Peer review of the pesticide risk assessment of the active substance propiconazole

Abstract

The conclusions of EFSA following the peer review of the initial risk assessments carried out by the competent authorities of the rapporteur Member State, Finland, and co‐rapporteur Member State, the United Kingdom, for the pesticide active substance propiconazole are reported. The context of the peer review was that required by Commission Implementing Regulation (EU) No 844/2012. The conclusions were reached on the basis of the evaluation of the representative use of propiconazole as a fungicide on wheat and barley. The reliable end points, appropriate for use in regulatory risk assessment are presented. Missing information identified as being required by the regulatory framework is listed. Concerns are identified.

Summary

Commission Implementing Regulation (EU) No 844/2012 (hereinafter referred to as ‘the Regulation’) lays down the procedure for the renewal of the approval of active substances submitted under Article 14 of Regulation (EC) No 1107/2009. The list of those substances is established in Commission Implementing Regulation (EU) No 686/2012. Propiconazole is one of the active substances listed in Regulation (EU) No 686/2012.

In accordance with Article 1 of the Regulation, the rapporteur Member State (RMS), Finland, and co‐rapporteur Member State (co‐RMS), the United Kingdom, received an application from Propiconazole Task Force comprised of Syngenta Crop Protection AG and Adama Agriculture B.V. for the renewal of approval of the active substance propiconazole. Complying with Article 8 of the Regulation, the RMS checked the completeness of the dossier and informed the applicants, the co‐RMS (the United Kingdom), the European Commission and the European Food Safety Authority (EFSA) about the admissibility.

The RMS provided its initial evaluation of the dossier on propiconazole in the renewal assessment report (RAR), which was received by EFSA on 7 June 2016. In accordance with Article 12 of the Regulation, EFSA distributed the RAR to the Member States and the applicants, Propiconazole Task Force comprised of Syngenta Crop Protection AG and Adama Agriculture B.V., for comments on 4 August 2016. EFSA also provided comments. In addition, EFSA conducted a public consultation on the RAR. EFSA collated and forwarded all comments received to the European Commission on 5 October 2016.

Following consideration of the comments received on the RAR, it was concluded that additional information should be requested from the applicants, and that EFSA should conduct an expert consultation in the areas of mammalian toxicology, residues and ecotoxicology.

In accordance with Article 13(1) of the Regulation, EFSA should adopt a conclusion on whether propiconazole can be expected to meet the approval criteria provided for in Article 4 of Regulation (EC) No 1107/2009 of the European Parliament and of the Council.

The conclusions laid down in this report were reached on the basis of the evaluation of the representative use of propiconazole as a fungicide on wheat and barley, as proposed by the applicants. Full details of the representative uses can be found in Appendix A of this report.

Data were submitted to conclude that the uses of propiconazole according to the representative uses proposed at European Union (EU) level result in a sufficient fungicidal efficacy against the target organisms.

A formal data gap was identified in the residue section for the RMS to present a detailed assessment of the results of the scientific peer‐reviewed open literature search in a revised RAR.

In the section identity, physical and chemical properties and analytical methods, data gaps were identified for a revised technical specification or quality control data to support the proposed specifications (Adama Agriculture B.V.), for octanol/water partition coefficient of all components of the residue definitions for risk assessment, for additional validation data for the methods used in data generation, for extraction efficiency of the multiresidue method DFG S19 in plant matrices and for a monitoring method for the determination of CGA91305 in animal matrices.

In the area of mammalian toxicology and non‐dietary exposure, data gaps were identified regarding the toxicological profile of some impurities and metabolites and further genotoxicity testing on propiconazole. An in vitro comparative metabolism study was not submitted leading to a data gap and issue that could not be finalised. Dietary and non‐dietary risk assessment of potential changes on the isomeric composition of propiconazole and its metabolites could not be finalised. The Risk Assessment Committee (RAC) of the European Chemicals Agency (ECHA) proposed classification of propiconazole for reproductive toxicity in category 1B leading to a critical area of concern concerning approval criteria and the relevance of groundwater metabolites. The potential endocrine disruption of propiconazole was identified both as an issue that could not be finalised and a critical area of concern. The lack of representativeness of batches used in toxicity studies compared to the technical specification is also leading to a critical area of concern.

In the residue section, a series of data gaps were identified and the consumer risk assessment cannot be finalised pending upon the toxicological assessment and the magnitude of all relevant compounds to be included in the residue definition for risk assessment for plants and a comprehensive livestock exposure assessment. A data gap was also identified with regard to potential residue levels of active substance and its metabolites in pollen and bee products.

For environmental fate and behaviour, data gaps were identified for: ground and surface water exposure assessment for propiconazole and metabolites SYN547889, NOA436613, CGA91305 and CGA71019 using the final agreed substance properties and information on the diastereoisomer composition with time of propiconazole in experiments in non‐sterile environmental matrices. However, the exposure assessment could be finalised at EU level using the available exposure estimations, with the exception that a data gap was identified for a refined aquatic exposure and risk assessment for metabolites SYN547889 and NOA436613. A data gap was identified for information on the effect of water treatment processes on the nature of residues of both the active substance and its identified metabolites potentially present in surface and groundwater, when surface water or groundwater are abstracted for drinking water. This gap leads to the consumer risk assessment from the consumption of drinking water being not finalised for all the representative uses. A high potential for groundwater exposure (80th percentile annual average recharge concentration moving below 1 m) above the parametric drinking water limit of 0.1 μg/L was indicated for relevant groundwater metabolites at all nine pertinent FOCUS groundwater scenarios for the representative uses assessed. This was identified as a critical area of concern.

In the area of ecotoxicology, some data gaps were identified for the bee risk assessment and as discussed above, a data gap was also identified for the aquatic risk assessment for metabolites SYN547889 and NOA436613 relating to uncertainty in enantiomer ratio exposure and possible differential enantiomer toxicity.

Background

Commission Implementing Regulation (EU) No 844/20121 (hereinafter referred to as ‘the Regulation’) lays down the provisions for the procedure of the renewal of the approval of active substances, submitted under Article 14 of Regulation (EC) No 1107/20092. This regulates for the European Food Safety Authority (EFSA) the procedure for organising the consultation of Member States, the applicant(s) and the public on the initial evaluation provided by the rapporteur Member State (RMS) and/or co‐rapporteur Member State (co‐RMS) in the renewal assessment report (RAR), and the organisation of an expert consultation where appropriate.

In accordance with Article 13 of the Regulation, unless formally informed by the European Commission that a conclusion is not necessary, EFSA is required to adopt a conclusion on whether the active substance can be expected to meet the approval criteria provided for in Article 4 of Regulation (EC) No 1107/2009 within 5 months from the end of the period provided for the submission of written comments, subject to an extension of up to 8 months where additional information is required to be submitted by the applicant(s) in accordance with Article 13(3).

In accordance with Article 1 of the Regulation, the RMS Finland and co‐RMS the United Kingdom received an application from Propiconazole Task Force comprised of Syngenta Crop Protection AG and Adama Agriculture B.V. for the renewal of approval of the active substance propiconazole. Complying with Article 8 of the Regulation, the RMS checked the completeness of the dossier and informed the applicants, the co‐RMS (the United Kingdom), the European Commission and EFSA about the admissibility.

The RMS provided its initial evaluation of the dossier on propiconazole in the RAR, which was received by EFSA on 7 June 2016 (Finland, 2016).

In accordance with Article 12 of the Regulation, EFSA distributed the RAR to the Member States and the applicants, Propiconazole Task Force comprised of Syngenta Crop Protection AG and Adama Agriculture B.V., for consultation and comments on 4 August 2016. EFSA also provided comments. In addition, EFSA conducted a public consultation on the RAR. EFSA collated and forwarded all comments received to the European Commission on 5 October 2016. At the same time, the collated comments were forwarded to the RMS for compilation and evaluation in the format of a reporting table. The applicants were invited to respond to the comments in column 3 of the reporting table. The comments and the applicants’ response were evaluated by the RMS in column 3.

The need for expert consultation and the necessity for additional information to be submitted by the applicants in accordance with Article 13(3) of the Regulation were considered in a telephone conference between EFSA, the RMS and the European Chemicals Agency (ECHA) on 22 November 2016. On the basis of the comments received, the applicants’ response to the comments and the RMS's evaluation thereof, it was concluded that additional information should be requested from the applicants, and that EFSA should conduct an expert consultation in the areas of mammalian toxicology, residues and ecotoxicology.

The outcome of the telephone conference, together with EFSA's further consideration of the comments, is reflected in the conclusions set out in column 4 of the reporting table. All points that were identified as unresolved at the end of the comment evaluation phase and which required further consideration, including those issues to be considered in an expert consultation, were compiled by EFSA in the format of an evaluation table.

The conclusions arising from the consideration by EFSA, and as appropriate by the RMS, of the points identified in the evaluation table, together with the outcome of the expert consultation and the written consultation on the assessment of additional information, where these took place, were reported in the final column of the evaluation table.

A final consultation on the conclusions arising from the peer review of the risk assessment took place with Member States via a written procedure in May–June 2017.

This conclusion report summarises the outcome of the peer review of the risk assessment of the active substance and the representative formulation, evaluated on the basis of the representative use of propiconazole as a fungicide on wheat and barley, as proposed by the applicants. A list of the relevant end points for the active substance and the formulation is provided in Appendix A.

In addition, a key supporting document to this conclusion is the peer review report (EFSA, 2017), which is a compilation of the documentation developed to evaluate and address all issues raised in the peer review, from the initial commenting phase to the conclusion. The peer review report comprises the following documents, in which all views expressed during the course of the peer review, including minority views, where applicable, can be found:

• the comments received on the RAR;

• the reporting table (23 November 2016);

• the evaluation table (6 June 2017);

• the report(s) of the scientific consultation with Member State experts (where relevant);

• the comments received on the assessment of the additional information (where relevant);

• the comments received on the draft EFSA conclusion.

Given the importance of the RAR, including its revisions (Finland, 2017), and the peer review report, both documents are considered as background documents to this conclusion and thus are made publicly available.

It is recommended that this conclusion report and its background documents would not be accepted to support any registration outside the European Union (EU) for which the applicant has not demonstrated that it has regulatory access to the information on which this conclusion report is based.

The active substance and the formulated product

Propiconazole is the ISO common name for (2RS,4RS;2RS,4SR)‐1‐[2‐(2,4‐dichlorophenyl)‐4‐propyl‐1,3‐dioxolan‐2‐ylmethyl]‐1H‐1,2,4‐triazole (IUPAC).

The representative formulated product for the evaluation was ‘A6097AF’ an emulsifiable concentrate (EC) containing 250 g/L propiconazole.

The representative uses evaluated were applications by foliar spraying against Puccinia recondita and Pyrenophora tritici‐repentis in wheat and against Pyrenophora teres and Puccinia hordei in barley. Full details of the Good Agricultural Practices (GAPs) can be found in the list of end points in Appendix A.

Data were submitted to conclude that the uses of propiconazole according to the representative uses proposed at EU level result in a sufficient fungicidal efficacy against the target organisms, following the guidance document SANCO/2012/11251‐rev. 4 (European Commission, 2014).

A scientific peer‐reviewed open literature search on the active substance dealing with side effects on health, the environment and non‐target species and published within the last 10 years before the date of submission of dossier, was submitted in accordance with the EFSA guidance on the submission of scientific peer‐reviewed open literature for the approval of pesticide active substances under Regulation (EC) No 1107/2009 (EFSA, 2011). However, for the residue section, a formal data gap has been identified as the RMS did not report in a revised RAR the full evaluation of the comprehensive assessment of the results of scientific peer‐reviewed open literature search conducted by the applicant in accordance with the EFSA guidance.

1. Identity, physical/chemical/technical properties and methods of analysis

The following guidance documents were followed in the production of this conclusion: SANCO/3029/99‐rev. 4 (European Commission, 2000a), SANCO/3030/99‐rev. 4 (European Commission, 2000b), SANCO/10597/2003‐rev. 10.1 (European Commission, 2012), SANCO/825/00‐rev. 8.1 (European Commission, 2010) and SANCO/10054/2013‐rev. 3 (European Commission, 2013).

Propiconazole consists of two diastereomeric pairs of enantiomers. The substance considered in the peer review had a range of the cis/trans isomer ratio of 1.25–1.6 (55.5–61.5% cis of pure propiconazole). Both Syngenta and Adama proposed their own specifications. It should be noted however that Adama proposed two different technical specifications. The new proposed specifications for propiconazole are based on batch data from industrial scale production. The minimum purity of the active substance as manufactured is 950 g/kg for both members of the task force. The specifications for some impurities were not supported by batch data in the case of Adama, as a consequence a data gap was identified for a revised technical specification or quality control data to support the proposed specifications. The minimum purity meets the requirements of the FAO specification available for propiconazole (FAO specification 408/TC/S/F in FAO, (1995)) of not less than 880 g/kg propiconazole, developed under the old procedure.

The assessment of the data package revealed no issues that need to be included as critical areas of concern with respect to the identity, physical, chemical and technical properties of propiconazole or the representative formulation. A data gap was identified for the octanol/water partition coefficient of all components of the residue definition for risk assessment (see Sections 3 and 4). The main data regarding the identity of propiconazole and its physical and chemical properties are given in Appendix A.

Adequate analytical methods are available for the determination of propiconazole in the technical material and in the representative formulation. The available validation data for the methods used in data generation were not meeting completely the requirements of the guidance document (European Commission, 2000a), as a consequence a data gap was identified for additional data.

Propiconazole residues can be monitored in food and feed of plant origin by the extended multiresidue method DFG S19 using liquid chromatography with tandem mass spectrometry (LC–MS/MS) in all commodity groups with a limit of quantification (LOQ) of 0.01 mg/kg. A data gap was however identified for the determination of the extraction efficiency of DFG S19 in plant matrices. The residue definition for monitoring in food of animal origin was defined as metabolite CGA91305 (free and conjugated, see Section 3), as a consequence a data gap was identified for a monitoring method in animal matrices.

Residues of propiconazole in soil, water and air can be monitored by LC–MS/MS with LOQs of 1 μg/kg, 0.05 μg/L and 1.2 μg/m³, respectively.

Propiconazole residues in body tissues can be determined by the multiresidue method DFG S19, using LC–MS/MS with a LOQ of 0.01 mg/kg, while monitoring in body fluids can be done by the Quick, Easy, Cheap, Effective, Rugged, and Safe (QuEChERS) multiresidue method using LC–MS/MS with a LOQ of 0.01 mg/kg in blood and 0.05 mg/L in urine.

2. Mammalian toxicity

The toxicological profile of the active substance propiconazole and its metabolites was discussed at the Pesticides Peer Review Experts’ Meeting 155 and assessed based on the following guidance documents: SANCO/221/2000‐rev. 10‐final (European Commission, 2003a), SANCO/10597/2003‐rev. 10.1 (European Commission, 2012), Guidance on Dermal Absorption (EFSA PPR Panel, 2012) and Guidance on the Application of the CLP Criteria (ECHA, 2015).

The batches used in toxicity studies were not representative of the Syngenta technical specification leading to a critical area of concern. For impurities, no sufficient information is available to exclude their relevance from the toxicological point of view. The representativeness of the toxicity studies compared to the technical specifications (as proposed by Adama) should be reconsidered once the data gap identified in Section 1 is fulfilled.

In the toxicokinetics studies, propiconazole was extensively and rapidly absorbed. Bioavailability is approximately 91%. There was no evidence for accumulation. Excretion of substance was predominantly through the bile route but with appreciable amounts excreted in urine. The main metabolic pathway identified was oxidation, cleavage and hydroxylation reactions. It is unknown whether unique human metabolites might be formed since an in vitro comparative metabolism study was not submitted leading to a data gap and issue that could not be finalised.

In the acute toxicity studies, the substance has low acute toxicity when administered dermally or by inhalation and moderate acute toxicity when administered orally to rats. It is not a skin or eye irritant but a skin sensitiser. A phototoxicity and photogenotoxicity test is not required for propiconazole.

In short‐term oral toxicity studies, the target organ of toxicity was the liver in rats and mice, whereas the pituitary might be considered the target organ of toxicity in dogs. The relevant short‐term oral no observed adverse effect level (NOAEL) is 2.7 mg/kg body weight (bw) per day (17‐week mouse study).

The genotoxic potential of propiconazole was discussed during the experts’ meeting. No evidence of mutagenicity was observed in available in vitro and in vivo genotoxicity studies. However, there were some uncertainties regarding the clastogenic and aneugenic potential of propiconazole. The design of the in vitro clastogenicity assay showed some limitations and in the in vivo micronucleus test some experts including the RMS considered that there was no clear evidence that the bone marrow was reached in sufficient amount. EFSA considered that overall, available information suggests no evidence of genotoxicity of propiconazole. However, the experts considered that the submission of a new in vitro micronucleus test will decrease the uncertainties regarding the clastogenic and aneugenic endpoint and strengthen the genotoxicity data package on propiconazole (data gap).

In long‐term toxicity and carcinogenicity studies, the target organ of toxicity was adrenals in rats and liver in mice. The rat was the most sensitive species. The relevant long‐term NOAELs are 3.6 mg/kg bw per day for the rat and 10 mg/kg bw per day for the mouse. Propiconazole induced liver tumours in male CD‐1 mice at dose levels of 107.8 and 344.3 mg/kg bw per day. No discussion on classification for carcinogenicity took place during the experts’ meeting. The Risk Assessment Committee (RAC) of ECHA considered that overall available information suggests that the liver tumours found in mice after exposure to propiconazole is not of concern for humans and that no classification for carcinogenicity of propiconazole is warranted (ECHA, 2016).

In the two‐generation study, propiconazole showed reproductive toxicity (i.e. decreased litter size and decreased number of pups delivered viable) at higher dose levels than those producing parental toxicity. The agreed parental NOAEL is 8.4 mg/kg bw per day, whereas the reproductive and offspring NOAELs are 43.7 mg/kg bw per day. In the developmental toxicity studies, the relevant maternal NOAELs are 30 mg/kg bw per day for the rat and 100 mg/kg bw per day for the rabbit. Based on skeletal variations and cleft palate in rat and increased incidence of fully formed 13th rib, increased incidence of resorptions, abortions and early deliveries in rabbit, the developmental NOAELs are 30 mg/kg bw per day for the rat and 250 mg/kg bw per day for the rabbit. No discussion on classification for reproductive toxicity took place during the experts’ meeting. The RAC of ECHA adopted an opinion on proposed harmonised classification of propiconazole as toxic for reproduction category 1B (H360D): May damage the unborn child (ECHA, 2016). A critical area of concern is identified with regard to the approval criteria of Annex II, Point 3.6.4 of Regulation (EC) No 1107/2009.

The applicant did not submit neurotoxicity studies, however, no potential for neurotoxicity was observed in the standard toxicity studies.

Propiconazole is proposed to be classified as toxic for reproduction category 1B by the RAC of ECHA, in accordance with the provisions of Regulation (EC) No 1272/2008, and toxic effects on the endocrine organs have been observed in the available data. Should the second interim provision of Annex II, Point 3.6.5 of Regulation (EC) No 1107/2009 applicable to category 1B, propiconazole may be considered to have endocrine disrupting properties, leading to a critical area of concern. Regarding the scientific risk assessment the majority of the experts agreed that given the positive results in vitro for oestrogen and androgen receptor antagonism, AhR agonism and aromatase inhibition and in the absence of a full investigation of the possibly related endpoints in the two‐generation study (in particular the lack of sperm parameters), the possibility that propiconazole is an endocrine disruptor cannot be excluded. Given the uncertainties described above, EFSA would propose a data gap for further investigation of the endocrine disruption potential of propiconazole on male reproductive toxicity including a complete sperm analysis leading to an issue that could not be finalised.

The re‐assessment of the toxicological profile of propiconazole leads to a revision of the existing acute reference dose (ARfD; European Commission, 2003b). An ARfD of 0.3 mg/kg bw was set during the first review on the basis of developmental toxicity in rats. The experts agreed to maintain the same starting point, i.e. developmental NOAEL of 30 mg/kg bw per day for developmental toxicity observed at 90 mg/kg bw per day in the developmental toxicity study in rats. A standard uncertainty factor (UF) of 100 was applied during the first review. The experts agreed to apply an additional UF of 3 to the standard UF of 100 to provide a margin of safety of 900 relative to the lowest observable adverse effect level (LOAEL) for developmental toxicity in rats. The resulting ARfD is 0.1 mg/kg bw. The experts agreed to set an acute acceptable operator exposure level (AAOEL) of 0.1 mg/kg bw on the same basis than the ARfD. No correction factor for oral absorption is needed to derive the AAOEL.

The acceptable daily intake (ADI) set during the first review was 0.04 mg/kg bw per day (rounded value). The experts agreed to maintain it. The ADI is based on the relevant long‐term NOAEL of 3.6 mg/kg bw per day in the 2‐year study in rats based on adrenal toxicity at 18.1 mg/kg bw per day. An UF of 100 was applied.

The systemic acceptable operator exposure level (AOEL) set during the first review was 0.1 mg/kg bw per day on the basis of parental toxicity in the two‐generation study in rats. The experts agreed to base it on the same basis, i.e. the relevant parental NOAEL of 8.6 mg/kg bw per day in the two‐generation study in rats based on liver toxicity at 48.8 mg/kg bw per day. An uncertainty factor of 100 was applied. No correction factor for oral absorption is needed to derive the AOEL. The resulting value for the AOEL is 0.08 mg/bw per day. EFSA considered appropriate to round the value to 0.1 mg/kg bw per day as it was done during the first review for the AOEL and on the same basis.

The RMS estimated non‐dietary exposure (i.e. operator, worker, bystander and resident) considering dermal absorption values of propiconazole in ‘A6097AF’ of 5% for the concentrate and of 8% for the dilution as input values. The RMS assessed the representative use as fungicide in cereals. The operator exposure was below the AOEL (54%3 of the AOEL) without the use of personal protective equipment (PPE) according to the German Model. Re‐entry worker exposure (crop inspection) was below the AOEL without the use of PPE (2.5% of the AOEL). Bystander and resident exposure was below the AOEL (maximum 1% of the AOEL; child bystander; 10 m buffer zone4).

An issue that could not be finalised is identified regarding non‐dietary and dietary (see Section 3) risk assessment of potential changes on the isomeric composition of propiconazole and its metabolites.

The toxicological profile of metabolites was discussed during the experts’ meeting. The majority of experts agreed that weight of evidence suggested that metabolites SYN547889, NOA436613 and CGA91305 are unlikely to be genotoxic. The experts noted that the negative in vivo micronucleus test on CGA91305 showed deviations according to the OECD guideline and proposed a data gap for further analysis of the results of the test. No conclusion on genotoxicity could be drawn for CGA118244 (clastogenicity and aneugenicity not addressed), CGA91304 and CGA118245. No conclusion on general toxicity could be drawn for any of the metabolites.

Data gaps on the genotoxicity potential and toxicological profile of CGA118244 and CGA91305 (as residues) are identified following the discussion on see Section 3 (see specific data gaps in Section 7). Both metabolites are included in the residue definition for risk assessment in livestock, whereas CGA118244 (free and conjugated) is also included in the residue definition for risk assessment in primary crops (see Section 3). Further toxicity data on metabolites SYN547889 and NOA436613 as residues might be needed pending the data gap on rotational crops (see Section 3). During the experts’ meeting, no discussion on triazole common metabolites (see Section 3) took place since confirmatory data are ongoing (United Kingdom, 2016) and (EFSA, 2016) leading to an issue that could not be finalised. Metabolites SYN547889, NOA436613 and CGA91305 are predicted to occur in groundwater above 0.1 μg/L (see Section 4). Groundwater metabolites are considered relevant since it cannot be excluded that the metabolites share the reproductive toxicity potential of propiconazole leading to a critical area of concern.

3. Residues

The assessment in the residue section is based on the OECD guidance document on overview of residue chemistry studies (OECD, 2009), the OECD publication on maximum residue level (MRL) calculations (OECD, 2011), the European Commission guideline document on MRL setting (European Commission, 2011) and the Joint Meeting on Pesticide Residues (JMPR) recommendations on livestock burden calculations (JMPR, 2004, 2007).

Propiconazole was discussed at the Pesticides Peer Review experts’ Meeting 156.

A formal data gap was identified in the residue section for the RMS to report the full assessment of the results of the scientific peer‐reviewed open literature search in a revised RAR.

Metabolism of propiconazole was investigated after foliar applications in fruit (grapes), cereals and grass crops (wheat, rice), pulses and oilseeds crops (peanuts) using propiconazole ¹⁴C‐labelled in the substituted phenyl ring and on the triazolyl ring and on root crops (carrot) and leafy crops (celery) using propiconazole ¹⁴C‐labelled on phenyl ring. Propiconazole was the main component of the total radioactive residues (TRR) in grapes (22.7% TRR), rice (grain and rest of the plant) (27.7–72.6% TRR), carrot (root and leaves) (56–91.2% TRR) and in celery (whole plant) (95% TRR).

For the ¹⁴C‐phenyl labelled treated crops, CGA118244 under its free and glucoside conjugated form was present as the pertinent metabolite of the total residues in wheat whole plant (38% TRR), wheat grain (32.4% TRR) and straw (19.6% TRR) and in carrot leaves only (12.4% TRR). CGA91304 metabolite accounted for 33% TRR in grapes only. For the triazolyl labelling form, the CGA131013 (TA) compound was found predominantly in grape juice (44.2% TRR), in wheat grain (53.8% TRR), in peanuts (50% TRR) and in rice grain (22% TRR) while the conjugates of CGA142856 (TAA) were recovered at significant proportions in rice grain only (35.3% TRR). It is noted that the metabolism data in wheat forage did not enable the identification of a predominant compound in the bulk of metabolites that accounted for 42–64% TRR (CGA91304, CGA118244, CGA118245, conjugates of CGA136735). Overall, the metabolic picture is consistent and qualitatively comparable across the different categories of crops.

Based on the metabolism data in primary crops, propiconazole was the pertinent compound of the residues in fruit crops, root crops and leafy crops while it was not recovered in wheat grain. Considering the predominant compounds recovered in rice grain (CGA131013 (TA) and CGA142856 (TAA)) and in wheat grain (CGA131013 (TA) and conjugates of CGA118244), the experts discussed the need to include these compounds as potential markers specifically for cereal grain. It is, however, noted that CGA131013 (TA) and CGA142856 (TAA) compounds are not specific to propiconazole. Furthermore and from the residue trials compliant with the representative uses on barley and wheat propiconazole residues above the LOQ of the method were found in barley grain and straw supporting that propiconazole alone can be considered as a relevant marker for residue monitoring in primary crops. The majority of the experts therefore agreed to set the residue definition for monitoring as ‘propiconazole (sum of isomers)’ for all categories of crops. A minority opinion proposed to consider for monitoring purposes either ‘the total propiconazole, including all compounds convertible to the 2,4‐dichlorobenzoic acid moiety and expressed as propiconazole equivalents’ or ‘propiconazole and CGA118244 (free and conjugated)’. For risk assessment, the majority opinion was to derive the residue definition as:

1. propiconazole (sum of isomers);

2. CGA118244 free and glucoside conjugated – whether the parent compound and this compound have to be considered together or separately is pending upon the submission of toxicological data to address the toxicity profile of CGA118244 (see data gap in Section 2);

3. CGA142856 (TAA) and CGA131013 (TA), using the toxicological reference values that will be agreed in the framework of the confirmatory data (United Kingdom, 2016) and (EFSA, 2016).

A minority opinion was in favour of a residue definition as ‘the total propiconazole, including all compounds convertible to the 2,4‐dichlorobenzoic acid moiety and expressed as propiconazole equivalents’. The experts unanimously agreed that these triazole metabolites should be included in the residue definition for risk assessment. Therefore, sufficient field residue trials, respectively, on wheat and barley and analysing for the magnitude of residues of, respectively, CGA118244 (free and conjugated) and the relevant triazole metabolites (CGA142856 (TAA) and CGA131013 (TA)) should be provided in order to finalise the risk assessment residue definition in plants (data gap).

A confined rotational crop metabolism study was conducted with a bare soil application of propiconazole labelled on the phenyl and triazolyl ring, respectively, at a dose rate of application of 510 g a.s./ha (4N rate) without ploughing. Lettuce, radish and wheat were planted at different plant back intervals (PBIs) (30, 120 and 270 days). Propiconazole was recovered at a trace level (< 0.01 mg eq/kg) in all crop parts at all PBIs, except in immature lettuce at 30‐day PBI (13.2% TRR; 0.041 mg eq/kg) while CGA118244 conjugates accounted for a maximum level of 11.5% TRR (0.011 mg eq/kg) in mature lettuce at 30‐day PBI. A preferential uptake of the major soil metabolites was observed with the occurrence of SYN547889 (20–51.5% TRR), NOA436613 (16.5–39% TRR) and CGA91305 (11.5–36.5% TRR); all these compounds were present under their free and conjugated forms. Besides, the triazole derivative metabolites (CGA131013 (TA), CGA142856 (TAA) and CGA205369 (TLA)) were also recovered at significant proportions in all crop parts with up to 89% TRR for CGA131013 (TA), 50% TRR for CGA142856 (TAA) and up to 73% TRR for CGA205369 (TLA). Hence, the metabolic pathway in the rotational crops is not deemed to be similar to that depicted in the primary crops and is mainly driven by the uptake of major soil metabolites. Since the residue definitions for rotational crops cannot be confidently concluded based on the available data, a data gap was set to conduct rotational crops field trials on leafy crops, root crops and small grain crops to address the magnitude of the free and conjugated forms of SYN547889, NOA436613, CGA91305 and the relevant triazole metabolites, considering the persistence of these compounds (data gap). Meanwhile, the residue definitions for rotational crops remain open.

Although propiconazole labelled on the triazole moiety was shown to be stable under the standard hydrolysis conditions representative of pasteurisation, baking/brewing/boiling and sterilisation, a data gap was set to address the nature of the residues for all compounds included in the residue definition for risk assessment in primary crops at processing and in accordance with the current data requirement. Meanwhile, the risk assessment residue definition for processed commodities remains open.

Seven and eight residue trials on barley and compliant respectively with the northern Europe (NEU) and southern Europe (SEU) critical Good Agricultural Practices (cGAPs) were submitted. For the wheat use, seven residue trials compliant, respectively, with the NEU and SEU cGAPs were provided, determining residues of parent propiconazole only. The proposed MRLs on these crops should be regarded as provisional considering the outstanding data on the toxicity and the magnitude of the pertinent metabolites included in the residue definition for risk assessment for primary crops. The field residue trials are supported by acceptable storage stability data for propiconazole demonstrated to be stable for up to 24 months in barley grain, sugar beet roots and tops, apples and for up to 30 months in soya bean seeds. Storage stability data for propiconazole residues in cereal straw were not provided and are requested (data gap). Furthermore, storage stability data covering the maximum storage time period of the requested residue trials analysing for the relevant compounds both in primary crops and in rotational crops are requested (data gap).

Metabolism in livestock (laying hens and lactating goats) was investigated with propiconazole labelled on the phenyl and triazolyl ring, respectively. The predominant compounds of the total residues in poultry and ruminant matrices were CGA91305 (free and conjugated) (up to 80% TRR) and CGA118244 (up to 51% TRR). The triazole derivative metabolite (CGA71019 (1,2,4‐triazole)) also occurred at significant proportions in all matrices (17–87.6% TRR). The parent compound was recovered at very low proportions mainly in liver, kidney and muscle (2–14% TRR), at a level up to 40% TRR and 27% TRR in fat and eggs, respectively, while it was not detected in milk. Based on the overall metabolic pattern, the experts agreed that CGA91305 is a valid residue marker in animal commodities and the residue definition for monitoring was set as ‘CGA91305 (free and conjugated)’. For risk assessment, the residue definition was derived as:

1. propiconazole, CGA91305 (free and conjugated) and CGA118244 – the way the residue definition will be expressed is pending upon the requested toxicological profile of CGA91305 and CGA118244 (See Section 2);

2. CGA71019 (1,2,4‐triazole).

Ruminants and poultry feeding studies were conducted with propiconazole and analysing for propiconazole and for total propiconazole (propiconazole and its metabolites containing the 2,4‐dichlorobenzoic acid moiety) only, while the magnitude of CGA91305 (free and conjugated), CGA118244 and CGA71019 in animal matrices was not addressed. Since quantifiable residue levels cannot be excluded both in poultry and ruminant matrices based on the preliminarily dietary burden calculation in regard to propiconazole residues in cereal grain and straw, these studies are not acceptable and new ruminants and poultry feeding studies analysing for all the pertinent compounds included in the livestock residue definition are requested (data gap). It is also acknowledged that pending upon the outcome of the outstanding data on the magnitude of the pertinent compounds identified in primary and rotational crops, their toxicity and whether these compounds significantly contribute to the livestock dietary burden, their potential transfer in animal matrices may need to be further investigated in the feeding studies (data gap).

The dietary burden calculation for fish should be provided to decide on whether a fish metabolism study is needed as this is a data requirement (data gap).

A data gap was also identified with regard to potential residue levels for the active substance and its metabolites in pollen and bee products.

For the time being, a consumer risk assessment through dietary intake can only be provisionally conducted for parent propiconazole and for plant matrices only as MRLs for animal commodities cannot be derived based on the current assessment. Using the EFSA Pesticide Residues Intake Model (PRIMo) model, long‐term and short‐term intake concerns were not identified for the consumers since the highest chronic and acute intakes were estimated to be < 1% of the ADI (WHO Cluster diet B) and < 1% of the ARfD (wheat), respectively. However, the consumer risk assessment cannot be finalised considering the outstanding data on the toxicological assessment and the magnitude of the relevant compounds to be included in the residue definition for risk assessment in plants and to perform a comprehensive livestock exposure assessment. It is also highlighted that chiral analysis of residues was not conducted and no information is available on the potential isomeric degradation of propiconazole and metabolites in plant and animal matrices (data gap). This provides an additional uncertainty with regard to the consumer exposure assessment.

The residue definition for risk assessment for plants and the residue definitions for enforcement and risk assessment for animal matrices have been changed compared to those used in the review of the existing MRLs for propiconazole (EFSA, 2015). A revision of the MRLs under article 12 may be necessary considering the outcome of the outstanding data to finalise the residue definition for risk assessment in plants and the livestock exposure assessment. In addition, the ARfD (0.1 mg/kg bw) for propiconazole that has been derived during the peer review has been reduced compared to the ARfD (0.3 mg/kg bw) that was used at the time of the review of the existing MRLs for propiconazole. An acute intake concern cannot be excluded when the CXLs for peaches and tomatoes are included in the consumer dietary intake calculation and considering the agreed ARfD of 0.1 mg/kg bw (international estimated short‐term intake (IESTI) = 130% ARfD and 102% ARfD, respectively).

4. Environmental fate and behaviour

The rates of dissipation and degradation in the environmental matrices investigated were estimated using FOCUS (2006) kinetics guidance. While the analytical (non chiral chromatographic) methods used in these investigation should have provided the possibility of separating diastereoisomer pairs of propiconazole (due to their different physical properties), even the two diastereoisomers were not resolved by the chromatography used in the available studies. Consequently, propiconazole analytical results were only available as the sum of all four isomers. The provision of information on the diastereoisomer composition with time of propiconazole in experiments in non‐sterile environmental matrices has been identified as a data gap (see Section 7), but did not result in an assessment not finalised for parent propiconazole, due to the margins between hazard endpoints and predicted environmental concentrations (PEC) indicated in the available environmental risk assessments (see Section 5). For the first transformation, product of each parent isomer results for each diastereoisomer pair were reported separately and ascribed different compound codes (SYN547889 and NOA436613). Chiral separations or chiral detectors were not used so levels determined were always sum of enantiomers (SYN547889, NOA436613 and subsequent metabolite SYN547889). In soil laboratory incubations under aerobic conditions in the dark, propiconazole (sum of four isomers) exhibited moderate to high persistence, forming the major (> 10% applied radioactivity (AR)) metabolites SYN547889 (max. 15.4% AR sum of enantiomers), NOA436613 (max. 12.3% AR sum of enantiomers), CGA91305 (max. 8.0% AR sum of enantiomers), which exhibited moderate to very high persistence and metabolite 1,2,4‐triazole (CGA71019, max. 43% AR), which exhibited low to moderate persistence. Mineralisation of the triazole ring ¹⁴C radiolabel to carbon dioxide accounted for 34% AR after 181 days. The formation of unextractable residues (not extracted by acetonitrile/water) for this radiolabel accounted for 3.4–47.3% AR after 120 days. Mineralisation of the phenyl ring ¹⁴C radiolabel to carbon dioxide accounted for 29.3–35.4% AR after 84 days. The formation of unextractable residues (not extracted by acetonitrile/water) for this radiolabel accounted for 23.3–27.3% AR after 84 days. In anaerobic soil incubations, propiconazole was essentially stable. Propiconazole exhibited medium to low mobility in soil. Metabolites SYN547889 and NOA436613 (diastereoisomers of each other) exhibited very high soil mobility, CGA91305 exhibited high to medium soil mobility and metabolite CGA71019 exhibited very high to medium soil mobility. It was concluded that the adsorption of propiconazole and its metabolites was not pH dependent.

In field dissipation studies carried out at four sites in Germany, one in Spain and one in Italy (spray application to the soil surface on bare soil plots in late spring) propiconazole (sum of isomers) exhibited low to medium persistence. However, the field studies were conducted in sites where grass was sown immediately prior to the application and allowed to develop and therefore plant uptake could not be completely discounted. On balance, any degradation endpoints coming from the field studies were considered unreliable. Consequently, only dissipation endpoints were derived from these studies. For metabolite 1,2,4‐triazole (CGA71019), field degradation endpoints from the triazole task force were used in assessments (endpoints were those already published in the EFSA (2013a) conclusion for ipconazole).

In laboratory incubations in dark aerobic natural sediment water systems, propiconazole (sum of isomers) exhibited very high persistence forming no major metabolites (> 5% AR). The unextractable sediment fraction (not extracted by acetonitrile/water) for the triazole ring ¹⁴C radiolabel accounted for 7.6–9.1% AR at the study end (after 175 days). Mineralisation of this radiolabel accounted for only 0.4% AR at the end of the study (after 175 days). The rate of decline of propiconazole in a laboratory sterile aqueous photolysis experiment was slow relative to that occurred in the aerobic sediment water incubations. No chromatographically resolved component (excluding propiconazole) accounted for > 10% AR.

The necessary surface water and sediment exposure assessments ((PEC) calculations) were carried out for the enantiomer pair metabolites SYN547889, NOA436613 and CGA91305 as well as 1,2,4‐triazole (CGA71019), using the FOCUS (2001) Step 1 and Step 2 approach (version 2.1 of the Steps 1–2 in FOCUS calculator). For the active substance propiconazole (sum of isomers), in addition to steps 1 and 2 calculations, appropriate step 3 (FOCUS, 2001) calculations were available.5 As margins in the toxicity exposure ratio (TER) calculations for aquatic organisms did not cover an additional factor of 2 to cover uncertainty of possible differential toxicity between the enantiomers of metabolites SYN547889 and NOA436613, a data gap was identified for a refined risk assessment (see Sections 5 and 7).

The necessary groundwater exposure assessments were carried out using FOCUS (2009) scenarios and the models PEARL 4.4.4, PELMO 5.5.35 for propiconazole and its metabolites SYN547889, NOA436613, CGA91305 and 1,2,4‐triazole (CGA71019). Two sets of calculations were performed using annual application and biennial application. The potential for groundwater exposure from the representative uses by propiconazole and metabolite 1,2,4‐triazole (CGA71019) above the parametric drinking water limit of 0.1 μg/L was concluded to be low in geoclimatic situations that are represented by all nine FOCUS groundwater scenarios. For representative uses on winter cereals, the 80th percentile annual average recharge concentrations leaving the top 1 m soil layer were estimated to be > 0.1 μg/L at eight out of nine scenarios for metabolites SYN547889 and CGA091305 and all nine scenarios for metabolite NOA436613, considering annual application. These concentrations leaving the top 1 m soil layer were estimated to be > 0.1 μg/L at eight out of nine scenarios for metabolite SYN547889, two out of nine scenarios for CGA091305 and all nine scenarios for metabolite NOA436613 considering biennial applications. For representative uses on spring cereals, these concentrations leaving the top 1 m soil layer were estimated to be > 0.1 μg/L at all six scenarios for metabolite SYN547889 and NOA436613 and five out of six scenarios for CGA091305, considering annual application. While these concentrations leaving the top 1 m soil layer were estimated to be > 0.1 μg/L at all six scenarios for metabolite SYN547889 and NOA436613 and two out of six scenarios for CGA91305, considering biennial applications.

It should be noted that the ground and surface water exposure assessment for propiconazole and metabolites SYN547889, NOA436613, CGA091305 and CGA71019 was not updated considering the degradation endpoints agreed during the peer review; therefore, a data gap was identified for this to be done (see Section 7). The available (slightly incorrect) PEC values were used as the basis of this conclusion.

The applicant did not provide appropriate information to address the effect of water treatment processes on the nature of the residues that might be present in surface water and groundwater, when surface water or groundwater are abstracted for drinking water. This has led to the identification of a data gap (see Section 7) and results in the consumer risk assessment not being finalised (see Section 9).

The PEC in soil, surface water, sediment, and groundwater covering the representative uses assessed can be found in Appendix A of this conclusion.

5. Ecotoxicology

The risk assessment was based on the following documents: European Commission (2002a,b), SETAC (2001), EFSA (2009), EFSA PPR Panel (2013) and EFSA (2013c). According to Commission Regulation (EU) No 283/20136, data should be provided regarding the acute and chronic toxicity to honeybees and data to address the development of honeybee brood and larvae. As the European Commission (2002a) does not provide a risk assessment scheme which is able to use the chronic toxicity data for adult honeybees and the honeybee brood, when performing the risk assessment according to European Commission (2002a), the risk to adult honeybees from chronic toxicity and the risk to bee brood, could not be finalised due to the lack of a risk assessment scheme. Therefore, the EFSA (2013c) was used for risk assessment in order to reach a conclusion for the representative uses.

The endpoint used for the wild mammals long‐term risk assessment was discussed and agreed at the Pesticide Peer Review Meeting 157 (April 2017). Based on the available data and risk assessment, a low acute and long‐term risk via dietary exposure to birds and wild mammals was concluded for all representative uses of propiconazole. A low risk for both birds and wild mammals was also concluded from secondary poisoning and from exposure via contaminated water.

A low acute and chronic risk to all aquatic organisms was concluded for all representative uses of propiconazole using PEC_sw calculated with FOCUS Steps 1–2. However, propiconazole is constituted by four stereoisomers and no information on specific toxicity or exposure is available (see Sections 1 and 4). The worst‐case scenario would be to consider that both the toxicity and the exposure are due to a single isomer; therefore, a further factor of 4 would be needed to cover for this uncertainty. The uncertainty is not covered using PEC_sw at FOCUS Step 2, but is covered using the highest calculated PEC_sw at FOCUS Step 3.

The acute risk assessment for the pertinent metabolites (i.e. SYN547889, NOA436613, CGA91305 and CGA71019) was carried out using the available experimental data. For the chronic risk, a screening assessment was performed by considering the metabolites ten times more toxic than the parent. Based on TER values, a low acute and chronic risk was indicated for all pertinent metabolites. Nevertheless, the metabolites, SYN547889 and NOA436613, are constituted by couples of isomers, for which no specific information is available regarding both exposure and effects. The uncertainty would be covered if the TER would be greater than the trigger by an additional factor of 2. Using the available PEC_sw at FOCUS Step 2, the uncertainty is not covered; therefore, a data gap was identified. For the assessment of the endocrine disruptive potential of propiconazole to fish, please see the relevant paragraph below.

The RMS has assessed the risk to honeybees in accordance with EFSA (2013c). A low risk to adult (acute oral, acute contact and chronic) and to larvae honey bees was concluded at the screening step for all representative uses of propiconazole. The risk assessment for consumption of contaminated water was not performed (data gap). No assessment was available for effects on hypopharyngeal glands (HPG) (data gap). No assessment for accumulative effects was available. No information was available regarding metabolites occurring in pollen and nectar. Therefore, a data gap was identified.

No data were available for bumblebees and solitary bees.

Tier I data were available for four species of non‐target arthropods. The hazard quotients (HQs) based on these studies were all below the trigger value for in‐field and off‐field. No reliable tier I endpoint was available for Typhlodromus pyri. Nevertheless, tier II (aged residue) studies were conducted with Aphidius rhopalosiphi and T. pyri. A field study carried out on predatory mite populations in a Portuguese orchard was also available. No significant treatment‐related effects were observed in this study. Based on all the available studies, a low risk was concluded for all representative uses of propiconazole.

Experimental data for propiconazole and all the pertinent soil metabolites (i.e. SYN547889, NOA436613, CGA91305 and CGA71019) were available for earthworms, other soil macroorganisms, and soil microorganisms. On the basis of these data, a low risk was concluded for propiconazole and its metabolites. A low risk was also concluded for non‐target terrestrial plants and biological methods of sewage treatment.

Based on the available data in vitro and in vivo on mammals, no final conclusion on the endocrine disruption potential of propiconazole was achieved in Section 2. In the ecotoxicology section, no further relevant data were available for birds, but some relevant information was available for fish (two full life cycle studies, one short‐term reproductive assay and one short‐term literature studies). Positive and consistent mechanistic in vitro data on different cell lines suggested that propiconazole acts as an aromatase inhibitor. In vivo measurements of oestradiol level (E2) levels were available in one short‐term literature study, where a rather clear dose‐dependent reduction of this parameter was seen. In the same study and in other two studies, exposure to propiconazole caused a reduction of vitellogenin levels in females and histopathological effects in gonads, followed by a reduction in fecundity (egg production). Dose concordance and consistency among all the available data was observed. The potential for endocrine disrupting activity of propiconazole was discussed at the Pesticide Peer Review Meeting 157. The available evidence was found to be broadly in line with the ‘adverse outcome pathway on aromatase inhibition leading to reproductive dysfunction in fish’, as defined by the OECD (Villeneuve, 2016). Overall, the experts agreed that endocrine disruptive properties of propiconazole to fish cannot be excluded.

It has to be noted that a low chronic risk to fish was demonstrated for all the representative uses of propiconazole by using the lowest available endpoint based on fecundity, which is the apical effect related to the assumed pathway.

The impurity content for some batches used in old ecotoxicological test is not known, therefore the compliance with the technical specification cannot be assessed (data gap).

6. Overview of the risk assessment of compounds listed in residue definitions triggering assessment of effects data for the environmental compartments (Tables 1–4)

Table 1.

Soil

Compound (name and/or code)	Persistence	Ecotoxicology
Propiconazole	Moderate to high persistence Single first‐order and bi‐phasic kinetics DT50 28.0–131 days (DT90 92.9 – > 1,000 days; laboratory conditions at 25–20°C, 40% MWHC 60–75% FC – pF2) EU field dissipation studies biphasic kinetics DT50 6.18–96.3 days	Low risk to soil organisms
SYN547889	Moderate to very high persistence Single first‐order DT50 16.8–1,000 days (DT90 55.7–234 days; laboratory conditions at 20°C, pF2)	Low risk to soil organisms
NOA436613	Moderate to very high persistence Single first‐order DT50 19.2–1,000 days (DT90 63.9–461 days; laboratory conditions at 20°C, pF2)	Low risk to soil organisms
CGA91305	Moderate to very high persistence Single first order DT50 10.5–1,000 days (DT90 34.9–265 days; laboratory conditions at 20°C, pF2)	Low risk to soil organisms
1,2,4‐triazole (CGA71019)	Low to moderate persistence EU field dissipation studies biphasic kinetics DT50 6.8–28.1 days (DT90 109.3–366.7 days; laboratory conditions at 20°C)	Low risk to soil organisms

DT₅₀: period required for 50% dissipation; DT₉₀: period required for 90% dissipation; MWHC: maximum water‐holding capacity.

Table 4.

Air

Compound (name and/or code)	Toxicology
Propiconazole	Rat LC50 inhalation > 5.8 mg/L air/4 h (nose only)

LC₅₀: lethal concentration, median.

Table 2.

Groundwater

Compound (name and/or code)	Mobility in soil	> 0.1 μg/L at 1 m depth for the representative usesa	Pesticidal activity	Toxicological relevance
Propiconazole	Medium to low mobility KFoc 387–1,817 mL/g	No	Yes	Yes
SYN547889	Very high mobility KFoc 23.0–48.7 mL/g	Yes 8/9 FOCUS scenarios	No	Yes (it cannot be excluded that it shares the reproductive toxicity potential of propiconazole; unlikely to be genotoxic)
NOA436613	Very high mobility KFoc 14.9–29.2 mL/g	Yes 9/9 FOCUS scenarios	No	Yes (it cannot be excluded that it shares the reproductive toxicity potential of propiconazole; unlikely to be genotoxic)
CGA91305	High to medium mobility KFoc 122–305 mL/g	Yes 8/9 FOCUS scenarios	No	Yes (it cannot excluded that it shares the reproductive toxicity potential of propiconazole; unlikely to be genotoxic)
1,2,4‐triazole (CGA71019)	Very high to medium mobility KFoc 43–202 mL/g	No	Assessment not triggered	Assessment not triggered (confirmatory data are ongoing)

K_Foc: Freundlich organic carbon adsorption coefficient; FOCUS: Forum for the Co‐ordination of Pesticide Fate Models and their Use.

^aAt least one FOCUS scenario or a relevant lysimeter.

Table 3.

Surface water and sediment

Compound (name and/or code)	Ecotoxicology
Propiconazole	Low risk to aquatic organisms
SYN547889	Data gap
NOA436613	Data gap
CGA91305	Low risk to aquatic organisms
1,2,4‐triazole (CGA71019)	Low risk to aquatic organisms

7. Data gaps

This is a list of data gaps identified during the peer review process, including those areas in which a study may have been made available during the peer review process but not considered for procedural reasons (without prejudice to the provisions of Article 56 of Regulation (EC) No 1107/2009 concerning information on potentially harmful effects).

• Revised technical specification or quality control data to support the proposed specifications, the relevance of impurities and compliance of toxicity studies compared to technical specification (relevant for the Adama source; submission date proposed by the applicants: unknown, see Sections 1 and 2).

• Octanol/water partition coefficient of all components of the residue definition for risk assessment (relevant for all representative uses evaluated; submission date proposed by the applicants: unknown, see Sections 1, 3 and 4).

• Additional validation data for the methods used in data generation (relevant for all representative uses evaluated; submission date proposed by the applicants: unknown, see Sections 1, 2, 3, 4 and 5).

• Extraction efficiency of the multiresidue method DFG S19 in plant matrices (relevant for all representative uses evaluated; submission date proposed by the applicants: unknown, see Section 1).

• Monitoring method for the determination of CGA91305 in animal matrices (relevant for all representative uses evaluated; submission date proposed by the applicants: unknown, see Sections 1 and 3).

• Toxicological relevance of impurities (relevant for Syngenta; submission date proposed by the applicants: unknown; see Section 2).

• Comparative in vitro metabolism study on propiconazole (relevant for all representative uses evaluated; submission date proposed by the applicants: ongoing; see Section 2).

• The aneugenicity and clastogenicity of propiconazole should be further investigated. An in vitro micronucleus test on propiconazole should be first conducted. The study should be OECD and GLP compliant and performed with the proposed technical specification. In case of positive results, the nature of positive results (aneugenicity/clastogenicity) should be investigated. An in vivo test other than the in vivo bone marrow micronucleus test should be conducted (e.g. in vivo comet assay on CD‐1 mice might be a suitable test for clastogenicity) (relevant for all representative uses evaluated; submission date proposed by the applicants: ongoing; see Section 2).

• Further investigation of the endocrine disruption potential of propiconazole on male reproductive toxicity including a complete sperm analysis (relevant for all representative uses evaluated; submission date proposed by the applicants: unknown; see Section 2).

• Toxicological data on metabolite GA118244 to assess the clastogenic and aneugenic potential and general toxicity (relevant for all representative uses evaluated; submission date proposed by the applicants: unknown; see Sections 2 and 3).

• Re‐analysis of the results of the in vivo micronucleus test on metabolite CGA91305 to count at least 4,000 polychromatic erythrocytes (PCE) in line with OECD guideline (relevant for all representative uses evaluated; submission date proposed by the applicants: ongoing; see Sections 2 and 3).

• Toxicological data on metabolite CGA91305 to assess general toxicity (relevant for all representative uses evaluated; submission date proposed by the applicants: a developmental toxicity study is ongoing; see Sections 2 and 3).

• Data gap for the RMS to report the full assessment of the results of the scientific peer reviewed open literature search (relevant for all representative uses evaluated; submission date proposed by the applicants: submitted; see Section 3).

• Sufficient residue field trials respectively on wheat and barley and analysing for the magnitude of residues of, respectively, CGA118244 (free and conjugated) and the relevant triazole metabolites (CGA142856 (TAA) and CGA131013 (TA)) (relevant for all representative uses evaluated; submission date proposed by the applicants: unknown; see Section 3).

• Rotational crop field trials on leafy crops, root crops and small grain crops to address the magnitude of the free and conjugated form of SYN547889, NOA436613, CGA91305 and the relevant triazole metabolites (CGA131013 (TA), CGA142856 (TAA) and CGA205369 (TLA)) considering the persistence of these compounds (relevant for all representative uses evaluated; submission date proposed by the applicants: unknown; see Section 3).

• The nature of the residues for all compounds included in the residue definition for risk assessment in primary crops under the standard hydrolysis conditions at processing (relevant for all representative uses evaluated; submission date proposed by the applicants: unknown; see Section 3).

• Storage stability data for propiconazole residues in cereal straw and covering the maximum storage time period of the residue samples from the residue trials on barley and wheat (relevant for all representative uses evaluated; submission date proposed by the applicants: unknown; see Section 3).

• Storage stability data covering the maximum storage time period of the requested residue trials analysing for all the relevant compounds both in primary crops and in rotational crops (relevant for all representative uses evaluated; submission date proposed by the applicants: unknown; see Section 3).

• Ruminants and poultry feeding studies analysing for all the pertinent compounds included in the livestock residue definitions (relevant for all representative uses evaluated; submission date proposed by the applicants: unknown; see Section 3).

• Potential transfer of relevant compounds identified in primary and rotational crops to animal matrices need to be further investigated from the feeding studies (relevant for all representative uses evaluated; submission date proposed by the applicants: unknown; see Section 3).

• The dietary burden calculation for fish should be provided (relevant for all representative uses evaluated; submission date proposed by the applicants: unknown; see Section 3).

• Potential residue levels in pollen and bee products (relevant for all representative uses evaluated; submission date proposed by the applicants: unknown; see Section 3).

• Non‐dietary and dietary risk assessment to potential changes on the isomeric composition of propiconazole and its metabolites (relevant for all representative uses evaluated; submission date proposed by the applicants: unknown; see Sections 2 and 3).

• Information on the diastereoisomer composition with time of propiconazole in experiments in non‐sterile environmental matrices was not available (relevant for all representative uses evaluated; submission date proposed by the applicants: unknown; information not essential for finalising the representative uses assessed at EU level, see Sections 4 and 5).

• Ground and surface water exposure assessment for propiconazole and metabolites SYN547889, NOA436613, CGA91305 and CGA71019 using endpoints agreed by the peer review were not available (relevant for all representative uses evaluated; submission date proposed by the applicants: unknown; see Section 4).

• Information on the effect of water treatment processes on the nature of residues of both the active substance and its identified metabolites potentially present in surface and groundwater, when surface water or groundwater are abstracted for drinking water, were not sufficient in order to assess the consumer risk from the consumption of drinking water (relevant for all representative uses evaluated, submission date proposed by the applicants: unknown; see Section 4).

• Information on the exposure and the effects of the single isomers constituted in metabolites SYN547889 and NOA436613. Alternatively, a risk assessment that is sufficiently protective for this uncertainty could be provided (relevant for all representative uses evaluated; submission date proposed by the applicants: unknown; see Sections 4 and 5).

• Based on EFSA (2013c), a suitable risk assessment for bees exposed to propiconazole via consumption of contaminated water (relevant for all representative uses evaluated; submission date proposed by the applicants: unknown; see Section 5).

• Based on EFSA (2013c), suitable data to address the risk of sublethal effects (i.e. HPG development effects) to honeybees due to exposure to propiconazole (relevant for all representative uses evaluated; submission date proposed by the applicants: unknown; see Section 5).

• Information to assess the risk to honeybees due to plant metabolites occurring in pollen and nectar (relevant for all representative uses evaluated; submission date proposed by the applicants: unknown; see Section 5).

• The impurity content for some batches used in old ecotoxicological test is not known; therefore, the compliance with the technical specification cannot be assessed (relevant for all representative uses evaluated; submission date proposed by the applicants: unknown; see Section 5).

8. Particular conditions proposed to be taken into account to manage the risk(s) identified

No particular conditions are proposed for the representative uses evaluated.

9. Concerns

9.1. Issues that could not be finalised

An issue is listed as ‘could not be finalised’ if there is not enough information available to perform an assessment, even at the lowest tier level, for the representative uses in line with the uniform principles in accordance with Article 29(6) of Regulation (EC) No 1107/2009 and as set out in Commission Regulation (EU) No 546/20117 and if the issue is of such importance that it could, when finalised, become a concern (which would also be listed as a critical area of concern if it is of relevance to all representative uses).

An issue is also listed as ‘could not be finalised’ if the available information is considered insufficient to conclude on whether the active substance can be expected to meet the approval criteria provided for in Article 4 of Regulation (EC) No 1107/2009.

• 1The need for further tests and risk assessment to unique human metabolites could not be finalised while an in vitro comparative metabolism study was not submitted (see Section 2).
• 2Dietary and non‐dietary exposure assessment of potential changes on the isomeric composition of propiconazole and its metabolites cannot be finalised (see Sections 2 and 3).
• 3The endocrine disruptive properties of propiconazole to human and to wild terrestrial vertebrates cannot be finalised (see Sections 2 and 5).
• 4The consumer dietary risk assessment cannot be finalised considering the outstanding data to finalise the residue definition for risk assessment for plants and the livestock exposure assessment including the toxicological assessment of metabolites (see Sections 2 and 3).
• 5The consumer risk assessment from the consumption of water could not be finalised, while satisfactory information was not available to address the effect of water treatment processes on the nature of the residues that might be present in surface water and groundwater, when surface water or groundwater are abstracted for drinking water (see Section 4).

9.2. Critical areas of concern

An issue is listed as a critical area of concern if there is enough information available to perform an assessment for the representative uses in line with the uniform principles in accordance with Article 29(6) of Regulation (EC) No 1107/2009 and as set out in Commission Regulation (EU) No 546/2011, and if this assessment does not permit the conclusion that, for at least one of the representative uses, it may be expected that a plant protection product containing the active substance will not have any harmful effect on human or animal health or on groundwater, or any unacceptable influence on the environment.

An issue is also listed as a critical area of concern if the assessment at a higher tier level could not be finalised due to lack of information, and if the assessment performed at a lower tier level does not permit the conclusion that, for at least one of the representative uses, it may be expected that a plant protection product containing the active substance will not have any harmful effect on human or animal health or on groundwater, or any unacceptable influence on the environment.

An issue is also listed as a critical area of concern if, in the light of current scientific and technical knowledge using guidance documents available at the time of application, the active substance is not expected to meet the approval criteria provided for in Article 4 of Regulation (EC) No 1107/2009.

• 6The batches used in toxicity studies were not representative of the proposed technical specifications for the active substance and associated impurities (see Section 2).
• 7The RAC of ECHA proposed harmonised classification and labelling for propiconazole as toxic for reproduction category 1B, and a critical area of concern is identified with regard to the approval criteria, Annex II, 3.6.4 of Regulation (EC) No 1107/2009 (see Section 2).
• 8Propiconazole is proposed to be classified as toxic for reproduction category 1B by the RAC of ECHA, in accordance with the provisions of Regulation (EC) No 1272/2008, and toxic effects on the endocrine organs have been observed in the available data. Should the second interim provision of Annex II, Point 3.6.5 of Regulation (EC) No 1107/2009 applicable to category 1B, propiconazole may be considered to have endocrine disrupting properties, leading to a critical area of concern (see Section 2).
• 9Groundwater metabolites are considered relevant since it cannot be excluded that the metabolites share the reproductive toxicity potential of propiconazole. The relevant metabolite NOA436613 has the potential to exceed the parametric drinking water limit of 0.1 μg/L in geoclimatic conditions representing all nine FOCUS groundwater scenarios while relevant metabolites SYN547889 has this potential in 8/9 FOCUS groundwater scenarios, both for all the representative uses assessed (see Sections 2 and 4).

9.3. Overview of the concerns identified for each representative use considered

(If a particular condition proposed to be taken into account to manage an identified risk, as listed in Section 8, has been evaluated as being effective, then ‘risk identified’ is not indicated in Table 5.)

Table 5.

Overview of concerns

Representative use		Wheat annual application	Wheat biennial application	Barley annual application	Barley biennial application
Operator risk	Risk identified
	Assessment not finalised
Worker risk	Risk identified
	Assessment not finalised
Resident/bystander risk	Risk identified
	Assessment not finalised
Consumer risk	Risk identified
	Assessment not finalised	X4,5	X4,5	X4,5	X4,5
Risk to wild non‐target terrestrial vertebrates	Risk identified
	Assessment not finalised
Risk to wild non‐target terrestrial organisms other than vertebrates	Risk identified
	Assessment not finalised
Risk to aquatic organisms	Risk identified
	Assessment not finalised
Groundwater exposure to active substance	Legal parametric value breached
	Assessment not finalised
Groundwater exposure to metabolites	Legal parametric value breacheda	X9	X9	X9	X9
	Parametric value of 10 μg/Lb breached
	Assessment not finalised

Columns are grey if no safe use can be identified. The superscript numbers relate to the numbered points indicated in Sections 9.1 and 9.2. Where there is no superscript number, see Sections 2, 3, 4, 5–6 for further information.

^aWhen the consideration for classification made in the context of this evaluation under Regulation (EC) No 1107/2009 and ECHA Risk Assessment Committee is confirmed under Regulation (EC) No 1272/2008 of the European Parliament and of the Council of 16 December 2008.

^bValue for non‐relevant metabolites prescribed in SANCO/221/2000‐rev. 10 final, European Commission (2003a).

All columns are grey, as the technical material specification proposed was not comparable to the material used in the testing that was used to derive the toxicological reference values.

Abbreviations

a.s.

active substance

AAOEL

acute acceptable operator exposure level

ADI

acceptable daily intake

AOEL

acceptable operator exposure level

AR

applied radioactivity

ARfD

acute reference dose

bw

body weight

CXL

Codex maximum residue limit

DT₅₀

period required for 50% dissipation (define method of estimation)

DT₉₀

period required for 90% dissipation (define method of estimation)

EC

emulsifiable concentrate

ECHA

European Chemicals Agency

EEC

European Economic Community

f(twa)

Time‐weighted average factor

FAO

Food and Agriculture Organization of the United Nations

FOCUS

Forum for the Co‐ordination of Pesticide Fate Models and their Use

GAP

Good Agricultural Practice

GLP

good laboratory practice

HPG

hypopharyngeal glands

HQ

hazard quotient

HR

hazard rate

IESTI

international estimated short‐term intake

ISO

International Organization for Standardization

IUPAC

International Union of Pure and Applied Chemistry

JMPR

Joint Meeting of the FAO Panel of Experts on Pesticide Residues in Food and the Environment and the WHO Expert Group on Pesticide Residues (Joint Meeting on Pesticide Residues)

K_Foc

Freundlich organic carbon adsorption coefficient

LC₅₀

lethal concentration, median

LC–MS/MS

liquid chromatography with tandem mass spectrometry

LOAEL

lowest observable adverse effect level

LOQ

limit of quantification

MRL

maximum residue level

MWHC

maximum water‐holding capacity

NEU

northern Europe

NOAEL

no observed adverse effect level

OECD

Organisation for Economic Co‐operation and Development

PBI

plant back interval

PCE

polychromatic erythrocytes

PEC

predicted environmental concentration

PEC_sw

predicted environmental concentration in surface water

P_ow

partition coefficient between n‐octanol and water

PPE

personal protective equipment

PRIMo

(EFSA) Pesticide Residues Intake Model

QuEChERS

Quick, Easy, Cheap, Effective, Rugged, and Safe (analytical method)

RAC

Risk Assessment Committee

RAR

renewal assessment report

RMS

rapporteur Member State

SET

southern Europe

SMILES

simplified molecular‐input line‐entry system

TER

toxicity exposure ratio

TRR

total radioactive residue

UF

uncertainty factor

WHO

World Health Organization

Appendix A – List of end points for the active substance and the representative formulation

Appendix A can be found in the online version of this output (‘Supporting information’ section): https://doi.org/10.2903/j.efsa.2017.4887

Appendix B – Used compound codes

Code/trivial namea	Chemical name/SMILES notation	Structural formula
CGA148750	1‐{[(2R,4S)‐2‐(2,4‐dichlorophenyl)‐4‐propyl‐1,3‐dioxolan‐2‐yl]methyl}‐1H‐1,2,4‐triazole Clc1ccc(c(Cl)c1)[C@@]3(Cn2ncnc2)OC[C@H](CCC)O3
CGA148751	1‐{[(2S,4R)‐2‐(2,4‐dichlorophenyl)‐4‐propyl‐1,3‐dioxolan‐2‐yl]methyl}‐1H‐1,2,4‐triazole Clc1ccc(c(Cl)c1)[C@]3(Cn2ncnc2)OC[C@@H](CCC)O3
CGA148752	1‐{[(2S,4S)‐2‐(2,4‐dichlorophenyl)‐4‐propyl‐1,3‐dioxolan‐2‐yl]methyl}‐1H‐1,2,4‐triazole Clc1ccc(c(Cl)c1)[C@]3(Cn2ncnc2)OC[C@H](CCC)O3
CGA148753	1‐{[(2R,4R)‐2‐(2,4‐dichlorophenyl)‐4‐propyl‐1,3‐dioxolan‐2‐yl]methyl}‐1H‐1,2,4‐triazole Clc1ccc(c(Cl)c1)[C@@]3(Cn2ncnc2)OC[C@@H](CCC)O3
SYN547889	(2R,4R)‐2‐(2,4‐dichlorophenyl)‐2‐(1H‐1,2,4‐triazol‐1‐ylmethyl)‐1,3‐dioxolane‐4‐carboxylic acid O=C(O)[C@H]2CO[C@@](Cn1ncnc1)(O2)c3ccc(Cl)cc3Cl (2S,4S)‐2‐(2,4‐dichlorophenyl)‐2‐(1H‐1,2,4‐triazol‐1‐ylmethyl)‐1,3‐dioxolane‐4‐carboxylic acid O=C(O)[C@@H]2CO[C@](Cn1ncnc1)(O2)c3ccc(Cl)cc3Cl
NOA436613	(2S,4R)‐2‐(2,4‐dichlorophenyl)‐2‐(1H‐1,2,4‐triazol‐1‐ylmethyl)‐1,3‐dioxolane‐4‐carboxylic acid O=C(O)[C@H]2CO[C@](Cn1ncnc1)(O2)c3ccc(Cl)cc3Cl (2R,4S)‐2‐(2,4‐dichlorophenyl)‐2‐(1H‐1,2,4‐triazol‐1‐ylmethyl)‐1,3‐dioxolane‐4‐carboxylic acid O=C(O)[C@@H]2CO[C@@](Cn1ncnc1)(O2)c3ccc(Cl)cc3Cl
CGA91305	(1RS)‐1‐(2,4‐dichlorophenyl)‐2‐(1H‐1,2,4‐triazol‐1‐yl)ethanol OC(Cn1cncn1)c2ccc(Cl)cc2Cl
CGA91304	1‐(2,4‐dichlorophenyl)‐2‐(1H‐1,2,4‐triazol‐1‐yl)ethanone O=C(Cn1cncn1)c2ccc(Cl)cc2Cl
CGA118244	3,5‐dideoxy‐1,2‐O‐[(1RS)‐1‐(2,4‐dichlorophenyl)‐2‐(1H‐1,2,4‐triazol‐1‐yl)ethylidene]‐d,l‐pentitol CC(O)CC2COC(Cn1ncnc1)(O2)c3ccc(Cl)cc3Cl
CGA118245	3‐[(2RS,4RS)‐2‐(2,4‐dichlorophenyl)‐2‐(1H‐1,2,4‐triazol‐1‐ylmethyl)‐1,3‐dioxolan‐4‐yl]propan‐1‐ol Clc1ccc(c(Cl)c1)C3(Cn2ncnc2)OCC(CCCO)O3
1,2,4‐triazole (CGA71019)	1H‐1,2,4‐triazole c1nncn1
CGA142856 (TAA)	1H‐1,2,4‐triazol‐1‐ylacetic acid O=C(O)Cn1cncn1
CGA205369 (TLA)	(2RS)‐2‐hydroxy‐3‐(1H‐1,2,4‐triazol‐1‐yl)propanoic acid OC(Cn1cncn1)C(=O)O
CGA131013 (TA)	3‐(1H‐1,2,4‐triazol‐1‐yl)‐d,l‐alanine NC(Cn1cncn1)C(=O)O
CGA136735	(2RS)‐1‐[(2RS,4RS)‐2‐(2,4‐dichlorophenyl)‐2‐(1H‐1,2,4‐triazol‐1‐ylmethyl)‐1,3‐dioxolan‐4‐yl]butan‐2‐ol CCC(O)CC2COC(Cn1ncnc1)(O2)c3ccc(Cl)cc3Cl

SMILES: simplified molecular‐input line‐entry system.

^aThe compound name in bold is the name used in the conclusion.

Supporting information

List of end points for the active substance and the representative formulation

Suggested citation: EFSA (European Food Safety Authority) , Arena M, Auteri D, Barmaz S, Bellisai G, Brancato A, Brocca D, Bura L, Byers H, Chiusolo A, Court Marques D, Crivellente F, De Lentdecker C, De Maglie M, Egsmose M, Erdos Z, Fait G, Ferreira L, Goumenou M, Greco L, Ippolito A, Istace F, Jarrah S, Kardassi D, Leuschner R, Lythgo C, Magrans JO, Medina P, Miron I, Molnar T, Nougadere A, Padovani L, Parra Morte JM, Pedersen R, Reich H, Sacchi A, Santos M, Serafimova R, Sharp R, Stanek A, Streissl F, Sturma J, Szentes C, Tarazona J, Terron A, Theobald A, Vagenende B, Verani A and Villamar‐Bouza L, 2017. Conclusion on the peer review of the pesticide risk assessment of the active substance propiconazole. EFSA Journal 2017;15(7):4887, 28 pp. 10.2903/j.efsa.2017.4887