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A large majority of chemicals is converted into metabolites through xenobiotic-metabolising enzymes. Metabolites may present a spectrum of characteristics varying from similar to vastly different compared with the parent compound in terms of both toxicokinetics and toxicodynamics. In the pesticide arena, the role of metabolism and metabolites is increasingly recognised as a significant factor particularly for the design and interpretation of mammalian toxicological studies and in the toxicity assessment of pesticide/metabolite-associated issues for hazard characterization and risk assessment purposes, including the role of metabolites as parts in various residues in ecotoxicological adversities. This is of particular relevance to pesticide metabolites that are unique to humans in comparison with metabolites found in in vitro or in vivo animal studies, but also to disproportionate metabolites (quantitative differences) between humans and mammalian species. Presence of unique or disproportionate metabolites may underlie potential toxicological concerns. This review aims to present the current state-of-the-art of comparative metabolism and metabolites in pesticide research for hazard and risk assessment, including One Health perspectives, and future research needs based on the experiences gained at the European Food Safety Authority.

Abstract Groundwater monitoring is the highest tier in the leaching assessment of plant protection products in the EU. The European Commission requested EFSA for a review by the PPR Panel of the scientific paper of Gimsing et al. (2019) on the design and conduct of groundwater monitoring studies. The Panel concludes that this paper provides many recommendations; however, specific guidance on how to design, conduct and evaluate groundwater monitoring studies for regulatory purposes is missing. The Panel notes that there is no agreed specific protection goal (SPG) at EU level. Also, the SPG has not yet been operationalised in an agreed exposure assessment goal (ExAG). The ExAG describes which groundwater needs to be protected, where and when. Because the design and interpretation of monitoring studies depends on the ExAG, development of harmonised guidance is not yet possible. The development of an agreed ExAG must therefore be given priority. A central question in the design and interpretation of groundwater monitoring studies is that of groundwater vulnerability. Applicants must demonstrate that the selected monitoring sites represent realistic worst‐case conditions as specified in the ExAG. Guidance and models are needed to support this step. A prerequisite for the regulatory use of monitoring data is the availability of complete data on the use history of the products containing the respective active substances. Applicants must further demonstrate that monitoring wells are hydrologically connected to the fields where the active substance has been applied. Modelling in combination with (pseudo)tracer experiments would be the preferred option. The Panel concludes that well‐conducted monitoring studies provide more realistic exposure assessments and can therefore overrule results from lower tier studies. Groundwater monitoring studies involve a high workload for both regulators and applicants. Standardised procedures and monitoring networks could help to reduce this workload.

Furathiocarb is a carbamate insecticide found in marine ecosystems as well as river water and sediments. The aim of this study was to characterize species differences in the in vitro metabolism of furathiocarb in seven mammalian species (human, monkey, minipig, rat, mouse, dog, rabbit) analyzed by LC-TOF-MS/MS, in order to provide qualitative and quantitative chemical-specific data to enhance toxicological risk assessment. Furathiocarb was mainly biotransformed to carbofuran metabolic pathway via (N-S) bond-cleavage. Two hydroxylated and sulfoxidated metabolites of furathiocarb were also detected (oxidation pathway). No unique human metabolites were detected. The carbofuran metabolic pathway was more predominant than the furathiocarb oxidation pathway in all species studied; differences based on hepatic clearance rates (CLH), were up to 9.4-fold in monkey and 7-fold in rats, while it was 4.3-fold in human. Animal to human differences in the carbofuran pathway are within the default toxicokinetic uncertainty factor, except for mouse (3.9-fold). Our findings on metabolic profiling and in vitro-in vivo extrapolations are helpful for the interpretation of toxicological findings and chemical risk assessment of furathiocarb.

Furathiocarb is a carbamate insecticide detected in ecosystems. Its main metabolite carbofuran has been alluded to affect birth outcomes and disturb hormone levels in humans. The metabolism of furathiocarb in humans has not been characterized. The metabolism studies were performed using hepatic microsomes from ten donors and fifteen human cDNA-expressed CYPs. The initial screening and identification of the metabolites were performed by LC-TOF. Quantifications and fragmentations were performed by LC/MS-MS. Furathiocarb was metabolized to eight phase I metabolites via two general pathways, carbofuran metabolic pathway and furathiocarb oxidation pathway. Six metabolites in the carbofuran metabolic pathway (carbofuran, 3-hydroxycarbofuran, 3-ketocarbofuran, 3-keto-7-phenolcarbofuran, 3-hydroxy-7-phenolcarbofuran, and 7-phenolcarbofuran) were identified with the help of authentic standards. The two unidentified metabolites in the furathiocarb oxidation pathway are probably hydroxylated and sulfoxidated derivatives of furathiocarb. The carbofuran metabolic pathway was more predominant than the furathiocarb oxidation pathway, ratios ranged from 24- to 115-fold in a 10-donor panel of hepatic microsomes. On the basis of recombinant CYP studies, the carbofuran pathway was dominated by CYP3A4 (95.9%); contributions by CYP1A2 (1.3%) and CYP2B6 (2.0%) were minor. The minor furathiocarb oxidation pathway was catalyzed by CYP2C19 and CYP2D6 (hydroxylated/sulfoxidated metabolite A) and by CYP3A5, CYP3A4 and CYP2A6 (metabolite B). High and significant correlation between carbofuran metabolic pathway and CYP3A4 marker activities (midazolam-1'-hydroxylation and omeprazole-sulfoxidation) were observed. Ketoconazole, a CYP3A4-inhibitor, inhibited the carbofuran pathway by 32–86% and hydroxylated/sulfoxidated metabolite-B formations by 41–62%. The data suggest that in humans, the carbofuran metabolic pathway is dominant, and CYP3A4 is the major enzyme involved. These results provide useful scientific information for furathiocarb risk assessment in humans.

Abstract Development of adverse outcome pathways (AOPs) for uterine adenocarcinoma can provide a practical tool to implement the EFSA‐ECHA Guidance (2018) for the identification of endocrine disruptors in the context of Regulations (EU) No 528/2012 and (EC) No 1107/2009. AOPs can give indications about the strength of the relationship between an adverse outcome (intended as a human health outcome) and chemicals (pesticides but not only) affecting the pathways. In this scientific opinion, the PPR Panel explored the development of AOPs for uterine adenocarcinoma. An evidence‐based approach methodology was applied, and literature reviews were produced using a structured framework assuring transparency, objectivity, and comprehensiveness. Several AOPs were developed; these converged to a common critical node, that is increased estradiol availability in the uterus followed by estrogen receptor activation in the endometrium; therefore, a putative AOP network was considered. An uncertainty analysis and a probabilistic quantification of the weight of evidence have been carried out via expert knowledge elicitation for each set of MIEs/KEs/KERs included in individual AOPs. The collected data on the AOP network were evaluated qualitatively, whereas a quantitative uncertainty analysis for weight of the AOP network certainty has not been performed. Recommendations are provided, including exploring further the uncertainties identified in the AOPs and putative AOP network; further methodological developments for quantifying the certainty of the KERs and of the overall AOPs and AOP network; and investigating of NAMs applications in the context of some of the MIEs/KEs currently part of the putative AOP network developed.

Abstract The EFSA Panel on Plant Protection Products and their Residues was requested by the European Commission, to conclude based upon available evidence if metabolites 3‐phenoxybenzoic acid (PBA) and 3‐(4′‐hydroxyphenoxy)benzoic acid (PBA(OH)), common to several pyrethroid compounds, have genotoxic properties, if they share the (neuro)toxicity profile of their parent compounds, and if evidence allows to conclude on their health‐based guidance values. Available body of evidence consisted of studies from regulatory dossiers submissions, as well as from public literature. In addition, the data gap for short‐term toxicity profile of PBA was addressed by read‐across. Assessment revealed that PBA and PBA(OH) do not raise a concern with respect to genotoxicity. As regards general toxicity, PBA and PBA(OH) have different qualitative (no neurotoxic mechanism) and quantitative (higher NOAELs) toxicity compared to the parent pyrethroid compounds. For both metabolites, acceptable daily intake (ADI) and acute reference dose (ARfD) values were derived at 0.1 mg/kg body weight (bw) per day and 1 mg/kg bw, respectively.

Abstract Flupyradifurone is a novel butenolide insecticide, first approved as an active substance for use in plant protection products by Commission Implementing Regulation (EU) 2015/2084. Following concerns that this substance may pose high risks to humans and the environment, the French authorities, in November 2020, asked the Commission to restrict its uses under Article 69 of Regulation (EC) No 1107/2009. To support this request, competent Authorities from France cited a series of literature papers investigating its hazards and/or exposure to humans and the environment. In addition, in June 2020, the Dutch Authorities notified the Commission, under Article 56 of Regulation (EC) No 1107/2009, of new information on flupyradifurone on the wild bee species Megachile rotundata. This notification is also referred to in the French notification on flupyradifurone. Consequently, the EFSA PPR Panel was mandated to quantify the likelihood of this body of evidence constituting proof of serious risks to humans or the environment. Therefore, the EFSA PPR Panel evaluated the likelihood of these studies indicating new or higher hazards and exposure to humans and the environment compared to previous EU assessments. A stepwise methodology was designed, including: (i) the initial screening; (ii) data extraction and critical appraisal based on the principles of OHAT/NTP; (iii) weight of evidence, including consideration of the previous EU assessments; (iv) uncertainty analysis, followed, whenever relevant, by an expert knowledge elicitation process. For the human health, only one study was considered relevant for the genotoxic potential of flupyradifurone in vitro. These data did not provide sufficient information to overrule the EU assessment, as in vivo studies already addressed the genotoxic potential of flupyradifurone. Environment: All available data investigated hazards in bee species. For honey bees, the likelihood of the new data indicating higher hazards than the previous EU assessment was considered low or moderate, with some uncertainties. However, among solitary bee species – which were not addressed in the previous EU assessment – there was evidence that Megachile rotundata may be disproportionately sensitive to flupyradifurone. This sensitivity, which may partially be explained by the low bodyweight of this species, was mechanistically linked to inadequate bodily metabolisation processes.

Abstract Acetamiprid is a pesticide active substance with insecticidal action currently under the third renewal (AIR3) of the Commission implementing regulation (EU) No 844/2012. Following concerns that this substance may pose high risks to humans and the environment, the French authorities asked the Commission to restrict its uses under Article 69 of Regulation (EC) No 1107/2009. To support this request, competent Authorities from France cited a series of literature papers investigating its hazards and/or exposure to humans and the environment. Consequently, the EFSA PPR Panel was mandated to advise on the likelihood that body of evidence would constitute proof of serious risks to humans or the environment. Therefore, the EFSA PPR Panel evaluated the likelihood of these studies indicating new or higher hazards and exposure to humans and the environment compared to previous EU assessments.A stepwise methodology was designed, including: (i) the initial screening; (ii) the data extraction and critical appraisal based on the principles of OHAT/NTP; (iii) the weight of evidence, including consideration of the previous EU assessments; (iv) the uncertainty analysis, followed, whenever relevant, by an expert knowledge elicitation process. For human health, no conclusive evidence of higher hazards compared to previous assessment was found for genotoxicity, developmental toxicity, neurotoxicity including developmental neurotoxicity and immunotoxicity. However, due to the lack of adequate assessment of the current data set, the PPR Panel recommends conducting an assessment of endocrine disrupting properties for acetamiprid in line with EFSA/ECHA guidance document for the identification of endocrine disruptors. For environment, no conclusive, robust evidence of higher hazards compared to the previous assessment was found for birds, aquatic organisms, bees and soil organisms. However, the potential of high inter‐species sensitivity of birds and bees towards acetamiprid requires further consideration.

Abstract EFSA asked the Panel on Plant Protection Products and their residues to deliver a Scientific Opinion on testing and interpretation of comparative in vitro metabolism studies for both new active substances and existing ones. The main aim of comparative in vitro metabolism studies of pesticide active substances is to evaluate whether all significant metabolites formed in the human in vitro test system, as a surrogate of the in vivo situation, are also present at comparable level in animal species tested in toxicological studies and, therefore, if their potential toxicity has been appropriately covered by animal studies. The studies may also help to decide which animal model, with regard to a particular compound, is the most relevant for humans. In the experimental strategy, primary hepatocytes in suspension or culture are recommended since hepatocytes are considered the most representative in vitro system for prediction of in vivo metabolites. The experimental design of 3 × 3 × 3 (concentrations, time points, technical replicates, on pooled hepatocytes) will maximise the chance to identify unique (UHM) and disproportionate (DHM) human metabolites. When DHM and UHM are being assessed, test item‐related radioactivity recovery and metabolite profile are the most important parameters. Subsequently, structural characterisation of the assigned metabolites is performed with appropriate analytical techniques. In toxicological assessment of metabolites, the uncertainty factor approach is the first alternative to testing option, followed by new approach methodologies (QSAR, read‐across, in vitro methods), and only if these fail, in vivo animal toxicity studies may be performed. Knowledge of in vitro metabolites in human and animal hepatocytes would enable toxicological evaluation of all metabolites of concern, and, furthermore, add useful pieces of information for detection and evaluation of metabolites in different matrices (crops, livestock, environment), improve biomonitoring efforts via better toxicokinetic understanding, and ultimately, develop regulatory schemes employing physiologically based or physiology‐mimicking in silico and/or in vitro test systems to anticipate the exposure of humans to potentially hazardous substances in plant protection products.

Abstract The EFSA Panel on Plant Protection Products and their Residues (PPR) has developed, as a self‐task mandate (EFSA‐Q‐2019‐00100), two adverse outcome pathway (AOP)‐informed integrated approach to testing and assessment (IATA) case studies to answer a developmental neurotoxicity (DNT) hazard identification and characterisation problem formulation that could support the regulatory decisions for the pesticide active substances deltamethrin and flufenacet. The IATA were developed to assess the applicability of the DNT in vitro testing battery (IVB), designed to explore fundamental neurodevelopmental processes, in the regulatory risk assessment of pesticides. For this purpose, an evidence‐based‐approach methodology was applied: 1) systematic literature review and critical appraisal of all the evidence i.e. human observational studies, in vivo data from rodent models and new approach methodologies (NAMs, i.e. in vitro studies including high‐throughput testing from IVB and zebrafish studies from the literature) for both case studies; 2) a quantitative uncertainty analysis of all the evidence using expert knowledge elicitation (EKE) and a probabilistic approach; 3) integration of all the evidence using the AOP conceptual framework. This stepwise approach resulted in the postulation of an evidence‐based AOP network for one of the case studies. A probabilistic quantification of the weight of evidence (WoE) using Bayesian network analysis allowed the assessment and the quantification of the uncertainty in the postulated AOP. The approach taken allowed conclusions to be drawn with an acceptable level of certainty in DNT hazard identification and characterisation of deltamethrin and that flufenacet is not a developmental neurotoxicant, supporting the relevance of the mechanistic understanding. The case studies show the applicability of the DNT‐IVB for hazard identification and characterisation and illustrate the usefulness of an AOP‐informed IATA for regulatory decision making. The overall activity led to improved interpretation of human data by providing a plausible mechanistic link to adverse outcomes, which would support their contextualisation in the risk assessment process. This Scientific Opinion allows the PPR Panel to draft several recommendations for the implementation of the AOP‐informed IATA methodology and of the DNT‐IVB in the regulatory risk assessment of pesticides.

Abstract The European Commission asked the European Food Safety Authority (EFSA) to prepare a statement on a framework for the environmental risk assessment (ERA) of transition metals (e.g. iron and copper) used as active substances in plant protection products (PPPs). Non‐degradability, essentiality and specific conditions affecting fate and behaviour as well as their toxicity are distinctive characteristics possibly not covered in current guidance for PPPs. The proposed risk assessment framework starts with a preliminary phase, in which monitoring data on transition metals in relevant environmental compartments are provided. They deliver the metal natural background and anthropogenic residue levels to be considered in the exposure calculations. A first assessment step is then performed assuming fully bioavailable residues. Should the first step fail, refined ERA can, in principle, consider bioavailability issues; however, non‐equilibrium conditions need to be taken into account. Simple models that are fit for purpose should be employed in order to avoid unnecessary complexity. Exposure models and scenarios would need to be adapted to address environmental processes and parameters relevant to the fate and behaviour of transition metals in water, sediment and soils (e.g. speciation). All developments should follow current EFSA guidance documents. If refined approaches have been used in the risk assessment of PPPs containing metals, post‐registration monitoring and controlled long‐term studies should be conducted and assessed. Utilisation of the same transition metal in other PPPs or for other uses will lead to accumulation in environmental compartments acting as sinks. In general, it has to be considered that the prospective risk assessment of metal‐containing PPPs can only cover a defined period as there are limitations in the long‐term hazard assessment due to issues of non‐degradability. It is therefore recommended to consider these aspects in any risk management decisions and to align the ERA with the goals of other overarching legislative frameworks.

Abstract The European Commission requested EFSA to provide scientific advice on the translocation potential by Pseudomonas chlororaphis MA342 in plants after seed treatment of cereals and peas and, if applicable, for a revision of the assessment of the risk to humans by its metabolite 2,3‐deepoxy‐2,3‐didehydro‐rhizoxin (DDR) and this based on the evidence available in the dossier for renewal of the approval. The information from other P. chlororaphis strains than MA342 was taken into account with care, because the studies available in the dossier did not confirm the identity of the strain MA342 as belonging to the species P. chlororaphis. It has been concluded that there is a potential for translocation of P. chlororaphis MA342 to edible plant parts following seed treatment till an estimated concentration up to about 105 cfu/g and some exposure can be assumed by consumption of fresh commodities. Also, production of the metabolite DDR in the plant cannot be excluded. Regarding levels of DDR in the raw agricultural commodities, exposure estimates based on the limit of quantification (LOQ) for DDR in cereals cannot be further refined while there is no information on the levels of DDR in peas in the dossier. As regards genotoxicity, DDR induced chromosomal damage; however, it was not possible to conclude whether it is through an aneugenic or clastogenic mechanism. Hence, it is not possible to draw a reliable conclusion that DDR is producing an aneugenic effect nor to determine a threshold dose for aneugenicity. Thus, it is not possible to revise the human risk assessment as regards exposure to DDR. The concerns identified in the EFSA conclusion of 2017 remain.

Abstract The Panel received a mandate from the European Commission to assess the genotoxic potential of triazine amine based on available information submitted by the applicants. Available information includes experimental genotoxicity data on triazine amine, Quantitative Structure–Activity Relationship (QSAR) analysis and read across with structurally similar compounds. Based on the overall weight of evidence, the Panel, in agreement with the cross‐cutting Working Group Genotoxicity, concluded that there is no concern for the potential of triazine amine to induce gene mutations and clastogenicity; however, the potential to induce aneugenicity was not adequately investigated. For a conclusion, an in vitro micronucleus assay performed with triazine amine would be needed.

Abstract Bats are an important group of mammals, frequently foraging in farmland and potentially exposed to pesticides. This statement considers whether the current risk assessment performed for birds and ground dwelling mammals exposed to pesticides is also protective of bats. Three main issues were addressed. Firstly, whether bats are toxicologically more or less sensitive than the most sensitive birds and mammals. Secondly, whether oral exposure of bats to pesticides is greater or lower than in ground dwelling mammals and birds. Thirdly, whether there are other important exposure routes relevant to bats. A large variation in toxicological sensitivity and no relationship between sensitivity of bats and bird or mammal test‐species to pesticides could be found. In addition, bats have unique traits, such as echolocation and torpor which can be adversely affected by exposure to pesticides and which are not covered by the endpoints currently selected for wild mammal risk assessment. The current exposure assessment methodology was used for oral exposure and adapted to bats using bat‐specific parameters. For oral exposure, it was concluded that for most standard risk assessment scenarios the current approach did not cover exposure of bats to pesticide residues in food. Calculations of potential dermal exposure for bats foraging during spraying operations suggest that this may be a very important exposure route. Dermal routes of exposure should be combined with inhalation and oral exposure. Based on the evidence compiled, the Panel concludes that bats are not adequately covered by the current risk assessment approach, and that there is a need to develop a bat‐specific risk assessment scheme. In general, there was scarcity of data to assess the risks for bat exposed to pesticides. Recommendations for research are made, including identification of alternatives to laboratory testing of bats to assess toxicological effects.

Abstract The EFSA Panel on Plant Protection Products and their Residues was requested to establish health‐based reference values for groundwater metabolites (LM2, LM3, LM4, LM5 and LM6) of the active substance terbuthylazine based on the available evidence, unless the evidence was considered insufficient to do so. The request was accepted under the explicit circumstance that the reassessment would be made according to a different methodology than the routine methodology currently applied for the assessment of metabolites in groundwater. While for metabolites LM2, LM4 and LM5, it was concluded that the reference values for terbuthylazine are applicable, substance‐specific reference values could not be derived for metabolites LM3 and LM6. The applied threshold of toxicological concern (TTC) approach has shown that metabolites LM3 and LM6 are of potential concern for consumer health, since at least one representative groundwater leaching scenario results in exposure above the relevant threshold. Moreover, other sources of exposure to LM3 and LM6 could not be excluded with certainty. It is therefore recommended to address the specific toxicities of metabolites LM3 and LM6.

Abstract The EFSA Panel on Plant Protection Products and their Residues reviewed the guidance on how aged sorption studies for pesticides should be conducted, analysed and used in regulatory assessment. The inclusion of aged sorption is a higher tier in the groundwater leaching assessment. The Panel based its review on a test with three substances taken from a data set provided by the European Crop Protection Association. Particular points of attention were the quality of the data provided, the proposed fitting procedure of aged sorption experiments and the proposed method for combining results obtained from aged sorption studies and lower‐tier studies on degradation and adsorption. Aged sorption was a relevant process in all cases studied. The test revealed that the guidance could generally be well applied and resulted in robust and plausible results. The Panel considers the guidance suitable for use in the groundwater leaching assessment after the recommendations in this Scientific Opinion have been implemented, with the exception of the use of field data to derive aged sorption parameters. The Panel noted that the draft guidance could only be used by experienced users because there is no software tool that fully supports the work flow in the guidance document. It is therefore recommended that a user‐friendly software tool be developed. Aged sorption lowered the predicted concentration in groundwater. However, because aged sorption experiments may be conducted in different soils than lower‐tier degradation and adsorption experiments, it cannot be guaranteed that the higher tier predicts lower concentrations than the lower tier, while lower tiers should be more conservative than higher tiers. To mitigate this problem, the Panel recommends using all available higher‐ and lower‐tier data in the leaching assessment. The Panel further recommends that aged sorption parameters for metabolites be derived only from metabolite‐dosed studies. The formation fraction can be derived from parent‐dosed degradation studies, provided that the parent and metabolite are fitted with the best‐fit model, which is the double first‐order in parallel model in the case of aged sorption.

Abstract Following a request from EFSA, the Panel on Plant Protection Products and their Residues (PPR) developed an opinion on the state of the art of Toxicokinetic/Toxicodynamic (TKTD) models and their use in prospective environmental risk assessment (ERA) for pesticides and aquatic organisms. TKTD models are species‐ and compound‐specific and can be used to predict (sub)lethal effects of pesticides under untested (time‐variable) exposure conditions. Three different types of TKTD models are described, viz., (i) the ‘General Unified Threshold models of Survival’ (GUTS), (ii) those based on the Dynamic Energy Budget theory (DEBtox models), and (iii) models for primary producers. All these TKTD models follow the principle that the processes influencing internal exposure of an organism, (TK), are separated from the processes that lead to damage and effects/mortality (TD). GUTS models can be used to predict survival rate under untested exposure conditions. DEBtox models explore the effects on growth and reproduction of toxicants over time, even over the entire life cycle. TKTD model for primary producers and pesticides have been developed for algae, Lemna and Myriophyllum. For all TKTD model calibration, both toxicity data on standard test species and/or additional species can be used. For validation, substance and species‐specific data sets from independent refined‐exposure experiments are required. Based on the current state of the art (e.g. lack of documented and evaluated examples), the DEBtox modelling approach is currently limited to research applications. However, its great potential for future use in prospective ERA for pesticides is recognised. The GUTS model and the Lemna model are considered ready to be used in risk assessment.

Abstract Following a request from the European Commission, the EFSA Panel on Plant Protection Products and their Residues (PPR Panel) prepared a scientific opinion to provide a comprehensive evaluation of pesticide residues in foods for infants and young children. In its approach to develop this scientific opinion, the EFSA PPR Panel took into account, among the others, (i) the relevant opinions of the Scientific Committee for Food setting a default maximum residue level (MRL) of 0.01 mg/kg for pesticide residues in foods for infants and young children; (ii) the recommendations provided by EFSA Scientific Committee in a guidance on risk assessment of substances present in food intended for infants below 16 weeks of age; (iii) the knowledge on organ/system development in infants and young children. For infants below 16 weeks of age, the EFSA PPR Panel concluded that pesticide residues at the default MRL of 0.01 mg/kg for food for infants and young children are not likely to result in an unacceptable exposure for active substances for which a health‐based guidance value (HBGV) of 0.0026 mg/kg body weight (bw) per day or higher applies. Lower MRLs are recommended for active substances with HBGVs below this value. For infants above 16 weeks of age and young children, the established approach for setting HBGVs is considered appropriate. For infants below 16 weeks of age the approach may not be appropriate and the application of the EFSA guidance on risk assessment of substances present in food intended for infants below 16 weeks of age is recommended. The contribution of conventional food to the total exposure to pesticide residues is much higher than that from foods intended for infants and young children. Because of the increased intake of conventional food by young children, these have the highest exposure to pesticide residues, whereas infants 3–6 months of age generally have lower exposure. The impact of cumulative exposure to pesticide residues on infants and young children is not different from the general population and the EFSA cumulative risk assessment methodology is also applicable to these age groups. Residue definitions established under Regulation (EC) No 396/2005 are in general considered appropriate also for foods for infants and young children. However, based on a tier 1 analysis of the hydrolysis potential of pesticides simulating processing, the particular appropriateness of existing residue definitions for monitoring to cover processed food, both intended for infants and young children as well as conventional food, is questionable.

Abstract Following a request from EFSA, the Panel on Plant Protection Products and their Residues developed an opinion on the science to support the potential development of a risk assessment scheme of plant protection products for amphibians and reptiles. The coverage of the risk to amphibians and reptiles by current risk assessments for other vertebrate groups was investigated. Available test methods and exposure models were reviewed with regard to their applicability to amphibians and reptiles. Proposals were made for specific protection goals aiming to protect important ecosystem services and taking into consideration the regulatory framework and existing protection goals for other vertebrates. Uncertainties, knowledge gaps and research needs were highlighted.

Abstract In 2013, EFSA published a comprehensive systematic review of epidemiological studies published from 2006 to 2012 investigating the association between pesticide exposure and many health outcomes. Despite the considerable amount of epidemiological information available, the quality of much of this evidence was rather low and many limitations likely affect the results so firm conclusions cannot be drawn. Studies that do not meet the ‘recognised standards’ mentioned in the Regulation (EU) No 1107/2009 are thus not suited for risk assessment. In this Scientific Opinion, the EFSA Panel on Plant Protection Products and their residues (PPR Panel) was requested to assess the methodological limitations of pesticide epidemiology studies and found that poor exposure characterisation primarily defined the major limitation. Frequent use of case–control studies as opposed to prospective studies was considered another limitation. Inadequate definition or deficiencies in health outcomes need to be avoided and reporting of findings could be improved in some cases. The PPR Panel proposed recommendations on how to improve the quality and reliability of pesticide epidemiology studies to overcome these limitations and to facilitate an appropriate use for risk assessment. The Panel recommended the conduct of systematic reviews and meta‐analysis, where appropriate, of pesticide observational studies as useful methodology to understand the potential hazards of pesticides, exposure scenarios and methods for assessing exposure, exposure–response characterisation and risk characterisation. Finally, the PPR Panel proposed a methodological approach to integrate and weight multiple lines of evidence, including epidemiological data, for pesticide risk assessment. Biological plausibility can contribute to establishing causation.

Abstract In 2013, EFSA published a literature review on epidemiological studies linking exposure to pesticides and human health outcome. As a follow up, the EFSA Panel on Plant Protection Products and their residues (PPR Panel) was requested to investigate the plausible involvement of pesticide exposure as a risk factor for Parkinson's disease (PD) and childhood leukaemia (CHL). A systematic literature review on PD and CHL and mode of actions for pesticides was published by EFSA in 2016 and used as background documentation. The Panel used the Adverse Outcome Pathway (AOP) conceptual framework to define the biological plausibility in relation to epidemiological studies by means of identification of specific symptoms of the diseases as AO. The AOP combines multiple information and provides knowledge of biological pathways, highlights species differences and similarities, identifies research needs and supports regulatory decisions. In this context, the AOP approach could help in organising the available experimental knowledge to assess biological plausibility by describing the link between a molecular initiating event (MIE) and the AO through a series of biologically plausible and essential key events (KEs). As the AOP is chemically agnostic, tool chemical compounds were selected to empirically support the response and temporal concordance of the key event relationships (KERs). Three qualitative and one putative AOP were developed by the Panel using the results obtained. The Panel supports the use of the AOP framework to scientifically and transparently explore the biological plausibility of the association between pesticide exposure and human health outcomes, identify data gaps, define a tailored testing strategy and suggests an AOP's informed Integrated Approach for Testing and Assessment (IATA).

Abstract Following a request from EFSA, the Panel on Plant Protection Products and their Residues developed an opinion on the science behind the risk assessment of plant protection products for in‐soil organisms. The current risk assessment scheme is reviewed, taking into account new regulatory frameworks and scientific developments. Proposals are made for specific protection goals for in‐soil organisms being key drivers for relevant ecosystem services in agricultural landscapes such as nutrient cycling, soil structure, pest control and biodiversity. Considering the time‐scales and biological processes related to the dispersal of the majority of in‐soil organisms compared to terrestrial non‐target arthropods living above soil, the Panel proposes that in‐soil environmental risk assessments are made at in‐ and off‐field scale considering field boundary levels. A new testing strategy which takes into account the relevant exposure routes for in‐soil organisms and the potential direct and indirect effects is proposed. In order to address species recovery and long‐term impacts of PPPs, the use of population models is also proposed.

Research on herbal medicinal products is increasingly published in “Western” scientific journals dedicated primarily to conventional medicines. Publications are concerned mainly not only on the issues of safety and interactions, but also on efficacy. In reviews, a recurring complaint has been a lack of quality studies. In this opinion article, we present the case of Chinese herbal medicines as an example, as they have been extensively used in the global market and increasingly studied worldwide. We analyze the potential reasons for problems and propose some ways forward. As in the case of any drug, clinical trials for safety, efficacy, and/or effectiveness are the ultimate demonstration of therapeutic usefulness of herbal products. These will only make scientific sense when the tested herbal products are authentic, standardized, and quality controlled, if good practice guidelines of evidence-based medicine are followed, and if relevant controls and outcome measures are scientifically defined. Herbal products are complex mixtures, and for such complexity, an obvious approach for mechanistic studies is network pharmacology based on omic tools and approaches, which has already begun to revolutionize the study of conventional drugs, emphasizing networks, interactions, and polypharmacological features behind the action of many drugs.

The objective of these investigations was to determine the possible effects of the novel selective estrogen receptor modulator, ospemifene, on cytochrome P450 (CYP)-mediated drug metabolism. Ospemifene underwent testing for possible effects on CYP enzyme activity in human liver microsomes and in isolated human hepatocytes. Based on the results obtained in vitro, three Phase 1 crossover pharmacokinetic studies were conducted in healthy postmenopausal women to assess the in vivo effects of ospemifene on CYP-mediated drug metabolism. Ospemifene and its main metabolites 4-hydroxyospemifene and 4'-hydroxyospemifene weakly inhibited a number of CYPs (CYP2B6, CYP2C9, CYP2C19, CYP2C8, and CYP2D6) in vitro. However, only CYP2C9 activity was inhibited by 4-hydroxyospemifene at clinically relevant concentrations. Induction of CYPs by ospemifene in cultured human hepatocytes was 2.4-fold or less. The in vivo studies showed that ospemifene did not have significant effects on the areas under the plasma concentration-time curves of the tested CYP substrates warfarin (CYP2C9), bupropion (CYP2B6) and omeprazole (CYP2C19), demonstrating that pretreatment with ospemifene did not alter their metabolism. Therefore, the risk that ospemifene will affect the pharmacokinetics of drugs that are substrates for CYP enzymes is low.