Peer review of the pesticide risk assessment of the active substance iprodione
2016; Wiley; Volume: 14; Issue: 11 Linguagem: Inglês
10.2903/j.efsa.2016.4609
ISSN1831-4732
Tópico(s)Insect and Pesticide Research
ResumoEFSA JournalVolume 14, Issue 11 e04609 Conclusion on Pesticides Peer ReviewOpen Access Peer review of the pesticide risk assessment of the active substance iprodione European Food Safety Authority (EFSA), European Food Safety Authority (EFSA)Search for more papers by this author European Food Safety Authority (EFSA), European Food Safety Authority (EFSA)Search for more papers by this author First published: 28 November 2016 https://doi.org/10.2903/j.efsa.2016.4609Citations: 6 Correspondence: pesticides.peerreview@efsa.europa.eu Requestor: European Commission Question number: EFSA-Q-2014-00814 Approved: 14 October 2016 AboutSectionsPDF ToolsExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat 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, France, and co-rapporteur Member State, Belgium, for the pesticide active substance iprodione 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 iprodione as a fungicide on carrots and lettuce. The reliable endpoints, 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. Iprodione 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), France, and co-rapporteur Member State (co-RMS), Belgium, received an application from BASF Agro BV for the renewal of approval of the active substance iprodione. Complying with Article 8 of the Regulation, the RMS checked the completeness of the dossier and informed the applicant, the co-RMS, the European Commission and the European Food Safety Authority (EFSA) about the admissibility. The RMS provided its initial evaluation of the dossier on iprodione in the renewal assessment report (RAR), which was received by EFSA on 3 November 2015. In accordance with Article 12 of the Regulation, EFSA distributed the RAR to the Member States and the applicant, BASF Agro BV, for comments on 9 December 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 8 February 2016. 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, environmental fate and behaviour and ecotoxicology. In accordance with Article 13(1) of the Regulation, EFSA should adopt a conclusion on whether iprodione 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 iprodione as a fungicide on field application carrots and lettuce and greenhouse application in lettuce, 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 proposed representative uses of iprodione result in a sufficient fungicidal efficacy against the target organisms. A data gap was identified for a more detailed assessment of the literature review for relevant metabolites of iprodione in the residue, environmental fate and behaviour and ecotoxicology Sections and published within 10 years before the date of submission of the dossier, to be conducted and reported in accordance with EFSA guidance. In the area of identity, physical and chemical properties and analytical methods, data gaps were identified for the data generation methods, the assessment of the extraction efficiency of the methods for the determination of residues in plant and animal matrices, for a method of monitoring a metabolite in groundwater and for a method for body fluids and tissues. In the area of mammalian toxicology and non-dietary exposure, data gaps, issues that could not be finalised and critical area of concerns were identified. The technical specification is not covered by toxicity studies, the genotoxic potential of metabolite RP 30228 cannot be excluded, the peer review classification of iprodione as 'Carc. Cat. 1B (H350)', the potential for endocrine disruption of iprodione and the relevance of groundwater metabolites RP 35606 and RP 30181 were considered critical areas of concern. Operator exposure estimates according to the supported indoor uses in lettuce could not be finalised. Data gaps were identified to support the technical specification and the maximum content of RP 30228 and to address the toxicological profile of metabolites RP 35606, RP 30181, RP 25040, RP 37176, RP 36112, RP 36221 and LS 720942. In the area of residues, a number of data gaps were identified and only provisional residue definitions for risk assessment could be derived. Based on a preliminary consumer risk assessment, that is likely underestimating exposure to metabolite 3,5-dichloroaniline, acute intake concerns cannot be excluded for the representative uses (carrots and lettuce). Moreover, a genotoxicity concern could not be excluded for the major residue metabolite RP 30228. Both issues have been identified as critical area of concern. The data available on environmental fate and behaviour are sufficient to carry out the required environmental exposure assessments at the European Union (EU) level for the representative uses with some notable exceptions. 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. Furthermore, the proposed route of degradation in soil was incomplete since it was based only on phenyl-labelled iprodione studies. This leads to a data gap for investigating the fate and behaviour of the hydantoin moiety iprodione in soil. The potential for groundwater exposure by metabolite RP 35606 (in acidic soils only), and by metabolite RP 30181 is predicted to be high over a wide range of geoclimatic conditions represented by the Forum for the Co-ordination of Pesticide Fate Models and their Use (FOCUS) groundwater scenarios. According to the information available in the mammalian toxicology Section, these metabolites are considered relevant due to the proposed classification for parent compound by the peer review experts as carcinogenic and toxic for the development and reproduction leading to a critical area of concern. In the area of ecotoxicology, data gaps have been identified for birds, mammals, aquatic organisms, bees and to further address the potential for endocrine disruption of iprodione in fish. The long-term risk assessment for wild mammals could not be finalised due to the lack of a reliable endpoint. Critical areas of concerns have been identified to further address the long-term risk for aquatic organisms to iprodione and for the compliance of the batches used in the ecotoxicity studies with the technical specification. 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 the 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 France and co-RMS Belgium received an application from BASF Agro BV for the renewal of approval of the active substance iprodione. Complying with Article 8 of the Regulation, the RMS checked the completeness of the dossier and informed the applicant, the co-RMS, the European Commission and EFSA about the admissibility. The RMS provided its initial evaluation of the dossier on iprodione in the RAR, which was received by EFSA on 3 November 2015 (France, 2015). In accordance with Article 12 of the Regulation, EFSA distributed the RAR to the Member States and the applicant, BASF Agro BV, for consultation and comments on 9 December 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 8 February 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 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, the RMS France and co-RMS Belgium on 25 March 2016. 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, 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 the Member States via a written procedure in September 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 iprodione as a fungicide on carrots and lettuce as proposed by the applicant. 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, 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 (25 March 2016); the evaluation table (11 October 2016); the report(s) of the scientific consultation with the Member State experts; the comments received on the assessment of the additional information; the comments received on the draft EFSA conclusion. Given the importance of the RAR, including its revisions (France, 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 Iprodione is the ISO common name for 3-(3,5-dichlorophenyl)-N-isopropyl-2,4-dioxoimidazolidine-1-carboxamide (IUPAC). The representative formulated product for the evaluation was 'Rovral WG (BAS 610 06 F)' a water-dispersible granule (WG) containing 750 g/kg iprodione. The representative uses evaluated were foliar spray field applications for the control of fungal diseases in carrots and lettuce and greenhouse application in lettuce. 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 representative uses of iprodione proposed at the EU level result in a sufficient fungicidal efficacy against the target organisms, following the guidance document SANCO/10054/2013-rev. 3 (European Commission, 2013). A data gap has been identified for a search of the scientific peer-reviewed open literature on metabolites RP 25040, LS 720942 and RP 30181, dealing with side effects on the environment and non-target species and for an updated literature search for 3,5-dichloroaniline for residue Section 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 first approval was updated. The proposed specification is based on batch data from industrial scale production and on quality control data. The minimum purity of the active substance as manufactured is 980 g/kg, meeting the requirements of the FAO specification under the new procedure (FAO, 2006) of min. 960 g/kg. The impurity 3,5-dichloroaniline (RP 32596) was considered relevant with a maximum amount of 0.5 g/kg, while the maximum level of the relevant impurity RP 30228 could not be established (See Section 2). 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 iprodione or the representative formulation. The main data regarding the identity of iprodione and its physical and chemical properties are given in Appendix A. The methods for the generation of pre-approval data required for the risk assessment, in the physicochemical tests, toxicity and ecotoxicity studies, except residues, were not adequately addressed (data gap). High-pressure/high-performance liquid chromatography-ultraviolet (HPLC-UV) methods are available for the determination of iprodione in the technical material and in the representative formulation, and for the determination of the respective impurities in the technical material. Iprodione residues can be monitored in food and feed of plant origin by HPLC with tandem mass spectrometry (HPLC–MS/MS) with a limit of quantification (LOQ) of 0.01 mg/kg in all plant commodity groups. Extraction efficiency was, however, demonstrated only for high water content commodities. An adequate HPLC–MS/MS method exists for the determination of RP 32490 in products of animal origin with a LOQ of 0.01 mg/kg in milk, egg, meat, liver, kidney and fat. A data gap was, however, identified for demonstration of the extraction efficiency in animal matrices. Residues of iprodione in soil can be determined by HPLC–MS/MS with a LOQ of 0.005 mg/kg, while in air by gas chromatography-electron capture detector (GC-ECD) with a LOQ of 2 μg/m3. Monitoring of the compounds of the residue definition for surface water (iprodione and metabolite RP 35606) can be done by HPLC–MS/MS with LOQs of 0.03 μg/L for each compound. As the residue definition for monitoring in ground water was defined as iprodione and metabolites RP 35606 and RP 30181 (see Sections 2 and 4), a data gap was identified for a method for the determination of metabolite RP 30181 in ground water. A data gap was identified for a method for monitoring iprodione in body fluids and tissues. 2 Mammalian toxicity The toxicological profile of the active substance iprodione was discussed at the Pesticides Peer Review Experts' Meeting 143 and assessed based on the following guidance documents: SANCO/221/2000-rev. 10-final (European Commission, 2003), 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). To assess the toxicological profile of the active substance, the applicant submitted a set of toxicity studies. The toxicity studies, however, were not representative of the proposed technical specification for the active substance and associated impurities leading to a critical area of concern. 3,5-dichloroaniline (RP 32596) is a relevant impurity (maximum content 0.5 g/kg). Impurity RP 30228 is considered potentially relevant based on genotoxic concerns; however, its maximum content from the toxicological point of view cannot be established (data gap, see Section 7). In the toxicokinetics studies, iprodione was extensively and rapidly absorbed. Oral absorption was estimated to be greater than 60%. There was no evidence for accumulation. Excretion of the active substance was predominantly through the urine but with appreciable amounts excreted in the faeces. The main metabolic pathway identified was hydroxylation of the aromatic ring, degradation of the isopropylcarbamoyl chain and rearrangement followed by cleavage of the hydantoin moiety. Metabolic patterns in rats and humans were similar. No unique human metabolite is expected. In the acute toxicity studies, the substance has low acute toxicity when administered orally, dermally or by inhalation to rats. It is not a skin or eye irritant or a skin sensitiser. A phototoxicity and photogenotoxicity test are not required for iprodione. In short-term oral toxicity studies with rats, mice and dogs, the toxicity targets were the adrenals (rats, mice, dogs), liver (mice), haematology (dogs), kidney (dogs), prostate (dogs), uterus and ovary (rats). Non-specific critical effects as reduced body weight gain and food consumption were also observed in rats. Although the dog was considered the most sensitive species during expert consultation some effects were observed in rats at similar dose range than in dogs. It was considered probable (due to dose-dependent increases) that there were some effects in the liver, adrenals and prostate at 500 ppm (30.8 mg/kg body weight (bw) per day) onwards, but the majority of experts considered that these are not adverse (in this study) at 500 ppm. The overall relevant short-term oral no observed adverse effect level (NOAEL) is 17.5 mg/kg bw per day (1-year dog studies). During the expert consultation, it was also discussed whether the adrenals effects (considered effects on a target organ) would give rise to a possible classification as STOT RE 2. These effects were consistent among studies and species and probably related to more than one mechanism. It was concluded that the severity of the effects at the relevant dose levels for classification may be considered as marginal. Based on available genotoxicity studies, the substance is unlikely to be genotoxic. However, data gaps were identified for a new in vitro gene mutation and an Ames test including strain TA102 performed with the representative technical specification. In long-term toxicity and carcinogenicity studies with rats and mice, the toxicity targets were the liver, adrenals, testes, epidydimides, seminal vesicles, prostate and spleen in rats and the liver, testes, non-glandular stomach, uterus, ovaries, spleen, kidney and adrenals in mice. The rat was the most sensitive species. The long-term NOAEL in the 2-year rat study was discussed during the expert's meeting: the experts considered that effects observed at the lowest dose of 6.1 mg/kg bw per day tested were adverse and a NOAEL could not be identified (i.e. NOAEL < 6 mg/kg bw per day). On the basis of the reassessment of long-term toxicity and carcinogenicity studies, new mechanistic data and taking into account guidance on the application of the new classification, labelling and packaging (CLP) Criteria (ECHA, 2015), the carcinogenic potential was also discussed during the experts' meeting: the majority of the experts considered that tumours observed in several organs and in different species (interstitial Leydig cell tumours in rats and ovary luteomas, benign and malignant liver cell tumours in mice), as well as progression to malignancy in liver tumours (and possibly pituitary adenocarcinoma); and a plausible endocrine-mediated (antiandrogenic) mode of action would suggest that classification as 'Carc. Cat. 1B (H350)' would be more appropriate for iprodione than current harmonised classification as 'Carc. Cat. 2 (H351)'3 leading to a critical area of concern. In reproductive toxicity studies, fertility and overall reproductive performance was not impaired; however, increased abnormal sperm was observed in F1. Iprodione has been shown to induce developmental toxicity, i.e. delayed onset of male puberty and persistence of areolas in the two-generation study and umbilical hernia in the rabbit developmental toxicity study. Mechanistic studies indicated that iprodione is an antiandrogenic compound. The parental NOAEL is 26.9 mg/kg bw per day, whereas a reproductive and offspring NOAEL could not be identified (i.e. the lowest dose tested of 26.9 mg/kg bw per day was the lowest observable adverse effect level (LOAEL)). In developmental toxicity studies, the maternal NOAEL is 20 mg/kg bw per day for both rats and rabbits, the developmental NOAEL is 20 mg/kg bw per day for the rat, whereas a developmental NOAEL in rabbits could not be identified (i.e. the lowest dose tested of 20 mg/kg per day was the LOAEL). On the basis of the reassessment of reproductive toxicity studies, new mechanistic data and taking into account guidance on the application of the CLP Criteria (ECHA, 2015) the adverse effects observed in the reproductive toxicity studies and adverse effects in reproductive organs in other toxicity studies, as well as the results of the mechanistic studies, suggest that classification regarding reproductive toxicity would be required for iprodione as 'toxic for reproduction category 2 (H361df)'3. The applicant did not submit neurotoxicity studies; however, no potential for neurotoxicity was observed in the standard toxicity studies. Iprodione has currently harmonised classification as carcinogenic category 2. During the experts' meeting, the experts considered more appropriate classification as carcinogenic category 1B and toxic for reproduction category 2. On this basis 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 met leading to a critical area of concern. This is supported by the available scientific evidence where iprodione is shown to be antiandrogenic compound and has adverse effects on different endocrine organs at the dose levels triggering the LOAEL in several toxicity studies. During the first review of iprodione (European Commission, 2002a), the NOAEL of 6 mg/kg bw per day from the 2-year rat study was used for setting the acceptable daily intake (ADI) of 0.06 mg/kg bw per day, applying an uncertainty factor (UF) of 100. The previously considered NOAEL for the 2-year rat study of 6 mg/kg bw per day has been changed to a LOAEL. Therefore, the experts proposed an additional UF of 3. Consequently, the ADI is set at 0.02 mg/kg bw per day instead of the previous one of 0.06 mg/kg bw per day. An acute reference dose (ARfD) was not set during the first review. The experts agreed that an ARfD was needed for iprodione on the basis of developmental toxicity. The agreed ARfD is 0.06 mg/kg bw based on the LOAEL of 20 mg/kg bw per day for increased incidence of umbilical hernia observed in the developmental toxicity study in rabbits. An additional UF of 3 to the standard 100 considering the use of a LOAEL was applied. During the first review of iprodione, the systemic acceptable operator exposure level (AOEL) was set at 0.3 mg/kg bw per day based on the results of the 90-day rat study (NOAEL of 31 mg/kg bw per day) and using an UF of 100. The experts considered more appropriate to set the AOEL on the same basis of the ARfD. A correction factor of 60% for oral absorption is needed to derive the AOEL. The agreed AOEL is 0.04 mg/kg bw per day. The experts agreed to set the systemic acute acceptable operator exposure level (AAOEL) on the same basis of the AOEL. The agreed AAOEL is 0.04 mg/kg bw. The RMS estimated non-dietary exposure (i.e. operator, worker, bystander and resident) considering dermal absorption values of iprodione in 'BAS 610 06 F' of 0.2% for the concentrate and of 12% for the dilution as input values. The intended use with 'BAS 610 06 F' is as a fungicide in lettuce and carrots for open field and lettuce for greenhouse (protected permanent structure). Non-dietary exposure estimates are below the AOEL for the operator (wearing personal protective equipment (PPE)), the bystander, the resident4 and the worker5 (wearing PPE) for the intended uses of 'BAS 610 06 F'. However, operator exposure in greenhouse was estimated according to the European Crop Protection Association (ECPA) greenhouse model that it is not an agreed EU model. The applicant was requested to provide non-dietary exposure estimates according to the Dutch model. Nevertheless, the applicant only submitted worker exposure calculation according to the European Predictive Operator Exposure Model (EUROPOEM) II/Dutch model leading to a data gap and issue that could not be finalised for operator exposure estimates for indoor lettuce use. Available information on metabolites RP 32490 and RP 36114 indicated that the reference values for iprodione are applicable to both metabolites. Metabolite 3,5-dichloroaniline (RP 32596) is unlikely to be genotoxic. The ADI for the metabolite is 0.0005 mg/kg bw per day, based on the NOAEL of 1 mg/kg bw per day for anaemic changes observed in the 90-day study in rats, applying an UF of 2,000. The ARfD is 0.0075 mg/kg bw, based on the NOAEL of 7.5 mg/kg bw per day for haematological changes from the 28-day study in rats applying an UF of 1,000. Reference values of 3,5-dichloroaniline are also applicable to metabolite M 610F007. Metabolite RP 30228 is predicted to occur in groundwater above 0.1 μg/L in one scenario according to the representative uses (see Section 4). The metabolite is considered relevant due to genotoxic concerns (i.e. positive in the in vitro micronucleus (MN) test and equivocal in the in vivo MN test) and due to the proposed classification for the parent compound by the peer review experts as carcinogenic and toxic for the development and reproduction. Metabolite RP 30228 is also found on crop metabolism studies (see Section 3). Since there are genotoxicity concerns, the setting of reference values for the metabolite is not possible leading to a critical area of concern. No conclusion could be reached regarding the genotoxic potential or toxicological profile of RP 25040, RP 37176 and RP 36112. Metabolites RP 36221 and LS 720942 are unlikely to be genotoxic. However, no conclusion was reached regarding their toxicological profile. No data on metabolite RP 35606 predicted to occur in groundwater above 0.1 μg/L are ava
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