Reasoned opinion on the modification of the existing MRLs for tebuconazole in cucumbers and courgettes 1

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1 EFSA Journal 2015;13(1):4000 ABSTRACT REASONED OPINION Reasoned opinion on the modification of the existing MRLs for tebuconazole in cucumbers and courgettes 1 European Food Safety Authority 2 European Food Safety Authority (EFSA), Parma, Italy In accordance with Article 6 of Regulation (EC) No 396/2005, Italy, hereafter referred to as the evaluating Member State (EMS), received an application from Oxon Italia S.p.A. to modify the existing MRLs for the active substance tebuconazole in cucumbers and courgettes. In order to accommodate for the intended uses of tebuconazole, Italy proposed to raise the MRL from 0.2 mg/kg to 0.5 mg/kg. Italy drafted an evaluation report in accordance with Article 8 of Regulation (EC) No 396/2005, which was submitted to the European Commission and forwarded to EFSA. According to EFSA the data are sufficient to derive an MRL proposal of 0.6 mg/kg for the proposed uses on cucumbers and courgettes. Adequate analytical enforcement methods are available to control the residues of tebuconazole in the plant matrices under consideration. Based on the risk assessment results, EFSA concludes that the proposed use of tebuconazole on cucumbers and courgettes will not result in a consumer exposure exceeding the toxicological reference values. European Food Safety Authority, 2015 KEY WORDS tebuconazole, cucumbers and courgettes, MRL application, Regulation (EC) No 396/2005, consumer risk assessment, triazole, triazole derivative metabolites 1 On request from the European Commission, Question No EFSA-Q , approved on 20 January Correspondence: pesticides.mrl@efsa.europa.eu Suggested citation: EFSA (European Food Safety Authority), Reasoned opinion on the modification of the existing MRLs for tebuconazole in cucumbers and courgettes. EFSA Journal 2015;13(1):4000, 24 pp. doi: /j.efsa Available online: European Food Safety Authority, 2015

2 SUMMARY In accordance with Article 6 of Regulation (EC) No 396/2005, Italy, hereafter referred to as the evaluating Member State (EMS), received an application from Oxon Italia S.p.A. to modify the existing MRLs for the active substance tebuconazole in cucumbers and courgettes. In order to accommodate for the intended uses of tebuconazole, Italy proposed to raise the MRL from 0.2 mg/kg to 0.5 mg/kg. Italy drafted an evaluation report in accordance with Article 8 of Regulation (EC) No 396/2005, which was submitted to the European Commission and forwarded to EFSA on 1 September EFSA bases its assessment on the evaluation report submitted by the EMS, the Draft Assessment Report (DAR) and its addenda prepared under Council Directive 91/414/EEC, the Commission Review Report, the conclusion on the peer review of the pesticide risk assessment of the active substance tebuconazole, the JMPR Evaluation reports as well as the conclusions from previous EFSA opinions on tebuconazole. The toxicological profile of tebuconazole was assessed in the framework of the peer review under Directive 91/414/EEC and the data were sufficient to propose an ADI of 0.03 mg/kg bw per day and an ARfD of 0.03 mg/kg bw. The metabolism of tebuconazole in primary crops was investigated in the cereal (wheat), oilseed (peanut) and fruit crop groups (grape). From these studies the residue definition for monitoring was provisionally proposed as tebuconazole (sum of enantiomers), pending the outcome of a global risk assessment approach for triazole derivative metabolites (TMDs). For risk assessment, the residue definition was proposed as tebuconazole (sum of enantiomers), but it was highlighted that an additional separate residue definition is needed for TDMs, harmonised for all active substances of the triazole chemical class. EFSA concludes that the submitted supervised residue trials are sufficient to derive an MRL proposal of 0.6 mg/kg for the proposed uses on cucumbers and courgettes. Adequate analytical enforcement methods are available to control the residues of tebuconazole in the plant matrices under consideration at the validated LOQ of 0.02 mg/kg. Specific studies investigating the magnitude of tebuconazole residues in processed commodities were not provided and are not required, as the contribution of the residues in cucumbers and courgettes to overall dietary consumer exposure is low. Based on the available information, EFSA concluded that residues of tebuconazole are not expected to be present in significant levels in rotational crops when the active substance is applied on cucumbers and courgettes according to the proposed GAPs. In contrast, the magnitude of the TDMs residues in rotational crops could not be addressed. Residues of tebuconazole in commodities of animal origin were not assessed in the framework of this application, since the crops under consideration are not fed to livestock. The consumer risk assessment was performed with revision 2 of the EFSA Pesticide Residues Intake Model (PRIMo). In the framework of the Article 12 MRL review, a comprehensive acute and longterm exposure assessment was performed, taking into account all existing uses of tebuconazole at EU level. EFSA now updates this risk assessment considering the median and highest residue values derived from the residue trials conducted on courgettes and cucumbers and the median and highest residue values reported in EFSA reasoned opinions issued after Article 12 review. Codex values (CXLx) implemented in the EU legislation were also taken into account. No long term consumer intake concern was identified. The maximum International Estimated Daily Intake (IEDI) was calculated to be 15 % of the ADI (WHO cluster B). The contribution of tebuconazole residues in cucumbers and courgettes the overall dietary exposure, was estimated to be EFSA Journal 2015;13(1):4000 2

3 0.4 % and 0.2 % of the ADI, respectively. No short term consumer intake concern was identified. The maximum International Estimated Short Term Intake (IESTI) was calculated to be 57 % of the ARfD for cucumbers (NL Child). However, EFSA emphasises that the above assessment does not take into consideration triazole derivative metabolites. Since these metabolites may be generated by several pesticides belonging to the group of triazole fungicides, EFSA recommends that a separate risk assessment should be performed for TDMs as soon as the confirmatory data requested for triazole compounds in the framework of Regulation (EC) No 1107/2009 have been evaluated and a general methodology on the risk assessment of triazole compounds and their triazole derivative metabolites is available. EFSA concludes that the proposed use of tebuconazole on cucumbers and courgettes will not result in a consumer exposure exceeding the toxicological reference values and therefore, is unlikely to pose a consumer health risk. Thus EFSA proposes to amend the existing MRLs as reported in the summary table. SUMMARY TABLE Code number (a) Commodity Existing EU MRL Enforcement residue definition: Fluopyram Proposed EU MRL Justification for the proposal Cucumbers MRL derived from indoor trials conducted on cucumbers and courgettes. No consumer intake concerns were identified based on Courgettes the risk assessment conducted for tebuconazole. However the contribution of TDMs to the consumer intake has not been considered. (a): According to Annex I of Regulation (EC) No 396/2005. EFSA Journal 2015;13(1):4000 3

4 TABLE OF CONTENTS Abstract... 1 Summary... 2 Background... 5 Terms of reference... 5 The active substance and its use pattern... 5 Assessment Method of analysis Methods for enforcement of residues in food of plant origin Methods for enforcement of residues in food of animal origin Mammalian toxicology Residues Nature and magnitude of residues in plant Primary crops Rotational crops Nature and magnitude of residues in livestock Consumer risk assessment Conclusions and recommendations References Appendices Appendix A. Good Agricultural Practice (GAPs) Appendix B. Pesticide Residue Intake Model (PRIMo) Appendix C. List of metabolites and related structural formula Abbreviations EFSA Journal 2015;13(1):4000 4

5 BACKGROUND Regulation (EC) No 396/ establishes the rules governing the setting of pesticide MRLs at European Union level. Article 6 of that Regulation lays down that any party having a legitimate interest or requesting an authorisation for the use of a plant protection product in accordance with Council Directive 91/414/EEC, 4 repealed by Regulation (EC) No 1107/2009, 5 shall submit to a Member State, when appropriate, an application to modify a MRL in accordance with the provisions of Article 7 of that Regulation. Italy, hereafter referred to as the evaluating Member State (EMS), received an application from the company Oxon Italia S.p.A. 6 to modify the existing MRLs for the active substance tebuconazole in cucumbers and courgettes. This application was notified to the European Commission and EFSA and was subsequently evaluated by the EMS in accordance with Article 8 of the Regulation. After completion, the evaluation report was submitted to the European Commission who forwarded the application, the evaluation report and the supporting dossier to EFSA on 1 September The application was included in the EFSA Register of Questions with the reference number EFSA-Q and the following subject: Tebuconazole - Application to modify the existing MRLs in cucumbers and courgettes For cucumbers and courgettes, Italy proposed to raise the existing MRLs of tebuconazole from the current MRL value of 0.2 mg/kg to 0.5 mg/kg. EFSA proceeded with the assessment of the application and the evaluation report as required by Article 10 of the Regulation. TERMS OF REFERENCE In accordance with Article 10 of Regulation (EC) No 396/2005, EFSA shall, based on the evaluation report provided by the evaluating Member State, provide a reasoned opinion on the risks to the consumer associated with the application. In accordance with Article 11 of that Regulation, the reasoned opinion shall be provided as soon as possible and at the latest within three months (which may be extended to six months where more detailed evaluations need to be carried out) from the date of receipt of the application. Where EFSA requests supplementary information, the time limit laid down shall be suspended until that information has been provided. In this particular case the deadline for providing the reasoned opinion is 1 December THE ACTIVE SUBSTANCE AND ITS USE PATTERN Tebuconazole is the ISO common name for (RS)-1-p-chlorophenyl-4,4-dimethyl-3-(1H-1,2,4-triazol- 1-ylmethyl)-pentan-3-ol (IUPAC). The chemical structure of the compound is reported below. 3 Regulation (EC) No 396/2005 of the Parliament and of the Council of 23 February 2005 on maximum residue levels of pesticides in or on food and feed of plant and animal origin and amending Council Directive 91/414/EEC. OJ L 70, , p Council Directive 91/414/EEC of 15 July 1991 concerning the placing of plant protection products on the market. OJ L 230, , p 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 Oxon Italia S.p.A, Via Sempione 195, 20016, Pero, Italy EFSA Journal 2015;13(1):4000 5

6 HO C H 3 CH3 CH 3 Cl N N Molecular weight: g/mol N Tebuconazole is a systemic fungicide belonging to the class of triazoles. The compound acts as an ergosterol biosynthesis inhibitor (EBI). The lack of normal sterol production inhibits the growth of the fungus, hereby effectively preventing further infection and/or invasion of host tissues. The active substance is used against a wide range of fungal pathogens in a large number of agricultural crops. Tebuconazole was evaluated in the framework of Council Directive 91/414/EEC with Denmark designated as rapporteur Member State (RMS). The representative uses evaluated in the peer review were outdoor foliar applications on grape and cereals, in northern and southern Europe and seed treatment on barley in northern Europe. Tebuconazole was included in Annex I of this Directive by Directive 2008/125/EC 7 which entered into force on 1 September 2009 for use as fungicide only. In accordance with Commission Implementing Regulation (EU) No 540/ tebuconazole is approved under Regulation (EC) No 1107/2009, repealing Council Directive 91/414/EEC. In 2010, in accordance with Article 7 of Regulation (EC) No 1107/2009, Denmark received an application from Bayer Crop Science for amendment to the conditions of approval of the active substance in order to lift the restriction and allow the use of tebuconazole as a plant growth regulator. Denmark provided an addendum to the Draft Assessment Report (Denmark, 2012), which was peer reviewed by EFSA. An updated conclusion was issued by EFSA on the basis of the uses of tebuconazole as a fungicide on cereals and grape and as a plant growth regulator on oilseed rape, as proposed by the applicant (EFSA, 2014). The EU MRLs for tebuconazole were first established in Annex IIIA of Regulation (EC) No 396/2005 by means of Regulation (EC) No 149/ which were based on MRLs previously established at national level (EFSA, 2011a). From this date, several MRL applications were submitted and modifications of the MRLs were recommended by EFSA for the following crops: Swedes and turnips (EFSA, 2009a), mandarins and passion fruit (EFSA, 2009b), various citrus fruits (EFSA, 2010), pulses (EFSA, 2011b), lettuce and other salad plants including Brassicacea, herbs (EFSA, 2012), poppy seeds (EFSA, 2013). 7 Commission Directive 2008/125/EC of 19 December 2008, amending Council Directive 91/414/EEC to include aluminium phosphide, calcium phosphide, magnesium phosphide, cymoxanil, dodemorph, 2,5-dichlorobenzoic acid methylester, metamitron, sulcotrione, tebuconazole and triadimenol as active substances, OJ L 344, , p Commission Implementing Regulation (EU) No 540/2011 of 23 May 2011 implementing Regulation (EC) No 1107/2009 of the European Parliament and of the Council as regards the list of approved active substances. OJ L 153, , p Commission Regulation (EC) 149/2008 of 29 January 2008, amending Regulation (EC) No 396/2005 of the European Parliament and of the Council by establishing Annexes II, III and IV setting maximum residue levels for products covered by Annex I thereto, OJ L 58, , p EFSA Journal 2015;13(1):4000 6

7 The MRL proposals recommended by EFSA for the crops mentioned above were considered in Regulations (EC) 459/2010, 10 (EU) 750/2010, 11 (EU) 524/ and (EU) 500/ Finally, the MRL proposals made by EFSA in the framework of the review of the existing MRLs under Article 12 of Regulation (EC) 396/2005 (EFSA 2011a) have been recently implemented in the European legislation by Regulation (EU) 61/ MRLs for cucumbers and courgettes in the EU legislation are currently set at 0.2 mg/kg. Codex Alimentarius has established CXLs for a wide range of commodities, including a CXL of 0.15 mg/kg for cucumbers. The details of the intended GAPs for tebuconazole are given in Appendix A. 10 Commission Regulation (EC) 459/2010 of 27 May 2010, amending Annexes II, III and IV to Regulation (EC) No 396/2005 of the European Parliament and of the Council as regards maximum residue levels for certain pesticides in or on certain products, OJ L 129, , p Commission Regulation (EU) 750/2010 of 07 July 2010, amending Annexes II and III to Regulation (EC) No 396/2005 of the European Parliament and of the Council as regards maximum residue levels for certain pesticides in or on certain products, OJ L 220, , p Commission Regulation (EU) 524/2011 of 26 May 2011, amending Annexes II and III to Regulation (EC) No 396/2005 of the European Parliament and of the Council as regards maximum residue levels for biphenyl, deltamethrin, ethofumesate, isopyrazam, propiconazole, pymetrozine, pyrimethanil and tebuconazole in or on certain products, OJ L 142, , p Commission Regulation (EU) 500/2013 of 30 May 2013, amending Annexes II, III and IV to Regulation (EC) No 396/2005 of the European Parliament and of the Council as regards maximum residue levels for acetamiprid, Adoxophyes orana granulovirus strain BV-0001, azoxystrobin, clothianidin, fenpyrazamine, heptamaloxyloglucan, metrafenone, Paecilomyces lilacinus strain 251, propiconazole, quizalofop-p, spiromesifen, tebuconazole, thiamethoxam and zucchini yellow mosaic virus - weak strain in or on certain products, OJ L 151, , p Commission Regulation (EU) 61/2014 of 24 January 2014, amending Annexes II and III to Regulation (EC) No 396/2005 of the European Parliament and of the Council as regards maximum residue levels for cyromazine, fenpropidin, formetanate, oxamyl and tebuconazole in or on certain products, OJ L 22, , p EFSA Journal 2015;13(1):4000 7

8 ASSESSMENT EFSA bases its assessment on the evaluation report submitted by the EMS (Italy, 2014), the Draft Assessment Report (DAR) and its addendum prepared under Council Directive 91/414/EEC (Denmark, 2008a, 2008b, 2013), the Commission Review Report on tebuconazole (EC, 2008), the conclusion on the peer review of the pesticide risk assessment of the active substance tebuconazole (EFSA, 2008, 2014), the JMPR Evaluation report (FAO, 1994, 2009a,b, 2010, 2011) as well as the conclusions from previous EFSA opinions on tebuconazole (EFSA, 2009a,b, 2010, 2011a,b, 2012, 2013). The assessment is performed in accordance with the legal provisions of the Uniform Principles for the Evaluation and the Authorisation of Plant Protection Products adopted by Commission Regulation (EU) No 546/ and the currently applicable guidance documents relevant for the consumer risk assessment of pesticide residues (EC, 1996, 1997a-g, 2000, 2010a,b, 2011; OECD, 2011). 1. Method of analysis 1.1. Methods for enforcement of residues in food of plant origin Analytical methods for the determination of tebuconazole residues in plant commodities were assessed during the peer review under Directive 91/414/EEC (EFSA, 2008, 2014). The multi-residue method DFG-S19 using GC-MS quantification and its ILV were evaluated and adequately validated for the determination of tebuconazole in plant matrices with high water content (tomato, onion, cauliflower), high fat content (rape), acidic (orange) and dry (wheat) commodities, with a LOQ of 0.02 mg/kg. The multi-residue QuEChERS method using HPLC-MS/MS described in the European Standard EN 15662:2008 is also applicable for the determination of tebuconazole in high water content, acidic and dry commodities (CEN, 2008). EFSA concludes that sufficiently validated analytical methods for enforcing the proposed MRLs for tebuconazole in food of plant origin are available Methods for enforcement of residues in food of animal origin Analytical methods for the determination of residues in food of animal origin are not assessed in the current application, since cucumbers and courgettes are normally not fed to livestock. 2. Mammalian toxicology The toxicological profile of the active substance tebuconazole was assessed in the framework of the peer review under Directive 91/414/EEC (EFSA, 2008, 2014). The data were sufficient to derive toxicological reference values for tebuconazole. Metabolism studies in both mammalians and plants have shown that active substances belonging to the chemical class of triazoles to be degraded/metabolized to a certain extent to common metabolites known as triazole derivative metabolites (TDMs), the major ones being the metabolites 1,2,4-triazole, triazole alanine, triazole lactic acid and triazole acetic acid. In 2007 the toxicological profile of TMDs was discussed in the EFSA Pesticide Risk Assessment Peer Review (PRAPeR) Expert Meeting 14 and toxicological reference values for the TDMs were finally published in the EFSA conclusion on difenoconazole, another active substance belonging to the triazole class (EFSA, 2011c). All toxicological endpoints are summarized in the Table 2-1 below. EFSA Journal 2015;13(1):4000 8

9 Table 2-1: Overview of the toxicological reference values Source Year Value Study relied upon Safety factor Tebuconazole (sum of enantiomers) ADI EFSA mg/kg bw per day Dog, 1 year study (supported by developmental mouse study; with safety factor of 300) ARfD EFSA mg/kg bw Mouse, developmental study 300 1,2,4-triazole, triazole acetic acid and triazole lactic acid ADI EFSA 2011c 0.02 mg/kg bw per day Rat, multigeneration study 1000 ARfD EFSA 2011c 0.06 mg/kg bw Rat, developmental study 500 triazole alanine ADI EFSA 2011c 0.10 mg/kg bw per day Rat, developmental study 1000 ARfD EFSA 2011c 0.10 mg/kg bw Rat, developmental study Residues 3.1. Nature and magnitude of residues in plant Primary crops Nature of residues The metabolism of tebuconazole in primary crops was reported and evaluated by Denmark (Denmark, 2008a) and reviewed by EFSA in the framework of the peer review under Directive 91/414/EEC (EFSA, 2008,2014). Details of the metabolism studies are reported in the EFSA reasoned opinion related to the Article 12 MRL review (EFSA, 2011a). Table 3-1: Summary of available metabolism studies in plants 100 Crop group Crop Method, F or G (a) Rate (No g/ha) Application details Sampling Fruit Grape Foliar, F , 3, 7, 14, 21 and 28 DAT Pulses/ oilseeds Peanut Foliar, G weeks after last application Foliar, G weeks after last application Foliar, G weeks after last application Cereals Wheat Foliar, G , 7, 14, 21, 28 and 50 DAT Seed, G 11 g/100 kg 38 and 66 days after planting (a): Outdoor/field application (F) or glasshouse/protected crops/indoor application (G) Remarks Based on these data, the residue definition for monitoring was provisionally proposed as tebuconazole (sum of enantiomers) in the conclusion of the peer review, pending the outcome of a global risk assessment approach for TMDs (EFSA, 2014). For risk assessment, the residue definition was proposed as tebuconazole (sum of enantiomers), but it was highlighted that a separate additional residue definition is needed for TDMs, harmonised for all active substances of the triazole chemical class. Such an harmonised residue definition has not yet EFSA Journal 2015;13(1):4000 9

10 been proposed for TMDs. These residue definitions were confirmed in the framework of the Article 12 MRL review (EFSA, 2011a). The current enforcement residue definition in Regulation (EC) No 396/2005 is parent tebuconazole. For the uses on courgettes and cucumbers, EFSA concludes that the metabolism of tebuconazole is sufficiently addressed and the residue definitions for enforcement and risk assessment agreed in the peer review are applicable Magnitude of residues In support of the MRL application, supervised trials conducted on cucumbers and courgettes under greenhouse conditions were submitted. Trials were found to comply with the proposed GAP. Tebuconazole residue levels were in the range of to mg/kg, leading to an MRL proposal of 0.6 mg/kg. No information was provided on the possible TDMs residue levels. The results of the residue trials, the input values for risk assessment (STMR, HR) and the MRL proposal are summarised in Table 3-2. The storage stability of tebuconazole was investigated in the framework of the peer review under Directive 91/414/EEC (EFSA, 2014). Residues of tebuconazole were found to be stable at -20 C for up to 30 months in high water-, high acid-, and high oil-content matrices as well as in dry matrices. As samples from the residue trials on cucumbers and courgettes were stored frozen at ca -18 C for a maximum period of 7 months, it is concluded that the residue data are valid with regard to storage stability. According to the EMS, the analytical methods used to analyse the samples from the residue trials conducted on cucumbers and courgettes have been sufficiently validated and were proven to be fit for the purpose (Italy, 2014). EFSA concludes that the data are sufficient to derive a MRL proposal of 0.6 mg/kg 15 for the indoor uses of tebubuconazole on courgettes and cucumbers in the EU. 15 In the application form, the applicant proposed to set an MRL value of 0.5 mg/kg. EFSA recommend the value of 0.6 mg/kg as derived using the OECD calculator. EFSA Journal 2015;13(1):

11 Table 3-2: Overview of the available residues trials data Commodity Residue region (a) Individual trial results Enforcement and risk assessment residue definition (tebuconazole, sum of enantiomers) Comments (b) EU MRL proposal HR (c) STMR (b) Courgette and cucumber Indoor EU 0.025; 0.037; 0.041; 0.074; 0.083; 0.111; 0.189; 0.260; Trials on cucumbers are underlined. MRL OECD : 0.52/ (a): NEU (Northern and Central Europe), SEU (Southern Europe and Mediterranean), EU (i.e. indoor use) or Import (country code) (EC, 2011). (b): Statistical estimation of MRLs according to OECD methodology; unrounded/rounded values (OECD, 2011). (c): HR: Highest value of the individual trial results according to the residue definition for risk assessment. (d): STMR: Median value of the individual trial results according to the residue definition for risk assessment. EFSA Journal 2015;13(1):

12 Effect of industrial processing and/or household preparation The effect of processing on the nature of tebuconazole was investigated in standard hydrolysis studies representing pasteurisation, baking/brewing/boiling and sterilisation and was reported in the conclusion of the peer review (EFSA, 2014). Tebuconazole is hydrolytically stable under the representative processing conditions and therefore, the residue definitions set for plant commodities are also applicable to processed commodities. Specific studies investigating the magnitude of tebuconazole residues in processed commodities were not provided and are not required, as the contribution of the residues in cucumbers and courgettes to overall dietary consumer exposure is low (see section 4) Rotational crops Available information on rotational crops upon treatment with tebuconazole on primary crops is reported in the EFSA conclusion (EFSA, 2008, 2014). The metabolites identified in rotational crops were in accordance with the metabolic pathway observed in primary crops and it was concluded that the uptake by plants is not expected to lead to residues of tebuconazole in rotational crops above the LOQ. In contrast, since a significant uptake of the triazole derivative metabolites was observed in rotational crops, it was recommended to reconsider the residue in rotational crops once a general methodology on the risk assessment of triazole compounds and their triazole derivative metabolites is available. Additional data on rotational crops were not provided in the framework of this MRL application. Based on the available information, EFSA concluded that residues of tebuconazole are not expected to be present in significant levels in rotational crops when the active substance is applied on cucumbers and courgettes according to the proposed GAPs. In contrast the magnitude of the TDM residue levels in rotational crops could not be addressed Nature and magnitude of residues in livestock Since cucumbers and courgettes are not normally fed to livestock, the nature and magnitude of tebuconazole residues in livestock is not assessed in the framework of this application (EC, 1996). 4. Consumer risk assessment The consumer risk assessment was performed with revision 2 of the EFSA Pesticide Residues Intake Model (PRIMo). This exposure assessment model contains the relevant European food consumption data for different sub-groups of the EU population 16 (EFSA, 2007). In the framework of the review of the existing MRLs according to Article 12 of Regulation (EC) No 396/2005 a comprehensive acute and long-term exposure assessment was performed, taking into account the existing uses of tebuconazole at EU level. EFSA now updates this risk assessment with the STMR and HR values: - derived from the residue trials on courgettes and cucumbers (Table 3-2), - reported in EFSA reasoned opinion issued after Article 12 review and related to citrus, lettuce, chives and parsley (EFSA, 2012), - proposed for poppy seeds and not yet implemented in the EU legislation (EFSA, 2013), - and the STMR and HR values derived by the 2008 and 2010 JMPR meetings, adopted by the 2012 Codex Alimentarius Commission and implemented in the EU legislation. 16 The calculation of the long-term exposure (chronic exposure) is based on the mean consumption data representative for 22 national diets collected from MS surveys plus 1 regional and 4 cluster diets from the WHO GEMS Food database; for the acute exposure assessment the most critical large portion consumption data from 19 national diets collected from MS surveys is used. The complete list of diets incorporated in EFSA PRIMo is given in its reference section (EFSA, 2007). EFSA Journal 2015;13(1):

13 All input values used for the dietary exposure calculation are summarised in Table 4-1. For the food commodities not listed in Table 4-1, the LOQ values reported in Regulation (EU) 61/2014 were used as input values. The acute exposure assessment was performed only with regard to the commodities under consideration, assuming the consumption of a large portion of the food item as reported in the national food surveys and that these items contained residues at the highest level as observed in supervised field trials. A variability factor accounting for the inhomogeneous distribution on the individual items consumed was included in the calculation, when required (EFSA, 2007). Table 4-1: Commodities Input values for the consumer dietary exposure assessment (Changes in input values after Article 12 review are shown in grey) Chronic exposure Acute exposure Input Comment Input Comment Remarks Oranges 0.05 STMR PF 0.07 HR PF (EFSA, 2011) Other citrus 0.24 STMR PF pulp 0.32 HR PF pulp (EFSA, 2012) Tree nuts 0.05 STMR 0.05 HR (EFSA, 2011) Apples/Pears 0.13 STMR 0.26 HR (EFSA, 2011) Other pome fruits 0.19 STMR 0.47 HR (JMPR, 2008) Apricots/Peach 0.16 STMR 0.32 HR (EFSA, 2011) Cherries 0.37 STMR 0.74 HR (EFSA, 2011) Plums 0.08 STMR 0.47 HR (JMPR, 2011 Table grapes 0.17 STMR 0.42 HR (EFSA, 2011) Wine grapes 0.37 STMR 0.55 HR (EFSA, 2011) Cane fruits 0.1 STMR 0.22 HR (EFSA, 2011) Other small fruits 0.52 STMR 1.2 HR (EFSA, 2011) Table olives 0.05 STMR 0.05 HR (EFSA, 2011) Passion fruit 0.03 STMR PF 0.05 HR PF (EFSA, 2011) Banana 0.01 STMR 0.03 HR (JMPR, 2011) Mangoes 0.05 STMR 0.1 HR (EFSA, 2011) Papaya 0.36 STMR 1.2 HR (EFSA, 2011) Carrots/Horseradish/ Parsnips/Parsley/Salsify 0.15 STMR 0.22 HR (EFSA, 2011) Celeriac 0.08 STMR 0.34 HR (EFSA, 2011) Swedes/Turnips 0.12 STMR 0.22 HR (EFSA, 2011) Turnips 0.12 STMR 0.22 HR (EFSA, 2011) Garlic/Onions 0.04 STMR 0.06 HR (EFSA, 2011) Shallots 0.04 STMR 0.05 HR (EFSA, 2011) Spring onions 0.11 STMR 0.32 HR (EFSA, 2011) Tomatoes 0.23 STMR 0.46 HR (EFSA, 2011) Peppers 0.26 STMR 0.4 HR (EFSA, 2011) Aubergines 0.11 STMR 0.15 HR (EFSA, 2011) EFSA Journal 2015;13(1):

14 Commodities Chronic exposure Acute exposure Input Comment Input Comment Cucumbers/courgettes 0.08 STMR 0.29 HR Remarks Melons 0.09 STMR 0.1 HR (EFSA, 2011) Pumpkins/Watermelons 0.04 STMR 0.09 HR (EFSA, 2011) Sweet corn 0.06 STMR 0.36 HR (JMPR, 2011) Broccoli 0.04 STMR 0.12 HR (EFSA, 2011) Cauliflower 0.05 STMR 0.05 HR (EFSA, 2011) Brussels sprouts 0.06 STMR 0.49 HR (EFSA, 2011) Head cabbage 0.05 STMR 0.56 HR (EFSA, 2011) Lettuce other salad plants 0.05 STMR 0.25 HR (EFSA, 2012) Witloof 0.05 STMR 0.06 HR (EFSA, 2011) Chives, parsley 0.58 STMR 0.98 HR (EFSA, 2012) Beans/Peas (with pods) 0.49 STMR 1.2 HR (JMPR, 2008) Beans (without pods) 0.49 STMR 1.2 HR (JMPR, 2008) Celery 0.19 STMR 0.21 HR (EFSA, 2011) Globe artichokes 0.15 STMR 0.32 HR (EFSA, 2011) Leek 0.21 STMR 0.44 HR (EFSA, 2011) Beans (dry) 0.07 STMR 0.12 HR (EFSA, 2011) Lentils/Peas/Lupin 0.05 STMR 0.17 HR (EFSA, 2011) Linseed 0.14 STMR 0.3 HR (EFSA, 2011) Peanuts STMR 0.08 HR (JMPR, 2011) Poppy seed 0.04 STMR 0.11 HR (EFSA, 2013) Rape seed/gold of pleasure 0.10 STMR 0.28 HR (EFSA, 2011) Soya bean 0.02 STMR 0.07 HR (EFSA, 2011) Mustard seed 0.05 STMR 0.19 HR (EFSA, 2011) Olives (oil production) 0.05 STMR 0.05 HR (EFSA, 2011) Barley/Oats grain 0.68 STMR 1.10 HR (EFSA, 2011) Rice grain 0.28 STMR 0.97 HR (EFSA, 2011) Rye/Wheat grain 0.05 STMR 0.06 HR (EFSA, 2011) Coffee beans 0.04 STMR 0.06 HR JMPR (2011) Hops (dried) 9.65 STMR 21 HR (EFSA, 2011) Spices (seeds) 0.4 STMR 0.68 HR (EFSA, 2011) Risk assessment residue definition: sum of tebuconazole, hydroxy-tebuconazole and their conjugates expressed as tebuconazole Mammalian meat/fat 0.1 LOQ 0.1 LOQ (EFSA, 2011) Mammalian liver/kidney 0.06 STMR 0.15 HR (JMPR, 2011) Poultry products 0.1 LOQ 0.1 LOQ (EFSA, 2011) Milk 0.02 LOQ 0.02 LOQ (EFSA, 2011) EFSA Journal 2015;13(1):

15 The estimated exposure was then compared with the toxicological reference values derived for tebuconazole (see Table 2-1). The results of the intake calculation are presented in Appendix B to this reasoned opinion. No long-term consumer intake concerns were identified for any of the European diets incorporated in the EFSA PRIMo. The maximum calculated intake value was 15 % of the ADI (WHO cluster B). The contribution of tebuconazole residues in cucumbers and courgettes the overall dietary exposure, was estimated to be 0.4 % and 0.2 % of the ADI, respectively. No acute consumer risk was identified in relation to the MRL proposals for cucumber, courgette. The calculated maximum acute exposure was estimated to be 57 % of the ARfD for cucumbers (NL Child) and 45 % of the ARfD for courgettes (UK toddler). EFSA concludes that the intended use of tebuconazole on cucumber, courgette will in principle not result in a consumer exposure exceeding the toxicological reference values and therefore is unlikely to pose a public health concern. However, EFSA emphasises that the above assessment does not yet take into consideration triazole derivative metabolites (TDMs). Since these metabolites may be generated by several pesticides belonging to the group of triazole fungicides, EFSA recommends that a separate risk assessment should be performed for TDMs as soon as the confirmatory data requested for triazole compounds in the framework of Regulation (EC) No 1107/2009 have been evaluated and a general methodology on the risk assessment of triazole compounds and their triazole derivative metabolites is available. CONCLUSIONS AND RECOMMENDATIONS CONCLUSIONS The toxicological profile of tebuconazole was assessed in the framework of the peer review under Directive 91/414/EEC and the data were sufficient to propose an ADI of 0.03 mg/kg bw per day and an ARfD of 0.03 mg/kg bw. The metabolism of tebuconazole in primary crops was investigated in the cereal (wheat), oilseed (peanut) and fruit crop groups (grape). From these studies the residue definition for monitoring was provisionally proposed as tebuconazole (sum of enantiomers), pending the outcome of a global risk assessment approach for triazole derivative metabolites (TMDs). For risk assessment, the residue definition was proposed as tebuconazole (sum of enantiomers), but it was highlighted that an additional separate residue definition is needed for TDMs, harmonised for all active substances of the triazole chemical class. EFSA concludes that the submitted supervised residue trials are sufficient to derive an MRL proposal of 0.6 mg/kg for the proposed uses on cucumbers and courgettes. Adequate analytical enforcement methods are available to control the residues of tebuconazole in the plant matrices under consideration at the validated LOQ of 0.02 mg/kg. Specific studies investigating the magnitude of tebuconazole residues in processed commodities were not provided and are not required, as the contribution of the residues in cucumbers and courgettes to overall dietary consumer exposure is low. Based on the available information, EFSA concluded that residues of tebuconazole are not expected to be present in significant levels in rotational crops when the active substance is applied on cucumbers and courgettes according to the proposed GAPs. In contrast, the magnitude of the TDMs residues in rotational crops could not be addressed. EFSA Journal 2015;13(1):

16 Residues of tebuconazole in commodities of animal origin were not assessed in the framework of this application, since the crops under consideration are not fed to livestock. The consumer risk assessment was performed with revision 2 of the EFSA Pesticide Residues Intake Model (PRIMo). In the framework of the Article 12 MRL review, a comprehensive acute and longterm exposure assessment was performed, taking into account all existing uses of tebuconazole at EU level. EFSA now updates this risk assessment considering the median and highest residue values derived from the residue trials conducted on courgettes and cucumbers and the median and highest residue values reported in EFSA reasoned opinions issued after Article 12 review. Codex values (CXLx) implemented in the EU legislation were also taken into account. No long term consumer intake concern was identified. The maximum International Estimated Daily Intake (IEDI) was calculated to be 15 % of the ADI (WHO cluster B). The contribution of tebuconazole residues in cucumbers and courgettes the overall dietary exposure, was estimated to be 0.4 % and 0.2 % of the ADI, respectively. No short term consumer intake concern was identified. The maximum International Estimated Short Term Intake (IESTI) was calculated to be 57 % of the ARfD for cucumbers (NL Child). However, EFSA emphasises that the above assessment does not take into consideration triazole derivative metabolites. Since these metabolites may be generated by several pesticides belonging to the group of triazole fungicides, EFSA recommends that a separate risk assessment should be performed for TDMs as soon as the confirmatory data requested for triazole compounds in the framework of Regulation (EC) No 1107/2009 have been evaluated and a general methodology on the risk assessment of triazole compounds and their triazole derivative metabolites is available. EFSA concludes that the proposed use of tebuconazole on cucumbers and courgettes will not result in a consumer exposure exceeding the toxicological reference values and therefore, is unlikely to pose a consumer health risk. Thus EFSA proposes to amend the existing MRLs as reported in the summary table. Summary table Code number (a) Commodity Existing EU MRL Enforcement residue definition: Fluopyram Proposed EU MRL Justification for the proposal Cucumbers MRL derived from indoor trials conducted on cucumbers and courgettes. No consumer intake concerns were identified based on Courgettes the risk assessment conducted for tebuconazole. However the contribution of TDMs to the consumer intake has not been considered. (a): According to Annex I of Regulation (EC) No 396/2005. EFSA Journal 2015;13(1):

17 REFERENCES CEN (European Committee for Standardisation), Foods of plant origin - Determination of pesticide residues using GC-MS and/or LC-MS/MS following acetonitrile extraction/partitioning and clean-up by dispersive SPE. QuEChERS-method. EN November Denmark, 2008a. Draft assessment report on the active substance tebuconazole prepared by the rapporteur Member State Denmark in the framework of Council Directive 91/414/EEC, April Denmark, 2008b. Final addendum to the draft assessment report on the active substance tebuconazole prepared by the rapporteur Member State Denmark in the framework of Council Directive 91/414/EEC, July Denmark, Final addendum to the compiled addendum to the Draft Assessment Report (DAR) on the active substance tebuconazole, compiled by EFSA, October EC (European Commission), Appendix G. Livestock Feeding Studies. 7031/VI/95-rev.4. EC (European Commission), 1997a. Appendix A. Metabolism and distribution in plants. 7028/IV/95- rev.3. EC (European Commission), 1997b. Appendix B. General recommendations for the design, preparation and realisation of residue trials. Annex 2. Classification of (minor) crops not listed in the Appendix of Council Directive 90/642/EEC. 7029/VI/95-rev.6. EC (European Commission), 1997c. Appendix C. Testing of plant protection products in rotational crops. 7524/VI/95-rev.2. EC (European Commission), 1997d. Appendix E. Processing studies. 7035/VI/95-rev.5. EC (European Commission), 1997e. Appendix F. Metabolism and distribution in domestic animals. 7030/VI/95-rev.3. EC (European Commission), 1997f. Appendix H. Storage stability of residue samples. 7032/VI/95- rev.5. EC (European Commission), 1997g. Appendix I. Calculation of maximum residue level and safety intervals. 7039/VI/95. EC (European Commission), Residue analytical methods. For pre-registration data requirement for Annex II (part A, section 4) and Annex III (part A, section 5 of Directive 91/414). SANCO/3029/99-rev.4. EC (European Commission), 2010a. Classes to be used for the setting of EU pesticide Maximum Residue Levels (MRLs). SANCO 10634/2010 Rev. 0, finalised in the Standing Committee on the Food Chain and Animal Health at its meeting of March EC (European Commission), 2010b. Residue analytical methods. For post-registration control. SANCO/825/00-rev.8.1. EC (European Commission), Appendix D. Guidelines on comparability, extrapolation, group tolerances and data requirements for setting MRLs. 7525/VI/95-rev.9. EC (European Commission), Review report for the active substance tebuconazole. Finalised in the Standing Committee on the Food Chain and Animal Health at its meeting on 28 October 2008 in view of the inclusion of tebuconazole in Annex I of Council Directive 91/414/EEC. SANCO/171/08-rev. 2, 11 July 2014, 09 pp. EFSA (European Food Safety Authority), Reasoned opinion on the potential chronic and acute risk to consumers health arising from proposed temporary EU MRLs according to Regulation (EC) No 396/2005 on Maximum Residue Levels of Pesticides in Food and Feed of Plant and Animal Origin. 15 March The EFSA Journal 2007, 32r, Available online: EFSA Journal 2015;13(1):

18 EFSA (European Food Safety Authority), Conclusion on the peer review of the pesticide risk assessment of the active substance tebuconazole. The EFSA Journal 2008, 176r, 109 pp. doi: /j.efsa r EFSA (European Food Safety Authority), 2009a. Reasoned opinion of EFSA prepared by the Pesticides Unit (PRAS) on the modification of the existing MRLs for tebuconazole in swedes and turnips. The EFSA Journal 2009, 318r, 30 pp. doi: /j.efsa r EFSA (European Food Safety Authority), 2009b. Reasoned opinion of EFSA prepared by the Pesticides Unit (PRAS) on the modification of the existing MRLs for tebuconazole in mandarins and passion fruit. EFSA Journal, 2009:7(10):1368, 27 pp. doi: /j.efsa EFSA (European Food Safety Authority), Reasoned opinion of EFSA prepared by the Pesticides Unit (PRAS) on the modification of the existing MRLs for tebuconazole in various citrus fruits. EFSA Journal 2010;8(11):1896, 30 pp. doi: /j.efsa EFSA (European Food Safety Authority), 2011a. Review of the existing maximum residue levels (MRLs) for tebuconazole according to article 12 of Regulation (EC) No 396/2005. EFSA Journal 2011;9(8):2339, 96 pp. doi: /j.efsa EFSA (European Food Safety Authority), 2011b. Reasoned opinion of EFSA prepared by the Pesticides Unit (PRAS) on the modification of the existing MRLs for tebuconazole in pulses. EFSA Journal 2011;9(6):2282, 30 pp. doi: /j.efsa EFSA (European Food Safety Authority), 2011c. Conclusion of EFSA prepared by PRAPeR on the peer review of pesticide risk assessment of the active substance difenoconazole. EFSA Journal 2011;9(1):1967, 71 pp. doi: /j.efsa EFSA (European Food Safety Authority), Reasoned opinion on the modification of the existing MRLs for tebuconazole in citrus (except oranges), lettuce and other salad plants, parsley and chives. EFSA Journal 2012;10(9):2898, 37 pp. doi: /j.efsa EFSA (European Food Safety Authority), Reasoned opinion on the modification of the existing MRL for tebuconazole in poppy seed. EFSA Journal 2013;11(5):3248, 31 pp. doi: /j.efsa EFSA (European Food Safety Authority), Conclusion on the peer review of the pesticide risk assessment of the active substance tebuconazole. EFSA Journal 2014;12(1):3485, 98 pp. doi: /j.efsa FAO (Food and Agriculture Organization of the United Nations), Submission and evaluation of pesticide residues data for the estimation of Maximum Residue Levels in food and feed. Pesticide Residues. 2nd Ed. FAO Plant Production and Protection Paper 197, 264 pp. Italy, Evaluation report on the modification/deletion of MRLs for tebuconazole in cucumber and courgette prepared by the evaluating Member State Italy under Article 8 of Regulation (EC) No 396/2005, July 2014, 43 pp. Meier U, Growth Stages of mono- and dicotyledonous plants. BBCH Monograph, 2nd Ed., Federal Biological Research Centre of Agriculture and Forest. Braunschweig, Germany. OECD (Organisation for Economic Co-operation and Development), OECD MRL Calculator: spreadsheet for single data set and spreadsheet for multiple data set, 2 March In: Pesticide Publications/Publications on Pesticide Residues. EFSA Journal 2015;13(1):

19 APPENDICES Appendix A. Good Agricultural Practice (GAPS) Crop and/or situation (a) Member State or Country F G or I (b) Pests or Group of pests controlled (c) Preparation Type (d-f) Conc. as (i) Method (f-h) Application Growth stage & season (j) Number (k) Interval between applications g as/hl minmax (l) Application rate per treatment water L/ha min-max g as/ha min-max (l) PHI (days) (m) Remark Cucumber EU G Erysiphe cichoraceum, Sphaerotheca fuliginea Botritis, Cladosporium, Sclerotinia spp. EC 250 Overall spray BBCH Courgette EU G Erysiphe cichoraceum, Sphaerotheca fuliginea Botritis, Cladosporium, Sclerotinia spp. EC 250 Overall spray BBCH Remarks: (a) (b) (c) (d) (e) (f) (g) For crops, EU or other classifications, e.g. Codex, should be used; where relevant, the use situation should be described (e.g. fumigation of a structure) Outdoor or field use (F), glasshouse application (G) or indoor application (I) e.g. biting and sucking insects, soil born insects, foliar fungi, weeds e.g. wettable powder (WP), emulsifiable concentrate (EC), granule (GR) GCPF Technical Monograph No 2, 4 th Ed., 1999 or other codes, e.g. OECD/CIPAC, should be used All abbreviations used must be explained Method, e.g. high volume spraying, low volume spraying, spreading, dusting, drench (h) (i) (j) (k) (l) (m) Kind, e.g. overall, broadcast, aerial spraying, row, individual plant, between the plants - type of equipment used must be indicated g/kg or g/l Growth stage at last treatment (Growth stages of mono-and dicotyledonous plants. BBCH Monograph, 2 nd Ed., 2001), including where relevant, information on season at time of application The minimum and maximum number of application possible under practical conditions of use must be provided PHI - minimum pre-harvest interval Remarks may include: Extent of use/economic importance/restrictions (i.e. feeding, grazing) EFSA Journal 2015;13(1):

20 Appendix B. Pesticide Residue Intake Model (PRIMO) Tebuconazole Status of the active substance: Approved Code no. LOQ (mg/kg bw): 0.02 proposed LOQ: Toxicological end points ADI (mg/kg bw/day): 0.03 ARfD (mg/kg bw): 0.03 Source of ADI: EFSA Source of ARfD: EFSA Year of evaluation: 2008 Year of evaluation: 2008 Prepare workbook for refined calculations Undo refined calculations Highest calculated TMDI values in % of ADI MS Diet TMDI (range) in % of ADI minimum - maximum 3 15 No of diets exceeding ADI: --- Highest contributor to MS diet (in % of ADI) Chronic risk assessment - refined calculations Commodity / group of commodities 2nd contributor to MS diet (in % of ADI) Commodity / group of commodities 3rd contributor to MS diet (in % of ADI) Commodity / group of commodities 15 WHO Cluster diet B 2 Tomatoes 2 Wine grapes 1 Wheat DE child 5 Apples 1 Milk and milk products: Cattle 1 Tomatoes IE adult 3 Barley 2 Wine grapes 1 Grapefruit NL child 3 Apples 2 Milk and milk products: Cattle 1 Beans (with pods) WHO cluster diet E 2 Wine grapes 2 Barley 1 Wheat FR toddler 2 Beans (with pods) 1 Carrots 1 Apples FR all population 5 Wine grapes 1 Wheat 0 Tomatoes PT General population 3 Wine grapes 1 Rice 1 Tomatoes FR infant 2 Milk and milk products: Cattle 1 Beans (with pods) 1 Carrots WHO regional European diet 1 Tomatoes 1 Barley 0 Wheat WHO Cluster diet F 1 Barley 1 Wine grapes 1 Wheat ES child 1 Milk and milk products: Cattle 1 Tomatoes 1 Wheat WHO cluster diet D 1 Wheat 1 Tomatoes 1 Rice NL general 1 Barley 1 Wine grapes 1 Apples DK child 1 Apples 1 Wheat 1 Oats ES adult 1 Barley 1 Tomatoes 1 Wine grapes UK Toddler 2 Sugar beet (root) 1 Apples 1 Wheat SE general population 90th percentile 1 Milk and milk products: Cattle 1 Tomatoes 1 Wheat UK Infant 1 Apples 1 Sugar beet (root) 1 Carrots IT kids/toddler 1 Wheat 1 Tomatoes 0 Apples DK adult 2 Wine grapes 0 Apples 0 Wheat UK vegetarian 1 Wine grapes 0 Tomatoes 0 Rice UK Adult 1 Wine grapes 0 Rice 0 Tomatoes LT adult 1 Apples 0 Tomatoes 0 Swine: Meat IT adult 1 Tomatoes 1 Wheat 0 Apples PL general population 1 Apples 1 Tomatoes 0 Potatoes FI adult 0 Wine grapes 0 Tomatoes 0 Oats 0.1 ptmrls at LOQ (in % of ADI) Conclusion: The estimated Theoretical Maximum Daily Intakes (TMDI), based on ptmrls were below the ADI. A long-term intake of residues of Tebuconazole is unlikely to present a public health concern. EFSA Journal 2015;13(1):