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While whole animal studies have their place in risk assessment of food and feed components, it is thought that more modern approaches such as human focused new approached methodologies (NAMs) would bring advantages including a greater focus to the human species, a focus on molecular mechanism and kinetics and the possibility of addressing susceptible populations. This report outlines the thinking from the authors and culminates in activity proposals in seven distinct but interacting scientific areas i.e. development of additional AOPs/AOP networks (AOPs), advanced cell culture models including Organ on a chip (OoC), toxicokinetic assessment with a focus on physiological based kinetic modelling (PBK), exposome, human susceptibility, data integration and new concepts in human risk assessment. Furthermore, the development of a Forum is proposed to facilitate the implementation of new approaches and concepts in risk assessment. The report was compiled by the project team, renowned experts in the various areas, and recommendations were discussed with EFSA and further refined following consultation with external experts via a dedicated workshop. The authors are convinced that if the recommendations are taken up, there will be a significant impact in the field, resulting in increasing the uptake and utilisation of these emerging technologies by all stakeholders involved.

The EFSA has updated the Guidance on risk assessment of the application of nanoscience and nanotechnologies in the food and feed chain, human and animal health. It covers the application areas within EFSA’s remit, including novel foods, food contact materials, food/feed additives and pesticides. The updated guidance, now Scientific Committee Guidance on nano risk assessment (SC Guidance on Nano‐RA), has taken account of relevant scientific studies that provide insights to physico‐chemical properties, exposure assessment and hazard characterisation of nanomaterials and areas of applicability. Together with the accompanying Guidance on Technical requirements for regulated food and feed product applications to establish the presence of small particles including nanoparticles (Guidance on Particle‐TR), the SC Guidance on Nano‐RA specifically elaborates on physico‐chemical characterisation, key parameters that should be measured, methods and techniques that can be used for characterisation of nanomaterials and their determination in complex matrices. The SC Guidance on Nano‐RA also details aspects relating to exposure assessment and hazard identification and characterisation. In particular, nanospecific considerations relating to in vitro/in vivo toxicological studies are discussed and a tiered framework for toxicological testing is outlined. Furthermore, in vitro degradation, toxicokinetics, genotoxicity, local and systemic toxicity as well as general issues relating to testing of nanomaterials are described. Depending on the initial tier results, additional studies may be needed to investigate reproductive and developmental toxicity, chronic toxicity and carcinogenicity, immunotoxicity and allergenicity, neurotoxicity, effects on gut microbiome and endocrine activity. The possible use of read‐across to fill data gaps as well as the potential use of integrated testing strategies and the knowledge of modes or mechanisms of action are also discussed. The Guidance proposes approaches to risk characterisation and uncertainty analysis., This publication is linked to the following EFSA Journal article: http://onlinelibrary.wiley.com/doi/10.2903/j.efsa.2021.6769/full This publication is linked to the following EFSA Supporting Publications article: http://onlinelibrary.wiley.com/doi/10.2903/sp.efsa.2021.EN-6804/full

The EFSA Scientific Committee was asked to provide guidance on the most appropriate in vivo tests to follow up on positive in vitro results for aneugenicity, and on the approach to risk assessment for substances that are aneugenic but not clastogenic nor causing gene mutations. The Scientific Committee confirmed that the preferred approach is to perform an in vivo mammalian erythrocyte micronucleus test with a relevant route of administration. If this is positive, it demonstrates that the substance is aneugenic in vivo. A negative result with evidence that the bone marrow is exposed to the test substance supports a conclusion that aneugenic activity is not expressed in vivo. If there is no evidence of exposure to the bone marrow, a negative result is viewed as inconclusive and further studies are required. The liver micronucleus assay, even though not yet fully validated, can provide supporting information for substances that are aneugenic following metabolic activation. The gastrointestinal micronucleus test, conversely, to be further developed, may help to assess aneugenic potential at the initial site of contact for substances that are aneugenic in vitro without metabolic activation. Based on the evidence in relation to mechanisms of aneugenicity, the Scientific Committee concluded that, in principle, health‐based guidance values can be established for substances that are aneugenic but not clastogenic nor causing gene mutations, provided that a comprehensive toxicological database is available. For situations in which the toxicological database is not sufficient to establish health‐based guidance values, some approaches to risk assessment are proposed. The Scientific Committee recommends further development of the gastrointestinal micronucleus test, and research to improve the understanding of aneugenicity to support risk assessment., This publication is linked to the following EFSA Supporting Publications article: http://onlinelibrary.wiley.com/doi/10.2903/sp.efsa.2021.EN-6814/full

This Statement presents a proposal for harmonising the establishment of Health‐Based Guidance Values (HBGVs) for regulated products that are also nutrients. This is a recurrent issue for food additives and pesticides, and may occasionally occur for other regulated products. The Statement describes the specific considerations that should be followed for establishing the HBGVs during the assessment of a regulated product that is also a nutrient. It also addresses the elements to be considered in the intake assessment; and proposes a decision tree for ensuring a harmonised process for the risk characterisation of regulated products that are also nutrients. The Scientific Committee recommends the involvement of the relevant EFSA Panels and units, in order to ensure an integrated and harmonised approach for the hazard and risk characterisation of regulated products that are also nutrients, considering the intake from all relevant sources., This publication is linked to the following EFSA Supporting Publications article: http://onlinelibrary.wiley.com/doi/10.2903/sp.efsa.2021.EN-6480/full

This Guidance document describes harmonised risk assessment methodologies for combined exposure to multiple chemicals for all relevant areas within EFSA's remit, i.e. human health, animal health and ecological areas. First, a short review of the key terms, scientific basis for combined exposure risk assessment and approaches to assessing (eco)toxicology is given, including existing frameworks for these risk assessments. This background was evaluated, resulting in a harmonised framework for risk assessment of combined exposure to multiple chemicals. The framework is based on the risk assessment steps (problem formulation, exposure assessment, hazard identification and characterisation, and risk characterisation including uncertainty analysis), with tiered and stepwise approaches for both whole mixture approaches and component‐based approaches. Specific considerations are given to component‐based approaches including the grouping of chemicals into common assessment groups, the use of dose addition as a default assumption, approaches to integrate evidence of interactions and the refinement of assessment groups. Case studies are annexed in this guidance document to explore the feasibility and spectrum of applications of the proposed methods and approaches for human and animal health and ecological risk assessment. The Scientific Committee considers that this Guidance is fit for purpose for risk assessments of combined exposure to multiple chemicals and should be applied in all relevant areas of EFSA's work. Future work and research are recommended., This publication is linked to the following EFSA Supporting Publications article: http://onlinelibrary.wiley.com/doi/10.2903/sp.efsa.2019.EN-1589/full, http://onlinelibrary.wiley.com/doi/10.2903/sp.efsa.2019.EN-1602/full

Multiple non-animal-based test methods have never been formally validated. In order to use such new approach methods (NAMs) in a regulatory context, criteria to define their readiness are necessary. The field of developmental neurotoxicity (DNT) testing is used to exemplify the application of readiness criteria. The costs and number of untested chemicals are overwhelming for in vivo DNT testing. Thus, there is a need for inexpensive, high-throughput NAMs, to obtain initial information on potential hazards, and to allow prioritization for further testing. A background on the regulatory and scientific status of DNT testing is provided showing different types of test readiness levels, depending on the intended use of data from NAMs. Readiness criteria, compiled during a stakeholder workshop, uniting scientists from academia, industry and regulatory authorities are presented. An important step beyond the listing of criteria, was the suggestion for a preliminary scoring scheme. On this basis a (semi)-quantitative analysis process was assembled on test readiness of 17 NAMs with respect to various uses (e.g. prioritization/screening, risk assessment). The scoring results suggest that several assays are currently at high readiness levels. Therefore, suggestions are made on how DNT NAMs may be assembled into an integrated approach to testing and assessment (IATA). In parallel, the testing state in these assays was compiled for more than 1000 compounds. Finally, a vision is presented on how further NAM development may be guided by knowledge of signaling pathways necessary for brain development, DNT pathophysiology, and relevant adverse outcome pathways (AOP).

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.

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.

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.

Multiple non-animal-based test methods have never been formally validated. In order to use such new approach methods (NAMs) in a regulatory context, criteria to define their readiness are necessary. The field of developmental neurotoxicity (DNT) testing is used to exemplify the application of readiness criteria. The costs and number of untested chemicals are overwhelming for in vivo DNT testing. Thus, there is a need for inexpensive, high-throughput NAMs to obtain initial information on potential hazards, and to allow prioritization for further testing. A background on the regulatory and scientific status of DNT testing is provided showing different types of test readiness levels, depending on the intended use of data from NAMs. Readiness criteria, compiled during a stakeholder workshop that united scientists from academia, industry and regulatory authorities, are presented. An important step beyond the listing of criteria was the suggestion of a preliminary scoring scheme. On this basis a (semi)-quantitative analysis process was assembled on test readiness of 17 NAMs with respect to various uses (e.g., prioritization/screening, risk assessment). The scoring results suggest that several assays are currently at high readiness levels. Therefore, suggestions are made on how DNT NAMs may be assembled into an integrated approach to testing and assessment (IATA). In parallel, the testing state in these assays was compiled for more than 1000 compounds. Finally, a vision is presented on how further NAM development may be guided by knowledge of signaling pathways necessary for brain development, DNT pathophysiology, and relevant adverse outcome pathways (AOP).

The Panel has interpreted the Terms of Reference by carrying out a stepwise evaluation of the BEEHAVE simulation model with a view to assessing its suitability for use in a regulatory context and for risk assessment of multiple stressors at the landscape level. The EFSA opinion on good modelling practice was used to evaluate the model and its documentation systematically. The overall conclusion is that BEEHAVE performs well in modelling honeybee colony dynamics, and the supporting documentation is generally good but does not fully meet the criteria of the good modelling opinion. BEEHAVE is not yet usable in a regulatory context primarily because it needs a pesticide module. BEEHAVE has a Varroa/virus module, although this seems to underestimate the impact of Varroa/virus on colony survival, and additional stressors (chemical and biological) would need to be added to allow investigation of the effects of interactions of pesticides with multiple stressors. BEEHAVE currently uses a very simple representation of a landscape and this should be extended. There is only one environmental scenario in the present version of BEEHAVE (European central zone-weather scenarios for Germany and the UK) and extension to other European zones would be needed. The supporting data and default parameter values should be further evaluated and justified. The modelling environment used by BEEHAVE (NetLogo) has an excellent user interface but provides limited opportunities for extending the model. The Panel recommends that BEEHAVE should be adopted as the basis for modelling the impact on honeybee colonies of pesticides and other stressors, but that further development should use a standard, object-oriented language rather than NetLogo.

Following a request from the European Food Safety Authority, the Panel on Plant Protection Products and their Residues developed an opinion on the science to support the development of a risk assessment scheme of plant protection products for non-target arthropods. The current risk assessment scheme is reviewed, taking into consideration recent workshops and progress in science. Proposals are made for specific protection goals which aim to protect important ecosystem services such as food web support, pest control and biodiversity. In order to address recovery and source-sink population dynamics, conducting a landscape-level risk assessment is suggested. A new risk assessment scheme is suggested which integrates modelling approaches. The main exposure routes for non-target arthropods are identified and proposals are made on how to integrate them in the risk assessment. The appropriateness of the currently used vegetation distribution factor was investigated. It is proposed that new tests be included in order to address exposure via oral uptake of residues and uncertainties related to differences in species sensitivity.

The European Food Safety Authority (EFSA) asked the Panel on Plant Protection Products and their Residues to prepare a scientific opinion on the Food and Environment Research Agency guidance proposal 'Guidance on how aged sorption studies for pesticides should be conducted, analysed and used in regulatory assessments'. The Panel concluded that the experimental and modelling approaches described in the proposed guidance are reasonable compromises between the required effort and what is desirable from a theoretical point of view. However, the Panel has concerns about the interpretation of the experiments and how the results of the experiments should be used in the leaching assessment. The Panel investigated options for improvement, but could not complete its evaluation on these two topics because underlying data to test these options were not made available to the Panel. For this reason, the Panel prepared a statement instead of a scientific opinion. Therefore, the Panel cannot recommend the use of the guidance for the time being.

Following a request from the European Food Safety Authority, the Panel on Plant Protection Products and their Residues developed an opinion on the science to support the development of a risk assessment scheme of plant (crop) protection products on non-target terrestrial plants (NTTPs). This scientific opinion is largely a literature review on the most up-to-date knowledge of factors influencing phytotoxicity testing and risk assessment of NTTPs. Specific protection goals (SPGs) were defined for off-field, in-field and endangered species. SPGs are closely linked to ecosystem services and functions, and include maintaining provision of water regulation, food web support, aesthetic values, genetic resources and biodiversity. Gaps were identified in standard guidelines currently used in lower tier testing (tier I/II). In these guidelines, tests are conducted at the seedling/juvenile stage using mostly annual crops, and effects are recorded at the juvenile/vegetative stage under greenhouse conditions with plants grown individually or in monoculture. Endpoints measured do not include the overall effect on the whole life cycle (germinating seeds, seedling, juvenile stages, flowering, and seed production and germinability). It is also noted that it is unknown whether the following groups of organisms are covered by the plant risk assessment as it is carried out now: ferns, mosses, liverworts, hornworts, horsetails, lichens or woody species. In terms of exposure, droplet drift is considered to be the most important factor for off-field emissions to non-target areas. Models are available to calculate loadings from spray drift. Higher tier assessment is not required if the risk based on the tier II level can be managed by risk mitigation measures. When required, higher tier tests should be conducted under more realistic conditions. They may include additional laboratory/greenhouse tests (e.g. to measure reproductive endpoints or species interactions), microcosms or field experiments with experimentally or already established species. Other issues were considered, including exposure to mixtures, adjuvants, co-formulants and metabolites. Recommendations for the improvement of current guidelines and the elaboration of new guidelines and risk assessment schemes are provided.

The Panel has interpreted the Terms of Reference as a stepwise analysis of issues relevant to both the development and the evaluation of models to assess ecological effects of pesticides. The regulatory model should be selected or developed to address the relevant specific protection goal. The basis of good modelling practice must be the knowledge of relevant processes and the availability of data of sufficient quality. The opinion identifies several critical steps in order to set models within risk assessment, namely: problem formulation, considering the specific protection goals for the taxa or functional groups of concern; model domain of applicability, which drives the species and scenarios to model; species (and life stage) selection, considering relevant life history traits and toxicological/toxicokinetics characteristics of the pesticide; selection of the environmental scenario, which is defined by a combination of abiotic, biotic and agronomic parameters to provide a realistic worst-case situation. Model development should follow the modelling cycle, in which every step has to be fully documented: (i) problem definition; (ii) model formulation, i.e. design of a conceptual model; (iii) model formalisation, in which variables and parameters are linked together into mathematical equations or algorithms; (iv) model implementation, in which a computer code is produced and verified; (v) model setup, including sensitivity analysis, uncertainty analysis and comparison with observed data, that delivers the regulatory model; (vi) prior to actual use in risk assessment, the regulatory model should be evaluated for relevance to the specific protection goals; (vii) feedback from risk assessor with possible recommendations for model improvement. Model evaluation by regulatory authorities should consider each step of the modelling cycle: the opinion identifies points of particular attention for the use of mechanistic effect models in pesticide risk assessment. It is recommended that models be documented in a complete and transparent way, that a feedback platform be established involving risk assessors and model developers, and that a set of agreed models be made available.

Following a request from the European Commission, the Panel on Plant Protection Products and their Residues (PPR) was asked to deliver a scientific opinion on the report of the FOCUS groundwater working group (FOCUS, 2009) with respect to the higher tier leaching assessments. The PPR Panel is of the general opinion that, as suggested in the FOCUS report, substance parameter refinement can be applied in risk assessment. State of the art knowledge has developed to such an extent that scenario refinement is feasible as well, but will make assessment more complex unless embedded in basic tools and adequate guidance. The same is true for spatial modelling but establishment of adequate databases will require quite some effort. The Panel considers current knowledge on groundwater hydrology insufficient for implementation of monitoring as the highest tier of the assessment at the European level. The implementation of scenario refinement and spatial modelling requires clear criteria on the extent of arable surface areas with estimated leaching rates below the threshold level.

The European Food Safety Authority (EFSA) asked the Panel on Plant Protection Products and their Residues (PPR Panel) to develop a Scientific Opinion on the relevance of dissimilar mode of action and its appropriate application for cumulative risk assessment of pesticides residues in food. The present opinion was preceded by three previous opinions of the PPR Panel (EFSA, 2008, 2009, 2013). The purpose of the present opinion was to assess the relevance of dissimilar modes of action (MoA) for cumulative risk assessment, to evaluate the existing methods for assessing chemicals acting by dissimilar MoA and to identify which methods need to be considered. The PPR Panel restricted its considerations of pesticide combinations with dissimilar modes of action to substances that produce a common adverse effect on the same organ/system. The PPR Panel noted that there is no case documented in the scientific literature where independent action provided more conservative predictions of combination effects than dose addition, and where at the same time independent action also produced accurate predictions. The use of independent action as an assessment concept for combination effects requires demonstration that modes of action of individual substances in a mixture are strictly independent, a condition that can rarely be met in practice. The PPR Panel also noted that there is no cumulative risk assessment method derived from independent action. The PPR Panel therefore recommends using cumulative risk assessment methods derived from dose addition also for the assessment of mixtures of pesticides with dissimilar modes of action, provided they produce a common adverse outcome. Pesticides that produce common adverse outcomes on the same target organ/system should be grouped together in CAGs, and their combined effects assessed by using the concept of dose addition as a pragmatic and conservative default approach for the purpose of assessing cumulative risk in relation to MRL setting or risk assessment of chemical mixtures in practice.

The European Food Safety Authority asked the Panel on Plant Protection Products and their Residues to develop an Opinion on the identification of pesticides to be included in cumulative assessment groups (CAGs) on the basis of their toxicological profile. In 2008, the PPR Panel adopted an Opinion on the suitability of existing methodologies for cumulative risk assessment of pesticides and a tiered approach was proposed, which was applied to a selected group of triazole pesticides in 2009. The present Opinion suggests a methodology for grouping of pesticides based on phenomenological effects and provides CAGs for the thyroid and nervous system. This approach can be applied even when the underlying biochemical events mediating the effects are not understood, and is based on a standardised and thorough review of Draft Assessment Reports (DARs) supporting the approval of all pesticides in Europe, and on recommendations from the European Commission. Pesticidal active substances exhibiting neurotoxic properties were allocated to CAGs for acute effects on motor, sensory and autonomic divisions of the nervous system and neurochemical endpoints. Chronic effects across the same divisions/endpoints and neuropathological effects were collated. Active substances having adverse effects on the thyroid system were allocated to CAGs for effects either on C-cells/the calcitonin system or on follicular cells/the T3/T4 system. The PPR Panel notes that the resulting groups encompass many pesticides and also that individual pesticides could appear in several groups and therefore the data entries for performing cumulative risk assessment (CRA) are of considerable magnitude. Although some CAGs contain a large number of pesticides, little indication of cumulative risk may be inferred from the size of CAGs per se. The PPR Panel recommends that the methodology is implemented for all major organ/systems but the approach used should be considered specific for pesticides.

The European Food Safety Authority asked the Panel on Plant Protection Products (PPR) and their residues to deliver a Scientific Opinion on the developmental neurotoxicity (DNT) potential of the neonicotinoid insecticides acetamiprid and imidacloprid. An in vitro study (Kimura-Kuroda et al., 2012) suggested that excitation and/or desensitisation of nicotinic acetylcholine receptors (nAChRs) by these compounds might affect developing mammalian nervous systems as occurs with nicotine. To evaluate the DNT potential of acetamiprid and imidacloprid, the PPR Panel scrutinised the open literature, the draft assessments reports and dossiers submitted for approval. The Panel concludes that both compounds may affect neuronal development and function, although several methodological limitations have been identified. Considering the available DNT studies for imidacloprid and acetamiprid, important uncertainties still remain and further in vivo studies following OECD test guideline (TG) 426 are required to robustly characterise a DNT potential and dose-response relationships, particularly for acetamiprid. The Panel considers that current ARfDs may not be protective enough for the possible DNT of acetamiprid and imidacloprid and no reliable conclusion can be drawn as regards the ADI for acetamiprid. More conservative reference values are proposed based on the analysis of the existing toxicological data. However, the current ADI for imidacloprid is considered adequate to protect against its potential developmental neurotoxic effects. Limitations of the in vitro system used by Kimura-Kuroda et al. (2012) prevent its current use as a screening tool in the regulatory arena. The PPR Panel encourages the definition of clear and consistent criteria at EU level to trigger submission of mandatory DNT studies, which could include development of an integrated DNT testing strategy composed of robust, reliable and validated in vitro assays and other alternative methods complementary to the in vivo TG 426 for assessing the DNT potential of substances.

EFSA's Panel on Plant Protection Products and their Residues (PPR) was tasked to revise the Guidance Document (GD) on Aquatic Ecotoxicology under Council Directive 91/414/EEC (SANCO/3268/2001 rev.4 (final), 17 October 2002). This Guidance of the PPR Panel is the first of three requested deliverables within this mandate. It has its focus on tiered acute and chronic effect assessment schemes with detailed guidance on tier 1 and higher tier effect assessments for aquatic organisms in edge-of-field surface waters and on proposals regarding how to link effects to exposure estimates. The exposure assessment methodology was not reviewed and it is assumed that the current FOCUS surface water exposure assessment methodology will continue to be used for exposure assessment at EU level. The current GD is intended to be used for authorisation of active substances at EU level as well as for plant protection products at Member State level. The effect assessment schemes in this GD allow for the derivation of regulatory acceptable concentrations (RACs) on the basis of two options: (1) the ecological threshold option (ETO), accepting negligible population effects only, and (2) the ecological recovery option (ERO), accepting some population-level effects if ecological recovery takes place within an acceptable time period. In the tiered effect assessment schemes, in principle, all tiers (1, 2 and 3) are able to address the ETO, while the model ecosystem approach (tier 3), under certain conditions, is able to also address the ERO. The GD provides the scientific background for the risk assessment to aquatic organisms in edge-of-field surface waters and is structured to give detailed guidance on all assessment steps. An executive summary joining all parts of the guidance and decision schemes in a concise way is provided and is intended to help applicants and regulatory authorities in day-to-day use.

The European Food Safety Authority (EFSA) asked the Panel on Plant Protection Products and their Residues (PPR) to develop an opinion on approaches to evaluate the toxicological relevance of metabolites and degradates of pesticide active substances in dietary risk assessment. This opinion identifies the threshold of toxicological concern (TTC) concept as an appropriate screening tool. The TTC values for genotoxic and toxic compounds were found to be sufficiently conservative for chronic exposure, as a result of a validation study with a group of pesticides belonging to different chemical classes. Three critical steps were identified in the application of a TTC scheme: 1) the estimate of the level of the metabolite, 2) the evaluation of genotoxicity alerts and 3) the detection of neurotoxic metabolites. Tentative TTC values for acute exposure were established by the PPR Panel by analysis of the lowest 5th percentiles of No Observed Adverse Effect Levels (NOAELs) used to establish the Acute Reference Doses (ARfD) for the EFSA pesticide data set. Assessment schemes for chronic and acute dietary risk assessment of pesticide metabolites, using the TTC approach and combined (Q)SAR and read across, are proposed. The opinion also proposes how the risk assessment of pesticide metabolites that are stereoisomers should be addressed due to isomer ratio changes reflected in the composition of metabolites. The approach is ready for use, but it is anticipated that on many occasions the outcome of the assessment scheme will be that further testing is needed to reach a firm conclusion on the toxicological relevance of the metabolite. However, the benefit of applying the approach is that it will allow prioritisation of metabolites for subsequent testing. EFSA will develop a Guidance Document based on the results in this opinion.

The European Food Safety Authority (EFSA) asked the Panel on Plant Protection Products and their Residues to provide guidance on methodology for performing probabilistic dietary exposure assessment of single or multiple active substances, as a potential additional tool to supplement or complement the standard deterministic methodologies which are currently used in the EU for conducting dietary exposure assessments for pesticides. Specific guidance is provided for basic assessments but not for refined assessments, where specialized expertise is required to select methods appropriate to the assessment in hand. The guidance includes probabilistic methods for quantifying some of the major sources of variability and uncertainty affecting dietary exposure to pesticides. Other important sources of variability and uncertainty might be quantified probabilistically in refined assessments but are addressed more simply in basic assessments by conducting alternative model runs with optimistic and pessimistic assumptions. Guidance is provided on problem formulation, including definition of appropriate scenarios for acute and chronic exposure assessment in the differing contexts of approval of new substances, MRL setting, authorisation of products, evaluation of residues found above the MRL, and annual reviews of residue monitoring data. Detailed guidance is provided on methodology for probabilistic modelling of acute and chronic exposures and for quantifying variability and uncertainty in food consumption and residues. For basic probabilistic assessments, optimistic and pessimistic assumptions are used for the effects of processing and for residues below the level of reporting. A separate section is devoted to additional approaches required for modelling exposure to multiple substances (cumulative assessment): the use of relative potency factors to cumulate exposures to different substances, and a basic methodology for addressing gaps in data on the co-occurrence of residues of different substances. Specific guidance is provided on the types and formats of outputs that should be produced from a probabilistic assessment. Particular emphasis is placed on characterising the upper tail of the exposure distribution and on 'drill down' techniques to evaluate the reliability of the estimates. A general approach is recommended for evaluating uncertainties affecting the model outputs. An appendix to the guidance describes uncertainties associated with the methodology recommended in this guidance, and provides a general evaluation of their potential impacts on estimated exposures. The guidance also includes a checklist of key issues to be considered when writing or peer-reviewing reports on probabilistic exposure assessments, a discussion of approaches to validating probabilistic assessment approaches, and a list of desirable characteristics of software for probabilistic exposure modelling. Some comments are provided on the interpretation of results, while recognising that risk management is outside the remit of EFSA. Case studies are included in an appendix, illustrating some but not all of the recommended approaches. Further work will be required to make the methods in this guidance available to end-users in more practical form, including software and more specific user instructions. Some recommendations on this are provided.

This guidance on the assessment of dermal absorption has been developed to assist notifiers, users of test facilities and Member State authorities on critical aspects related to the setting of dermal absorption values to be used in risk assessments of chemical plant protection products. It is based on the opinion on the science behind the revision of the guidance document on dermal absorption (EFSA, 2011) to which the guidance refers to in many instances. Basic details of experimental design, available elsewhere, have not been addressed but recommendations specific to performing and interpreting dermal absorption studies with plant protection products are given. Issues discussed include a brief description of the skin and its properties affecting dermal absorption. To facilitate use of the guidance, flow charts are included. Guidance is also provided, for example, when there are no data on dermal absorption for the product under evaluation. Elements for a tiered approach are presented including use of default values, data on closely related products, in vitro studies with human skin, data from experimental animals (rats) in vitro and in vivo and the so called "Triple pack" approach. Various elements of study design and reporting, that reduce experimental variation and aid consistent interpretation, are presented. A proposal for reporting data for Draft Assessment Reports and Registration Reports is also provided. The issue of nanoparticles in plant protection products is not addressed. Data from volunteer studies have not been discussed since their use is not allowed in EU for risk assessment of plant protection products.

Based on consultation with Member States, EFSA asked the Panel to prepare a revision of the Guidance Document on the persistence of plant protection products in soil (SANCO/9188VI/1997 of 12 July 2000) as scientific knowledge in this field has evolved in recent years. Therefore the Panel developed a revised methodology for the assessment of exposure of soil organisms to such products. Based on a previous Opinion of the Panel, this methodology has been developed both for the concentration in total soil and the concentration in the soil pore water. The goal of the exposure assessment has been chosen to be the 90th percentile of the exposure concentration in the intended area of use in each of the three regulatory geographical zones (North, Centre, South). The exposure assessment methodology is restricted to spray applications to annual crops under conventional or reduced tillage (excluding tillage systems with ridges and furrows). The Panel proposes a tiered approach. Tier 1 is based on a simple analytical model. Tier 2A is based on simulations with numerical models. To keep the approach as simple as possible, the Panel based Tiers 1 and 2A for each regulatory zone on only one scenario each for the concentration in total soil and for that in pore water. These scenarios are to be used for all these annual crops and for all plant protection products in each regulatory zone. Tiers 2B and 2C are also based on the simple analytical model but in these tiers a specific crop or crop group and an individual plant protection product are considered. Tier 3 is based on simulations with numerical models but, as in Tiers 2B and 2C, a specific crop or crop group and a specific plant protection product are considered. All tiers aim to assess the same exposure assessment goal. Given the complexity of the calculations in the different tiers, efficient use of this tiered approach in the regulatory process is impossible without software tools. Therefore the Panel recommends developing user-friendly software tools for the calculation of the exposure concentrations in the different tiers.

The PPR Panel was asked to deliver a scientific opinion on the science behind the development of a risk assessment of plant protection products on bees (Apis mellifera, Bombus spp. and solitary bees). Specific protection goals options were suggested based on the ecosystem services approach. The different routes of exposure were analysed in detail for different categories of bees. The existing test guidelines were evaluated and suggestions for improvement and further research needs were listed. A simple prioritisation tool to assess cumulative effects of single pesticides using mortality data is suggested. Effects from repeated and simultanous exposure and synergism are discussed. Proposals for separate risk assessment schemes, one for honey bees and one for bumble bees and solitary bees, were developed.

This opinion provides the relevant data, evaluations and references that support the criteria proposed in the new draft guidance needed to facilitate assessment of dermal absorption of plant protection products (PPPs) under Directive 91/414/EEC4 and Regulation (EC) No 1107/20095. The new guidance will be finalised and published only after adoption and publication of this opinion. This opinion has been developed after a public consultation of EFSA on the current guidance document and an outsourced project carried out by the UK Chemials Regulation Directorate (CRD, 2010). It is not intended to be an exhaustive review but builds on existing documents to which the reader is referred to, and addresses in more detail elements that are specifically relevant for the assessment of dermal absorption of plant protection products. It contains an overview on skin and substance properties and other determinants that have an impact on absorption, a description of important elements in the design of experimental studies and an analysis of available data on dermal absorption of PPPs. The PPR Panel concludes that assessment of dermal absorption in the absence of specific studies can be performed based on default values that the Panel derived from the analysis of the available databases. Elements for a tiered approach are described and commented on. The PPR Panel also concludes that in vitro human studies can be used as a stand alone test for assessment of dermal absorption. The Panel indicates some additional requirements to adapt existing OECD test guidelines to the special requirements of PPPs and their formulations. A harmonised reporting of the studies is also considered important. Some areas where further research could usefully be conducted have been identified.

A modelling approach for defining soil ecoregions within Europe was developed to improve the realism of exposure scenarios for plant protection products. Biological information on four soil animal groups (earthworms, enchytraeids, collembolans and isopods) was used to assign each species to different life forms, representing depth horizons in which they occur. Based on information from three countries covering a North-South gradient (Finland, Germany, Portugal), species presence-absence data were modelled using pedological and climatological information. With a triangular diagram it was possible to visualise life-form distributions for the organisms groups. Ecoregion maps were produced for earthworms and enchytraeids and revealed marked differences between the three countries. The information on the spatial distribution of the dominance classes could be transformed into depth profiles for any ecotoxicologically relevant concentration to be modelled. This procedure allows defining realistic "worst" case exposure depth profiles for risk assessment. The approach could be extended to the entire EU territory, provided more biogeographical data are available. A better resolution might also be achieved by adjusting the - presently geometrically derived - sizes of the 7 classes in the triangular diagrams. For an improved risk assessment of plant protection products it is recommended to extend exposure modelling to the litter layer. This approach would imply a refinement of the environmental risk assessment of plant protection products which needs to be discussed with risk managers. For most of the situations in Europe, the worst case soil depth profile for short term risk assessment would be litter (if present) or 0 to 1 cm depth instead of the currently used 0 to 5 cm depth.

The European Commission asked the Panel to revise the Guidance Document on persistence in soil (SANCO/9188VI/1997 of 12 July 2000). Therefore the Panel started the development of a revised methodology for the assessment of exposure of soil organisms. This opinion provides guidance on how to derive the half-life for degradation in the top 30 cm of soil at reference temperature and moisture conditions (i.e. 20oC and field capacity) from the results of field studies in which the plant protection product was sprayed onto the soil surface. This half-life is an important input parameter in model simulations of the exposure of organisms in soil for annual crops under conventional and reduced tillage and therefore this guidance is an important part of this revised methodology. The Panel proposes the splitting of field dissipation studies into two parts viz. before and after at least 10 mm of rain has fallen since application. The Panel recommends evaluating field dissipation studies with models capable of considering a biphasic decline and taking only the slow phase of this decline, taken to represent degradation in the soil matrix rather than loss processes from the soil surface, into account for estimating this half-life. If however, surface processes do not seem to occur the Panel proposes to use single first-order kinetics after eliminating data points before 10 mm of rain has fallen. The Panel proposes basing the relevant population of half-lives for a certain soil exposure scenario on the assumption that a half-life measured for any non-volcanic agricultural soil from temperate regions can be used to predict the half-life for any such soil within the EU. The aim is to estimate the geomean half-life of this relevant population. The Panel considers it necessary to include the uncertainty resulting from the sample size of the population in the estimation of this geomean. If the relevant population of half-lives for a certain exposure scenario consists of a mixture of values obtained in the laboratory and in the field, the Panel recommends rejecting the laboratory values only if the null hypothesis that laboratory and field half-lives are equal is rejected. The Panel considers that this guidance will also be useful to determine half-lives to be used in scenario calculations for the assessment of leaching to groundwater and surface water. Should the notifier want to use results of field dissipation studies for estimating the half-life in the top 30 cm of soil as an input parameter for exposure models, the Panel recommends incorporating the plant protection product to a depth of about 10 cm in soil immediately after application.

General protection goals are stated in European legislation but specific protection goals (SPGs) are not precisely defined. These are however crucial for designing appropriate risk assessment schemes. Here a process for defining SPG options is presented, which uses the ecosystem services approach as an overarching concept and could be used in consultation processes with risk managers and stakeholders. SPGs are defined in 6 dimensions: biological entity, attribute, magnitude of effect, temporal and geographical scale of the effect, and the degree of certainty that the specified level of effect will not be exceeded. SPG options are presented for 7 key drivers (microbes, algae, non target plants (aquatic and terrestrial), aquatic invertebrates, terrestrial non target arthropods including honeybees, terrestrial non-arthropod invertebrates, and vertebrates), covering all ecosystem services which could potentially be affected by the use of pesticides. To ensure ecosystem services, taxa representative for the key drivers identified need to be protected at the population level or higher. However, for aesthetic reasons (cultural ecosystem services) it may be decided to protect vertebrates at the individual level. To protect biodiversity, impacts at least need to be assessed at the scale of the watershed/landscape. The Panel also emphasizes the importance of a tiered approach for risk assessment, the essential linking of exposure and effect assessments in terms of spatial and temporal scales, and the relevance of ecological scenarios for appropriate pesticide risk assessments. It intends to use the presented concepts as input for the dialogue between risk managers and risk assessors during the next steps of the revision of the Ecotoxicology Guidance Documents.

The current/traditional human health risk assessment paradigm is challenged by recent scientific and technical advances, and ethical demands. The current approach is considered too resource intensive, is not always reliable, can raise issues of reproducibility, is mostly animal based and does not necessarily provide an understanding of the underlying mechanisms of toxicity. From an ethical and scientific viewpoint, a paradigm shift is required to deliver testing strategies that enable reliable, animal‐free hazard and risk assessments, which are based on a mechanistic understanding of chemical toxicity and make use of exposure science and epidemiological data. This shift will require a new philosophy, new data, multidisciplinary expertise and more flexible regulations. Re‐engineering of available data is also deemed necessary as data should be accessible, readable, interpretable and usable. Dedicated training to build the capacity in terms of expertise is necessary, together with practical resources allocated to education. The dialogue between risk assessors, risk managers, academia and stakeholders should be promoted further to understand scientific and societal needs. Genuine interest in taking risk assessment forward should drive the change and should be supported by flexible funding. This publication builds upon presentations made and discussions held during the break‐out session ‘Advancing risk assessment science – Human health’ at EFSA's third Scientific Conference ‘Science, Food and Society’ (Parma, Italy, 18–21 September 2018)., EFSA Journal, 17 (S1), ISSN:1831-4732, Proceedings of the Third EFSA Scientific Conference: Science, Food and Society

Environment international 134, 105267 (2020). doi:10.1016/j.envint.2019.105267, Published by Elsevier Science, Amsterdam [u.a.]