Scholarly article on topic 'Peer review of the pesticide risk assessment of the active substance propyzamide'

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Academic research paper on topic "Peer review of the pesticide risk assessment of the active substance propyzamide"

CONCLUSION ON PESTICIDES PEER REVIEW

EFSA Journal

APPROVED: 8 July 2016

doi: 10.2903/j.efsa.2016.4554

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

European Food Safety Authority (EFSA)

The conclusions of EFSA following the peer review of the initial risk assessments carried out by the competent authorities of the rapporteur Member State, Sweden, and co-rapporteur Member State, the United Kingdom, for the pesticide active substance propyzamide 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 uses of propyzamide as a herbicide on lettuce and winter oilseed rape. 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.

© 2016 European Food Safety Authority. EFSA Journal published by John Wiley and Sons Ltd on behalf of European Food Safety Authority.

Keywords: propyzamide, peer review, risk assessment, pesticide, herbicide

Requestor: European Commission Question number: EFSA-Q-2014-00823 Correspondence: pesticides.peerreview@efsa.europa.eu

Abstract

Suggested citation: EFSA (European Food Safety Authority), 2016. Conclusion on the peer review of the pesticide risk assessment of the active substance propyzamide. EFSA Journal 2016;14(8):4554, 25 pp. doi:10.2903/j.efsa.2016.4554

ISSN: 1831-4732

© 2016 European Food Safety Authority. EFSA Journal published by John Wiley and Sons Ltd on behalf of European Food Safety Authority.

This is an open access article under the terms of the Creative Commons Attribution-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited and no modifications or adaptations are made.

The EFSA Journal is a publication of the European Food OTC:] gm Safety Authority, an agency of the European Union.

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. Propyzamide 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), Sweden, and co-rapporteur Member State (co-RMS), the United Kingdom, received an application from Dow AgroSciences for the renewal of approval of the active substance propyzamide. Complying with Article 8 of the Regulation, the RMS checked the completeness of the dossier and informed the applicant, 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 propyzamide in the renewal assessment report (RAR), which was received by EFSA on 31 July 2015. In accordance with Article 12 of the Regulation, EFSA distributed the RAR to the Member States and the applicant, Dow AgroSciences, for comments on 7 September 2015. 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 9 November 2015.

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

In accordance with Article 13(1) of the Regulation, EFSA should adopt a conclusion on whether propyzamide 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 uses of propyzamide as a herbicide on lettuce and winter oilseed rape, as proposed by the applicant. Full details of the representative uses can be found in Appendix A of this report.

Data were submitted to conclude that the use of propyzamide according to the representative uses proposed at the European Union (EU) level results in a sufficient herbicidal efficacy against the target weeds.

A data gap was identified for a more detailed assessment of the literature review for the active substance and its relevant metabolites.

In the Section identity and analytical methods, data gaps were identified for additional validation data for the determination of two impurities in the technical material.

In the Section mammalian toxicology, a data gap was identified related to an assessment of the toxicological relevance of the impurities. Information on the batches used in the toxicity studies was missing in order to conclude that they were representative of the technical specification (critical area of concern). A second data gap was related to comparative in vitro metabolism data, addressing differences between species and humans. Furthermore, the need for additional investigations of the toxicity profile of significant plant metabolites in primary and rotational crops is also highlighted (data gap).

In the residue area, data gaps were identified for residue field trials, respectively, on lettuce and rapeseed, and analysing the magnitude of residues of all metabolites included in the residue definition for risk assessment, rotational crops field trials on leafy crops, root crops and small grain crops for the determination of propyzamide, mannoside conjugate of RH-25337 and glucoside of RH-26702 residues at 30 days plant back interval (PBI) and for the determination of the residues in pollen and bee products for human consumption resulting from residues taken up by honeybees from crops at blossom. The consumer dietary risk assessment cannot be concluded on considering the identified data gaps, the outstanding data on the toxicity profile of the metabolites relevant in primary and rotational crops and the finalisation of the residue definition for risk assessment in plants. The consumer risk assessment through drinking water with regard to metabolite RH-24580 is also not finalised.

With respect to the fate and behaviour into the environment, data gaps have been identified for investigation of degradation of metabolite RH-24580 in one additional soil and dark aerobic conditions and to address the effect of water treatment processes on the nature of residues present in ground water and surface water when water is abstracted for drinking water. A critical area of concern has

been identified for potential groundwater contamination by soil metabolite RH-24580 and lysimeter leachate metabolites U1 (two components), U3, U4 (two components), U5, U6 and U7.

In the ecotoxicology area, a data gap was identified for the assessment of the ecotoxicological relevance of the impurities and a critical area of concern was identified for the composition of some batches. A data gap was identified for a suitable reproductive avian endpoint leading to avian risk assessment not being finalised. Data gaps were also identified for addressing the long-term risk to wild mammals due to exposure to propyzamide and for addressing the risk of secondary poisoning due to exposure to the major soil metabolites. Data gaps were identified to address the risk to aquatic organisms, particularly macrophytes. Several data gaps were identified for bees. Finally, data gaps were identified for addressing the risk to soil organisms and to non-target terrestrial plants. A critical area of concern was identified for the risk to collembolans (Folsomia).

Table of contents

Abstract.................................................................................................................................................... 1

Summary.................................................................................................................................................. 3

Background.............................................................................................................................................. 6

The active substance and the formulated product........................................................................................ 7

Conclusions of the evaluation..................................................................................................................... 7

1. Identity, physical/chemical/technical properties and methods of analysis................................................ 7

2. Mammalian toxicity............................................................................................................................. 8

3. Residues............................................................................................................................................ 9

4. Environmental fate and behaviour....................................................................................................... 11

5. Ecotoxicology..................................................................................................................................... 13

6. Overview of the risk assessment of compounds listed in residue definitions triggering assessment of effects data for the environmental compartments................................................................................. 15

7. Data gaps.......................................................................................................................................... 16

8. Particular conditions proposed to be taken into account to manage the risk(s) identified......................... 18

9. Concerns........................................................................................................................................... 18

9.1. Issues that could not be finalised........................................................................................................ 18

9.2. Critical areas of concern...................................................................................................................... 19

9.3. Overview of the concerns identified for each representative use considered............................................ 19

References................................................................................................................................................20

Abbreviations............................................................................................................................................ 21

Appendix A - List of end points for the active substance and the representative formulation...........................23

Appendix B - Used compound codes..........................................................................................................24

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, Sweden, and the co-RMS, the United Kingdom, received an application from Dow AgroSciences for the renewal of approval of the active substance propyzamide. Complying with Article 8 of the Regulation, the RMS checked the completeness of the dossier and informed the applicant, the co-RMS (the United Kingdom), the European Commission and EFSA about the admissibility.

The RMS provided its initial evaluation of the dossier on propyzamide in the RAR, which was received by EFSA on 31 July 2015 (Sweden, 2015).

In accordance with Article 12 of the Regulation, EFSA distributed the RAR to the Member States and the applicant, Dow AgroSciences, for consultation and comments on 7 September 2015. 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 9 November 2015. At the same time, the collated comments were forwarded to the RMS for compilation and evaluation in the format of a reporting table. The applicant was invited to respond to the comments in column 3 of the reporting table. The comments and the applicant's 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 applicant in accordance with Article 13(3) of the Regulation were considered in a telephone conference between EFSA and the RMS on 17 December 2015. On the basis of the comments received, the applicant's response to the comments and the RMS's evaluation thereof, it was concluded that additional information should be requested from the applicant, and that EFSA should conduct an expert consultation in the areas of mammalian toxicology, residues, environmental fate and behaviour, 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 June 2016.

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 uses of propyzamide as a herbicide on lettuce and winter oilseed rape, as proposed by the applicant. A list of the relevant end points for the active substance and the formulation is provided in Appendix A.

1 Commission Implementing Regulation (EU) No 844/2012 of 18 September 2012 setting out the provisions necessary for the implementation of the renewal procedure for active substances, as provided for in Regulation (EC) No 1107/2009 of the European Parliament and of the Council concerning the placing of plant protection products on the market. OJ L 252, 19.9.2012, p. 26-32.

2 Regulation (EC) No 1107/2009 of 21 October 2009 of the European Parliament and of the Council concerning the placing of plant protection products on the market and repealing Council Directives 79/117/European Economic Community (EEC) and 91/414/EEC. OJ L 309, 24.11.2009, p. 1-50.

In addition, a key supporting document to this conclusion is the peer review report (EFSA, 2016), 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 (17 December 2015);

• the evaluation table (4 July 2016);

• the reports 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 (Sweden, 2016), 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

Propyzamide is the ISO common name for 3,5-dichloro-N-(1,1-dimethylprop-2-ynyl)benzamide (IUPAC).

The representative formulated product for the evaluation was 'Kerb Flo 400 (GF-3300)', a suspension concentrate (SC) containing 400 g/L propyzamide.

The representative uses evaluated were post-emergence spray applications in winter oilseed rape and lettuce, to control grasses and some broad leafed weeds. 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 use of propyzamide according to the representative uses proposed at the EU level results in a sufficient herbicidal efficacy against the target weeds following the guidance document SANCO/10054/2013 - rev. 3 (European Commission, 2013).

A data gap has been identified for a more detailed assessment of the literature review of the active substance and its relevant metabolites, dealing with side effects on health, the environment and non-target species and published within the 10 years before the date of submission of the dossier, to be conducted and reported in accordance with 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).

Conclusions of the evaluation

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).

The reference specification for the first approval was updated. The proposed specification is based on batch data from industrial scale production and quality control (QC) data. The minimum purity of the technical material is 950 g/kg.

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 propyzamide or the representative formulation. The main data regarding the identity of propyzamide and its physical and chemical properties are given in Appendix A.

Adequate methods are available for the generation of pre-approval data required for the risk assessment; however, data gaps were identified for additional validation data for two methods for the determination of impurities in the technical material. Methods of analysis are available for the determination of the active substance in the technical material and representative formulation.

The quick, easy, cheap, effective and safe (QuEChERS) multiresidue method and also a single residue method are available for monitoring propyzamide in food and feed of plant origin by liquid chromatography with tandem mass spectrometry (LC-MS/MS) with limit of quantifications (LOQs) of 0.01 mg/kg in each commodity group.

An analytical method for monitoring residues in food and feed of animal origin is not needed as no maximum residue levels (MRLs) were proposed for the animal matrices. An appropriate LC-MS/MS method is available enabling the determination of the compounds included in the residue definition proposed for monitoring purposes in soil (propyzamide and its metabolites RH-24644 and RH-24580) with LOQs of 5 ig/kg for each analyte.

Residues of propyzamide and its metabolite RH-24580 can be monitored in surface water and drinking water by LC-MS/MS with LOQs of 0.05 ig/L for both compounds. Residues of propyzamide in air can be determined by LC-MS/MS with a LOQ of 0.6 ig/m3. An LC-MS/MS method exists for monitoring propyzamide residues in urine and blood with a LOQs of 0.05 mg/L.

2. Mammalian toxicity

The following guidance documents were followed in the production of this conclusion: SANCO/221/ 2000-rev. 10-final (European Commission, 2003), SANCO/10597/2003-rev. 10.1 (European Commission, 2012) and Guidance on dermal absorption (EFSA PPR Panel, 2012).

Propyzamide was discussed by Member States experts in the teleconference TC 131 (April 2016).

The information provided in the dossier was considered insufficient to draw any conclusion on the toxicological relevance of the impurities (data gap), and information on the composition of batches used in toxicity studies was missing in order to conclude that they were representative of the technical specification (critical area of concern).

With an oral absorption value of 88%, propyzamide was shown to be well distributed, extensively metabolised and not bioaccumulating. Comparative in vitro metabolism data, addressing differences between test species and with humans were not available (data gap). Of low acute toxicity, it was not irritant to the skin or the eyes, not sensitiser and not predicted to have a phototoxic potential. In short-term studies, the target organ triggering the no observed adverse effect levels (NOAELs) was the liver. The NOAEL for the rat was 4.5 mg/kg body weight (bw) per day based on increased absolute liver weight (> 20%), the NOAEL for the mouse was 15 mg/kg bw per day based on increased liver weight and hepatocellular hypertrophy, whereas a lowest observable adverse effect level (LOAEL) of 12 mg/kg bw per day was identified in the 1-year dog study, based on an increased absolute and relative liver weight in females. No NOAEL could be derived in the 90-day and 2-year dog studies because of their limitations.

On the basis of the available in vitro and in vivo genotoxicity tests, propyzamide is considered as having no genotoxic potential relevant to humans. The long-term toxicity in rats is characterised by reduced body weight gain, liver effects (increased weight, centrilobular hypertrophy), thyroid effects (increased weight, follicular cell hyperplasia) and ovarian effect (sertoliform tubular hyperplasia), triggering a systemic NOAEL of 8.5 mg/kg bw per day. In mice, chronic effects included increased absolute and relative liver and kidney weights with a systemic NOAEL of 5 mg/kg bw per day. Tumours were observed in both species: benign Leydig cell and thyroid tumours in rats, liver adenomas and carcinomas in mice. The human relevance of these liver tumours could not be excluded based on the lack of human in vitro and epidemiological data on simultaneous constitutive androstane receptor (CAR) and peroxisome proliferator activated receptor alpha (PPARa) activation. For the thyroid tumours, considering the uncertainties about the contribution of alternative pathways, and recent data indicating deregulation of thyroid hormones in human cancer, the human relevance could not be excluded as well. For the Leydig cell tumours, it was agreed that these tumours are unlikely to be relevant to humans. The NOAELs for tumours in both species were the same as for systemic effects. The majority of the experts supported the classification as carcinogen category 2; H351 suspected of causing cancer, as reported in the Annex VI of Regulation (EC) No 1272/20083 (CLP Regulation) for propyzamide.

In the multigeneration rat study, no adverse effect was observed on the reproductive parameters up to the highest dose tested (97.7 mg/kg bw per day). The parental and offspring NOAEL was 12.1 mg/kg bw per day based on decreased body weight (parents and pups) and on histopathological

3 Regulation (EC) No 1272/2008 of the European Parliament and of the Council of 16 December 2008 on classification, labelling and packaging of substances and mixtures, amending and repealing Directives 67/548/EEC and 1999/45/EC, and amending Regulation (EC) No 1907/2006. OJ L 353, 31.12.2008, p. 1-1355.

findings in the liver, adrenal, thyroid and pituitary gland (parents only). In the developmental toxicity studies, no adverse effect was observed in fetuses up to the highest dose tested. The maternal NOAEL in rats was 20 mg/kg bw per day based on decreased body weight gain, whereas it was 5 mg/kg bw per day in rabbits based on clinical signs. Further investigations of potential endocrine-mediated effects were performed in a battery of in vitro and in vivo assays. Based on the available results, propyzamide was concluded as unlikely to have a direct effect on receptors of the endocrine system, including oestrogen, androgen and thyroid pathways. The antiandrogenic and antioestrogenic effects of propyzamide are likely to occur through modulating the metabolism of steroid hormones by inducing the liver metabolising enzymes.

Propyzamide is classified as carcinogen category 2 but not as reproductive toxicant, in accordance with the provisions of Regulation (EC) No 1272/2008, and therefore, the conditions of the interim provisions of Annex II, Point 3.6.5 of Regulation (EC) No 1107/2009 concerning human health for the consideration of endocrine-disrupting properties are not met. On the basis of the available data and current knowledge (OECD Conceptual Framework, as analysed in the EFSA Scientific Opinion on the hazard assessment of endocrine disruptors, (EFSA Scientific Committee, 2013)), it is concluded that propyzamide is unlikely to be an endocrine disruptor.

In the acute neurotoxicity study with propyzamide, a LOAEL of 40 mg/kg bw per day was identified on the basis of reduced motor activity on the first day after treatment. In the 90-day neurotoxicity study, no neurotoxic effect was observed up to the highest dose tested (60 mg/kg bw per day) and the systemic NOAEL was 2.4 mg/kg bw per day on the basis of decreased body weight.

Several metabolites were identified in significant concentrations in primary and rotational crops: conjugates of RH-24848, RH-25891, RH-26521, RH-26059, RH-25337, RH-26702, and free RH-24644. As they were not major metabolites identified in the rat metabolic pathway, their toxicological profile cannot be considered covered by the reference values of propyzamide (data gap). The groundwater metabolite RH-24580 is toxicologically relevant according to the guidance document (European Commission, 2003) because the available data were insufficient to demonstrate that it did not qualify for the same carcinogenic properties as propyzamide. It is noted that no reference values can be derived on the basis of the available data.

The acceptable daily intake (ADI) from the first peer review (amended in 2007) was 0.02 mg/kg bw per day based on the 2-year mouse study. The ADI agreed for the renewal is 0.05 mg/kg bw per day, taking into account the results of short-term and long-term studies, and applying an uncertainty factor (UF) of 100. No acute reference dose (ARfD) was derived from the first peer review. For the renewal, the agreed ARfD is 0.13 mg/kg bw, based on the acute neurotoxicity study, and applying an increased UF of 300 for the use of a LOAEL. The same value is valid for the acute acceptable operator exposure level (AAOEL). The acceptable operator exposure level (AOEL) from the first peer review was 0.08 mg/kg bw per day based on the rabbit developmental study and applying a correction factor for an oral absorption value of 80%. For the renewal, an AOEL of 0.05 mg/kg bw per day was agreed, taking into account the results of short-term and long-term studies, and applying an UF of 100 (without correction for the oral absorption value, considered higher than 80%).

In the absence of a dermal absorption study with the representative formulation, bridging of dermal absorption data for another formulation was discussed and considered acceptable. The resulting dermal absorption values for propyzamide in GF-3300 are 0.7% for the concentrate and 14% for the field dilution. The operator exposure estimates with the German model (75th percentile) are below the AOEL for the application in oilseed rape, with the use of personal protective equipment (PPE). For the application in lettuce, the operator exposure is predicted to be above the AOEL even with the use of PPE (German model). The exposure estimates for bystanders and residents were below the AOEL. Re-entry workers harvesting lettuce are supposed to use PPE in order to have exposure levels below the AOEL.

3. Residues

The assessment in the residue section is based on the European Commission guideline document on MRL setting (European Commission, 2015), the Joint Meeting on Pesticide Residues (JMPR) recommendations on livestock burden calculations (JMPR, 2004, 2007) and the OECD publication on MRL calculations (OECD, 2011).

Propyzamide was discussed in the teleconference TC 132 (April 2016).

Metabolism of propyzamide in primary crops was investigated in leafy (lettuce), pulses/oilseeds (alfalfa, rapeseed) and root (sugar beet) crop groups using the 14C-propyzamide labelled on the phenyl

ring. The active substance was applied both pre- and post-emergence on lettuce and post-emergence on alfalfa, rapeseed and sugar beet at early growth stages (GSs) BBCH 13-19. At harvest in mature plants, propyzamide was present in significant proportions in lettuce and in alfalfa (42.5% and 58% total radioactive residue (TRR), respectively). In rapeseed forage and root, it accounted for up to 15.5% TRR and the compound RH-24644 was identified predominantly in the roots (45% TRR). The parent compound was not detected in rapeseeds and in sugar beet leaves and root where the major part of the radioactive residues were characterised as polar compounds that accounted for 37% TRR in rapeseeds and up to 71% TRR in sugar beet root and leaves. Although recovered at low proportions (< 10% TRR) in lettuce only, the glucoside conjugated metabolites (aglycons RH-24848, RH-25891, RH-26521, RH-26059) (0.045-0.07 mg eq/kg), the malonyl glucoside conjugated metabolites (aglycons RH-24848, RH-25891, RH-26521) (0.082-0.29 mg eq/kg) and metabolite RH-24644 (0.11 mg eq/kg) were identified at high absolute concentrations considering the metabolism study conducted at a 1.5N rate. Residues of glucoside and malonyl glucoside conjugated forms of RH-26521 also occurred in alfalfa in significant proportions (14% TRR). It is noted that the available metabolism data did not enable the identification of a predominant compound in the bulk of the conjugated metabolites as the relative proportion of each individual compound/aglycon was not determined in this study.

A confined rotational crop metabolism study was conducted with bare soil application of propyzamide labelled on the phenyl ring at a dose of application of 4.48 kg a.s./ha (3N rate). Lettuce, carrot and wheat were planted at different plant back intervals (PBIs) (30, 180 and 365 days). TRRs in mature lettuce were significant at 30 days PBI (0.74 mg eq/kg) and decreased substantially to 0.05 mg eq/kg and 0.021 mg eq/kg at 180 days and 365 days PBIs, respectively. TRRs in carrot root were low at 180 days and 365 days PBIs (0.025 and < 0.01 mg eq/kg, respectively), while the total residues in wheat forage, straw and grain at 365 days PBI amounted up to, respectively, 0.1 mg eq/kg, 0.18 mg eq/kg and 0.038 mg eq/kg. Parent propyzamide was identified in significant proportions in lettuce (15-42% TRR) and in carrot top (17% TRR). The mannoside conjugate of RH-25337 was found to be a major compound of the total residues in lettuce (12-36% TRR), in carrot top (18-28% TRR) and in wheat forage and straw (26.6% TRR and 14.7% TRR, respectively), although the absolute concentrations of this compound in carrot and wheat plant parts were much lower compared to those recovered in lettuce. The glucoside of RH-26702 was the most abundant metabolite observed in lettuce (18-37% TRR). Metabolites' identification was not carried out in carrot root and wheat grain. Even though considering the overdosed metabolism study, significant residue levels of parent propyzamide and conjugates of RH-25337 and RH-26702 are expected for short-cycle crops as lettuce planted 30 days after treatment (DAT) and a data gap was set to conduct rotational crops field trials on leafy crops, root crops and small grain crops for the determination of propyzamide, mannoside conjugate of RH-25337 and glucoside of RH-26702 residues at 30 days PBI (data gap).

Overall, the major routes of metabolism of propyzamide in plants included hydroxylation, oxidation on the alkyl side chain, cyclisation with the formation of the oxazoline ring and conjugations. Based on the metabolism data in primary and rotational crops, the residue definition for monitoring was proposed as propyzamide only. For risk assessment, the experts of the meeting discussed the possibility to set a specific residue definition for risk assessment for leafy crops only as the relevant compounds were identified mostly in lettuce as a primary crop and as a crop grown in rotation. However, a general consensus was finally reached to derive the residue definition as sum of propyzamide and all metabolites (and their conjugates) bearing the 3,5-dichlorobenzoic acid (DCBA) moiety, expressed as propyzamide for all crop categories following foliar application. This residue definition should be regarded as provisional as the toxicological profile of the pertinent metabolites identified in primary and in rotational crops, i.e. conjugates of RH-24848, RH-25891, RH-26521, RH-26059, RH-25337, RH-26702 and free RH-24644 was not addressed and is required (see data gap Section 2). As the parent compound is classified as carcinogenic category 2, and in the absence of specific studies on the structurally related metabolites, these compounds should be considered as toxicologically relevant. If these metabolites were to be demonstrated as being of a different toxicity profile compared with propyzamide, the proposed residue definition for risk assessment will have to be revised accordingly. Furthermore, sufficient residue field trials, respectively, on lettuce and rapeseed and analysing the magnitude of residues of all metabolites included in the residue definition for risk assessment should also be provided in order to perform the consumer dietary risk assessment (data gap).

A sufficient number of residue field trials conducted according to the cGAP conditions are available, respectively, on lettuce and rapeseed, determining residues of parent propyzamide only. The results obtained in these residue field trials are supported by acceptable storage stability data for propyzamide. The proposed MRLs on these crops should, however, 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.

Propyzamide remained stable under the standard hydrolysis conditions representative of pasteurisation, baking/brewing/boiling and sterilisation.

The metabolism studies in livestock (laying hens and lactating goats) showed that the parent compound was predominant in milk (33% TRR), muscle (66% TRR), fat (88% TRR) and eggs (20% TRR), while it was extensively degraded in liver (2% TRR) and kidney (7.4% TRR). DCBA compound was a significant compound of the total residues in muscle, kidney and liver (17-18% TRR) and all the other identified metabolites were found to contain the DCBA moiety. Although the goat metabolism study was not conducted in accordance with the current guidance recommendations concerning the dosing period and the deficiencies identified in terms of rate of metabolites' identification in kidney and liver, the majority opinion was, however, that the metabolism of propyzamide in livestock was sufficiently addressed and was found to be similar to the rat metabolism. A pig metabolism study is therefore not required. Based on the overall metabolic pattern, the experts agreed that the parent compound is a valid residue marker in most of the animal commodities and the residue definition for monitoring was set as propyzamide only. For risk assessment, the residue is defined as sum of propyzamide and all metabolites (and their conjugates) bearing the DCBA moiety, expressed as propyzamide. For the time being and assuming that propyzamide alone is the relevant residue in feed items for livestock exposure and based on the livestock dietary burden, the metabolism studies indicated that residues > 0.01 m/kg are not expected in animal matrices and the transfer of residues into animal commodities does not need to be investigated. MRLs for livestock matrices are not required. This assessment should be reconsidered pending upon the outcome of the outstanding data on the magnitude of the pertinent compounds identified in primary and rotational crops and their relative toxicity. In that specific case, feeding studies may be requested to determine the residues of propyzamide alone and all components included in the residue definition for risk assessment.

The proposed residue definitions for monitoring and risk assessment set for plant and animal commodities have been changed compared with those proposed in the framework of the review of the existing MRLs for propyzamide (EFSA, 2012). Indeed for plants, the pertinent metabolites recovered at high concentrations in primary (lettuce) and rotational crops were not considered in the residue definition for risk assessment while propyzamide alone was not proposed as the valid residue marker to be enforced in livestock matrices as an analytical method for the determination of propyzamide was not available. Furthermore, the residue definitions for plants have been extended to all categories of crops considering the additional metabolism study on root crops submitted for the renewal of the approval of propyzamide. Furthermore, the ADI has been changed and an ARfD has been allocated for propyzamide. The established MRLs under Article 12 of Regulation (EC) No 396/2005 and the overall consumer dietary risk assessment have therefore to be revised.

Currently, a consumer risk assessment can only be provisionally conducted for parent propyzamide. Using the EFSA Pesticide Residues Intake Model (PRIMo), long-term and short-term intake concerns were not identified for the consumers as the highest chronic and acute intakes were estimated to be < 1% of the ADI (Spanish adult) and 12% of the ARfD (lettuce).The consumer risk assessment cannot be finalised with regard to all the pertinent metabolites (and their conjugates) bearing the DCBA moiety considering the outstanding data on their relative toxicity and their respective level in plants. Moreover, the level of metabolite RH-24580 in groundwater exceeding 0.75 ig/L for a number of lettuce and oilseed rape scenarios (Section 4) and the absence of toxicological reference values for this compound have led to the consumer risk assessment through drinking water not being conducted.

The data requirement for the determination of the residues in pollen and bee products for human consumption resulting from residues taken up by honeybees from crops at blossom could not be addressed considering the outstanding residue field trials on rapeseed and on rotational crops analysing the relevant metabolites (data gap).

4. Environmental fate and behaviour

Environmental exposure and fate and behaviour of propyzamide into the environment were discussed by Member States experts in the teleconference TC 129.

The route and rate of degradation of propyzamide (14C labelled at the phenyl ring) under dark aerobic conditions was investigated in eight different soils with reliable experiments. Propyzamide exhibited moderate to high persistence in these studies. Two major metabolites were identified: RH-24644 (max. 41.5% applied radioactivity (AR) after 71 days) and RH-24580 (max. 24% AR after

45 days). From the studies performed with the parent, it was possible to derive four formation fractions and associated degradation rates for metabolite RH-24644 (nevertheless due to volatilisation in two of the soils the formation fractions derived from these two kinetic analyses are considered to be underestimated). In these four experiments, this metabolite exhibited moderate to medium persistence. Degradation rate of metabolite RH-24580 was determined in two of the experiments performed applying the parent propyzamide. In these experiments, RH-24580 exhibited moderate to medium persistence. The peer review identified a data gap for a reliable aerobic soil period required for 50% dissipation (DT50) for metabolite RH-24580 from an incubation in at least a third soil where volatile trap analysis is included following Forum for the Co-ordination of Pesticide Fate Models and their Use (FOCUS) kinetic guidance regarding volatiles to complete the data set to the minimum of three reliable half-lives required by the guidance. Unextractable radioactivity increased up to 26.7% AR (after 120 days) and volatiles trapped in the alkaline trap (assumed to be CO2) increased up to a maximum of 47.6% AR (after 120 days).

Propyzamide degradation in soil under anaerobic conditions was investigated in one soil. In these conditions, the same metabolites already formed under aerobic conditions were identified.

Photolysis in soil was investigated in a soil under moist conditions (pF2) irradiated by a Xenon lamp at 20°C. Contribution of photolysis to degradation in soil of propyzamide was apparently marginal. No new metabolites were identified in this experiment.

Two of the field dissipation studies done in USA (Wisconsin and California), presented in the dossier for the first approval (Choo, 1996 in the RAR, 2015), have been found that meet the quality criteria and are still considered valid by the RMS. However, data from these studies would need to be reanalysed following current guidance and have not been used for this exposure assessment. Experiments in five European additional sites have been presented in the renewal dossier. Results from field dissipation studies are not normalised and are considered only as persistence trigger end points (propyzamide DissT90 = 65.2-215.5 days).

Predicted environmental concentration in soil (PECsoil) were calculated for parent propyzamide and metabolites RH-24644 and RH-24580 using worst-case laboratory aerobic half-life (DT50 = 195.2 days) and standard assumptions.

Reliable batch soil adsorption/desorption studies were performed with propyzamide (eight soils) and with metabolites RH-24644 (three soils), RH-24580 (four soils) and RH-24655 (seven soils). According to these studies, propyzamide and metabolite RH-24644 may be considered to exhibit slight to low mobility in soil, metabolite RH-24580 medium to high mobility and metabolite RH-24655 medium mobility.

A lysimeter study performed in Germany in two lysimeters for 1 and 2 years is also available. In both lysimeters, propyzamide and a number of metabolites are found in the leachate at levels above 0.1 ig/L.

Hydrolysis of propyzamide in water was investigated in buffered solutions (pH 5, 7 and 9) at 20 and 50°C. Propyzamide can be considered stable to hydrolysis under these conditions (< 10% hydrolysis).

Aqueous photolysis (direct and indirect) of propyzamide was investigated in different studies, both in buffered and natural water. According to these experiments, photolysis may contribute to the degradation of propyzamide into the aquatic environment, being the effect more significant in natural water or when indirect photolysis mechanisms can occur. Aqueous photolysis metabolites DCBA and 3,5-dichlorobenzamide trigger assessment with respect to the aquatic environment. In the absence of a readily biodegradation study, propyzamide is considered not to be readily biodegradable.

Propyzamide was stable under the conditions of the aquatic mineralisation study available (20°C). Fate and behaviour of propyzamide in dark water sediment systems under aerobic conditions was investigated in a study with two systems. Propyzamide partitioned slowly to the sediment (max. 44.5% AR after 30 days). Propyzamide was persistent in both systems (DT50 whole system = 79.5-119.6 days). One major metabolite was formed in the sediment phase: RH-24655 (max sed. 20.5% AR after 105 days, end of study). In the water phase, metabolite RH-23801 (max water 5% AR after 105 days, end of the study) was considered needing further assessment as its levels were still increasing at the end of the study.

PEC in surface water/sediment (PECSW/sed) were calculated for parent and metabolites RH-24644, RH-24580, RH-24655, DCBA, 3,5-dichlrobenzamide and RH-23801 with FOCUS SW tools up to step 2. FOCUS SW calculations up to step 3 were performed for parent and metabolites RH-24644, RH-24580, RH-24655. For parent propyzamide and metabolites, RH-24644 and RH-24580, it was necessary to consider possible mitigation equivalent to that resulting from 20 m buffer spray drift and run-off vegetative strips to conclude on the risk assessment. However, risk managers and others may wish to

note that while run-off mitigation is included in the step 4 calculations available, the FOCUS (FOCUS, 2007) report acknowledges that for substances with Freundlich organic carbon adsorption coefficient (KFoc) < 2,000 mL/g, the general applicability and effectiveness of run-off mitigation measures had been less clearly demonstrated in the available scientific literature, than for more strongly adsorbed compounds.

Potential for ground water contamination was assessed by calculation of 80th percentile of 20 years annual average leachate concentrations at 1 m depth with FOCUS GW PEARL 4.4.4 and FOCUS PELMO 5.5.3 models for the representative uses in winter oilseed rape and lettuce. For oilseed rape, different application dates (from September to February) were simulated. Also, yearly and triennial applications were simulated in order to take into account potential mitigating effect of rotation in this crop. Limit of 0.1 ig/L was not exceeded by parent propyzamide and metabolite RH-24644 for any of the seven relevant lettuce scenarios and of the six oilseed rape scenarios. Level of metabolite RH-24580 exceeded 0.1 ig/L in five to six lettuce scenarios and five of six oilseed rape scenarios when yearly application is simulated. In the case of triennial application in oilseed rape, metabolite RH-24580 still exceeds 0.1 ig/L in one of the scenarios. When yearly application is simulated, the calculated annual average concentration level of 0.75 ig/L in the leachate is exceeded by metabolite RH-24580 for a number of scenarios (four lettuce scenarios, one oilseed scenario for yearly applications). It is noted that as only two reliable soil degradation rates remain available for metabolite RH-24580 after the peer review, worst-case DT50 has been used for groundwater modelling following current guidance recommendations. Metabolite RH-24580 is considered a ground water toxicologically relevant metabolite as the parent is classified as carcinogenic category 2 and no studies are available to demonstrate that toxicological properties of the parent are not shared by RH-24580 (see Section 2). Therefore, a critical area of concern for potential ground water contamination is identified.

The fact that in the lysimeter experiments a number of metabolites are found in the leachate at annual average levels above 0.1 ig/L parent equivalents (one metabolite at the level > 0.75 ig/L) is considered a critical area of concern with respect to ground water contamination by propyzamide as long as the parent compound is classified as carcinogenic category 2 (in the absence of specific studies for the metabolites, these lysimeter metabolites should be considered as toxicologically relevant).

Propyzamide has been found at levels > 0.1 ig/L in ground water monitoring samples (Denmark, France, Italy and the UK) and in surface water (Denmark, France, Italy, Sweden and the UK). The highest reported concentration of propyzamide was 6 ig/L in ground water and 310 ig/L in surface water. During the peer review, some Member States informed that propyzamide is among the herbicides being detected in surface water, with reference to the Water Framework Directive4 and 0.1 ig/L limit and has been considered one of the top five surface water contaminants in the UK.

The applicant did not provide appropriate information to address the effect of water treatments 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; especially taking into account the findings of propyzamide in surface water and the classification of propyzamide as carcinogenic category 2. 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 is based on the following documents: SANCO/10329/2002 rev.2 final (European Commission, 2002a), SANCO/3268/2001 rev 4 (final) (European Commission, 2002b; SETAC, 2001; EFSA, 2009, 2013). According to Regulation (EU) No 283/20135, 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

4 Directive 2000/60/EC of the European Parliament and of the Council of 23 October 2000 establishing a framework for Community action in the field of water policy. OJ L 327, 22.12.2000, p. 1-72.

5 Commission Regulation (EU) No 283/2013 of 1 March 2013 setting out the data requirements for active substances, in accordance with Regulation (EC) No 1107/2009 of the European Parliament and of the Council concerning the placing of plant protection products on the market. OJ L 93, 3.4.2013, p. 44-127.

to the lack of a risk assessment scheme. Therefore, EFSA (2013) was used for risk assessment in order to reach a conclusion for the representative uses.

Propyzamide was discussed at the Pesticide Peer Review Meeting 144 (April 2016).

As indicated in the mammalian toxicology section, a data gap was identified for the assessment of the toxicological relevance of the impurities and a critical area of concern was identified for the composition of batches used in some (old) ecotoxicological studies, for which it was not possible to conclude whether they were representative of the technical specification.

A low acute risk via dietary exposure to birds and wild mammals was concluded for all representative uses of propyzamide.

Long-term reproductive studies were available for two avian species. The study on the species that appeared to be more sensitive (mallard duck) was discussed in the Pesticide Peer Review Meeting. The experts agreed that no reproductive no observed effect concentration (NOEC) could be set, as effects (up to 25%) on many parameters were detected at the lowest tested dose. Therefore, it was concluded that no suitable endpoint was available for the risk assessment (data gap).

A high long-term risk to wild mammals via dietary exposure was identified at the Tier I for all uses of propyzamide. A refined risk assessment was available. This was based on refined deposition factors on foodstuff together with residue decline data (refined time-weighted average factor (f(TWA))) on green matter. A low risk could be concluded for the lowest application rate of propyzamide on oilseed rape (500 g a.s./ha). However, a high risk was identified for all the other representative uses (data gap).

A low risk to wild mammals was concluded for exposure to propyzamide via secondary poisoning and via consumption of contaminated water. No toxicity data on terrestrial vertebrates were available for the two soil metabolites of propyzamide, RH-24644 and RH-24580. Based on the screening assessment (metabolites assumed 10 times more toxic than the parent), a high risk could not be excluded for earthworm-eating mammals (all uses and both metabolites) and for fish-eating mammals (uses on oilseed rape for RH-24644 only). A data gap is therefore identified.

The available data were sufficient to conclude a low acute and chronic risk to fish, aquatic invertebrates and algae exposed to propyzamide for all the uses and all the FOCUS step 3 scenarios, except the D2 for the representative uses on oilseed rape, where the chronic risk to fish was identified as high (toxicity exposure ratio (TER) slightly below the trigger). A high risk to macrophytes was identified for all scenarios and all uses in the risk assessment carried out with propyzamide PECs calculated with FOCUS step 3. Vegetated buffer strips up to 20 m wide were used as mitigation measures in the calculation of PECs at the step 4. With such PECs, high chronic risk to fish was still identified in the D2 scenario for the uses on oilseed rape (data gap). High risk to macrophytes was identified in four out of seven scenarios for the uses on lettuce and in two out of six scenarios for the uses on oilseed rape (data gap).

Only few experimental data were available to assess the risk posed by propyzamide metabolites to aquatic organisms. Where experimental data were not available, a screening assessment was carried out by considering that the metabolites were ten times more toxic than the parent.

Based on FOCUS step 4 PECs, a high chronic risk to fish due to exposure to the metabolite RH-24644 could not be excluded for one scenario for uses on both lettuce and oilseed rape. Also, a low risk to macrophytes due to exposure of both RH-24644 and RH-24580 could not be demonstrated for some FOCUS scenarios (data gap, applicable to all representative uses of propyzamide).

For the metabolites DCBA, 3,5-dichlorobenzamide and RH-23801 (UK1), PECs were only available at FOCUS step 1-2. Based on such PECs, a high risk could not be excluded for all uses (data gap). The assessment of the sediment metabolite RH-24655 (UK2) allowed concluding a low risk to sediment-dwelling organisms for all the representative uses of propyzamide.

The risk assessment to bees was performed by EFSA in accordance with EFSA (2013). No toxicity tests with the active substance were available. However, acute oral and contact studies were carried out with the formulation. Based on the endpoints from these tests, a low acute risk to honeybees was concluded for all routes of exposure. No information was provided regarding the chronic toxicity of propyzamide to adult honeybees and larvae (data gap). No assessment was available for sublethal effects (i.e. hypopharygeal glands (HPG), data gap) or for cumulative effects. No information was available regarding metabolites occurring in pollen and nectar (data gap). No data were available to perform a risk assessment for bumble bees and solitary bees.

A low risk to non-target arthropods was concluded for all representative uses of propyzamide.

In lack of toxicity data for the active substance propyzamide, the risk assessment to earthworms was carried out with the available data on the formulated product. A high risk to earthworms was identified for all uses of propyzamide with an application rate > 750 g a.s./ha (data gap). Folsomia

showed the greater sensitivity among soil organisms. A high risk to Folsomia was identified for all representative uses of propyzamide (data gap). The soil metabolite RH-24644 was also showing a high risk to earthworms (early application on lettuce, 1,500 g/ha) and to Folsomia (all uses of propyzamide on lettuce). No experimental data were available regarding the effects of the metabolite RH-24580 to earthworms. The screening assessment assuming that the metabolite is 10 times more toxic than the parent indicated that a high risk could not be excluded for any of the representative uses of propyzamide (data gap). A low risk was concluded for effects of propyzamide and its pertinent metabolites to Hypoaspis and soil microorganisms.

A high risk to non-target terrestrial plants was identified for all representative uses of propyzamide, unless mitigation measures are applied. No-spray buffer strips of from 5 to 10 m wide (depending on the application rate) are necessary to achieve a low risk for the uses of propyzamide on oilseed rape. For the uses on lettuce, a high risk was still identified even when 10 m buffer strips are in place (data gap).

A low risk is concluded for biological methods of sewage treatment.

With regard to the endocrine-disruption potential, as discussed in Section 2, it is unlikely that propyzamide is an endocrine disruptor in mammals. During the peer review, some concerns were raised regarding some alterations of the male vitellogenin (VGT) level and histopathological findings observed in one of the two short-term reproduction assays carried out with fish. Furthermore, some dose-unrelated effects were seen in one amphibian metamorphosis study. However, no clear evidence regarding endocrine-disrupting properties was identified. No firm conclusion can be drawn regarding fish and birds.

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

Propyzamide RH-24644 RH-24580 Moderate to high (DT50 = 13.9-271.3 days) Moderate to medium (DT50 = 24.5-65.2 days) Moderate to medium (DT50 = 52.2-71.8 days) High risk to soil organisms High risk to soil organisms High risk to soil organisms

DT50: period required for 50% dissipation.

Table 2: Groundwater

Compound (name

and/or code)

Mobility in soil

> 0.1 ig/L at 1 m depth for the representative uses

(at least one FOCUS scenario or relevant lysimeter)(a)

Pesticidal Toxicological activity relevance

Ecotoxicology

Propyzamide Slight to low (Kfoc = 7035,390 mL/g)

FOCUS GW: NO Lysimeter: No detected in leachate

High risk to aquatic

organisms living in surface waters

RH-24644 Slight to low FOCUS GW: No

(KFoc = 1,350- Lysimeter: No detected in 2,350 mL/g) leachate

Assessment Relevant because High risk to not of classification of aquatic

triggered the parent organisms living

compound as in surface carcinogen waters

category 2

Compound Mobi|ityin

^ d ) soil and/or code)

> 0.1 ig/L at 1 m depth for the representative uses

(at least one FOCUS scenario or relevant lysimeter)(a)

Pesticidal activity

Toxicological relevance

Ecotoxicology

RH-24580

Lysimeter metabolites U1 (2 components), U3, U4 (2 components), U5, U6 and U7 (all single component fractions if not indicated otherwise)

Medium to FOCUS GW: Yes, exceeded No data high 0.1 ig/L in five to six lettuce available

(KFoc = 112- scenarios (in four scenarios 210 mL/g) > 0.75 ig/L) and in five

oilseed rape scenarios (one > 0.75 ig/L) when yearly application is simulated. In the case of triennial application in oilseed rape metabolite, RH-24580 still exceeds 0.1 ig/L in one of the scenarios

No data FOCUS GW: No data No usable

(metabolites lysimeter: Yes, U1 up to data not chemically 0.24 ig/L, U3 up to available

identified) 0.24 ig/L, U4 up to

0.42 ig/L, U5 up to 0.77 ig/L, U6 up to 0.40 ig/L and U7 up to 0.20 ig/L (all given as parent equivalents)

Relevant because of classification of the parent compound as carcinogen category 2 No reference values can be set on the basis of the available data

Relevant because of classification of the parent compound as carcinogen category 2

High risk to aquatic

organisms living in surface waters

No data, not needed

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

(a): At least one FOCUS scenario or relevant lysimeter.

Table 3: Surface water and sediment

Compound (name and/or code)

Ecotoxicology

Propyzamide

RH-24644

RH-24580

RH-23801

RH-24655

3,5-Dichlorobenzoic acid 3,5-Dichlorobenzamide

High risk to aquatic organisms

High risk to aquatic organisms

High risk to aquatic organisms

High risk to aquatic organisms

Low risk to sediment-dwelling organisms

High risk to aquatic organisms

High risk to aquatic organisms

Table 4: Air

Compound (name and/or code) Toxicology

Propyzamide Rat LC50 > 2.1 mg/L air per 4 h

LC50: lethal concentration, median.

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).

• A more detailed assessment of the literature review for propyzamide and its relevant metabolites, dealing with side effects on health and published within 10 years before the date

of submission of the dossier, to be conducted and reported in accordance with 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) (relevant for all representative uses evaluated; submission date proposed by the applicant: unknown, relevant for all Sections).

• Validation data for method Kajdan for one impurity (relevant for all representative uses evaluated; submission date proposed by the applicant: unknown, see Section 1).

• Validation data of the method TM-87-34-01 for the determination of RH-20839 (relevant for all representative uses evaluated; submission date proposed by the applicant: unknown, see Section 1).

• Further assessment of the (eco)toxicological relevance of the impurities in the technical specification (relevant for all representative uses evaluated; submission date proposed by the applicant: unknown, see Sections 2 and 5).

• Comparative in vitro metabolism data addressing differences between the tested species and humans (relevant for all representative uses evaluated; submission date proposed by the applicant: unknown, see Section 2).

• Assessment of the toxicological profile of the plant metabolites identified in significant concentrations in primary and rotational crops (relevant for all representative uses evaluated; submission date proposed by the applicant: unknown, see Sections 2 and 3).

• Residue field trials, respectively, on lettuce and rapeseed and analysing the magnitude of residues of all metabolites included in the residue definition for risk assessment (relevant for all representative uses evaluated; submission date proposed by the applicant: unknown; see Section 3).

• Rotational crops field trials on leafy crops, root crops and small grain crops for the determination of propyzamide, mannoside conjugate of RH-25337 and glucoside of RH-26702 residues at 30 days PBI (relevant for all representative uses evaluated; submission date proposed by the applicant: unknown; see Section 3).

• Determination of the residues in pollen and bee products for human consumption resulting from residues taken up by honeybees from crops at blossom (relevant for the representative use on oilseed rape; submission date proposed by the applicant: unknown; see Section 3).

• A reliable aerobic soil DT50 for metabolite RH-24580 from an incubation in at least a third soil where volatile trap analysis is included following FOCUS kinetic guidance regarding volatiles is needed to complete the data set (relevant for all representative uses evaluated; submission date proposed by the applicant: unknown; see Section 4).

• Appropriate information to address the effect of water treatments 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 (relevant for all representative uses evaluated; submission date proposed by the applicant: unknown; see Section 4).

• A suitable reproductive avian endpoint for birds, protective for the effects seen on mallard duck (relevant for all representative uses evaluated; submission date proposed by the applicant: unknown; see Section 5).

• Further data to address the reproductive risk to wild mammals (relevant for all representative uses with an application rate > 500 g a.s./ha; submission date proposed by the applicant: unknown; see Section 5).

• Further data to address the risk to wild mammals due to exposure to RH-24644 and RH-24580 via secondary poisoning (relevant for all representative uses evaluated; submission date proposed by the applicant: unknown; see Section 5).

• Further data to address the chronic risk to fish due to exposure to propyzamide and the pertinent soil metabolites (RH-24644 and RH-24580) for the situations represented by the FOCUS scenarios where a high risk was identified (relevant for all representative uses evaluated; submission date proposed by the applicant: unknown; see Section 5).

• Further data to address the chronic risk to macrophytes due to exposure to propyzamide and the pertinent soil metabolites (RH-24644 and RH-24580) for the situations represented by the FOCUS scenarios where a high risk was identified (relevant for all representative uses evaluated; submission date proposed by the applicant: unknown; see Section 5).

• Further data to address the risk posed by the metabolites DCBA, 3,5-dichlorobenzamide and RH-23801 (UK1) to aquatic organisms (relevant for all representative uses evaluated; submission date proposed by the applicant: unknown; see Section 5).

• An oral chronic test on adult honeybees with propyzamide (relevant for all representative uses evaluated; submission date proposed by the applicant: unknown; see Section 5).

• Information to address the risk to bee brood posed by propyzamide (relevant for all representative uses evaluated; submission date proposed by the applicant: unknown; see Section 5).

• Suitable data to address the risk of sublethal effects (e.g. HPG development effects) to honeybees due to exposure to propyzamide (relevant for all representative uses evaluated; submission date proposed by the applicant: 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 applicant: unknown; see Section 5).

• Further data to address the risk posed by propyzamide to earthworms (relevant for all representative uses with an application rate > 750 g a.s./ha; submission date proposed by the applicant: unknown; see Section 5).

• Further data to address the risk posed by propyzamide to Folsomia candida (relevant for all representative uses evaluated; submission date proposed by the applicant: unknown; see Section 5).

• Further data to address the risk posed by propyzamide soil metabolites (RH-24644 and RH-24580) to soil organisms (relevant for all representative uses evaluated; submission date proposed by the applicant: unknown; see Section 5).

• Further data to address the risk to non-target terrestrial plants (relevant for the uses on lettuce; submission date proposed by the applicant: unknown; see Section 5).

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

• Vegetated buffer strips up to 20 m wide are necessary to protect aquatic organisms from exposure to propyzamide and its pertinent soil metabolites (RH-24644 and RH-24580) for the situations represented by some FOCUS scenarios (see details in the Appendix A and see Section 5).

• No-spray buffer zones up to 10 m are necessary to reduce the exposure of non-target terrestrial plants to propyzamide for the representative uses on oilseed rape (see Section 5).

• Use of PPE by the operators is required for the representative use on oilseed rape (see Section 2).

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 546/20116 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.

1) The consumer dietary risk assessment cannot be concluded on considering the identified data gaps, the outstanding data on the toxicity profile of the metabolites relevant in primary and rotational crops, ground water, water treatment procedures and the finalisation of the residue definition for risk assessment in plants (see Sections 2, 3 and 4).

2) Due to the lack of a suitable endpoint, protective for the effects seen on mallard duck, no reproductive risk assessment could be finalised for birds (see Section 5).

6 Commission Regulation (EU) No 546/2011 of 10 June 2011 implementing Regulation (EC) No 1107/2009 of the European Parliament and of the Council as regards uniform principles for evaluation and authorisation of plant protection products. OJ L 155, 11.6.2011, p. 127-175.

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 the 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.

3) High risk to F. candida was identified for all representative uses of propyzamide (see Section 5).

4) Potential groundwater contamination by soil metabolite RH-24580 and lysimeter leachate metabolites U1 (2 components), U3, U4 (2 components), U5, U6 and U7 (see Sections 4 and 5).

5) The batches used in the (eco)toxicological studies could not be concluded as representative of the technical specification (see Sections 2 and 5).

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

Lettuce 1,500 g a.s./ha BBCH 00-14

Lettuce 1,500 g a.s./ha BBCH 12-17

Winter Winter Winter

oilseed rape oilseed rape oilseed rape 840 g a.s./ha 750 g a.s./ha 500 g a.s./ha BBCH 1419 BBCH 1419 BBCH 1419

Operator risk

Worker risk

Resident/ bystander risk

Consumer risk

Risk to wild non-target terrestrial vertebrates

Risk identified Assessment not finalised Risk identified Assessment not finalised Risk identified Assessment not finalised Risk identified Assessment not finalised Risk identified Assessment not finalised

X1 X1 X1 X1 X1

X X X X

X2 X2 X2 X2 X2

Representative use

Lettuce 1,500 g a.s./ha BBCH 0014

Lettuce 1,500 g a.s./ha BBCH 1217

Winter Winter Winter

oilseed rape oilseed rape oilseed rape 840 g a.s./ha 750 g a.s./ha 500 g a.s./ha BBCH 1419 BBCH 1419 BBCH 1419

Risk to wild

non-target

terrestrial

organisms

other than

vertebrates

Risk to

aquatic

organisms

Groundwater exposure to active substance

Groundwater exposure to metabolites

Risk identified Assessment not finalised

Risk identified

Assessment not finalised Legal parametric value breached Assessment not finalised Legal parametric value breached Parametric value of 10 ig/L(a) breached

Assessment not finalised

(4 out of 7 FOCUS scenarios)

(4 out of 7 FOCUS scenarios)

(2 out of 6 FOCUS scenarios)

(2 out of 6 FOCUS scenarios)

(2 out of 6 FOCUS scenarios)

FOCUS: Forum for the Co-ordination of Pesticide Fate Models and their Use; a.s.: active substance; BBCH: growth stages of mono- and dicotyledonous plants.

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 2-6 for further information.

(a): Value for non-relevant metabolites prescribed in SANC0/221/2000-rev. 10 final, European Commission (2003).

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 (eco)toxicological reference values.

References

EFSA (European Food Safety Authority), 2009. Guidance on Risk Assessment for Birds and Mammals on request

from EFSA. EFSA Journal 2009;7(12):1438, 358 pp. doi:10.2903/j.efsa.2009.1438 EFSA (European Food Safety Authority), 2011. Submission of scientific peer-reviewed open literature for the approval of pesticide active substances under Regulation (EC) No 1107/2009. EFSA Journal 2011;9(2):2092,49 pp. doi:10.2903/j.efsa.2011.2092 EFSA (European Food Safety Authority), 2012. Reasoned opinion on the review of the existing maximum residue levels (MRLs) for propyzamide according to Article 12 of Regulation (EC) No 396/2005. EFSA Journal 2012; 10(4):2690, 54 pp. doi:10.2903/j.efsa.2012.2690 EFSA (European Food Safety Authority), 2013. EFSA Guidance Document on the risk assessment of plant protection products on bees (Apis mellifera, Bombus spp. and solitary bees). EFSA Journal 2013;11(7):3295, 268 pp., doi:10.2903/j.efsa.2013.3295 EFSA (European Food Safety Authority), 2016. Peer review report to the conclusion regarding the peer review of

the pesticide risk assessment of the active substance propyzamide. Available online: www.efsa.europa.eu EFSA PPR Panel (EFSA Panel on Plant Protection Products and their Residues), 2012. Guidance on dermal

absorption. EFSA Journal 2012;10(4):2665, 30 pp. doi:10.2903/j.efsa.2012.2665 EFSA Scientific Committee, 2013. Scientific Opinion on the hazard assessment of endocrine disruptors: scientific criteria for identification of endocrine disruptors and appropriateness of existing test methods for assessing effects mediated by these substances on human health and the environment. EFSA Journal 2013;11(3):3132, 84 pp. doi:10.2903/j.efsa.2013.3132

European Commission, 2000a. Residues: guidance for generating and reporting methods of analysis in support of pre-registration data requirements for Annex II (Part A, Section 4) and Annex III (Part A, Section 5) of Directive 91/414. SANCO/3029/99-rev. 4, 11 July 2000.

European Commission, 2000b. Technical material and preparations: guidance for generating and reporting methods of analysis in support of pre- and post-registration data requirements for Annex II (Part A, Section 4) and Annex III (Part A, Section 5) of Directive 91/414. SANCO/3030/99-rev. 4, 11 July 2000.

European Commission, 2002a. Guidance Document on Terrestrial Ecotoxicology under council directive 91/414/ EEC. SANCO/10329/2002-rev. 2 final, 17 October 2002.

European Commission, 2002b. Guidance Document on Aquatic Ecotoxicology under council directive 91/414/EEC. SANCO/3268/2001-rev. 4 final, 17 October 2002.

European Commission, 2003. Guidance Document on Assessment of the Relevance of Metabolites in Groundwater of Substances Regulated under Council Directive 91/414/EEC. SANCO/221/2000-rev. 10 final, 25 February 2003.

European Commission, 2007. Review report for the active substance propyzamide. Finalised in the Standing Committee on the Food Chain and Animal Health at its meeting on 26 February 2003 in view of the inclusion of propyzamide in Annex I of Council Directive 91/414/EEC. SANCO/6502/VI/99-Final, 9 October 2007 (final revision), 63 pp.

European Commission, 2010. Guidance Document on residue analytical methods. SANCO/825/00-rev. 8.1, 16 November 2010.

European Commission, 2012. Guidance document on the assessment of the equivalence of technical materials of substances regulated under Regulation (EC) No 1107/2009. SANCO/10597/2003-rev. 10.1, 13 July 2012.

European Commission, 2013. Guidance document on data requirements on efficacy for the dossier to be submitted for the approval of new active substances contained in plant protection products. SANCO/10054/ 2013-rev. 3, 11 July 2013.

European Commission, 2015. Guidelines on comparability, extrapolation, group tolerances and data requirements for setting MRLs. SANCO 7525/VI/95-rev. 10.1. December 2015. p.1-56.

FOCUS (Forum for the Co-ordination of Pesticide Fate Models and their Use), 2007. Landscape and mitigation factors in aquatic risk assessment. Volume 1. Extended summary and recommendations. Report of the FOCUS Working Group on Landscape and Mitigation Factors in Ecological Risk Assessment. EC Document Reference SANCO/10422/2005 v. 2.0, 169 pp.

JMPR (Joint Meeting on Pesticide Residues), 2004. Report of the Joint Meeting of the FAO Panel of Experts on Pesticide Residues in Food and the Environment and the WHO Core Assessment Group on Pesticide Residues, Rome, Italy, 20-29 September 2004, 383 pp.

JMPR (Joint Meeting on Pesticide Residues), 2007. Report of the Joint Meeting of the FAO Panel of Experts on Pesticide Residues in Food and the Environment and the WHO Core Assessment Group on Pesticide Residues, Geneva, Switzerland, 18-27 September 2007, 164 pp.

OECD (Organisation for Economic Co-operation and Development), 2011. OECD MRL calculator: spreadsheet for single data set and spreadsheet for multiple data set, 2 March 2011. In: Pesticide Publications/Publications on Pesticide Residues. Available online: www.oecd.org

SETAC (Society of Environmental Toxicology and Chemistry), 2001. Guidance document on regulatory testing and risk assessment procedures for plant protection products with non-target arthropods. ESCORT 2.

Sweden, 2015. Renewal assessment report (RAR) on the active substance propyzamide prepared by the rapporteur Member State Sweden in the framework of Regulation (EC) No 844/2012, July 2015. Available online: www.efsa.europa.eu

Sweden, 2016. Revised renewal assessment report (RAR) on propyzamide prepared by the rapporteur Member State Sweden in the framework of Regulation (EC) No 844/2012, April 2016. Available online: www.efsa.europa.eu

Abbreviations

a.s. active substance

ADI acceptable daily intake

AAOEL acute acceptable operator exposure level

AOEL acceptable operator exposure level

AR applied radioactivity

ARfD acute reference dose

BBCH growth stages of mono- and dicotyledonous plants

bw body weight

CAR constitutive androstane receptor

co-RMS co-rapporteur Member State

DAT days after treatment

DCBA 3,5-dichlorobenzoic acid

DT50 period required for 50% dissipation (define method of estimation)

F(twa)

LC-MS/MS

PECsed

PECsoil

PPARa PPE PRIMO QC

QuEChERS RAR RMS SC

SMILES

European Economic Community time-weighted average factor

Forum for the Co-ordination of Pesticide Fate Models and their Use Good Agricultural Practice growth stage hypopharygeal glands

International Organization for Standardization International Union of Pure and Applied Chemistry

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)

Freundlich organic carbon adsorption coefficient lethal concentration, median

liquid chromatography with tandem mass spectrometry

lowest observable adverse effect level

limit of quantification

maximum residue level

no observed adverse effect level

no observed effect concentration

Organisation for Economic Co-operation and Development plant back interval

predicted environmental concentration predicted environmental concentration in sediment predicted environmental concentration in soil predicted environmental concentration in surface water peroxisome proliferator-activated receptor alpha personal protective equipment (EFSA) Pesticide Residues Intake Model quality control

quick, easy, cheap, effective and safe method

renewal assessment report

rapporteur Member State

suspension concentrate

simplified molecular-input line-entry system

toxicity exposure ratio

total radioactive residue

time-weighted average

uncertainty factor

vitellogenin

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 OSupporting information' section): http://dx.doi.org/10.2903/j.efsa.2016.4554

Appendix B - Used compound codes

Code/trivial name(a) Chemical name/SMILES notation

Structural formula

RH-24644

RH-24580

RH-24848

RH-25891

2-(3,5-Dichlorophenyl)-4,4-dimethyl-5-methylene-

4,5-dihydro-1,3-oxazole

Clc1cc(Cl)cc(c1)C2=NC(C)(C)C(=C)O2

3,5-Dichloro-N-(2-methyl-3-oxobutan-2-yl)benzamide Clc1cc(cc(Cl)c1)C(=O)NC(C)(C)C(C)=O

3,5-Dichloro-N-(1-hydroxy-2-methylpropan-2-yl) benzamide

Clc1cc(cc(Cl)c1)C(=O)NC(C)(C)CO

[2-(3,5-Dichlorophenyl)-4,4-dimethyl-4,5-dihydro-1,3-

oxazol-5-yl]methanol

CC1(C)N=C(OC1CO)c2cc(Cl)cc(Cl)c2

O H3C HO

RH-26521

RH-26059

3,5-Dichloro-N-[(3RS)-3,4-dihydroxy-2-methylbutan- ci 2-yl]benzamide

Clc1cc(cc(Cl)c1)C(=O)NC(C)(C)C(O)CO

3-(3,5-Dichlorobenzamido)-3-methylbutanoic acid Clc1cc(cc(Cl)c1)C(=O)NC(C)(C)CC(=O)O

3,5-Dichlorobenzoic 3,5-Dichlorobenzoic acid acid (DCBA) Clc1cc(cc(Cl)c1)C(=O)O

3,5- 3,5-Dichlorobenzamide

Dichlorobenzamide Clc1cc(cc(Cl)c1)C(N)=O

CH3 OH

CH3 OH

RH-25337

3,5-Dichloro-N-[(3RS)-3-hydroxy-2-methylbutan-2-yl] Cl benzamide

Clc1cc(cc(Cl)c1)C(=O)NC(C)(C)C(C)O /

CH3 CH3

CH3 OH

Code/trivial name(a) Chemical name/SMILES notation

Structural formula

RH-26702

RH-24655 (UK2)

RH-23801 (UK1)

RH-27414

U1, U3, U4, U5, U6, U7

3,5-Dichloro-N-(4-hydroxy-2-methyl-3-oxobutan-2-yl) benzamide

Clc1cc(cc(Cl)c1)C(=O)NC(C)(C)C(=O)CO

3,5-Dichloro-N-(2-methylbut-3-en-2-yl)benzamide Clc1cc(cc(Cl)c1)C(=O)NC(C)(C)C=C

3-Chloro-N-(2-methylbut-3-yn-2-yl)benzamide O=C(NC(C)(C)C#C)c1cc(Cl)ccc1

(2RS)-3-(3,5-Dichlorobenzamido)-2-hydroxy-3-methylbutanoic acid

Clc1cc(cc(Cl)c1)C(=O)NC(C)(C)C(O)C(=O)O

Uncharacterised lysimeter metabolites

O O CH3

CH3 OH

Uncharacterised lysimeter metabolites

SMILES: simplified molecular-input line-entry system.

(a): The compound name in bold is the name used in the conclusion.