This report constitutes a document of major strategic importance for the European nutraceutical sector. By identifying, at an early stage, emerging risks associated with the consumption of food supplements (excluding vitamins and minerals), this text acts as an important signal of EFSA’s future priorities. It foreshadows the substances that may, in the short or medium term, be subject to an assessment procedure under Article 8 of Regulation (EC) No 1925/2006, potentially leading to restrictions or bans on placing them on the market. The project was coordinated by a consortium of experts bringing together 8 reference agencies and institutions (Anses (France, coordination), SPF (Belgium), DTU (Denmark), NVWA (Netherlands), ISS (Italy), FSAI (Ireland), as well as Portugal’s dual structure comprising ECTS-CBIOS and ASAE). This document is an External Scientific Report. It is essential to emphasise that it is not a scientific opinion adopted by EFSA, but rather work carried out under a grant agreement (Article 36), with no immediate regulatory effect. Nevertheless, it constitutes the technical foundation on which the Authority could rely for future mandates. Despite the absence of any direct legal constraint, the methodological rigour applied and the involvement of national agencies call for increased vigilance from economic operators. The report deploys a complementary methodological approach combining nutrivigilance, exploration of available toxicological data, product occurrence on the market and theoretical predictive approaches, with the aim of ensuring comprehensive monitoring across the spectrum of health safety. Nutrivigilance (Work Package 1) This component is based on the analysis of 130 serious cases (severity levels 3 and 4) with a strong level of causality (probable or very probable), collected through European nutrivigilance systems. Assessed according to the PECO framework, the scientific literature made it possible to isolate 61 “ingredient / adverse effect” pairs classified as category B1 (poorly documented), defining the grey area of potential emerging risks where a clinical signal from the field encounters an absence of validated pathophysiological mechanisms in humans or relies solely on animal data. Prioritised according to a concern score, this analysis highlighted 6 key ingredients (Bifidobacterium, Coleus, Guggul, Huperzia serrata, Raphanus sativus L., Panax ginseng), while also highlighting critical scientific gaps: recurrence is based on isolated cases, actual exposure and concentrations are not quantified, and data collection systems remain heterogeneous between Member States, explaining why these signals constitute uncertainties to be investigated rather than established risks. Compounds (Work Package 2) This chemical and analytical component is based on the identification of 52 substances of concern, selected from EFSA’s Compendium of Botanicals. This selection is based on experimental toxicological data for genotoxic molecules and on predictive QSAR (in silico) tools for molecules suspected of being carcinogenic or reprotoxic in the absence of experimental data. From the 229 plants containing the identified compounds, the agencies assessed their availability on the European market using a two-tier approach: Tier 1 (identification through national notification databases in 5 Member States) and Tier 2 (web searches simulating consumers’ access to unregistered products). This dual approach made it possible to identify substances whose presence on the European market appears disproportionate to the current safety assurances available. Three molecules show particularly widespread occurrence on the market: furfural (detected in 11 014 food supplements), emodin and chrysophanol. The scope of the results is tempered by conservative assumptions. The lack of specifications regarding the preparations (e.g. extracts vs. powders) and the absence of actual dosage data constitute major areas of uncertainty for a more precise risk assessment. The CEHTRA Experts’ Analysis For the ingredients and compounds identified by the report, anticipation is the key to avoiding sudden regulatory injunctions. The neutral nature of this report offers manufacturers an opportunity to strengthen their portfolio defence strategy before any potential activation of Article 8. Three pragmatic anticipation levers are recommended: Analytical characterisation: Moving from theoretical assumptions to tangible data through precise quantitative measurements of the compounds of interest present in raw materials and finished products. This characterisation makes it possible to address concerns regarding the potential presence of compounds of concern, either by demonstrating their absence or by demonstrating that toxicological reference values are not exceeded under the recommended conditions of use. Scientific evidence: Strengthening the available toxicological datasets by incorporating additional analyses of bioavailability and safety (particularly in relation to CMR effects). These elements are essential to reassess QSAR predictions, which are conservative by construction, and to demonstrate the actual physiological effects. Active vigilance: Integrating robust internal nutrivigilance systems in order to document, on well-characterised products, the absence of serious adverse effects under real-world conditions of use and to provide a scientific response to the signals reported by authorities for other products. Finally, toxicological profiles are not static data; they are expected to evolve as new scientific publications emerge. This report highlights that toxicological monitoring of strategic ingredients in the nutraceutical sector is no longer optional, but must be fully integrated into product lifecycle management in order to anticipate regulatory developments. In conclusion, transparency, toxicological monitoring and the proactive generation of high-quality scientific data remain the best safeguards for operators facing regulatory uncertainties at European level. Author: Marie LIAMIN, Head of Food Market and Toxicologist

Assessing the endocrine-disrupting potential of a substance rarely comes down to reviewing a single study or obtaining a simple positive or negative result. The real challenge lies in interpreting all available data: what is already known about the substance? Do the existing data adequately address endocrine activity and potential adverse effects? What uncertainties remain? And, most importantly, is it really necessary to generate additional data? For companies facing an assessment of endocrine-disrupting properties, defining the right strategy from the outset can therefore be just as important as generating the data itself. Start with the data already available Before considering additional testing, the first step is to establish a clear overview of all existing information. This may involve reviewing available regulatory studies, published scientific literature and any other relevant information that may provide evidence of endocrine activity and potential adverse effects. For the assessment of plant protection products and biocides, ECHA and EFSA guidance notably relies on considering all relevant information and applying a weight-of-evidence approach, rather than interpreting individual results in isolation. A structured initial review can help answer several key questions. Is the available dataset sufficiently complete? Can apparently conflicting findings be scientifically explained? Are the relevant endocrine pathways adequately covered? And, most importantly, which uncertainties could influence the regulatory conclusion? At CEHTRA, our endocrine disruption experts combine the analysis of existing regulatory data with targeted literature searches conducted in line with ECHA and EFSA guidance. Depending on the substance and the purpose of the assessment, additional sources of information, such as ToxCast data or in silico predictions, may also contribute to the analysis. Identify the data gaps that really matter The absence of a study does not automatically mean that a new study needs to be conducted. The key question is whether the missing information actually prevents a sufficiently robust conclusion from being reached. This distinction is particularly important in endocrine disruption assessment, where evaluations may rely on large and highly heterogeneous datasets. Generating new data without first clearly defining the scientific question they are expected to address can increase costs and timelines without necessarily strengthening the final assessment. A targeted data gap analysis therefore helps identify critical uncertainties and determine which additional information could genuinely contribute to the overall evaluation. This is where scientific judgement becomes particularly important. The approach recommended by ECHA and EFSA does not rely solely on the presence of positive or negative findings. It also takes into account factors such as study quality, consistency across the dataset and the biological plausibility of the relationship between endocrine activity and the observed adverse effects. Build a testing strategy around the scientific question When additional information is required, the next step is not simply to select an endocrine-related test. The testing strategy should first and foremost address the scientific question identified during the assessment. Depending on the available data and the regulatory context, this may involve in vitro or in vivo investigations, recognised OECD Test Guidelines, other established protocols or complementary computational approaches. The objective is to generate information that can reduce the identified uncertainties while avoiding unnecessary or insufficiently targeted testing. CEHTRA develops testing strategies tailored to each situation and can support both the monitoring and scientific interpretation of studies specifically related to endocrine disruption. Our experts can also integrate in silico screening approaches and (Q)SAR models when relevant to the assessment. This integrated approach is particularly valuable when several lines of evidence need to be considered together rather than interpreted separately. Turn heterogeneous data into a regulatory conclusion Collecting or generating data is only one part of the assessment. The next challenge is to organise and interpret all available evidence in a way that supports a transparent and scientifically justified conclusion. When assessing endocrine-disrupting properties, it is necessary to examine evidence of endocrine activity, evidence of adverse effects and the causal relationship between these two components. Under ECHA-EFSA guidance, this analysis notably relies on a weight-of-evidence approach and, where relevant, on mode-of-action analysis. The quality of the scientific reasoning is therefore essential. A robust assessment should make it possible to understand not only what the different studies show, but also why the overall available evidence does or does not support a conclusion on endocrine-disrupting properties. CEHTRA supports the preparation of endocrine disruption documentation for regulatory dossiers, particularly for plant protection products and biocides, as well as the preparation of information in appropriate regulatory formats such as IUCLID and EFSA tables. Assessments may also be conducted for internal strategic purposes when a company wishes to anticipate the potential regulatory implications for a substance before a formal submission. Build a scientifically defensible position The assessment does not necessarily end with dossier preparation. Questions raised by authorities, differing interpretations of certain studies or the emergence of new information during the evaluation process may require additional scientific justification. In such situations, it becomes particularly important to be able to clearly trace the reasoning that led to the conclusion. CEHTRA experts can conduct independent scientific assessments of endocrine-disrupting properties, contribute to evaluations in the context of CLP classification, prepare scientific position papers and support companies in their interactions with regulatory authorities. The objective is therefore not simply to generate more data, but to build a coherent position in which the available evidence, remaining uncertainties and scientific reasoning are clearly documented. A strategic approach to endocrine disruptor assessment There is no universal strategy for assessing the endocrine-disrupting properties of a substance. The appropriate approach depends on the substance concerned, the available data, the applicable regulatory framework and the scientific question that needs to be addressed. For some substances, an in-depth analysis of existing information may already provide sufficient evidence. For others, targeted generation of new data may be necessary before a conclusion can be reached. In more complex situations, the main challenge may lie in integrating several apparently conflicting lines of evidence or in providing a scientific justification for their interpretation. This is why endocrine disruptor assessment benefits from an approach that combines regulatory expertise, toxicology, ecotoxicology, data analysis and testing strategy from the very beginning of the project. Need support with the assessment of the endocrine-disrupting properties of a substance? CEHTRA can support different stages of your project, from the initial review of existing data and identification of data gaps to the development of an appropriate testing strategy, preparation of regulatory documentation and scientific defence of the assessment.

Regulatory compliance rarely involves a single question. Depending on the product, substance and target market, companies may need to address regulatory requirements, toxicological or ecotoxicological data, risk assessment, testing strategies, dossier preparation or ongoing regulatory monitoring. This is why effective regulatory compliance support often requires several areas of expertise working together. For more than 25 years, CEHTRA has supported manufacturers, formulators, distributors and importers across sectors including chemicals, biocides, plant protection products, cosmetics, pharmaceuticals, food products and packaging. Our multidisciplinary teams combine regulatory affairs with toxicology, ecotoxicology, risk assessment and international regulatory expertise. Regulatory and scientific support tailored to your project There is no single approach to regulatory compliance. A REACH registration project, for example, may involve dossier preparation or updates, IUCLID, testing strategies, scientific assessment and regulatory advice. A cosmetic project may instead require ingredient safety assessment, toxicological profiling, data gap analysis or preparation of a Cosmetic Product Safety Report. Plant protection projects can involve regulatory strategy, dossier preparation, human health and environmental risk assessment, modelling and post-submission support. The objective is therefore not simply to provide a standard service, but to identify the expertise required for each specific project and market. At CEHTRA, this support can cover regulatory strategy, scientific assessment, testing strategies, risk assessment, dossier preparation and regulatory submissions, depending on the sector and project. Digital tools to complement regulatory expertise Regulatory teams also need efficient ways to access, structure and monitor information. CEHTRA has developed digital solutions that complement its consulting activities. CEHTRAWATCH, for example, provides structured regulatory and toxicological monitoring focused on a company’s substance portfolio, while COSMETICK combines structured toxicological data with functionalities supporting cosmetic safety assessment. CEHTRA also provides digital and in silico approaches through solutions such as Simply Predict and ED Pedia. These tools are designed to support expert work rather than replace scientific or regulatory interpretation. CEHTRAWATCH itself is explicitly presented as a complement to internal teams and CEHTRA consultants. Expertise when and where your teams need it Regulatory needs can also change according to workload, internal resources or project timelines. Alongside consulting and digital solutions, CEHTRA offers expert outsourcing through Flex+, with profiles that can support one-off assignments or longer-term projects. CEHTRA also provides regulatory and scientific training across areas including REACH, biocides, cosmetics, packaging, plant protection, toxicology and ecotoxicology. This combination makes it possible to adapt the type of support to the situation: external consulting for a specific regulatory project, digital solutions for recurring activities, additional expert resources for internal teams, or training to strengthen in-house capabilities. One regulatory challenge, the right combination of expertise Whether the objective is to prepare a regulatory dossier, assess product safety, identify data gaps, monitor regulatory developments or strengthen an internal team, the first step is understanding exactly what the project requires. CEHTRA brings together regulatory, scientific and digital capabilities to build support adapted to the product, sector and target market in Europe and internationally. Facing a regulatory challenge or preparing your next project?

Careers in Regulatory Affairs, Toxicology & Chemical Safety Join CEHTRA, a leading regulatory affairs and toxicology consulting firm. Apply online easily through our application form – no CV upload required. Apply to CEHTRA Would you like to join a recognized consulting firm in regulatory affairs, toxicology and chemical risk assessment? CEHTRA regularly recruits scientific, regulatory and support profiles in France and internationally. Why join CEHTRA? For over 20 years, CEHTRA has been supporting industrial clients in sectors such as: Chemicals Cosmetics Biocides Pharmaceuticals Medical devices Food & feed What we offer: High-level scientific and regulatory projects Recognised European expertise A collaborative and people-focused environment Career development opportunities within a growing international group I am applying for the position of: First name* Last name* Phone* E‑mail* Curriculum Vitae* Import a file Cover Letter (optional) Import a file Apply Julien LEGHAIT "Working in a team with diverse points of view helps me to broaden my vision about things and allows me to take into account the elements that I wouldn’t have thought through otherwise."

Careers in Regulatory Affairs, Toxicology & Chemical Safety Join CEHTRA, a leading regulatory affairs and toxicology consulting firm. Apply online easily through our application form – no CV upload required. Apply to CEHTRA Would you like to join a recognized consulting firm in regulatory affairs, toxicology and chemical risk assessment? CEHTRA regularly recruits scientific, regulatory and support profiles in France and internationally. Why join CEHTRA? For over 20 years, CEHTRA has been supporting industrial clients in sectors such as: Chemicals Cosmetics Biocides Pharmaceuticals Medical devices Food & feed What we offer: High-level scientific and regulatory projects Recognised European expertise A collaborative and people-focused environment Career development opportunities within a growing international group I am applying for the position of: First name* Last name* Phone* E‑mail* Curriculum Vitae* Import a file Cover Letter (optional) Import a file Apply Julien LEGHAIT "Working in a team with diverse points of view helps me to broaden my vision about things and allows me to take into account the elements that I wouldn’t have thought through otherwise."

Explore career opportunities at CEHTRA, including roles for ecotoxicologists, toxicologists, physico-chemical experts and regulatory consultants. Join our international team committed to chemical safety and apply today. Join our team at CEHTRA Explore exciting job opportunities at CEHTRA for toxicologists, ecotoxicologists, regulatory affairs experts, engineers, and more — across 10 key sectors including REACH, biocides, cosmetics, and beyond. Filter by sector Cosmetics Dietary Supplements Packaging Sales Toxicologist M/F Dietary Supplements, Cosmetics Fixed-term (4 months) Saint-Ouen (Paris) ASAP Apply Read more PPWR / REP Packaging Regulatory Affairs Manager M/F Packaging Permanent, CDI Saint-Ouen (Paris), Lyon, Cenon ( Bordeaux) ASAP Apply Read more Sales Assistant M/F Customer Acquisition - Work-Study Program Sales Work-study program, Alternance, Bachelor's degree (Bac+3) Saint-Ouen (Paris) ASAP Apply Read more Careers at CEHTRA: What our team says Julien LEGHAIT "Working in a team with diverse points of view helps me to broaden my vision about things and allows me to take into account the elements that I wouldn’t have thought through otherwise."