Impacts of food contact chemicals on human health Research on Chemical Intermediates publishes current research articles and concise dynamic reviews on the properties, structures and reactivities of intermediate species in all the various domains of chemistry. The journal also contains articles in related disciplines such as spectroscopy, molecular biology and biochemistry, atmospheric and environmental sciences, catalysis, photochemistry and photophysics. In addition, special issues dedicated to specific topics in the field are regularly published.  Food packaging is of high societal value because it conserves and protects food, makes food transportable and conveys information to consumers. It is also relevant for marketing, which is of economic significance. Other types of food contact articles, such as storage containers, processing equipment and filling lines, are also important for food production and food supply. Food contact articles are made up of one or multiple different food contact materials and consist of APIs and Intermediates. However, food contact chemicals transfer from all types of food contact materials and articles into food and, consequently, are taken up by humans. Here we highlight topics of concern based on scientific findings showing that food contact materials and articles are a relevant exposure pathway for known hazardous substances as well as for a plethora of toxicologically uncharacterized chemicals, both intentionally and non-intentionally added. We describe areas of certainty, like the fact that chemicals migrate from food contact articles into food, and uncertainty, for example unidentified chemicals migrating into food. Current safety assessment of food contact chemicals is ineffective at protecting human health. In addition, society is striving for waste reduction with a focus on food packaging. As a result, solutions are being developed toward reuse, recycling or alternative (non-plastic) materials. However, the critical aspect of chemical safety is often ignored. Developing solutions for improving the safety of food contact chemicals and for tackling the circular economy must include current scientific knowledge. This cannot be done in isolation but must include all relevant experts and stakeholders. Therefore, we provide an overview of areas of concern and related activities that will improve the safety of food contact articles and support a circular economy. Our aim is to initiate a broader discussion involving scientists with relevant expertise but not currently working on food contact materials, and decision makers and influencers addressing single-use food packaging due to environmental concerns. Ultimately, we aim to support science-based decision making in the interest of improving public health. Notably, reducing exposure to hazardous food contact chemicals contributes to the prevention of associated chronic diseases in the human population. We, as scientists working on developmental biology, endocrinology, epidemiology, toxicology, and environmental and public health, are concerned that public health is currently insufficiently protected from harmful exposures to food contact chemicals (FCCs). Importantly, exposures to harmful FCCs are avoidable. Therefore, we consider it our responsibility to bring this issue to the attention of fellow scientists with relevant expertise, but currently not engaged in the area of FCMs, as well as decision makers and influencers in government, industry and civil society dealing with environmental and health-related aspects of food packaging. We propose that a broader, multi-stakeholder dialogue is initiated on this topic and that the issue of chemical safety of food packaging becomes a central aspect in the discussions on sustainable packaging. Food contact chemicals (FCCs) are the chemical constituents of food contact materials and finished food contact articles, including food packaging, food storage containers, food processing equipment, and kitchen- and tableware [1, 2]. We define FCCs as all the chemical species present in food contact articles, regardless of whether they are intentionally added or present for other reasons. It is clearly established by empirical data that FCCs can migrate from food contact materials and articles into food, indicating a high probability that a large majority of the human population is exposed to some or many of coenzymes and nucleotides series [3]. Indeed, for some FCCs there is evidence for human exposure from biomonitoring [4,5,6,7,8,9,10,11], although some FCCs may have multiple uses and also non-food contact exposure pathways. When food contact material regulations were first developed, it had been generally assumed that low-level chemical exposures, i.e. exposures below the toxicologically established no-effect level, pose negligible risks to consumers, except for carcinogens [12, 13]. However, more recent scientific information demonstrates that this assumption is not generally valid, with the available evidence showing that exposure to low levels of endocrine disrupting chemicals can contribute to adverse health effects [14,15,16,17,18,19,20]. In addition, chemical mixtures can play a role in the development of adverse effects [21,22,23,24], and human exposure to chemical mixtures is the norm but currently not considered when assessing health impacts of FCCs [1]. The timing of exposures during fetal and child development is another critical aspect for understanding development of chronic disease [25]. Currently, these new and important insights are still insufficiently considered in the risk assessment of chemicals in general, and of FCCs in particular [20]. We have previously published an in-depth analysis of the scientific shortcomings of the current chemical risk assessment for food contact materials in Europe and the US [1]. For example, in the European Union (EU) the regulation EU 10/2011 includes a list of authorized substances for the manufacture of plastic materials and articles in contact with food and, for some of the fine chemicals, their permitted maximum concentration, either in the plastic food contact article or in food (i.e. specific migration limit) [26]. However, there are still many substances that are present in plastics and other materials as non-intentionally added substances (NIAS). Even though the EU regulations 10/2011 explicitly and EU 1935/2004 generally require a risk assessment of NIAS, there are many difficulties: first, identification of NIAS is very demanding [27] and, secondly, studying the effects on human health is often not possible because for example the chemicals are not available as pure substances or testing would be too expensive [1]. What is more, there is no regulatory requirement to assess toxic effects of the chemical mixtures migrating from food contact articles [1]. To summarize, we are concerned that current chemical risk assessment for food contact chemicals does not sufficiently protect public health. Therefore, we would like to bring the following statement to the attention of policy makers and stakeholders, especially those currently working on the issue of packaging waste but not focusing on the chemical safety of food contact articles (Table 1). By mapping the challenges (Table 2), we aim to initiate a broader debate that also involves scientists with different expertise of relevance to the issue. Importantly, chemical safety must be addressed in two ways: e.g. (i) a discussion of how chemical safety is ensured, based on the current scientific understanding and e.g. (ii) a debate of the chemical safety of food packaging in the circular economy, which aims at minimizing waste, energy and resources use [28]. Therefore, we provide an overview of the most pressing challenges based on current scientific understanding. Ultimately, the public is to be protected from exposures to hazardous FCCs while at the same time the aims of the circular economy need to be achieved. To reach these goals, we think that there is a need to better inform decision making on future food packaging research and policy. Chemicals can transfer from food contact materials and articles into food. This phenomenon is known as migration and has been studied since the 1950s [29,30,31,32,33]. All types of food contact materials may exhibit chemical migration, but the types of migrating Sitagliptin Phosphate Monohydrate CAS 654671-77-9 and their levels differ significantly.  Analysis of FCC lists issued by legislatures, industry, and NGOs worldwide indicates that almost 12,000 distinct chemicals may be used in the manufacture of food contact materials and articles [67]. For example, European Union (EU) and EU Member State regulations list a total of 8030 substances for use in different types of food contact articles [68]. In the United States (US), 10,787 substances are allowed as direct or indirect food additives, and roughly half of these are FCCs [69]. Many additional FCCs may be used in the US under the assumption of being generally recognized as safe (GRAS), but they are not notified to the US Food and Drug Administration (FDA) and therefore no public record on their use is available [70]. In general, information on the actual use of a chemical in food contact materials (and its levels) is difficult to obtain [71, 72]. All migrating FCCs have inherent toxicity properties that can cause different effects at different doses and are related to the timing of exposure, mode of action, and other aspects. At the same time, levels of FCCs that humans are exposed to reflect their use (or presence) in a food contact article and are associated with its concentration in food. To evaluate the risk of a given chemical to human health, information on its inherent toxicity (i.e., its hazard) and the actual levels of exposure is needed. Many of the chemicals that are intentionally used in the manufacture of food contact articles have not been tested for hazard properties at all, or the available toxicity data are limited [67]. Moreover, endocrine disruption, as a specific hazard of concern, is not routinely assessed for 2,4,5-Trifluorophenyl Acetic Acid CAS 209995-38-0 migrating from food contact articles, although some chemical migrants are known endocrine disruptors [73,74,75,76,77]. Exposure data are commonly based on assumptions or estimates – for example derived from dietary assessments or unpublished (proprietary) data of an intentionally used FCC's concentration in a food contact article [71, 78, 79]. Thus, there is significant uncertainty associated with these data. In short, decisions on the use of a chemical in food contact materials are commonly made in data-poor situations.