food additives. A key activity was the organization of a workshop, gathering delegates from the regulatory, industrial and academic areas, to discuss the potentials and challenges related to the application of adverse outcome pathways in the safety assessment of food additives. The present paper describes the outcome of this workshop followed by a number of critical considerations and perspectives defined by the International Life Sciences Institute Europe expert group.

Mycotoxins are naturally present in cereal-based feed materials; however, due to adverse effects on animal health, their presence in derived animal feed should be minimized. A systematic literature search was conducted to obtain an overview of all factors from harvest onwards influencing the presence and concentration of mycotoxins in cereal-based feeds. The feed production processes covered included the harvest time, post-harvest practices (drying, cleaning, storage), and processing (milling, mixing with mycotoxin binders, extrusion cooking, ensiling). Delayed harvest supports the production of multiple mycotoxins. The way feed materials are dried after harvest influences the concentration of mycotoxins therein. Applying fungicides on the feed materials after harvest as well as cleaning and sorting can lower the concentration of mycotoxins. During milling, mycotoxins might be redistributed in cereal feed materials and fractions thereof. It is important to know which parts of the cereals are used for feed production and whether or not mycotoxins predominantly accumulate in these fractions. For feed production, mostly the milling fractions with outer parts of cereals, such as bran and shorts, are used, in which mycotoxins concentrate during processing. Wet-milling of grains can lower the mycotoxin content in these parts of the grain. However, this is typically accompanied by translocation of mycotoxins to the liquid fractions, which might be added to by-products used as feed. Mycotoxin binders can be added during mixing of feed materials. Although binders do not remove mycotoxins from the feed, the mycotoxins become less bioavailable to the animal and, in the case of food-producing animals, to the consumer, lowering the adverse effects of mycotoxins. The effect of extruding cereal feed materials is dependent on several factors, but in principle, mycotoxin contents are decreased after extrusion cooking. The results on ensiling are not uniform; however, most of the data show that mycotoxin production is supported during ensiling when oxygen can enter this process. Overall, the results of the literature review suggest that factors preventing mycotoxin production have greater impact than factors lowering the mycotoxin contents already present in feed materials.