European Food Safety Authority (EFSA), John Lucas, Quirico Migheli, Gianfranco Romanazzi, Ciro Gardi, Filippo Bergeretti, Zoltan Erdos.

Transcription

1 TECHNICAL REPORT APPROVED: 24 November 2017 doi: /sp.efsa.2017.en-1345 Protocol for the evaluation of data concerning the necessity of the application of fungicide 1 active substances to control a serious danger to plant health which cannot be contained by other available means, including non-chemical methods European Food Safety Authority (EFSA), John Lucas, Quirico Migheli, Gianfranco Romanazzi, Ciro Gardi, Filippo Bergeretti, Zoltan Erdos. Abstract Following a request from the European Commission, the European Food Safety Authority (EFSA) initiated a procedure for the evaluation of data supporting the necessity of the application of fungicide active substances to control a serious danger to plant health within the context of Article 4(7) of Regulation (EC) No. 1107/2009. EFSA established an ad hoc working group (WG) which proposed a methodology for conducting this type of evaluation. The draft protocol was circulated among European Union Member States (MS) for commenting. The aim of this protocol is to enable a consistent and transparent evaluation of submissions made by applicants according to the derogation detailed in Article 4(7) of Regulation (EU) No. 1107/2009 to assess the lack of other available means capable of controlling an identified serious danger to plant health. All the evaluations are performed separately for each specific crop/pathogen combination for which derogation is requested. Derogation for the use of a fungicidal active substance (a.s.) is not considered to be scientifically supported if an alternative control programme not requiring the application of a fungicide can manage the specific crop/pathogen combination under consideration; or if alternatively another a.s. from the same mode of action (MoA) as the a.s. under consideration is available (with the exception of the a.s. with unknown MoA). If these conditions are not verified, the process moves to the evaluation of: 1) the risk of resistance associated with the different MoA of all active substances for the specific crop/pathogen combination that are authorised in the MS; 2) the risk of resistance associated with the different pathogens; 3) the availability and durability of non-fungicide alternatives. European Food Safety Authority, 2017 Key words: pesticide, derogation, fungicide spectrum, fungicide resistance, integrated disease management, Article 4(7) of Regulation (EC) No. 1107/2009 Requestor: European Commission Question number: EFSA-Q Correspondence: alpha@efsa.europa.eu 1 In this protocol the term fungicide refers to both fungicides and bactericides EFSA Supporting publication 2017:EN-1345

2 Acknowledgements: EFSA wishes to thank the hearing expert Bart Fraaije and the reviewers Michael Jeger and Paloma Melgarejo Nardiz. Suggested citation: EFSA (European Food Safety Authority), Protocol for the evaluation of data concerning the necessity of the application of fungicide active substances to control a serious danger to plant health which cannot be contained by other available means, including non-chemical methods. EFSA supporting publication 2017:EN pp., doi: /sp.efsa.2017.en-1345 European Food Safety Authority, 2017 Reproduction is authorised provided the source is acknowledged. EFSA Supporting publication 2017:EN-1345

3 Summary Following a request of the European Commission (EC), the European Food Safety Authority (EFSA) initiated a procedure for the evaluation of data on concerning the necessity of the application of fungicide active substances (a.s.) to control a serious danger to plant health that cannot be contained by other available means, including non-chemical methods within the context of Article 4(7) of Regulation (EC) No. 1107/2009. EFSA established an ad hoc working group (WG) to develop a methodology for conducting such type of evaluation. The aim of this protocol is to enable a consistent and transparent evaluation of submissions made by applicants according to the derogation detailed in Article 4(7) of Regulation (EC) No. 1107/2009 to confirm the lack of other available means capable of controlling an identified serious danger to plant health. EFSA will act as the co-ordinator of the process, will ensure that the methodology is applied consistently, and will issue a scientific report on the evaluation of each fungicide a.s. for which derogation under Article 4(7) of Regulation (EC) No. 1107/2009 is requested. The protocol takes into account relevant international standards from the European and Mediterranean Plant Protection Organisation. The proposed methodology was also circulated among the European Member States (MS) for comment, and hence also their suggestions were assessed by the WG and taken into account where applicable. The applicant asking for a derogation under Article 4(7) of Regulation (EC) No. 1107/2009 should include in their dossier: information, data and evidence to demonstrate that the substance is necessary to control a serious danger to plant health that cannot be sufficiently contained by any other available means including non-chemical methods, following the methodology and harmonised template presented in this report. The MS will verify the information provided by the applicant and will provide supplementary information, data and evidence from their respective countries and may include other uses that were not requested by the applicant e.g. Article 51 extensions of minor use. The MS will evaluate the overall information based on the following methodology applied separately at national level to each specific crop/pathogen combination, for which a derogation is requested. The process starts by checking whether another a.s. from the same mode of action (MoA) as the a.s. under consideration is available (see MoA definition given in chapter ). In this case derogation is considered not to be scientifically supported. Likewise, if a non-fungicide control programme (that can include e.g. the use of resistance inducers or biological control agents) is sufficient to manage the pathogen/crop combination under consideration, derogation would be considered as not scientifically supported. Otherwise the process moves to the evaluation of: 1) the risk of resistance associated with the different MoA of all a.s. that are authorised in the MS; 2) the risk of resistance associated with the different pathogens; 3) the non-fungicide alternatives. Data on the combined resistance risk and the evaluation of non-fungicide alternatives will support the risk manager decision. 3 EFSA Supporting publication 2017:EN-1345

4 Table of contents Abstract... 1 Summary Introduction Background and terms of reference as provided by the requestor Additional information Legislation Plant health Fungicide resistance Non-fungicide methods... 8 Cultural control:... 8 Host genetic resistance:... 8 Biological control:... 9 Physical methods:... 9 Natural products and basic substances... 9 Resistance inducers: Data and methodologies Data and evidence List of authorised fungicide active substances on crop/pathogen combination Data on fungicide resistance risk Non-fungicide methods for plant disease management Methodology Step 1: Evaluation of fungicide alternatives with same MoA: Step 2: Evaluation of alternative non-fungicide programme: Step 3: Evaluation of alternative a.s. MoA: Step 4: Compute the following parameters and perform evaluations: Evaluation of fungicide/pathogen resistance management strategy based on remaining fungicide and non-fungicide alternatives Conclusions References Appendix A Flow chart of the methodology proposed for the evaluation of the necessity of given fungicide (start at the top-left of the flow chart) Appendix B Data collection form Appendix C Member States comments on the draft EFSA Technical Report EFSA Supporting publication 2017:EN-1345

5 1. Introduction 1.1. Background and terms of reference as provided by the requestor In January 2016, the European Commission (EC) asked in a general mandate to the European Food Safety Authority (EFSA) for scientific assistance related to the data concerning the necessity of the application of an active substance to control a serious danger to plant health that cannot be contained by other available means including non-chemical methods within the context of Article 4(7) of Regulation (EC) No. 1107/ because no clear instructions about how to handle Article 4(7) applications were available to the Member States and EFSA. The EC agreed that EFSA would provide a protocol on the methodology for each type of pesticide (e.g. herbicide (EFSA, 2016), insecticide (EFSA, 2017), fungicide (this opinion)) separately and afterwards the protocols would be merged to form a single guidance document, taking into consideration the experience gained through the application of the individual protocols to real cases. EFSA is requested, in accordance with Article 31 of Regulation (EC) No. 178/2002 3, to provide a protocol for the evaluation of data concerning the necessity of the application of fungicide active substances to control a serious danger to plant health which cannot be contained by other available means, including non-chemical methods within the context of Article 4(7) of Regulation (EC) No. 1107/2009. Therefore, in September 2016, EFSA set up a working group (WG) on fungicides Article 4(7) to address the above request of the EC. Before finalising the guidance, EFSA envisions a public consultation in addition to the consultation with the risk assessment organisations in the MS. The final guidance will be sent to the European Commission for consideration by risk managers. There are two possible situations in which applicants may submit information to demonstrate that Article 4(7) can be applied: or 1. When an active substance already has harmonised classification in accordance with Regulation (EC) No. 1272/ such that one or more of the approval criteria in Annex II, points 3.6.3, 3.6.4, or to Regulation (EC) No. 1107/2009 are not satisfied at the time of submission of the dossier 2. When the peer review of the active substance proposes a classification in accordance with the provisions of Regulation (EC) No. 1272/2008 such that one or more of the approval criteria in Annex II, points 3.6.3, 3.6.4, or to Regulation (EC) No. 1107/2009 are not satisfied. The process to be followed under situation 1 is as follows: the applicant should include information, data and evidence to demonstrate that the active substance is necessary to control a serious danger to plant health that cannot be contained by any other available means including non-fungicide alternatives as part of their (renewal of) approval dossier following the methodology and harmonised template proposed by EFSA. The rapporteur Member State (RMS) should present the applicant s submission as part of the Renewal Assessment Report or Draft Assessment Report (RAR/DAR). At the start of the peer review, Member States will be invited by EFSA to consider the information provided 2 Regulation (EC) No. 1107/2009 of the European Parliament and of the Council of 21 October 2009 concerning the placing of plant protection products on the market and repealing Council Directives 79/117/EEC and 91/414/EEC. OJ L 309, p Regulation (EC) No. 178/2002 of the European Parliament and of the Council of 28 January 2002 laying down the general principles and requirements of food law, establishing the European Food Safety Authority and laying down procedures in matters of food safety. OJ L 31, , p Regulation (EC) No. 1272/2008 of the European Parliament and of the Council of 16 December 2008 on classification, labelling and packaging of substances and mixtures, amending and repealing Directives 67/548/EEC and 1999/45/EC, and amending Regulation (EC) No. 1907/2006. OJ L 353, , p EFSA Supporting publication 2017:EN-1345

6 and to complete a standard template. Member States can supplement the information provided by the applicant with information from their own country. MS may also consider other uses that were not requested by the applicant e.g. Article 51 extensions of minor use at this stage. The process to be followed under situation 2 is as follows: following receipt of the EFSA Conclusion on the peer review of the active substance, the EC requests information from the applicant to demonstrate that Article 4(7) can be applied. The applicant should take note of the protocol prepared by EFSA and provide information, data and evidence outlined in the harmonised template proposed by EFSA. Following the applicant s submission to EFSA, the EC and RMS, EFSA requests all MS to consider and validate the information provided and to complete a standard template. MS can supplement the information provided by the applicant with information from their own country. MS may also consider other uses that were not requested by the applicant e.g. minor uses at this stage. The agreed protocol will be used by all MS when assessing applications for fungicide active substances within the context of Article 4(7) of Regulation (EC) No. 1107/2009. EFSA will act as the co-ordinator of the process, will ensure that the methodology is applied consistently and will issue a scientific report on the evaluation of each fungicide active substance for which derogation under Article 4(7) of Regulation (EC) No. 1107/2009 is requested. The process to consider whether an active substance can be approved under the provisions of Article 4(7) is distinct from the comparative assessment of plant protection products under the Guidance document on Comparative Assessment and Substitution of Plant Protection Products (European Commission, 2014) in accordance with Regulation (EC) No. 1107/2009. A decision in accordance with Article 4(7) is taken at EU level for the active substance, whereas comparative assessment is performed at MS level for individual products containing substances that are candidates for substitution. However, EFSA has been asked to take into account the principles of the Guidance on Comparative Assessment when developing the protocol to assess Article 4(7) submissions Additional information Legislation Regulation (EC) No. 1107/2009 lays down the rules for the placing of plant protection products on the market. Articles 4 to 13 of this Regulation outline the requirements, the conditions for approval, including the approval criteria (details given in Article 4 and under points 3.6, 3.7, 3.8, 3.9 and 3.10 of Annex II), and the procedure for the approval or non-approval at EU level of active substances contained in plant protection products. Under Article 4(7) of Regulation (EC) No. 1107/2009, derogation from the requirements and conditions for approval for an active substance is provided. Article 4(7) states that where on the basis of documented evidence included in the application an active substance is necessary to control a serious danger to plant health which cannot be contained by other available means including non-chemical methods, such active substance may be approved for a limited period necessary to control that serious danger but not exceeding five years even if it does not satisfy the criteria set out in points 3.6.3, 3.6.4, or of Annex II, provided that the use of the active substance is subject to risk mitigation measures to ensure that exposure of humans and the environment is minimised. For such substances maximum residue levels shall be set in accordance with Regulation (EC) No. 396/2005. This derogation shall not apply to active substances which are or have to be classified in accordance with Regulation (EC) No. 1272/2008, as carcinogenic category 1A, carcinogenic category 1B without a threshold, or toxic for reproduction category 1A. Member States may authorise plant protection products containing active substances approved in accordance with this paragraph only when it is necessary to control that serious danger to plant health in their territory. At the same time, MS shall draw up a phasing out plan concerning the control of the serious danger by other means, including non-chemical methods, and shall without delay transmit that plan to the Commission. 6 EFSA Supporting publication 2017:EN-1345

7 Complementary to Regulation (EC) No. 1107/2009, Directive 2009/128/EC 5 establishes a framework for Community action to achieve the sustainable use of pesticides as outlined in Article 1 by reducing the risks and impacts of pesticide use on human health and the environment and promoting the use of integrated pest management and of alternative approaches or techniques such as non-chemical alternatives to pesticides. Recital 19 of Directive 2009/128/EC reminds that on the basis of Regulation (EC) No. 1107/2009 and of this Directive, implementation of the principles of integrated pest management is obligatory and the subsidiarity principle applies to the way the principles for integrated pest management are implemented. Member States should describe in their National Action Plan how they ensure the implementation of the principles of integrated pest management, with priority given wherever possible to non-chemical methods of plant protection and pest and crop management. The recent legislation on invasive alien species (Regulation (EC) No 1143/ ) contains also indications relevant to management of fungi and other microorganisms, especially referring to the cases of alien species, except for those laid down under Art. 2, 2 (d), (f), (g) Plant health The definition of plant health may significantly vary depending on the perspectives and the approaches adopted. According to Döring et al. (2012) either a reductionist or a holistic approach can be adopted, with an anthropocentric or a biocentric perspective, respectively. In the context of this report we will adopt a reductionist approach with an anthropocentric perspective, defining plant health as the absence of damage to quality or quantity of plants for use, directly or indirectly by human beings, including non-crop uses. On the scale of possible impacts caused by fungal pathogens, it does not seem feasible to set a defined measure or threshold for defining these impacts as serious as they will vary depending on crops and other factors affecting crop performance, including social and cultural factors. Therefore, the decision on the classification of impacts on plant health as serious should be taken by the risk managers (e.g. European Commission) on a case by case basis (Jørgensen et al., 2017) Fungicide resistance Resistance is the naturally occurring, inheritable adjustment in the ability of individuals in a population to survive a plant protection product treatment that would normally give effective control. Although resistance can often be demonstrated in the laboratory, this does not necessarily mean that disease control in the field is reduced. Practical resistance is the term used for loss of field control due to a shift in sensitivity (EPPO 1988), cited in (EPPO 2015). Resistance can evolve in field populations of fungal plant pathogens due to several mechanisms (Leroux and Walker, 2011; Lucas et al., 2015). With site-specific fungicides, the most common cause is modification of the target-site either due to a single mutation or a combination of changes in the target protein. Target-site resistance often leads to a major reduction in sensitivity to the fungicide. Further mechanisms include: increased expression of the target protein (e.g. Cools et al. 2012; Rallos and Baudoin, 2016), or efflux of the fungicide by transporters in the cell membrane; often referred to as multidrug resistance (MDR) when multiple fungicides with unrelated modes of action are affected (e.g. Kretschmer et al., 2009). These can cause shifts in sensitivity, but may also occur in combination with target-site changes and give an overall increased level of resistance. Detoxification of the 5 Directive 2009/128/EC of the European Parliament and of the Council of 21 October 2009 establishing a framework for Community action to achieve the sustainable use of pesticides. OJ L 309, , p Regulation (EU) No 1143/2014 of the European Parliament and of the Council of 22 October 2014 on the prevention and management of the introduction and spread of invasive alien species. OJ L 317, , p EFSA Supporting publication 2017:EN-1345

8 fungicide through metabolism has been reported for kresoxim-methyl in Venturia inaequalis (Jabs et al., 2001) and prochloraz in Fusarium fujikuroi (Kim et al., 2010) but is not a common mechanism in fungal pathogens, unlike insects and weeds were many cytochrome P450 enzymes are involved in pesticide metabolism (e.g. Scott, 1999; Siminszky, 1999). As resistance is a genetically-based phenomenon, its dynamics will directly correlate with some intrinsic characteristics of the pathogen species such as: mutation rate, number of generations per season, type of reproduction (asexual or sexual), means of dispersal etc. Repetitive exposure to fungicides is the main force driving selection of resistant individuals in the pathogen population. The more often a single mode of action (MoA) is used the more likely the number of resistant individuals will increase in the population to the point where control in the field is compromised. The Fungicide Resistance Action Committee (FRAC) defines the main groups of MoA as well as subgroups (see Table 1 and Table 2 and visit for reference). In the case of target-site resistance, cross-resistance is likely to occur to all subgroups of the MoA, and alternation or mixture with alternative MoAs is recommended (e.g. van Hobbelen et al., 2013). Resistance due to efflux can act against unrelated compounds and resistance management should therefore be evaluated on a case by case basis related to the mechanism(s) involved. Assessing the likely impact of a requested derogation on the risk of resistance evolution to the a.s. under consideration requires a balanced judgement based on several parameters including the current status of the a.s. in terms of reported cases of resistance from monitoring programmes and given in the literature, the biological characteristics of the fungal pathogen in a given region, the agronomic system and other factors (e.g. resistance can persist in the population even when the selective agent is no longer used) (see Section b) Non-fungicide methods There are several examples of non-fungicide methods (as listed below), preventing plant disease occurrence or reducing the impact of pathogen populations. These non-fungicide methods are usually not sufficiently effective alone, however, these methods are usually only effective and used in practice within IPM strategies as stated by the Directive 2009/128/EC for establishing a framework for Community action to achieve the sustainable use of pesticides. In a number of cases, these alternative methods have even been proven more sustainable than fungicide treatments, because of their longterm effect (e.g., biological control: Bardin et al. 2015); durable resistance: (Willocquet et al., 2017), or because they are less likely than single site fungicides to select for resistance (Hollomon and Brent, 2009). Quite often alternative methods are applied in combination, in order to increase their efficacy. These combinations can include chemical or physical methods (e.g., soil solarisation followed by recolonisation by BCAs: Funahashi and Parke, 2016). Moreover, those alternatives include the use of basic substances (which are described in the recitals of Art.23 of Regulation (EC) 1107/2009 as "active substances, not predominantly used as plant protection products but which may be of value for plant protection, for which the economic interest of applying for approval may be limited and that are not substances of concern"). Several of these basic substances possess antimicrobial activity, together with the ability to increase the resistance of host tissue, and they may act as resistance inducers (Walters et al., 2013; Romanazzi et al., 2016). Cultural control: e.g., crop rotation (Dias et al, 2015), intercropping (Boudreau, 2013), change of planting or harvesting dates (Jørgensen et al., 2014), cover crop management (Larkin et al., 2010), tillage (Larkin, 2015), biofumigation (Friberg et al., 2009), mulching (Muñoz et al., 2017)l, grafting (Louws et al., 2010). Host genetic resistance: e.g., use of tolerant or resistant plant genotypes, including rootstocks (King et al., 2008), variety mixtures (Han et al, 2016; Mikaberidze et al, 2015) multiline cultivar 8 EFSA Supporting publication 2017:EN-1345

9 combinations (Finckh et al., 2000; Mundt, 2002; Iwai et al., 2006), genetic engineering and genome editing technology (Nekrasov et al. 2017). Biological control: i.e., the use of living organisms, also referred to as biocontrol agents - BCAs - to control one or more plant pathogens at pre-sowing, pre-planting, during vegetative growth, at preharvest or post-harvest stages; these can act directly as antagonists, or indirectly through induction of host resistance; Alabouvette et al., 2009; Harman, 2006; Xu et al., 2011; Romanazzi et al., 2012; Droby et al., 2009). Physical methods: e.g. soil solarisation (Gamliel & Katan, 2009), substrate and soil steaming (Sosnowski et al., 2009), UV treatment or sand filtration of nutrient solution (Vallance et al., 2010), UVc irradiation, ozone fumigation, hot water and hot air treatments, radio frequency and microwave, hypobaric and hyperbaric pressure (Usall et al., 2016) burning (Cox et al., 2005), cold storage (Mahajan et al., 2014). Natural products and basic substances 7, 8 : e.g., essential oils (Sivakumar ad Bautista-Banos, 2014; Prakash et al., 2015), plant extracts (Boutigny et al., 2008), laminarin (Aziz et al., 2003; Romanazzi et al., 2016a; Zhang et al., 2016), chitosan (Romanazzi et al., 2017). Resistance inducers: Resistance inducers are defined as compounds that show, together with antimicrobial activity or alone, the ability to increase the plant defences and prepare the host tissues to a subsequent infection by the pathogen (Walters et al., 2013). The application can occur in the field, for the control of pre and postharvest fungal diseases, or after harvest (Romanazzi et al., 2016). 2. Data and methodologies 2.1. Data and evidence This section outlines the data to be provided by applicants and MS, as well as the template and methodology for assessing the need for a fungicide a.s. (called the a.s. under consideration in this protocol) to control a serious danger to plant health. This protocol will be applied when evaluating the necessity of the application of the a.s. under consideration within the context of Article 4(7) of Regulation (EC) No 1107/2009. The applicant requesting a derogation under Article 4(7) of Regulation (EC) No 1107/2009 should include information, data and evidence to demonstrate that the substance is necessary to control a serious danger to plant health that cannot be contained by any other available means including nonfungicide alternatives in their dossier using the agreed methodology and the harmonised template presented in Appendix B. MS verify the information provided by the applicant and provide supplementary information, data and evidence from their respective countries and may include other uses that were not requested by the applicant e.g. minor uses. EFSA will consider the information provided by MS such as the non-fungicide alternatives, the resistance situation in their territory (until a valid and up-to-date resistance data bank has been established such as currently has been planned by EPPO) and the list of authorised fungicide a.s. as reliable and no further research will be performed for the validation of these data. Thus, MS have the full responsibility for the accuracy and correctness of the data provided to EFSA to perform the assessment. In providing the supporting information, the MS should take into account that all the information provided will be made publicly available as background documents to the EFSA Scientific Report. 7 European Commission, 2014a. Guidance on the procedure for application of basic substances to be approved in compliance with Article 23 of Regulation (EC) No 1107/2009. SANCO/10363/2012 rev.9 21 March For the purpose of this protocol basic substances, natural product and resistance inducers, are considered as non-fungicide. 9 EFSA Supporting publication 2017:EN-1345

10 List of authorised fungicide active substances on crop/pathogen combination A crop could refer to a single plant species (e.g. wheat - Triticum aestivum, oilseed rape - Brassica napus or horse-chestnut - Aesculus hippocastanum) or to a group of species (e.g. cereals, ornamentals), and can be differentiated depending on whether the cultivation takes place e.g. in open field or in protected cultivation eg a greenhouse, etc. In this protocol we consider as crop also the crop products (e.g. grains, tubers, fruits, etc.) kept in storehouses, silos, where fungicides can be applied. If relevant, crop destination (fresh consumption, industrial processing, etc.) should also be taken into account. The MS are requested to check the information submitted by the applicant and provide the list of authorised fungicide a.s. only for each crop/pathogen combination or non-agricultural use for which derogation is requested, using the template provided by EFSA (see Appendix B). If a registered product consists of two or more a.s. (coformulation), the information should be provided for each fungicidal a.s. in the coformulation separately. In addition to the list of authorised fungicide a.s. (column fungicide authorised ), MS are asked to include further information on each a.s. on other pathogens controlled (column other pathogen controlled ), exceptions (column exceptions ; species or groups of species that belong to this spectrum, but that are not controlled with a sufficient efficacy by the specific a.s.), period of application (column time of application ;) and MoA (column FRAC group/moa ) Data on fungicide resistance risk Taking into account the EPPO Standard on the Resistance Risk Analysis (EPPO, 2015) and the approach proposed by Grimmer et al. (2015), the applicant/ms is asked to evaluate the risk of resistance of the plant pathogen to be controlled towards the authorised fungicide a.s. This evaluation is based on Table 1 and on the instructions given in the sections and Report these data using the Excel file provided in Appendix B (column Resistance risk/global ). If, at MS level, cases of resistance for any of the fungicides a.s. exist, the applicant/ms should state this by indicating the fungal species (column Resistance risk/national ) and by providing the corresponding evidence (e.g. scientific or technical papers, field trial report in any language, including expert judgement). In this case, the overall classification for the risk of resistance will be set to high (column Overall classification ). Table 1 Classification of Mode of action and resistance risk for fungicides and bactericides used in disease control based on the FRAC Code List 2017 ( This Table is updated by FRAC on a regular basis taking account of the changing status of resistance in pathogen populations. Please note that some of the fungicide a.s. listed in this table are no longer authorised in Europe (European Commission, online). Target site and code Group name Examples of active substances FRAC code Risk of resistance 9,10,11 9 Intrinsic risk of resistance estimated as low, medium or high based on fungicide mode of action and properties according FRAC, and reported cases of resistance in lab mutants and field isolates in the literature. 10 Where resistance risk is estimated as Low-Medium, or Medium-High, the higher category has been used, based on a cautionary approach, indicated with an asterisk. 11 Risk of resistance is based on FRAC table and expert judgement. Where literature data are available, references are provided EFSA Supporting publication 2017:EN-1345

11 Target site and code Group name Examples of active substances FRAC code Risk of resistance 9,10,11 A1. Nucleic acids synthesis (RNA polymerase I) PA fungicides (Phenyl Amides) Benalaxyl 4 High A2. Nucleic acids synthesis (adenosine-deaminase) Hydroxyl (2-amino-) pyrimidines Bupirimate 8 Medium A3. Nucleic acids synthesis (DNA/RNA synthesis proposed) A4. Nucleic acids synthesis DNA topoisomerase type II (gyrase) Heteroaromatics Hymexazole 32 Medium (Al-Balushi et al., 2017) Carboxylic acids Oxolinic acid 31 Medium B1. Cytoskeleton and motor proteins (ß-tubulin assembly in mitosis) Methyl Benzimidazole Carbamates Benomyl 1 High B2. Cytoskeleton and motor proteins (ß-tubulin assembly in mitosis) B3. Cytoskeleton and motor proteins (ß-tubulin assembly in mitosis) B4. Cytoskeleton and motor proteins (cell division proposed) B5. Cytoskeleton and motor proteins (delocalisation of spectrin-like proteins) B6. Cytoskeleton and motor proteins (actin/myosin/fimbrin function) C1. Respiration (complex I NADH Oxido-reductase) N-phenyl carbamates Benzamides, Thiazole carboxamide Diethofencarp 10 High Oxamide, Ethaboxam 22 Medium* Phenylureas Pencycuron 20 Low Benzamides Fluopicolide 43 Medium (Wang et al., 2014) Cyanoacrylates Phenamycril 47 High* Pyrimidinamines, Pyrazole-MET1 Diflumetorim, Tolfenpyrad 39 Low C2. Respiration (complex II: succinate-dehydrogenase) Succinatedehydrogenase inhibitors Carboxin 7 High* C3. Respiration (complex III:cytochrome bc1 (ubiquinol oxidase) at Qo site (cyt b gene) C4. Respiration (complex III:cytochrome bc1 (ubiquinone reductase) at Qi site (cyt b gene) C5. Respiration (uncouplers of oxidative phosphorylation) QoI-fungicides (Quinone outside Inhibitors) QiI-fungicides (Quinone inside Inhibitors) Dinitrophenyl crotonates, 2,6-dinitro-anilines Azoxystrobin 11 High Cyazofamid 21 High* Binapacryl, Fluazinam 29 Medium 11 EFSA Supporting publication 2017:EN-1345

12 Target site and code Group name Examples of active substances FRAC code Risk of resistance 9,10,11 C6. Respiration (inhibitors of oxidative phosphorylation, ATP synthase) C7. Respiration (ATP production proposed) Organo tin compounds Thiophenecarboxamides Fentin acetate 30 Medium* Silthiofam 38 Low C8. Respiration complex III: cytochrome bc1 (ubiquinone reductase) at Qo site, stigmatellin binding sub-site D1. Amino acids and protein synthesis (methionine biosynthesis proposed) (cgs gene) D2. Protein synthesis Enopyranuronic acid antibiotic QoSI fungicides Ametoctradin 45 High* Anilino-pyrimidines Cyprodinil 9 Medium Blasticidin-S 23 Medium* D3. Protein synthesis Hexopyranosyl antibiotic Kasugamycin 24 Medium D4. Protein synthesis Glucopyranosyl antibiotic Streptomycin 25 High D5. Protein synthesis Tetracycline antibiotic Oxytetracycline 41 High E1. Signal transduction (mechanism unknown) E2. MAP/Histidine-Kinase in osmotic signal transduction (os-2, HOG1) E3. MAP/Histidine-Kinase in osmotic signal transduction (os-1, Daf1) F2. Lipid synthesis or transport/membrane integrity or function (phospholipid biosynthesis, methyltransferase) Azanaphthalenes Quinoxyfen 13 Medium Phenylpyrroles Fludioxonil 12 Medium* Dicarboximides Iprodione 2 High* Phosphorothiolates, dithiolanes Iprobenfos, isoprothiolane 6 Medium* F3. Lipid synthesis or transport/membrane integrity or function (lipid peroxidation proposed) Aromatic hydrocarbons, Heteroaromatics Tolclofos-Methyl, Etridiazole 14 Medium* F4. Lipid synthesis or transport/membrane integrity or function (cell membrane permeability, fatty acids proposed) F8. Lipid synthesis or transport/membrane integrity or function (ergosterol binding) Carbamates Propamocarb 28 Medium* Polyene Natamycin (Streptomyces natalensis) 48 Low (Streekstra et al., 2016) 12 EFSA Supporting publication 2017:EN-1345

13 Target site and code Group name Examples of active substances FRAC code Risk of resistance 9,10,11 F9. Lipid synthesis or transport/membrane integrity or function (lipid homeostasis and transfer/storage) G1. Sterol biosynthesis in membranes (C14-demethylase in sterol biosynthesis (erg11/cyp51)) OSBPI oxysterol binding protein homologue inhibition DeMethylation Inhibitors) (SBI: Class I) Oxathiapiprolin 49 High* Cyproconazole 3 Medium G2. Sterol biosynthesis in membranes ( 14-reductase and 8 7-isomerase in sterol biosynthesis (erg24, erg2) G3. Sterol biosynthesis in membranes (3-keto reductase, C4-demethylation (erg27)) G4. Sterol biosynthesis in membranes (squalene-epoxidase in sterol biosynthesis (erg1)) H4. Cell wall biosynthesis (chitin synthase) (19) Amines ( morpholines ) (SBI: Class II) Fenpropimorph 5 Medium* SBI: Class III Fenhexamid 17 Medium* SBI: Class IV Pyributicarb 18 Medium Polyoxins Polyoxin 19 Medium H5. Cell wall biosynthesis (cellulose synthase) Carboxylic acid amides Flumorph 40 Medium* I1. Melanin synthesis in cell wall (reductase in melanin biosynthesis) I2. Melanin synthesis in cell wall (dehydratase in melanin biosynthesis) I3. Melanin synthesis in cell wall (polyketide synthase in melanin biosynthesis) Melanin Biosynthesis Inhibitors Reductase Melanin Biosynthesis Inhibitors Dehydratase Melanin Biosynthesis Inhibitors Polyketide synthase U. Unknown mode of action Cyanoacetamide -oxime Tricyclazole 16.1 Low Carpropamid 16.2 Medium Tolprocarb 16.3 Low Cymoxanil 27 Medium* U. Unknown mode of action phosphonates Fosetyl-Al 33 Low U. Unknown mode of action Phthalamic acids Teclofthalam (Bactericide) 34 Low U. Unknown mode of action Benzotriazines Triazoxide 35 Low U. Unknown mode of action Benzenesulphonamides Flusulfamide 36 Low U. Unknown mode of action Pyridazinones Diclomezine 37 Low 13 EFSA Supporting publication 2017:EN-1345

14 Target site and code Group name Examples of active substances FRAC code Risk of resistance 9,10,11 U. Unknown mode of action Thiocarbamate Methasulfocarb 42 Low U. Unknown mode of action Phenyl-acetamide Cyflufenamid U 06 High U. Unknown mode of action (Actin disruption proposed) Aryl-phenyl -ketone Metrafenone U 08 Medium U. Unknown mode of action Guanidines Dodine U 12 Medium* (Cell membrane disruption proposed) U. Unknown mode of action Thiazolidine Flutianil U 13 Low U. Unknown mode of action Pyrimidinone -hydrazones Ferimzone U 14 Low U. Unknown mode of action 4-quinolylacetate Tebufloquin U 16 Medium (complex III: cytochrome bc1, unknown bindingsite proposed) U. Unknown mode of action Tetrazolyloxime Picarbutrazox U 17 Low Unknown (Inhibition of trehalase and induction of host plant defense by trehalose proposed) Glucopyranosyl antibiotic Validamycin U 18 Low Chemicals with multi-site activity Inorganic Copper (different salts M 01 Low Chemicals with multi-site activity Inorganic Sulphur M 02 Low Chemicals with multi-site activity Dithiocarbamates and relatives Ferbam M 03 Low Chemicals with multi-site activity Phthalimides Captam M 04 Low Chemicals with multi-site activity Chloronitriles (phthalonitriles) Chlorothalonil M 05 Low Chemicals with multi-site activity Sulfamides Dichlofluanid M 06 Low Chemicals with multi-site activity Bis-guanidines Guazatine M 07 Low Chemicals with multi-site activity Triazines Anilazine M 08 Low Chemicals with multi-site activity Quinones (anthraquinones) Dithianon M 09 Low Chemicals with multi-site activity Quinoxalines Chinomethionat M 10 Low Chemicals with multi-site activity Maleimide Fluoroimide M 11 Low 14 EFSA Supporting publication 2017:EN-1345

15 Table 2 Mode of action and risk for resistance development of non-fungicide agents used in disease control according the FRAC Code List 2017 ( Target site and code Group name Example of active substance F6. Lipid synthesis or transport/membrane integrity or function (microbial disrupters of pathogen cell membranes) (44) Bacillus sp. and the fungicidal lipopeptides produced Bacillus subtilis strain QST 713 FRAC code Risk of resistance Low F7. Lipid synthesis or transport/membrane integrity or function (cell membrane disruption proposed) (46) Plant extract extract from Melaleuca alternifolia (tea tree) 46 Low P1. Host plant defence Induction (salicylic acid pathway) Benzothiadiazole Acibenzolar-Smethyl P 01 Low P2. Host plant defence Induction Benzisothiazole Probenazole P 02 Low P3. Host plant defence Induction thiadiazolecarboxamide P4. Host plant defence Induction Natural compound Isotianil P 03 Low Laminarin P 04 Low P5. Host plant defence Induction Plant extract Extract from Reynoutria sachalinensis (giant knotweed) P6. Host plant defence Induction Microbial Bacillus mycoides isolate J Not Classified Diverse Mineral oils, organic oils, potassium bicarbonate, material of biological origin Biologicals with multiple modes of action: multiple effects on cell wall, ion membrane transporters; chelating effects Biologicals with multiple modes of action: competition, mycoparasitism, antibiosis, lytic enzymes and induced Polypeptide (from plant extract) Microbial (Trichoderma spp.) Extract from the cotyledons of lupine plantlets ( BLAD ) Trichoderma atroviride strain SC1 P 05 P 06 NC BM 01 BM 02 Low Low Low Low Low 12 Intrinsic risk of resistance is not known but most likely low in most cases due to host plant induction and multiple mode of actions. No records of resistance in the literature EFSA Supporting publication 2017:EN-1345

16 resistance Non-fungicide methods for plant disease management The applicant/ms is requested to provide data and comment on the non-fungicide alternatives for plant disease management, reported in Section and Table 3, using the Excel file provided in Appendix B. Additional methods, if any, can be added. For each of the methods, the following information should be provided: Is this method commonly available to farmers (e.g., resistant cultivar, machinery, BCAs, information, external support, sufficient expertise among farmers)? Column header: Availability' Response: 0: not available 1: available Is the method or combination of methods (fungicide or non-fungicide) providing a contribution to the effective control of the target pathogen/s? Column header: Effectiveness' Response: 0: not effective 1: moderately effective 2: highly effective Is this method used on a large scale in different cropping systems of the MS? Column header: Practised Usage' Response: 0: not applied 1: applied on up to 10% of the acreage of crop or non-agricultural use 2: applied on 10 50% of the acreage of crop or non-agricultural use 3: applied on more than 50% of the acreage of crop or non-agricultural use Are the conditions (e.g. pedoclimatic, economic, social) permitting the use of this method? Column header: Feasibility' Response: 0: not feasible 1: feasible with restriction 2: feasible Table 3 Main group Cultural control Classification of non-fungicide methods for disease control. Type Crop rotation 16 EFSA Supporting publication 2017:EN-1345

17 Main group Type Intercropping (mixed crops, row, strip) Change in planting/harvesting dates Seed density Fertilizers Soil tillage Biofumigation Raised beds Temperature and humidity management in protected crops Organic matter management Others Host genetic resistance Biological control Physical methods Natural products and basic substances Resistance inducers Tolerant or resistant plant genotypes Crop/cultivar associations, variety mixtures Multiline cultivar combinations Genetically engineered crops Gene editing Gene silencing, including virus and host induced gene-silencing (VIGS and HIGS) Others Competition Hyperparasitism Antibiosis Predation Soil suppressiveness enhancement Hypovirulence Others Heat (e.g. steam sterilisation, soil solarisation) Cold (e.g. cold storage techniques) Water (e.g. flooding) Radiation (e.g. UV treatment) Barriers and filters (e.g. sand filtration, vector insect-proof nets) Others Sodium hydrogen bicarbonate Calcium chloride Urtica spp. Others Synthetic inducers (e.g acibenzolar-s-methil, phosphites) Natural inducers (e.g. plant extracts, essential oils, laminarin, yeast extracts, silicon; animal extracts, e.g. chitosan) 17 EFSA Supporting publication 2017:EN-1345

18 Main group Type Others 2.2. Methodology A flow chart with the proposed methodology is shown in Appendix A. The starting point of the methodology is the list of fungicide a.s. authorised for a particular crop/pathogen combination or nonagricultural use in a MS where the applicant is requesting a derogation. The methodology is described below: Step 1: Evaluation of fungicide alternatives with same MoA: Are there other effective a.s. available sharing the same MoA? If yes => derogation is considered as not scientifically supported and the evaluation should stop here. However, if there are scientific and/or technical evidence to support the different performance of the a.s., provide evidence and go to step 2 If no => go to step Step 2: Evaluation of alternative non-fungicide programme: Is there at least one practical/established and sustainable/durable non-fungicide effective program (which could include the use of natural products) to manage the crop against the pathogen under consideration? If yes => there are enough alternatives and therefore derogation is not scientifically supported, and the evaluation should stop here. If no => go to step Step 3: Evaluation of alternative a.s. MoA: Are there other effective a.s. with different MoA available? If no => derogation is probably scientifically supported If yes => go to step Step 4: Compute the following parameters and perform evaluations: a) Fungicide risk of resistance (x) b) Pathogen risk of resistance (z) c) Evaluation of non-fungicide alternatives a. Evaluation of fungicide risk of resistance (x) Check, count and rank the number of different MoAs included in the list of a.s. authorised against the target pathogen in the crop under consideration and calculate the fungicide risk of resistance (x). Those MoAs for which relevant loss of efficacy due to resistance is already known for the pathogen 18 EFSA Supporting publication 2017:EN-1345

19 under consideration should not be included in x, but should be listed in the Excel file and the reason why it is not included has to be explained.. The value x is the sum of the number of alternative MoA multiplied by a weighing factor based on the risk of resistance development intrinsically linked to that MoA (see Table 1). If the MoA is classified as high risk multiply by 0.5, if the risk is moderate multiply by 0.75 and if it is low multiply by 1.0. For example: If there are 2 MoAs classified as high risk, 3 MoAs classified as moderate and 2 MoAs classified as low then: x= (2*0.5) + (3*0.75) + (2*1.0) = b. Evaluation of fungal pathogen risk of resistance (z) Assess the intrinsic risk of the fungal pathogen under consideration developing resistance within a cropping system (see examples below). The pathogen risk of resistance (z), is ranked as: 1-low, 2-moderate; 3-high). Large differences in pathogen risk can be found between certain classes, genera and species of plant pathogens (Brent and Hollomon, 2007). The most important factors determining pathogen resistance risk (Brent and Hollomon, 2007; Grimmer et al., 2015)are: generation time; abundance of sporulation; ability of spores to spread between plants, crops and regions; ability to infect at all crop stages; occurrence of a sexual stage in the life cycle; ability to mutate or to express mutant genes. To analyse the inherent risk of resistance development for the species under consideration on a given crop and to classify this risk of resistance as low, moderate or high, a simplified approach similar to that described in Rotteveel et al. (2011) has been used. This classification may differ among regions because of different climatic, pedobiological and agricultural situations which may influence e.g.: the sporulation rate, the number of infection cycles per year or that of applications needed to control them. Therefore, the analysis has to consider case by case and should be carried out separately by applicants and MS for each fungal species, crop and region. For instance, the classification of diseases in open field versus greenhouse conditions will often differ resulting in higher risks in greenhouses, as fungicide usage in greenhouses is usually higher due to increased host plant sensitivity, higher temperature and humidity, etc. Fungal pathogens are considered as low resistance risk 13 when (1) resistance to the relevant a.s. has not been reported and (2) selection pressure is low; e.g., the pathogen in that system is treated less than once per year because disease severity rarely exceeds the Economic Injury Level (EIL) (Nutter et al., 1993) to justify fungicide treatments, or fungicides are not sufficiently effective. Examples (modified after FRAC, online) of such low risk pathogens are: Soil-borne pathogens (e.g., Rhizoctonia solani, Sclerotium spp.). Vascular pathogens (e.g., Fusarium oxysporum, Verticillium spp.). Cankers on fruit trees (e.g., Valsa spp., Nectria spp., Phytophthora spp.). Smuts and bunts (e.g., Ustilago spp., Tilletia spp.). Fungal pathogens are considered as medium resistance risk when (1) resistance to the relevant a.s. has rarely been reported and/or (2) selection pressure is medium or low, sometimes due to the pattern of product use. Specific isolates may be classified as resistant, but in commercial practice resistance has not created major disease control problems. These pathogens are typically treated about once per year in that cropping system because they regularly exceed EIL or are exposed to treatments with the same MoA targeting other species in the same or in other crops in the region and have limited untreated areas in that region. 13 Resistance is a dynamic situation and reference should be made to the FRAC online pathogen list which is updated regularly EFSA Supporting publication 2017:EN-1345