Page 1 of 34 REGISTRATION REPORT Part A Risk Management Product code: 102000027828 Product name: KEYNOTE Active substances: bixafen, 65 g/l fluopyram, 65 g/l prothioconazole, 130 g/l COUNTRY: FRANCE Zonal Rapporteur Member State: France NATIONAL ASSESSMENT FRANCE (extension of use)
Page 2 of 34 Table of Contents 1 DETAILS OF THE APPLICATION... 3 1.1 APPLICATION BACKGROUND... 3 1.2 ACTIVE SUBSTANCE APPROVAL... 3 1.3 REGULATORY APPROACH... 5 1.4 DATA PROTECTION CLAIMS... 6 1.5 LETTER(S) OF ACCESS... 6 2 DETAILS OF THE AUTHORISATION... 7 2.1 PRODUCT IDENTITY... 7 2.2 CLASSIFICATION AND LABELLING... 7 2.2.1 Classification and labelling under Directive 99/45/EC... 7 2.2.2 Classification and labelling in accordance with Regulation (EC) No1272/2008... 7 2.2.3 Other phrases in compliance with Regulation (EU) No 547/2011... 8 2.2.4 Other phrases linked to the preparation... 8 2.3 PRODUCT USES... 10 3 RISK MANAGEMENT... 12 3.1 REASONED STATEMENT OF THE OVERALL CONCLUSIONS TAKEN IN ACCORDANCE WITH THE UNIFORM PRINCIPLES... 12 3.1.1 Physical and chemical properties... 12 3.1.2 Methods of analysis... 12 3.1.3 Mammalian Toxicology... 13 3.1.4 Residues and Consumer Exposure... 15 3.1.5 Environmental fate and behaviour... 17 3.1.6 Ecotoxicology... 18 3.1.7 Efficacy... 19 3.2 CONCLUSIONS ARISING FROM FRENCH ASSESSMENT... 21 3.3 SUBSTANCES OF CONCERN FOR NATIONAL MONITORING... 21 3.4 FURTHER INFORMATION TO PERMIT A DECISION TO BE MADE OR TO SUPPORT A REVIEW OF THE CONDITIONS AND RESTRICTIONS ASSOCIATED WITH THE AUTHORISATION... 21 3.4.1 Post-authorisation monitoring... 21 3.4.2 Label amendments... 21 APPENDIX 1 COPY OF THE FRENCH DECISION... 22 APPENDIX 2 COPY OF THE DRAFT PRODUCT LABEL AS PROPOSED BY THE APPLICANT... 28 APPENDIX 3 LETTER(S) OF ACCESS... 33
Page 3 of 34 PART A Risk Management The company BAYER S.A.S. has requested an extension to the existing marketing authorisation in France for the product KEYNOTE (originally known as ASCRA XPRO or alternatively as BIX+FLU+PTZ EC 260 ; formulation code: 102000027828), containing 65 g/l bixafen, 65 g/l fluopyram and 130 g/l prothioconazole, for use as a fungicide. The risk assessment conclusions are based on the information, data and assessments provided in Registration Report, Part B Sections 1-7 and Part C, and where appropriate the addenda for France. The information, data and assessments provided in Registration Report, Part B include assessment of further data or information as required at national registration by the EU peer reviews. It also includes assessment of data and information relating to KEYNOTE (102000027828) where those data have not been considered in the EU peer review process. Otherwise assessments for the safe use of KEYNOTE (102000027828) have been made using endpoints agreed in the EU peer reviews of the three active substances (a.s.s). This document describes the specific conditions of use and labelling required for France for the registration of KEYNOTE (102000027828). Appendix 1 of this document provides a copy of the French Decision. Appendix 2 of this document is a copy of the draft product label as proposed by the applicant. Appendix 3 of this document is a copy of the letter(s) of Access. 1 DETAILS OF THE APPLICATION 1.1 Application background The present registration report concerns the evaluation of BAYER S.A.S. s application to market KEYNOTE (102000027828) in France as a fungicide (product uses described under point 2.3). France acted as a zonal Rapporteur Member State (zrms) for this request and assessed the application submitted for the label extension to include use on barley and oats of this product in France and in other MSs of the Southern zone. 1.2 Active substance approval Bixafen Commission Implementing Regulation (EU) No 350/2013 of 17 April 2013 approving the active substance bixafen, in accordance with Regulation (EC) No 1107/2009 of the European Parliament and of the Council concerning the placing of plant protection products on the market, and amending the Annex to Commission Implementing Regulation (EU) No 540/2011. Specific provisions of Regulation (EU) No 350/2013 were as follows: For the implementation of the uniform principles as referred to in Article 29(6) of Regulation (EC) No 1107/2009, the conclusions of the review report on bixafen, and in particular Appendices I and II thereof, as finalised in the Standing Committee on the Food Chain and Animal Health on 15 March 2013 shall be taken into account. In this overall assessment Member States shall pay particular attention to: (a) the residues of bixafen and of its metabolites in rotational crops; (b) the protection of groundwater, when the substance is applied in regions with vulnerable soil and/or climatic conditions; (c) (d) the risk to aquatic organisms; the risk to soil and sediment-dwelling organisms. Conditions of use shall include risk mitigation measures, where appropriate.
Page 4 of 34 An EFSA conclusion is available (EFSA Journal 2012;10(11):2917). A Review Report is available (SANCO/10357/2013 rev 3, 15 March 2013). Fluopyram Commission Implementing Regulation (EU) No 802/2013 of 22 August 2013 approving the active substance fluopyram, in accordance with Regulation (EC) No 1107/2009 of the European Parliament and of the Council concerning the placing of plant protection products on the market, and amending the Annex to Commission Implementing Regulation (EU) No 540/2011 Specific provisions of Regulation (EU) No 802/2013 were as follows : For the implementation of the uniform principles as referred to in Article 29(6) of Regulation (EC) No 1107/2009, the conclusions of the review report on fluopyram, and in particular Appendices I and II thereof, as finalised in the Standing Committee on the Food Chain and Animal Health on 16 July 2013, shall be taken into account. In this overall assessment Member States shall pay particular attention to the risk to birds and aquatic organisms. Conditions of use shall include risk mitigation measures, where appropriate. The applicant shall submit confirmatory information as regards: (1) the long-term risk to insectivorous birds; (2) the potential for causing endocrine-disrupting effects in non-target vertebrates other than mammals. The applicant shall submit to the Commission, Member States and the Authority the information set out in point 1 by 1 February 2016 and the information set out in point 2 within two years after adoption of the corresponding OECD test guidelines on endocrine disruption. An EFSA conclusion is available (EFSA Journal 2013;11(4):3052). A Review Report is available (SANCO/11456/2013 rev 2, 16 July 2013). Prothioconazole Commission Implementing Regulation (EU) No 540/2011 of 25 May 2011 implementing Regulation (EC) No 1107/2009 of the European Parliament and of the Council as regards the list of approved active substances. Specific provisions of Regulation (EU) No 540/2011 were as follows : PART A Only uses as fungicide may be authorised. PART B For the implementation of the uniform principles as referred to in Article 29(6) of Regulation (EC) No 1107/2009, the conclusions of the review report on prothioconazole, and in particular Appendices I and II thereof, as finalised in the Standing Committee on the Food Chain and Animal Health on 22 January 2008 shall be taken into account. In this overall assessment Member States must pay particular attention to: the operator safety in spray applications. Conditions of use shall include adequate protective measures,
Page 5 of 34 the protection of aquatic organisms. Risk mitigation measures such as buffer zones shall be applied, where appropriate, the protection of birds and small mammals. Risk mitigation measures shall be applied, where appropriate. Conditions of use shall include risk mitigation measures, where appropriate. The concerned Member States shall request the submission of: information to allow the assessment of consumer exposure to triazole metabolite derivatives in primary crops, rotational crops, and products of animal origin, a comparison of the mode of action of prothioconazole and the triazole metabolite derivatives to allow the assessment of the toxicity resulting from the combined exposure to these compounds, information to further address the long-term risk to granivorous birds and mammals arising from the use of prothioconazole as a seed treatment. They shall ensure that the notifier at whose request prothioconazole has been included in this Annex provide such studies to the Commission within two years from the approval. An EFSA conclusion is available (EFSA Scientific Report (2007) 106, 1-98). A Review Report is available (SANCO/3923/07 - final, 10 December 2007). 1.3 Regulatory approach The present application (2015-1290) was evaluated in France by the French Agency for Food, Environmental and Occupational Health & Safety (Anses) 1 in the context of the zonal procedure for all Member States of the Southern zone, taking into account the worst-case uses ( risk envelope approach ) 2 the highest application rates over the Southern zone. When risk mitigation measures were necessary, they are adapted to the situation in France. According to the French law and procedures, specific conditions of use are set out in the Decision letter. The French Order of 4 may 2017 3 provides that: - unless formally stated in the product authorisation, the pre harvest interval (PHI) is at least three days; - unless formally stated in the product authorisation, the minimum buffer zone alongside a water body is five metres; - unless formally stated in the product authorisation, the minimum re-entry period is six hours for field uses and eight hours for indoor uses. Drift reduction measures such as low-drift nozzles are not considered within the decision-making process in France. However, drift buffer zones may be reduced under some circumstances as explained in Appendix 3 of the abovementioned French Order. The current document (RR) based on Anses s assessment of the application submitted for this product is in 1 2 3 French Food Safety Agency, Afssa, before 1 July 2010 SANCO document risk envelope approach, European Commission (14 March 2011). Guidance document on the preparation and submission of dossiers for plant protection products according to the risk envelope approach ; SANCO/11244/2011 rev. 5 https://www.legifrance.gouv.fr/eli/arrete/2017/5/4/agrg1632554a/jo/texte
Page 6 of 34 compliance with Regulation (EC) no 1107/2009 4, implementing regulations, and French regulations. The data taken into account are those deemed to be valid either at European Union level or at zonal/national level. This part A of the RR presents a summary of essential scientific points upon which recommendations are based and is not intended to show the assessment in detail. The conclusions relating to the acceptability of risk are based on the criteria indicated in Regulation (EU) No 546/2011 5, and are expressed as acceptable or not acceptable in accordance with those criteria. Finally, the French Order of 26 March 2014 6 provides that: - an authorisation granted for a reference crop applies also for linked crops, unless formally stated in the Decision - the reference and linked crops are defined in Appendix 1 of that French Order. Thus, at French national level, possible extrapolation of submitted data and the corresponding assessment from reference crops to linked ones are undertaken even if not clearly requested by the applicant in their drr, and a conclusion is reached on the acceptability of the intended uses on those linked crops. The aim of this Order, mainly based on the EU document on residue data extrapolation 7 is to supply minor crops with registered plant protection products. Therefore the GAP table (Section 2.3) and Decision may include uses on crops not originally requested by the applicant. The Decision, as reproduced in Appendix 1, takes also into account national provisions, including national mitigation measures. 1.4 Data protection claims Where protection for data is being claimed for information supporting registration of KEYNOTE (102000027828 8 ), it is indicated in the reference lists in Appendix 1 of the Registration Report, Part B Sections 1-7. 1.5 Letter(s) of Access Not necessary: the applicant has provided sufficient data to show that access is not required, except for certain shared metabolite data (see Appendix 3). 4 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 5 COMMISSION REGULATION (EU) No 546/2011 of 10 June 2011 implementing Regulation (EC) No 1107/2009 of the European Parliament and of the Council as regards uniform principles for evaluation and authorisation of plant protection products 6 http://www.legifrance.gouv.fr/eli/arrete/2014/3/26/agrg1407093a/jo 7 SANCO document guidance document:- Guidelines on comparability, extrapolation, group tolerances and data requirements for setting MRLs : SANCO/ 7525/VI/95 - rev.9 8 See Document C pp 12-13 for further information about the nomenclature of the specification.
Page 7 of 34 2 DETAILS OF THE AUTHORISATION 2.1 Product identity Product name (code) KEYNOTE (102000027828 9 ) Authorisation number 2160931 Function Applicant Composition Formulation type (code) Packaging 2.2 Classification and labelling Synonyms: ASCRA XPRO and BIX+FLU+PTZ EC 260 Second trade names: YONEERO, VELDIG, MACFARE, BENDAY, KARDIX Fungicide. BAYER S.A.S. 65 g/l bixafen 65 g/l fluopyram 130 g/l prothioconazole Emulsifiable concentrate (EC) 2.2.1 Classification and labelling under Directive 99/45/EC Not applicable after 1st June 2015. Polyamide (PA)/high-density polyethylene (HDPE) or ethylene vinyl alcohol (EVOH)/HDPE composite bottles or containers holding 1, 3, 5, 10 or 15 L product 2.2.2 Classification and labelling in accordance with Regulation (EC) No1272/2008 Physical hazards - Health hazards Acute toxicity (oral) Hazard Category 4, Environmental hazards Hazard pictograms Skin sensitisation Hazard Category 1 sub. cat.1b Serious eye damage, Hazard Category 1 Specific target organ toxicity, Hazard Category 3 respiratory irritation Reproductive Toxicity, Hazard Category 2 Hazardous to the aquatic environment, Chronic, Hazard Category 1 Signal word Danger, Warning Hazard statements H302 Harmful if swallowed H317 May cause an allergic skin reaction H318 Causes serious eye damage 9 See Document C pp 12-13 for further information about the nomenclature of the specification.
Page 8 of 34 Precautionary statements Supplementary information (in accordance with Article 25 of Regulation (EC) No 1272/2008) H335 May cause respiratory irritation H361d Suspected of damaging the unborn child H410 Very toxic to aquatic life with long-lasting effects For the P phrases, refer to the extant legislation See Part C for justifications of the classification and labelling proposals. 2.2.3 Other phrases in compliance with Regulation (EU) No 547/2011 The authorisation of the preparation is linked for professional uses only to the following conditions: SP 1 Do not contaminate water with the product or its container. Do not clean application equipment near surface water. Avoid contamination via drains from farmyards and roads. SPe 3 To protect aquatic organisms, respect an unsprayed buffer zone of 5 metres 10 with an unsprayed planted buffer zone of 5 metres to surface water bodies. SPa 1 To avoid the build-up of resistance do not apply this or any other product containing bixafen, fluopyram or prothioconazole, more than one application per crop cycle on barley or oat.. 2.2.4 Other phrases linked to the preparation Wear suitable personal protective equipment 11 : refer to the Decision in Appendix 1 for the details Re-entry period 12 : 48 hours Pre-harvest interval 13 : F- Application to barley and oats must be made at growth stage BBCH 61 at the latest Other mitigation measures: - In order to control risks of resistance with KEYNOTE (102000027828), it is recommended to follow the restrictions on use per chemical group put forward in French national note on resistance management of cereal diseases 14. The label may include the following recommendations: 10 11 12 13 14 The legal basis for this is Titre III Article 11 of the French Order of 4 may 2017 concerning the marketing and use of products encompassed by article L. 253-1 of the rural code [that is, plant protection products/pesticides] If a tractor with cab is used, wearing gloves during application is only required when working with the spray mixture The legal basis for this is Titre I Article 3 of the French Order of 4 may 2017 concerning the marketing and use of products encompassed by article L. 253-1 of the rural code [that is, plant protection products/pesticides] According to the French Order of 4 may 2017, PHI cannot be lower than 3 days unless specifically stated in the assessment and decision. Résistances aux fongicides Céréales à paille / Note commune 2017 INRA / Anses /Arvalis (available online in French at https://www.arvalis-infos.fr/file/galleryelement/pj/62/b2/92/91/note_commune_vf23janvier2017finale2239273787115362692.pdf
Page 9 of 34 The label must reflect the conditions of authorisation.
Page 10 of 34 2.3 Product uses Please note: The GAP Table below reports the intended uses proposed by the applicant, and possible extrapolation according to French Order of 26 March 2014 (highlighted in green), evaluated and concluded as safe uses by France as zrms. Those uses are then granted in France. PPP (product name/code) active substance 1 active substance 2 active substance 3 Applicant: Zone(s): Verified by MS: KEYNOTE/(102000027828) bixafen fluopyram prothioconazole BAYER S.A.S. southern EU yes Formulation type: Conc. of as 1: Conc. of as 2: Conc. of as 3: professional use non-professional use GAP rev 26/07/2017 emulsifiable concentrate (EC) 65 g/l 65 g/l 130 g/l Field of use: fungicide 1 2 3 4 5 6 7 8 10 11 12 13 14 Use- No. Member state(s) Crop and/ or situation (crop destination / purpose of crop) F G or I Pests or Group of pests controlled (additionally: developmental stages of the pest or pest group) 8 France Barley, F ERYSGH, RHYNSE, PYRNTE, PUCCHD, PSDCHE, RAMUCC, PUCCST, MICNNI, LEPTHE 10 France Oats F PUCCCA, ERYSGR, PSDCHE, MICNNI, LEPTHE, SEPTHE Method / Kind Overall spray Overall spray Application Application rate PHI Timing / Growth Max. number kg, L product / g, kg as/ha (days) Water L/ha stage of crop & (min. interval ha season between a) max. rate per a) max. rate per appl. applications) appl. b) max. total rate per min / max a) per use b) max. total rate crop/season b) per crop/ per crop/season season BBCH 30-61 a) 1 b) 1 BBCH 30-61 a) 1 b) 1 a) 1.2 b) 1.2 a) 1.2 b) 1.2 a) 78+78+156 b)78+78+156 a) 78+78+156 b)78+78+156 Remarks: 100-400 F Acceptable 100-400 F Acceptable
Page 11 of 34 Remarks columns: 1 Numeration necessary to allow references 2 Use official codes/nomenclatures of EU Member States 3 For crops, the EU and Codex classifications (both) should be used; when relevant, the use situation should be described (e.g. fumigation of a structure) 4 F: professional field use, Fn: non-professional field use, Fpn: professional and nonprofessional field use, G: professional greenhouse use, Gn: non-professional greenhouse use, Gpn: professional and non-professional greenhouse use, I: indoor application 5 Scientific names and EPPO-Codes of target pests/diseases/ weeds or, when relevant, the common names of the pest groups (e.g. biting and sucking insects, soil born insects, foliar fungi, weeds) and the developmental stages of the pests and pest groups at the moment of application must be named. 6 Method, e.g. high volume spraying, low volume spraying, spreading, dusting, drench Kind, e.g. overall, broadcast, aerial spraying, row, individual plant, between the plants - type of equipment used must be indicated. 7 Growth stage at first and last treatment (BBCH Monograph, Growth Stages of Plants, 1997, Blackwell, ISBN 3-8263-3152-4), including where relevant, information on season at time of application 8 The maximum number of application possible under practical conditions of use must be provided. 9 Minimum interval (in days) between applications of the same product 10 For specific uses other specifications might be possible, e.g.: g/m³ in case of fumigation of empty rooms. See also EPPO-Guideline PP 1/239 Dose expression for plant protection products. 11 The dimension (g, kg) must be clearly specified. (Maximum) dose of a.s. per treatment (usually g, kg or L product / ha). 12 If water volume range depends on application equipments (e.g. ULVA or LVA) it should be mentioned under application: method/kind. 13 PHI - minimum pre-harvest interval 14 Remarks may include: Extent of use/economic importance/restrictions
Page 12 of 34 3 RISK MANAGEMENT 3.1 Reasoned statement of the overall conclusions taken in accordance with the Uniform Principles 3.1.1 Physical and chemical properties Commercial packaging: 1, 3, 5, 10 and 15L HDPE/PA or HDPE/EVOH container KEYNOTE (102000027828) is a clear light brown liquid with rancid odour, emulsifiable concentrate. All studies have been performed in accordance with the current requirements and the results are deemed acceptable. It is not explosive and has no oxidising properties. The product has a flash point of 148 C and a self-ignition temperature of 360 C. In aqueous solution (1 %), it has a ph value of 5.9 at ambient temperature. There is no effect of low and high temperatures on the stability of the formulation, since after seven days at 0 C and 14 days at 54 C, neither the active substance content nor the technical properties were changed. The stability data indicate a shelf life of at least two years at ambient temperature when stored in HDPE/EVOH and HDPE/PA. The new use rates proposed are covered by the evaluation of the first authorisation. The technical characteristics are acceptable for an emulsifiable concentrate formulation. The formulation is not classified for the physico-chemical aspect. 3.1.2 Methods of analysis 3.1.2.1 Analytical method for the formulation Determination of the content of prothioconazole-desthio in the product has been performed twice. Once, the content was higher than 0.00657 % w/w (maximum acceptable limit in the product), but the second time the content of prothioconazole-desthio was finally determined to be below the acceptable limit of 0.00657 % w/w. An acceptable explanation has been provided by the applicant: some samples tested during the stability studies were exposed to sunlight. As prothioconazole is sensitive to light (DR 50 < two days) and degrades to prothioconazoledesthio, this may explain why content of this relevant impurity in the formulation exceeds the acceptable limit. Therefore as recommended by the applicant, the product must be stored away from light. Analytical methods for the determination of the active substances and relevant impurities in the formulation are available and validated. 3.1.2.2 Analytical methods for residues Analytical methods are available in the Draft Assessment Report (DAR) and in this dossier and validated for the determination of residues of prothioconazole, bixafen and fluopyram in plants (dry commodities), foodstuffs of animal origin, soil, water (surface and drinking) and air. The active substances are neither toxic nor very toxic, hence no analytical method is required for determination of their residues in biological fluids and tissues. The metabolite prothioconazole-desthio is toxic (T), therefore an analytical method is available in this dossier and validated for the determination of residues of prothioconazole-desthio in tissues and body fluids. Other data gaps in EFSA conclusion and in the review reports: Prothioconazole-desthio (EFSA Scientific Report (2007) 106, 1-98): A revised specification is required to include a proposed maximum limit for the relevant impurity prothioconazole-desthio and to correct the naming of the impurities with regard to R and S isomers (relevant for all uses evaluated; data gap identified by EFSA February 2007. Refer to chapter 1). Spectra for the relevant impurity prothioconazole-deschloro (relevant for all uses evaluated; data gap identified by EFSA April 2007; refer to chapter 1).
Page 13 of 34 Methodology to evaluate triazole metabolite derivatives is in the process of being validated at European Union level. 3.1.3 Mammalian Toxicology Endpoints used in risk assessment Active substance: bixafen ADI ARfD 0.02 mg kg bw/d 0.2 mg/kg bw/d Efsa (2012) AOEL Dermal absorption 0.13 mg/kg bw/d Default values according to guidance on dermal absorption (Efsa 2012): Concentrate Spray dilution (used in formulation) (used in formulation) 65 g/l 0.21 g/l Dermal absorption endpoints % 25 75 Active substance: fluopyram ADI ARfD 0.012 mg kg bw/d 0.5 mg/kg bw Efsa (2013) AOEL Dermal absorption 0.05 mg/kg bw/d Default values according to guidance on dermal absorption (Efsa 2012): Concentrate Spray dilution (used in formulation) (used in formulation) 65 g/l 0.2 g/l Dermal absorption endpoints % 25 75 Active substance: prothioconazole ADI ARfD 0.01 mg kg bw/d 0.01 mg/kg bw/d EU (2008) AOEL Dermal absorption 0.2 mg/kg bw/d Default values according to guidance on dermal absorption (Efsa 2012): Concentrate Spray dilution (used in formulation) (used in formulation) 130 g/l 0.34 g/l Dermal absorption endpoints % 25 75 Metabolite: desthio-prothioconazole (based on a 100% conversion) ADI 0.01 mg kg bw/d EU agreed endpoint (EFSA Scientific Report
Page 14 of 34 ARfD AOEL Dermal absorption 0.01 mg/kg bw/d 0.01 mg/kg bw/d (2007) 106, 1-98, Conclusion on the peer review of prothioconazole) Based on an in vivo monkey study performed on a similar formulation: Concentrate (480 g/l) Diluted formulation (1.61 g/l) In vitro (monkey) % 20 20 Concentrate (used in formulation) 130 g/l Spray dilution (used in formulation) 0.5 g/l Dermal absorption endpoints % 20 20 NB: It has been found that prothioconazole in diluted solutions can convert to prothioconazole-desthio during the drying process on clothing, skin or on certain plant surfaces. Prothioconazole-desthio is known to have an embryotoxic potential in experimental animals. Therefore three operator exposure studies were conducted to determine the exposure to prothioconazole as well as to prothioconazole-desthio under real use conditions (see Part B, 7.5.3). However, given the limitations of the field studies, it has been considered more appropriate to estimate operator exposure using the German BBA model, considering 100 % conversion. This is a conservative and precautionary approach. 3.1.3.1 Acute Toxicity KEYNOTE (102000027828) containing 65 g/l of bixafen, 65 g/l of fluopyram, 130 g/l of prothioconazole is classified for acute toxicity by the oral route, but has a low dermal and inhalational toxicity. It is not irritating to the rabbit skin, but is irritating to the rabbit eye, a respiratory irritant and a skin sensitiser. The classification proposed in accordance with Regulation (EC) No 1272/2008 is shown in Section 2.2. 3.1.3.2 Operator Exposure Summary of critical use patterns (worst cases): Crop F/G 15 Equipment Application rate L product/ha (g a.s./ha) Spray dilution (L/ha) Model Barley, Oat F Tractor-mounted boom sprayer 1.2 L/ha (82.08 g bixafen techn./ha, 81.24 g fluopyram techn. /ha, 160.8 g prothioconazole/ha, and 160.8 g desthioprothioconazole./ha ) 100-400 BBA Operator exposure has been previously assessed for similar uses in the open field at a higher application rate. It may be concluded that the risk for the operator using KEYNOTE (102000027828) is acceptable with a working coverall (90 % protection factor) and gloves during mixing/loading and application. For details of personal protective equipment for operators, refer to the Decision in Appendix 1. 15 Open field or glasshouse
Page 15 of 34 3.1.3.3 Bystander Exposure Bystander exposure has been previously assessed according to the EUROPOEM II. It may be concluded that there is no unacceptable risk for the bystander after incidental short-term exposure to KEYNOTE (102000027828). 3.1.3.4 Worker Exposure Worker exposure has been previously assessed according to the EUROPOEM II for the use of KEYNOTE (102000027828). It is concluded that, without taking into account a re-entry period, there is no unacceptable risk anticipated for the worker wearing a working coverall and gloves, when re-entering crops treated with KEYNOTE (102000027828). For details of personal protective equipment for workers, refer to the Decision in Appendix 1. 3.1.3.5 Resident exposure Residential exposure has been previously assessed according to the Martin et al. approach. It may be concluded that there is no unacceptable risk to the resident exposed to KEYNOTE (102000027828). 3.1.4 Residues and Consumer Exposure 3.1.4.1 Residues Summary of the evaluation KEYNOTE (102000027828) contains bixafen, prothioconazole and fluopyram. Table 1 Summary for bixafen Use- No.* Crop Plant metabolism covered? Sufficient residue trials? PHI sufficiently supported? Sample storage covered by stability data? MRL compliance Reg. 834/2013 Chronic risk for consumers identified? Acute risk for consumers identified? Comments / Barley and oat Yes Yes (12 NEU and 18 SEU) Yes Yes Yes No No * Use number(s) in accordance with the list of all intended GAPs in Part B, Section 0 should be given in column 1 The effects of processing on the nature of bixafen residues have been investigated. Data on effects of processing on the amount of residue have been submitted. These data were considered for risk assessment. Residues in succeeding crops have been sufficiently investigated taking into account the specific circumstances of the cgap uses being considered here. It is very unlikely that residues will be present in succeeding crops. Considering dietary burden and based on the intended uses, no significant modification of the intake was calculated for livestock. Further investigation of residues as well as the modification of MRLs in commodities of animal origin are therefore not necessary.
Page 16 of 34 Table 2 Summary for prothioconazole Use- No.* Crop Plant metabolism covered? Sufficient residue trials? PHI sufficiently supported? Sample storage covered by stability data? MRL compliance Reg. 2016-1092 Chronic risk for consumers identified? Acute risk for consumers identified? Comments / Barley and oats Yes Yes (16 NEU and 19 SEU) Yes Yes Yes No No * Use number(s) in accordance with the list of all intended GAPs in Part B, Section 0 should be given in column 1 The effects of processing on the nature of prothioconazole residues have been investigated. Data on effects of processing on the amount of residue have been submitted. These data were not considered for risk assessment. Residues in succeeding crops have been sufficiently investigated taking into account the specific circumstances of the cgap uses being considered here. It is very unlikely that residues will be present in succeeding crops. Considering dietary burden and based on the intended uses, no significant modification of the intake was calculated for livestock. Further investigation of residues as well as the modification of MRLs in commodities of animal origin are therefore not necessary. Table 3 Summary for fluopyram Use- No.* Crop Plant metabolism covered? Sufficient residue trials? PHI sufficiently supported? Sample storage covered by stability data? MRL compliance Reg 2017-626 Chronic risk for consumers identified? Acute risk for consumers identified? Comments / Barley and oat Yes Yes (11 NEU 8 SEU) Yes Yes Yes No No * Use number(s) in accordance with the list of all intended GAPs in Part B, Section 0 should be given in column 1 The effects of processing on the nature of fluopyram residues have been investigated. Data on effects of processing on the amount of residue have been submitted. These data were not considered for risk assessment. Residues in succeeding crops have been sufficiently investigated. MRLs in following crops have been proposed: 0.1 mg/kg for root and tuber vegetables and leafy crops; 0.01 mg/kg for cereals, oilseed crops and perennial crops; 0.01 mg/kg for fruits and fruiting vegetables. It is very unlikely that residues exceeding MRLs will be present in succeeding crops. Considering dietary burden and based on the intended uses, no significant modification of the intake was calculated for livestock. Further investigation of residues as well as the modification of MRLs in commodities of animal origin are therefore not necessary.
Page 17 of 34 Summary for KEYNOTE (102000027828) Crop PHI for KEYNOTE proposed by applicant PHI/ Withholding period* sufficiently supported for Bixafen Prothioconazole Fluopyram PHI for KEYNOTE (102000027828)proposed by zrms zrms Comments (if different PHI proposed) Barley and oat F** (BBCH 61) Yes Yes Yes F** (BBCH 61) NR: not relevant * Purpose of withholding period to be specified ** F: PHI is defined by the application stage at last treatment (time elapsing between last treatment and harvest of the crop). 3.1.4.2 Consumer exposure The data available are considered sufficient for risk assessment purposes. Any exceedence of the current MRL on barley and oat for bixafen, prothioconazole and fluopyram as laid down in Reg. (EU) 396/2005 is not expected. The chronic and the short-term intakes of bixafen, prothioconazole and fluopyram residues are unlikely to present a public health concern. As far as consumer health protection is concerned, France agrees with the authorisation of the intended uses. According to available data, no specific mitigation measures should apply. Data gaps No noticed data gaps. Data required post-authorisation None. It was not deemed necessary to define certain metabolites (particularly 1,2,4-triazole, triazole alanine and triazole acetic acid) as toxicologically relevant during the European evaluation of prothioconazole. Since they are common to many active substances in the triazole group, they are currently part of deliberations in Europe and around the world that could lead to an amendment to the residue definition at a later date. Data on these metabolites were provided with the present application and have been taken into account in the consumer risk evaluation, in accordance with EFSA recommendations (EFSA, 2009). 3.1.5 Environmental fate and behaviour The fate and behaviour in the environment of the formulation have been evaluated according to the requirements of Regulation (EC) No 1107/2009. Appropriate endpoints from the EU review were used to calculate predicted environmental concentrations (PECs) for the active substances and their metabolites for the intended use patterns. In cases where deviations from the EU agreed endpoints were considered appropriate (for example, when additional studies are provided), such deviations were highlighted and justified accordingly. The PEC values of bixafen, prothioconazole, fluopyram and their metabolites in soil, surface water and groundwater have been assessed according to FOCUS guidance documents, with standard FOCUS scenarios to obtain outputs
Page 18 of 34 from the FOCUS models, and the endpoints established in the EU peer reviews or agreed in the assessment based on new data provided. PECsoil and PECsw values derived for the active substances and their metabolites are used for the ecotoxicological risk assessment, and mitigation measures are proposed. PECgw values for bixafen, prothioconazole, fluopyram and their metabolites do not occur at levels exceeding those mentioned in Regulation (EC) N 1107/2009 and guidance document SANCO 221/2000 on the relevance of metabolites in groundwater. Therefore, no unacceptable risk of groundwater contamination is expected for the intended uses. Based on vapour pressure, information on volatilisation from plants and soil, and DT 50 calculation, no significant contamination of the air compartment is expected for the intended uses. 3.1.6 Ecotoxicology 3.1.6.1 Effects on Terrestrial Vertebrates The risk assessment for birds and mammals was carried out according to the EFSA Guidance Document on Risk Assessment for Birds and Mammals (2009) and considering the EU agreed endpoints of bixafen, prothioconazole and fluopyram. The toxicity:exposure ratio (TER) values, calculated for recommended scenarios, all exceed the trigger values of 10 for acute risk and 5 for long-term risk, indicating that the risk to birds and mammals (from direct dietary exposure, drinking water and secondary poisoning) is acceptable following use of KEYNOTE according to the proposed use patterns. 3.1.6.2 Effects on Aquatic Species The risk assessment for aquatic organisms was carried out according to the Guidance Document on Aquatic Ecotoxicology (Sanco/3268/2001) and considering the EU agreed endpoints of bixafen, prothioconazole, fluopyram and data on the formulation KEYNOTE (102000027828). The TER values for bixafen, prothioconazole and fluopyram exceed the relevant triggers, indicating that the risk to aquatic organisms is acceptable following use of KEYNOTE (102000027828) according to the proposed patterns, with an unsprayed planted buffer zone of 5 metres. 3.1.6.3 Effects on Bees and Other Arthropod Species Based on the guidance documents, the risks for bees and other non-target arthropods are acceptable for the intended uses. 3.1.6.4 Effects on Earthworms and Other Soil Macro-organisms The risk assessment for earthworms and other soil macro-organisms was carried out according to the Guidance Document on Terrestrial Ecotoxicology (Sanco/10329/2002) and considering the EU agreed endpoints of bixafen, prothioconazole, fluopyram, their metabolites and data on the formulation KEYNOTE (102000027828). The acute and chronic TER values for bixafen, prothioconazole, fluopyram, their metabolites and data on the formulation are greater than the triggers of 10 and 5 respectively, indicating that the risk to earthworms and other soil macro-organisms is acceptable according to the proposed use pattern. 3.1.6.5 Effects on organic matter breakdown (No information stated).
Page 19 of 34 3.1.6.6 Effects on Soil Non-target Micro-organisms The risk of KEYNOTE (102000027828) to soil micro-organisms was evaluated by comparison of no-effect concentrations, derived from laboratory tests, with PECsoil. The no-effect levels exceed the relevant PECsoil values, indicating that the risk to soil micro-organisms is acceptable following use of KEYNOTE (102000027828) according to the proposed pattern 3.1.6.7 Assessment of Potential for Effects on Other Non-target Organisms (Flora and Fauna) The risk assessment for non-target plants was again carried out according to the Guidance Document Sanco/10329/2002 and considering the endpoints of the formulation KEYNOTE (102000027828). The application of KEYNOTE (102000027828) does not cause unacceptable effects on non-target terrestrial plants when applied at a maximum application rate of 1.5 L/ha; this therefore covers the proposed new uses. 3.1.7 Efficacy This dossier is a request for extension of us of the product KEYNOTE (102000027828), containing bixafen, fluopyram and prothioconazole (respectively 65 + 65 + 130 g/l; EC). It is a fungicide, already authorised for use against wheat and rye diseases. It is now requested for use against barley and oat diseases. Considering the data submitted: The efficacy of KEYNOTE (102000027828) is considered satisfactory in the requested conditions. The phytotoxicity of KEYNOTE (102000027828) is considered negligible in the requested conditions. The risk of negative impact on yield, quality, transformation processes, propagation, non-target organisms, succeeding and adjacent crops is considered acceptable. There is a risk of resistance developing or appearing to prothioconazole for Oculimacula sp., in addition to bixafen and fluopyram for Pyrenophora graminea, therefore requiring monitoring and the setting-up of efficacy trials in situations of characterised resistance. To avoid the development of resistance of the three active substances, the number of applications is limited to one application per crop cycle (as proposed by the applicant). Restrictions: SPa 1: To avoid the build-up of resistance do not apply this or any other product containing bixafen, fluopyram or prothioconazole, more than one application per crop cycle on barley and oat.. To manage the risk of resistance with KEYNOTE (102000027828) it is recommended to follow the limitations of use by chemical group recommended by the French national note on resistance management of cereal diseases 16. Resistance monitoring data: A monitoring of resistance to prothioconazole for Oculimacula sp. and Pyrenophora graminea on barley, in addition to bixafen and fluopyram for Pyrenophora graminea on barley should be put in place and the setting-up of efficacy trials in situations of characterised resistance to bixafen and fluopyram 17 for Pyrenophora graminea on barley. Any new information which would change the resistance risk analysis should immediately be provided to Anses (France). 16 See Section 2.2.4 for the link to the full reference 17 bixafen and fluopyram are both succinate dehydrogenase inhibitors, acting on mitochondrial complex II.
Page 20 of 34 Use-No. Member state(s) Crop and/ or situation (crop destination / purpose of crop) F G or I Pests or Group of pests controlled (additionally: developmental stages of the pest or pest group) Method / Kind Application Timing / Growth stage of crop & season Max. number (min. interval between applications) a) per use b) per crop/ season kg, L product / ha a) max. rate per appl. b) max. total rate per crop/season Application rate g, kg a.s./ha a) max. rate per appl. b) max. total rate per crop/season Water L/ha min / max PHI (days) Efficacy conclusion 8 France Barley, spring F ERYSGH, RHYNSE, PYRNTE, PUCCHD, PSDCHE, RAMUCC, PUCCST, MICNNI, LEPTHE Overall spray BBCH 30-61 1 a) 1.2 b) 1.2 a) 78+78+156 b)78+78+156 100-400 * Acceptable 9 France Barley, winter F ERYSGH, RHYNSE, PYRNTE, PUCCHD, PSDCHE, RAMUCC, PUCCST, MICNNI, LEPTHE Overall spray BBCH 30-61 1 a) 1.2 b) 1.2 a) 78+78+156 b)78+78+156 100-400 * Acceptable 10 France Oats F PUCCCA, ERYSGR, PSDCHE, MICNNI, LEPTHE, SEPTHE Overall spray BBCH 30-61 1 a) 1.2 b) 1.2 a) 78+78+156 b)78+78+156 100-400 * Acceptable
Page 21 of 34 3.2 Conclusions arising from French assessment Taking into account the above assessment, an authorisation can be granted as proposed in Appendix 1 Copy of the product Decision. 3.3 Substances of concern for national monitoring No information stated. 3.4 Further information to permit a decision to be made or to support a review of the conditions and restrictions associated with the authorisation 3.4.1 Post-authorisation monitoring Monitoring of resistance to prothioconazole for Oculimacula sp. and Pyrenophora graminea on barley, in addition to bixafen and fluopyram for Pyrenophora graminea on barley should be put in place and the setting-up of efficacy trials in situations of characterised resistance to succinate dehydrogenase inhibitors (SDHI) for Pyrenophora graminea on barley. Any new information which would change the resistance risk analysis should immediately be provided to Anses (France). 3.4.2 Label amendments The draft label proposed by the applicant in Appendix 2 may be corrected with consideration of any new element under points 2.2.1 (or 2.2.2), 2.2.3 and 2.2.4. The label shall reflect the detailed conditions stipulated in the Decision.
Page 22 of 34 Appendix 1 Copy of the French Decision
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Page 28 of 34 Appendix 2 Copy of the draft product label as proposed by the applicant
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Page 33 of 34 Appendix 3 Letter(s) of Access Co-ownership of metabolite studies
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