Conclusion on the peer review of the pesticide human health risk assessment of the active substance chlorpyrifos 1

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1 EFSA Journal 2014;12(4):3640 ABSTRACT CONCLUSION ON PESTICIDE PEER REVIEW Conclusion on the peer review of the pesticide human health risk assessment of the active substance chlorpyrifos 1 European Food Safety Authority 2 European Food Safety Authority (EFSA), Parma, Italy The European Food Safety Authority (EFSA) was asked by the European Commission to perform a human health risk assessment of chlorpyrifos. In this context the conclusions of EFSA concerning the toxicological risk assessment and the human health risk assessment for the active substance chlorpyrifos are reported. The context of the evaluation was that required by the European Commission in accordance with Article 21 of Regulation (EC) No 1107/2009 to review the approval of active substances in light of new scientific and technical knowledge and monitoring data. The conclusions were reached on the basis of the evaluation of the authorised representative uses of chlorpyrifos as an insecticide on table and wine grapes. The reliable endpoints concluded as being appropriate for use in regulatory risk assessment, derived from the available studies and literature in the dossier peer reviewed, are presented. Missing information identified as being required by the regulatory framework is listed. Concerns are identified for re-entry workers for all representative uses. The use of chlorpyrifos on table grapes according to the GAP defined as a single application at 648 g a.s./ha leads to a significant exceedance of the acute reference dose (ARfD). European Food Safety Authority, 2014 KEY WORDS chlorpyrifos, peer review, risk assessment, pesticide, insecticide 1 On request from the European Commission, Question No EFSA-Q , approved on 7 April Correspondence: pesticides.peerreview@efsa.europa.eu Suggested citation: EFSA (European Food Safety Authority), Conclusion on the peer review of the pesticide human health risk assessment of the active substance chlorpyrifos. EFSA Journal 2014;12(4):3640, 34 pp. doi: /j.efsa Available online: European Food Safety Authority, 2014

2 SUMMARY Chlorpyrifos was included in Annex I to Directive 91/414/EEC on 1 July 2006 by Commission Directive 2005/72/EC, and has been deemed to be approved under Regulation (EC) No 1107/2009, in accordance with Commission Implementing Regulation (EU) No 540/2011, as amended by Commission Implementing Regulation (EU) No 541/2011. In June 2011, chlorpyrifos has been subject to a US EPA preliminary human health risk assessment based on new toxicological studies which lead to determination of toxicological reference values lower than those identified from EU assessment outcomes. On 6 June 2012, DG SANCO required the Task Force representative for chlorpyrifos to provide to the Commission, to EFSA and to Spain as rapporteur Member State (RMS), the toxicological studies which have been published since the approval of the substance and which constitute scientific peer reviewed open literature and also those studies which have been submitted to the US EPA review. On 19 July 2012, DG SANCO sent a mandate to the RMS to prepare Addenda to the original Assessment Report, taking into account those recent studies. The RMS finalised these Addenda in March 2013 and forwarded them to the Commission and EFSA. On 29 April 2013 EFSA received a request from the Commission to organise an expert consultation and to provide its conclusions concerning an updated toxicological risk assessment of chlorpyrifos and to review completely the human health risk assessment. EFSA prepared an Addendum giving an overview of the concerns of the chlorpyrifos mammalian toxicological risk assessment in May June On 19 June 2013 the EFSA Addendum and the RMS Addenda were distributed to Member States and the applicant for consultation and comments. The comments received were collated by EFSA and compiled in the format of a Reporting Table. The RMS and the applicant were invited to respond to the comments in column 3 of the Reporting Table. Following consideration of the comments received on the Addenda, expert consultation points were proposed and discussed in the Pesticide Peer Review meeting 106 on mammalian toxicology in September The experts agreed on the use of the Red Blood Cell cholinesterase inhibition to derive the reference values. As this is not a standard approach, EFSA proposed to seek endorsement of this new approach by its Panel on Plant Protection Products and their Residues (PPR Panel) at its meeting of February 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 March The conclusions laid down in this report were reached on the basis of the evaluation of the authorised representative uses of chlorpyrifos as an insecticide on table and wine grapes. Full details of the representative uses can be found in Appendix A to this report. The new available toxicological data lead to the decrease of the reference values established in 2005: the Pesticides Peer Review meeting agreed on a new ADI and AOEL of mg/kg bw per day, and an ARfD of mg/kg bw, based on significant decrease of RBC ChE in rats, using an uncertainty factor of 100. This approach was endorsed by the PPR Panel. The operator exposure assessment shows levels below the AOEL only with the use of Personal Protective Equipment; for all the re-entry scenarios the exposure exceeds the AOEL. It is noted, however, that the dermal absorption value applied for the estimates is based on human data and is not specific for the different formulations considered in this conclusion. EFSA Journal 2014;12(4):3640 2

3 Considering the new toxicological reference values proposed for chlorpyrifos, EFSA recommends to set two separate residue definitions and to perform two separate consumer risk assessments, for chlorpyrifos and TCP respectively. Insufficient data were submitted to confirm that the uses of chlorpyrifos on table and wine grapes according the cgap initially supported for Annex I inclusion will not result in a consumer health risk. The alternative cgap proposed for table grapes and defined as a single application at 648 g a.s./ha with a 21 day PHI, results in a significant exceedance of the ARfD. No acute or chronic consumer intake concerns were identified when chlorpyrifos is applied on wine grapes with two applications at 360 g a.s./ha and a 21 day PHI. However, some uncertainties related to the residue definition applicable to processed commodities need to be addressed. The environmental risk assessment is out of the scope of this mandate and has not been performed. It needs to be highlighted that in the original DAR of chlorpyrifos the GAP was at a dose of 342 g a.s./ha. However, after the ecotoxicology evaluation, the dose was reduced to 245 g a.s./ha to identify a safe use. No environmental risk assessment has been performed for the new critical GAPs defined as one application at 648 g a.s./ha for table grapes and two applications at 360 g/ha for wine grapes. EFSA Journal 2014;12(4):3640 3

4 TABLE OF CONTENTS Abstract... 1 Summary... 2 Table of contents... 4 Background... 5 The active substance and the formulated product... 7 Conclusions of the evaluation Mammalian toxicity Residues Residue definitions MRL proposals Consumer risk assessment List of studies to be generated, still ongoing or available but not peer reviewed Particular conditions proposed to be taken into account to manage the risk(s) identified Concerns Issues that could not be finalised Critical areas of concern Overview of the concerns identified for each representative use considered References Appendices Abbreviations EFSA Journal 2014;12(4):3640 4

5 BACKGROUND Chlorpyrifos was evaluated under the first stage of the review programme of Directive 91/414/EEC 3 when EFSA was not yet in charge of the risk assessment of active substances. The evaluation resulted in the inclusion of the substance in Annex I to Directive 91/414/EEC on 1 July 2006 by Commission Directive 2005/72/EC 4, and has been deemed to be approved under Regulation (EC) No 1107/2009 5, in accordance with Commission Implementing Regulation (EU) No 540/2011 6, as amended by Commission Implementing Regulation (EU) No 541/ In June 2011, chlorpyrifos has been subject to a US EPA preliminary human health risk assessment based on new toxicological studies which lead to determination of toxicological reference values lower than those identified from EU assessment outcomes. On 6 June 2012, DG SANCO required the applicant, the Task Force representative, to provide to the Commission, to EFSA and to Spain as rapporteur Member State (RMS), the toxicological studies which have been published since the approval of the substance and which constitute scientific peer reviewed open literature and also those studies which have been submitted to the US EPA review. On 19 July 2012, DG SANCO sent a mandate to the RMS to prepare Addenda to the original Assessment Report, taking into account those recent studies. The RMS finalised these Addenda (Spain, 2013) in March 2013 and forwarded them to the Commission and EFSA. On 29 April 2013 EFSA received a request from the Commission to organise an expert consultation and to provide its conclusions concerning an updated toxicological risk assessment of chlorpyrifos and to review completely the human health risk assessment. EFSA prepared an Addendum giving an overview of the concerns of the chlorpyrifos mammalian toxicological risk assessment in May June On 19 June 2013 the EFSA Addendum and the RMS Addenda were distributed to Member States and the applicant for consultation and comments. The comments received were collated by the EFSA and compiled in the format of a Reporting Table. The RMS and the applicant were invited to respond to the comments in column 3 of the Reporting Table. Following consideration of the comments received on the Addenda, expert consultation points were proposed and discussed in the Pesticide Peer Review meeting 106 on mammalian toxicology in September The experts agreed on the use of the Red Blood Cell cholinesterase inhibition to derive the reference values. As this is not a standard approach, EFSA proposed to seek endorsement of this new approach by its Panel on Plant Protection Products and their Residues (PPR Panel) at its meeting of February 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 March Council Directive 91/414/EEC of 15 July 1991 concerning the placing of plant protection products on the market. OJ L 230, , p. 1-32, as last amended. 4 Commission Directive 2005/72/EC of 21 October 2005 amending Council Directive 91/414/EEC to include chlorpyrifos, chlorpyrifos-methyl, mancozeb, maneb, and metiram as active substances. OJ L 279, , p Regulation (EC) No 1107/2009 of the European Parliament and of the Council of 21 October 2009 concerning the placing of plant protection products on the market and repealing Council Directives 79/117/EEC and 91/414/EEC. OJ L 309, , p Commission Implementing Regulation (EU) No 540/2011 of 25 May 2011 implementing Regulation (EC) No 1107/2009 of the European Parliament and of the Council as regards the list of approved active substances. OJ L 153, , p Commission Implementing Regulation (EU) No 541/2011 of 1 June 2011 amending Implementing Regulation (EU) No 540/2011 implementing Regulation (EC) No 1107/2009 of the European Parliament and of the Council as regards the list of approved active substances. OJ L 153, , p EFSA Journal 2014;12(4):3640 5

6 The conclusions laid down in this report were reached on the basis of the evaluation of the authorised representative uses of chlorpyrifos as an insecticide on table and wine grapes. Full details of the representative uses can be found in Appendix A to this report. A key background document to this conclusion is the Peer Review Report, which is a compilation of the documentation developed to evaluate and address all issues raised in the peer review. The Peer Review Report (EFSA, 2014) 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 Spanish and EFSA Addenda, the Reporting Table (13 August 2013), the report of the scientific consultation with Member States, the comments received on the draft EFSA conclusion. The RMS Addenda and the EFSA Addenda (including the Technical notes on chlorpyrifos for the PPR Panel (16 January 2014)) were compiled in the Final Addendum (Spain, 2014). EFSA Journal 2014;12(4):3640 6

7 THE ACTIVE SUBSTANCE AND THE FORMULATED PRODUCT Chlorpyrifos is the ISO common name for O,O-diethyl-O-3,5,6-trichloro-2-pyridyl phosphorothioate (IUPAC). The representative uses evaluated comprise application as an insecticide on table and wine grapes. Full details of the GAP can be found in the list of end points in Appendix A. CONCLUSIONS OF THE EVALUATION Foreword Several uses on numerous crops were reported and evaluated by the RMS in the original DAR of May 1999 (Spain, 1999). Following the 2 nd tripartite meeting of February 2004, the representative uses were restricted to table and wine grapes only and defined as a single application at 245 g a.s./ha with a PHI of 21 days. Further information was provided and assessed by the RMS in the Addendum IV B-6 of April 2004 (Spain, 2004) and the data were considered sufficient to support the inclusion of the active substance chlorpyrifos in Annex I of Directive 91/414/EEC. Following the review of the toxicological end points by the Pesticides Peer Review Expert meeting, the RMS provided an Addendum V B-6 of October 2013 (Spain, 2014), where the consumer risk assessment was reconsidered, taking into account the new dietary reference values proposed for chlorpyrifos. This Addendum included the GAP initially supported for Annex I inclusion, but the evaluation was predominantly based on new critical GAPs defined as: - Table grapes: One application at 648 g a.s./ha, PHI 21 days - Wine grapes: Two applications at 360 g a.s./ha (interval 14 days), PHI 21 days Additional residue data sets, including supervised residue trials conducted either with an EC formulation (EF-1551), a WG formulation (EF-1315) or a CS formulation (GF-1668) were provided and evaluated in support to these new cgaps. These new critical GAPs and the residue trials reported in the Addendum V B-6 of October 2013 have already been submitted to EFSA in the framework of an MRL application under Article 10 of Regulation (EC) No 396/ received from Dow AgroSciences. These data were evaluated by EFSA in combination with an additional MRL application submitted by Makhteshim Chemical Works Ltd where these critical GAPs were supported for the use of a CS formulation (Pyrinex 25CS). A Reasoned Opinion considering these two MRL applications was adopted by EFSA in January 2012 (EFSA, 2012). In order to provide a comprehensive assessment of the uses of chlorpyrifos on wine and table grapes, the initial critical GAPs supported for Annex I inclusion (1 x 245 g a.s./ha, PHI 21 days) and the new critical GAPs reported under Article 10 and in the Addendum V B-6 (1 x 648 g a.s./ha for table grapes, 2 x 360 g/ha for wine grapes, PHI 21 days) are considered in this conclusion. To give an overall picture of the uses of chlorpyrifos on grapes, the information provided by Makhteshim Chemical Works Ltd for the formulation Pyrinex 25CS is also taken into account. 8 Regulation (EC) No 396/2005 of the European Parliament and of the Council of 23 February 2005 on maximum residue levels of pesticides on or on food and feed of plant and animal origin and amending Council Directive 91/414/EEC. OJ L 70, , p EFSA Journal 2014;12(4):3640 7

8 1. Mammalian toxicity Peer review of the pesticide human health risk assessment of the active substance chlorpyrifos According to the Review Report (European Commission, 2005), chlorpyrifos is rapidly and almost completely absorbed after ingestion, and almost completely excreted via urine after 48 hours from exposure. It is acutely toxic via oral route (classified as T; R25 or Acute Tox. 3 according to Regulation (EC) No 1272/ ), harmful if dermally absorbed (X n ; R21), but it is not acutely toxic via inhalation. It is not a skin or eye irritant, nor a skin sensitiser. The relevant No Observed Adverse Effect Level (NOAEL) for repeated exposure was established as 1 mg/kg bw per day in both shortand long-term assays, based on acetylcholinesterase decrease in all species (following the Joint Meeting on Pesticide Residues (JMPR, 1995) only the decrease of brain cholinesterase was considered as toxicologically relevant). Chlorpyrifos does not show genotoxic and carcinogenic potential; it is not a reproductive and developmental toxicant. The following reference values were established during the peer review and reported in the Review Report (European Commission, 2005), based on the available toxicological database: the Acceptable Daily Intake (ADI) and Acceptable Operator Exposure Level (AOEL) were 0.01 mg/kg bw per day, based on long- and short-term studies respectively, in all species tested, with the application of an uncertainty factor (UF) of 100. The Acute Reference Dose (ARfD) was 0.1 mg/kg bw based on the NOAEL of acute and delayed neurotoxicity studies in rats, with an UF of 100. In 2011, the US Environmental Protection Agency (US EPA, 2011) prepared a Preliminary Human Health Risk Assessment based on new toxicological studies which lead to the determination of toxicological reference values lower than those identified from the EU assessment peer review; the three new studies were submitted by the Task Force: Comparative cholinesterase assay (CCA) Inhalation toxicity study Immunotoxicity study The new data were discussed in a meeting of mammalian toxicology experts (Pesticides Peer Review meeting 106). Considering the available studies, cholinesterase inhibition was still considered the most sensitive endpoint on which reference values should be based. It was proposed to use the Red Blood Cell (RBC) cholinesterase (ChE) inhibition (>20 % decrease), decreasing earlier and more than brain cholinesterase, and considered as reliable and relevant surrogate to brain cholinesterase inhibition to derive reference values. In 2000 US EPA (US EPA, 2011) concluded that for chlorpyrifos inhibition of ChE was the most sensitive effect in rats, mice, rabbits, dogs and in humans, regardless of exposure duration. In animals, significant inhibition of plasma and RBC ChE occurs at doses below those that cause brain ChE inhibition. The approach was agreed by the experts. As for the CCA study, after repeated exposure, the NOAEL is 0.1 mg/kg bw per day for chlorpyrifos and the NOAEL is 0.01 mg/kg bw per day for chlorpyrifos-oxon, both based on RBC ChE inhibition. After acute exposure, the NOAEL is 0.5 mg/kg bw per day for chlorpyrifos. The experts agreed on the following reference values for chlorpyrifos: the NOAELs of the 2-year rat and dog studies were proposed to derive the ADI, choosing as the most sensitive end point the inhibition of RBC ChE. An UF of 100 was applied resulting in an ADI of mg/kg bw per day. the repeated dose CCA study in juvenile and adult rats was used to establish the AOEL. In this study a NOAEL of 0.1 mg/kg bw per day based on RBC ChE inhibition was identified and an UF of 100 applied, resulting in an AOEL of mg/kg bw per day. 9 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, , p EFSA Journal 2014;12(4):3640 8

9 the ARfD was derived from the same study, but after a single dose exposure, where a NOAEL of 0.5 mg/kg bw per day was established from the most sensitive endpoint (RBC ChE inhibition) in pups, and an UF of 100 applied. The ARfD is therefore mg/kg bw. It was noted that US EPA had used the Benchmark Dose (BMD) approach to derive reference values (based on RBC ChE inhibition), resulting in slightly lower values (than the ones agreed during the Pesticides Peer Review meeting 106 using the conventional approach). However, no assessment using BMD was submitted for the EU peer review. With regard to the assessment of the literature search submitted by the applicant and assessed by the RMS in an Addendum IV B-6 (Spain, 2014), despite its deficiencies (several articles were considered as not relevant even though they may have given further information to address some concerns, furthermore no justification was given by the applicant for the articles that were dismissed), the experts agreed not to increase the uncertainty factors of the reference values and to highlight the general concerns and the specific concerns on genotoxicity, endocrine disruption and developmental neurotoxicity in the EFSA conclusion. Based on the outcome of the Pesticides Peer Review meeting, indicating the need of lowering the current reference values of chlorpyrifos based on the Red Blood Cell cholinesterase inhibition, it was decided to consult the EFSA PPR Panel to endorse the EFSA conclusion on the setting of health based reference values. A document ( Technical note on chlorpyrifos for the PPR Panel (Spain, 2014)) was prepared by the Pesticides Unit with the purpose to summarise the key elements that characterised the decision of the Pesticides Peer Review meeting. The main issue discussed during the written procedure prior to the PPR Plenary, and during the Plenary 10 itself, was related to the relevance of the RBC ChE inhibition compared to the brain ChE inhibition. The proposal of the Pesticides Peer Review meeting to lower the chlorpyrifos reference values based on the RBC ChE inhibition, as more sensitive, conservative and critical toxicological end point for human health risk assessments (US EPA, 2011), was endorsed by the PPR Panel. With regard to the use of the benchmark dose approach (BMD), it was acknowledged that the risk assessment of pesticides should make progress in implementing this methodology; as for the literature search data that were discussed in the Pesticides Peer Review meeting report (EFSA, 2014), the PPR Panel commented that no sufficient data were available to proceed with an independent assessment (in line with what was concluded in the Pesticides Peer Review meeting). According to the Review Report (European Commission, 2005) the residue definition for risk assessment was chlorpyrifos + 3,5,6-trichloropyridinol (TCP) + conjugates, expressed as chlorpyrifos, in the assumption that TCP, which is a major metabolite in products of both animal and plant origin, was not of higher toxicity than chlorpyrifos, as it does not contain the organophosphate toxicophore and, therefore, the reference values of chlorpyrifos were applicable to TCP in case a risk assessment was needed. After the approval of chlorpyrifos, further specific toxicological data on TCP were made available during the peer review of triclopyr (EFSA, 2005): the data package for TCP was incomplete with regard to long-term studies; however based on the available data, the use of the ADI of triclopyr (0.03 mg/kg bw per day) to perform a consumer risk assessment for TCP was considered justified. As for the ARfD of TCP, a value of 0.25 mg/kg bw from the teratogenicity study in rabbit (UF of 100) was considered reliable. The AOEL of TCP was set at 0.05 mg/kg bw per day. As for chlorpyrifos-oxon, the RMS view is that it is not expected to change the consumer risk assessment as it is very unstable. However, the information received on chlorpyrifos-oxon is limited and the experts agreed that no specific reference values could be derived. No toxicological data on the metabolite desethyl chlorpyrifos were retrieved in the DAR and Addenda of chlorpyrifos EFSA Journal 2014;12(4):3640 9

10 Revised operator, worker and bystander exposure assessments were provided by the RMS. The dermal absorption value of 1% was considered based on a human study (European Commission, 2005). EFSA highlights that for the current risk assessment the dermal absorption values of 1% is used, regardless the type of formulation considered (for this reason a data gap to define relevant dermal absorption values for the different formulations has been identified). Furthermore it needs to be highlighted that the impact of multiple applications is unknown. The formulation Pyrinex 25CS is a CS-slow release formulation, whose impact on the re-entry exposure cannot be established as no data are available (data gap). The estimated exposure levels for this formulation are considered to represent the worst case except for re-entry workers, whose exposure is estimated immediately after treatment (single application); however, if the a.s. is released slowly, the most significant exposure during re-entry could take place days after the application, when it is usually considered safer. In the assumption that the same dermal absorption value of 1% would apply as for the other representative formulations, the estimated worker exposure would exceed the AOEL. The operator exposure assessment shows levels below the AOEL only with the use of Personal Protective Equipment; the re-entry exposure exceeds the AOEL in all scenarios and a critical area of concern was identified (but refinement with the use of gloves was not provided). The estimated exposure levels, considering the highest application rates, can be found in the list of end points. 2. Residues The assessment in the residue section is based on the following Guidance Documents: European Commission, 1999; JMPR, 2004 and 2007, and OECD, 2011a and 2011b. 2.1 Residue definitions The plant residue definition was discussed during the experts' meeting ECCO 133 of March 2003, considering new metabolism studies conducted on orange and cabbage, and assessed by the RMS in the Addendum III B-6 of March 2003 (Spain, 2003). Additional studies on tomato and lettuce, using the active substance chlorpyrifos-methyl were also submitted as surrogate for chlorpyrifos and taken into account in this assessment. The studies on apple, maize, sugar beet and soybean, presented in the initial DAR of May 1999 (Spain, 1999) and examined in the course of the first experts' meeting ECCO 97 of April 2000, were considered as informative only, as not supported by a sufficient identification or characterisation of the radioactive residues. Chlorpyrifos, its metabolite 3,5,6-trichloropyridinol (TCP) and several polar fractions were identified as the main components of the radioactive residues. Further investigations of the polar fractions accounting for more than 50% TRR in cabbage and tomato were finally characterised as TCP conjugates (mainly as glucose and malonic acid conjugates). Based on these data, the residue definition for monitoring was limited to chlorpyrifos. Assuming that the toxicological reference values proposed for chlorpyrifos are also applicable to TCP, the residue definition for risk assessment was under the first review proposed as sum chlorpyrifos, TCP and its conjugates expressed as chlorpyrifos. It is noted that two recent metabolism studies (2006) conducted on pea and radish and evaluated by the RMS in the framework of the Article 10 of the Regulation (EC) No 396/2005 (Spain, 2010a), confirmed the residue definitions proposed for chlorpyrifos under the peer review process. Based on a limited residue data set, the setting of a conversion factor for risk assessment was considered unnecessary for table and wine grapes in the conclusion of the peer review. This assertion is however fully invalidated by the data provided in the framework of the Article 10 of Regulation (EC) No 396/2005 (EFSA, 2012) and of the current evaluation under Article 21 of Regulation (EC) No 1107/2009 (Spain, 2014). TCP was found to represent a significant part of the residues in grapes, and based on the residue definitions agreed during the peer review for the Annex I inclusion, a conversion factor of 2 would be appropriate for table and wine grapes. EFSA Journal 2014;12(4):

11 The plant residue definition set for chlorpyrifos in the course of the peer review was proposed assuming that the toxicological reference values set for chlorpyrifos are also applicable to TCP. This statement is however no longer valid considering the recent toxicological evaluation resulting in a significant decrease of the ADI and ARfD values for chlorpyrifos. Since different toxicological end points are now proposed for chlorpyrifos and TCP (see section 1), EFSA is of the opinion that two separate consumer risk assessments have to be conducted for chlorpyrifos and TCP respectively, and taking into account the following reference values: 1) For chlorpyrifos, considering the ADI of mg/kg bw per day and ARfD of mg/kg bw, 2) For TCP and its conjugates, considering an ADI of 0.03 mg/kg bw per day and an ARfD of 0.25 mg/kg bw (EFSA, 2005). As grape vine is a perennial crop and grapes and grapes by-products are not used as feed items, residues in rotational crops and in products of animal origin were not considered in the framework of this assessment. The nature of the residues in processed commodities was investigated in the framework of the peer review for the Annex I inclusion (Spain, 1999). A standard hydrolysis study was submitted but considered inconclusive as low recoveries were observed under sterilisation conditions (57% to 71% AR) and large amounts of the radioactive residues were not identified under boiling and sterilisation conditions (20% to 66% AR) and referenced as Unknown 1 or Region 2. In March 2003, an additional study, restricted to the sterilisation conditions, was provided and assessed by the RMS in the Addendum IV B-6 (Spain, 2004). Unknown 1 was concluded to be an artefact of the former test procedure and Region 2, as mainly composed of the metabolite desethyl chlorpyrifos (up to 87%). No information was provided on the toxicological profile of the desethyl chlorpyrifos metabolite. EFSA is of the opinion that the nature of the residues in processed commodities has not been sufficiently addressed, based on unsatisfactory recoveries and resolution of the residues in the submitted studies. It cannot be excluded that desethyl chlorpyrifos might represent a significant part of the residues, requiring its inclusion in the residue definition for risk assessment for processed commodities. A data gap is identified for a new standard hydrolysis study where all fractions are unambiguously identified and the toxicological profile of all identified metabolites needs to be addressed. It is obvious that, if present, desethyl chlorpyrifos is taken into account when samples are analysed for total residue as TCP. Such an approach is however only acceptable if TCP and desethyl chlorpyrifos denote similar toxicological profiles. Pending the outcome of this data gap, further processing studies on grapes may be required. Two processing studies on red wine and one on white wine were submitted. In one study, red wine was produced following two different methods; by maceration and by heating. Total TCP levels were up to 0.03 mg/kg in wine and chlorpyrifos was not detected at the LOQ of 0.01 mg/kg. It should be highlighted that these studies were conducted with low residue levels in grapes, in the range of 0.03 to 0.05 mg/kg, while pending the formulation, residues up to 0.62 or 1.40 mg/kg were observed in wine grapes in the residue trials. Based on these studies, processing factors of 0.2 and 0.4 were calculated for chlorpyrifos and TCP respectively. The residue definitions and processing factors proposed for wine should however be considered provisional, pending the submission of a new standard hydrolysis study requested above. Validated analytical methods were provided to analyse separately chlorpyrifos and its metabolite TCP, achieving a LOQ of 0.01 mg/kg for each analyte. The analytical method for TCP includes a hydrolysis step, assumed to convert chlorpyrifos, the metabolites containing the TCP moiety and TCP conjugates to free TCP. However, information was not provided to confirm whether the hydrolysis is efficient in converting all chlorpyrifos residues to free TCP and a data gap was identified. EFSA Journal 2014;12(4):

12 2.2 MRL proposals Peer review of the pesticide human health risk assessment of the active substance chlorpyrifos The residue trials provided in support to the different uses and critical GAPs defined for chlorpyrifos in the Addendum IV B-6 (Spain, 2004), Addendum V B-6 (Spain, 2014) and in the Evaluation reports under Article 10 (Spain 2010a, 2010b) were considered to derive different MRL proposals for table and wine grapes. Samples from these residue trials were analysed separately for chlorpyrifos and total TCP, assuming that the analytical methods were efficient in converting chlorpyrifos residues to free TCP. TCP levels (sum free TCP and TCP conjugates) were therefore derived by subtraction as total TCP minus chlorpyrifos expressed as TCP cgap supported for Annex I inclusion under Directive 91/414/EEC (Spain, 2004) The representative use for Annex I inclusion was defined for table and wine grapes as a single application at 245 g a.s./ha with a PHI of 21 days. Only 3 NEU and 4 SEU trials were submitted but conducted with an application rate of 340 g a.s./ha to 540 g a.s./ha, significantly exceeding the acceptable deviation of ±25%. Moreover, samples were analysed for chlorpyrifos and TCP in 4 trials only. Contrary to the statement of the RMS in the Addendum IV B-6 (Spain, 2004) and the conclusion reported in the Review Report (European Commission, 2005), no residue trials are available to derive an MRL proposal in compliance with the cgap proposed for Annex I inclusion and a data gap was identified cgaps reported under Article 10 (Reg. (EC) No 396/2005) or Article 21 (Reg. (EC) No 1107/2009), Formulations EC (EF-1551), WG (EF-1315) and CS (GF-1668) (Spain, 2010a, 2014) Table grapes: 24 SEU and 1 NEU residue trials conducted over 3 growing seasons were submitted in support to the critical GAP defined for table grapes as a single application at 648 g/ha and a 21 day PHI. Six trials referred to bridging studies where the impact of the three formulation types [EC (EF-1551), WG (EF-1315) and CS (GF-1668)] was investigated. No significant differences were observed in the residue levels resulting from the use of the different formulations (F test, 5%) and therefore, all trials were considered together. The equivalence of the formulation types was confirmed in a report provided by the RMS, where it was additionally reported that the WG formulation has to be considered as a CS formulation, since initially manufactured as a capsule suspension which is further spray-dried and agglomerated to a WG formulation. Upon mixing in the spray tank, the WG formulation reverts to a dilute capsule suspension. Furthermore, this CS formulation is of rapidrelease type and therefore shows EC characteristics once applied. Only two SEU trials were effectively performed according to the proposed GAP with a single application. Other trials were conducted with 2 applications but with intervals of 35 to 87 days. The impact of the 1 st application was therefore considered negligible, as confirmed by the analyses conducted on samples collected just before the 2 nd application, where residues were almost all <0.01 mg/kg. Two trials with positive residues in the samples collected just before the 2 nd application were disregarded from the MRL calculation. The NEU trial was disregarded as well and, when different formulations were experimented within the same site, the highest value was taken into account for MRL calculation. Finally, an MRL proposal of 0.5 mg/kg for table grapes was derived from a total of 16 SEU trials (STMR: 0.05 mg/kg; HR 0.26 mg/kg). Wine grapes: 16 NEU and 8 SEU trials conducted over 4 growing seasons (2004 to 2007) were submitted in support to the cgap defined for wine grapes as 2 applications at 360 g/ha and a 21 day EFSA Journal 2014;12(4):

13 PHI. Trials were performed either with an EC, WG or CS formulations. In NEU, 8 trials using the EC formulation were disregarded as conducted with an interval of 55 to 97 days between applications, resulting in significant lower residues than the trials compliant with a 14 day interval (U-test, 5%). One additional study using the WG and CS formulations was not considered as performed with an interval of 30 days between applications. For SEU, all trials were conducted in accordance with the proposed cgap and the CS formulation. However, one trial was not considered for MRL calculation, as the residue level of 0.86 mg/kg measured after 21 days was not consistent with the levels of 0.57 and 0.26 mg/kg observed 7 and 14 days after the last application. As the NEU and SEU data sets were not significantly different (U-test, 5%), all values were grouped together to derive an MRL proposal of 0.8 mg/kg (STMR: 0.12 mg/kg, HR: 0.62 mg/kg) cgaps reported under Article 10 (Reg. (EC) No 396/2005) (Spain, 2010b). CS formulation Pyrinex 25CS Residue levels were significantly different (U-test, 5%) in the trials submitted by Makhteshim Agan Ltd and Dow AgroSciences respectively. Residues 21 days after the last application were in the range of 0.35 to 0.91 mg/kg (STMR 0.66 mg/kg) for the Pyrinex 25CS, while in the range of 0.09 to 0.62 mg/kg (STMR 0.09 mg/kg) with the GF-1668 formulation. These findings are consistent with the information provided on the nature of the capsule suspension formulations; Pyrinex 25CS is a slow release type while EF-1315 (WG) and GF-1668 (CS) are rapid release type formulations. In order to provide a comprehensive assessment of the uses of chlorpyrifos on wine and table grapes, the results obtained with the Pyrinex 25CS formulation were also considered in this evaluation. Table grapes: Only 3 trials reflecting the proposed GAP for table grapes were available in SEU, conducted with the Pyrinex 25CS formulation and a single application at 500 to 735 g/ha (within the ±25 % tolerance). Residues were in the range of 0.57 to 3.70 mg/kg 21 days after treatment, significantly higher than those observed in the 6 SEU trials using the CS formulation (GF-1668) (0.02 to 0.20 mg/kg). Therefore, these different data sets cannot be merged together to derive an MRL proposal, and it is concluded that an insufficient number of residue trials was provided to cover the use of the Pyrinex 25CS formulation on table grapes. Wine grapes: A total of 8 NEU and 11 SEU trials were submitted, using the Pyrinex 25CS formulation according to the proposed GAP defined as 2 applications at 360 g/ha and a PHI of 21 days. When different experimental conditions were investigated in a location, the highest value was considered for MRL calculation. It is highlighted that Pyrinex 25CS formulation results in an unusual residue behaviour. The highest residue level was often observed for longer intervals than the proposed PHI of 21 days. In 8 NEU trials out of 11, the highest level was observed in samples collected 28 to 42 days after the last application. When relevant, the highest value measured at longer PHI intervals was considered for MRL calculation. Based on the residue trials conducted with the Pyrinex 25CS, an MRL of 2 mg/kg is proposed for wine grapes (STMR: 0.49 mg/kg, HR: 1.40 mg/kg). 2.3 Consumer risk assessment The consumer risk assessment was conducted using the EFSA PRIMo model and the STMR and HR values derived from the residue trials conducted according to the different cgap and formulations. EFSA Journal 2014;12(4):

14 For wine grapes, the provisional processing factors of 0.2 and 0.4 derived for chlorpyrifos and TCP were included in the calculation as well as a yield factor 11 of 0.7. Two separate risk assessments, summarised in the tables below, were conducted for chlorpyrifos for TCP respectively. Table 2.3-1: Consumer risk assessment for chlorpyrifos (ADI mg/kg bw per day, ARfD mg/kg bw) Chlorpyrifos HR (mg/kg) Acute risk assessment STMR (mg/kg) cgap: 1x 245 g/ha, PHI 21 d (cgap supported for Annex I inclusion) Table and wine grapes Chronic risk assessment An acute or chronic risk assessment cannot be performed, since trials conducted in compliance with the proposed cgap have not been submitted. cgap: 1x 648 g/ha - 2x 360 g/ha (table - wine grapes), PHI 21 d, Formulations EC, WG or CS (GF-1668) Table grapes 0.26 IESTI: 340% ARfD 0.05 Highest IEDI: 7% ADI Wine grapes 0.62 IESTI: 13% ARfD 0.12 (FR All population) cgap: 1x 648 g/ha - 2x 360 g/ha (table - wine grapes), PHI 21 d, Formulation Pyrinex 25CS Table grapes (3.7) a IESTI: 4850% ARfD (0.97) a Highest IEDI: 123% ADI (DE child) (27% ADI if wine grapes only) Wine grapes 1.4 IESTI: 30% ARfD 0.49 a : Insufficient number of trials to derive an MRL proposal. Provisional STMR and HR derived from the 3 available trials. Table 2.3-2: Consumer risk assessment for TCP (ADI 0.03 mg/kg bw per day, ARfD 0.25 mg/kg bw) TCP HR (mg/kg) Acute risk assessment STMR (mg/kg) cgap: 1x 245 g/ha, PHI 21 d (cgap supported for Annex I inclusion) Table and wine grapes Chronic risk assessment An acute or chronic risk assessment cannot be performed, since trials conducted in compliance with the proposed cgap have not been submitted. cgap: 1x 648 g/ha - 2x 360 g/ha (table - wine grapes), PHI 21 d, Formulations EC, WG or CS (GF-1668) Table grapes 0.07 IESTI: 2% ARfD 0.02 Highest IEDI: <1% ADI Wine grapes 0.18 IESTI: <1% ARfD 0.01 (DE child) cgap: 1x 648 g/ha - 2x 360 g/ha (table - wine grapes), PHI 21 d, Formulation Pyrinex 25CS Table grapes (1.75) a IESTI: 46% ARfD (0.55) a Highest IEDI: 2% ADI Wine grapes 0.65 IESTI: 1% ARfD 0.10 (DE child) a : Insufficient number of trials to derive an MRL proposal. Provisional STMR and HR derived from the 3 available trials. Insufficient information is available to conclude that the cgap supported for Annex I inclusion according to the Directive 91/414/EEC and defined as a single application at 245 g/ha with a 21 day PHI, will not result in an exceedance of the acute or chronic reference doses proposed for chlorpyrifos. For table grapes, the cgap defined as a single application at 648 g/ha with a 21 PHI, leads to significant exceedance of the acute reference dose when considering the uses of the EC formulation (EF-1551), WG formulation (EF-1315) or CS formulation (GF-1668) (IESTI 340% ARfD). Taking into account the limited information available on table grapes, a large exceedance of the ARfD is foreseen for the use of the formulation Pyrinex 25CS on table grapes (IESTI 4850% of the ARfD). No acute concerns were observed for wine grapes, the estimated IESTI being in the range of 13% to 30% of the ARfD. However, some uncertainties related to the possible presence of the desethyl chlorpyrifos metabolite in wine need to be addressed. 11 Yield factor (YF): Consumption figures for wine grape in the PRIMo are expressed as kg wine grapes. A YF of 0.7 is used to convert the consumption figure to L wine, assuming that 100 kg of grapes give 70 L of wine. EFSA Journal 2014;12(4):

15 A chronic intake concern is identified for the use of the formulation Pyrinex 25CS when both, table and wine grapes are considered together. However, the IEDI value is reduced to 27% ADI when wine grape is considered solely. No acute or chronic concerns resulting from the presence of TCP residues in wine or table grapes are expected. All estimated intakes were calculated to be below the toxicological reference values proposed for TCP. EFSA Journal 2014;12(4):

16 3. List of studies to be generated, still ongoing or available but not peer reviewed This is a list of the data gaps identified during this focussed peer review process. Specific dermal absorption data for the formulations EF-1551, GF-1668, EF-1315 (relevant for representative uses on grapes; submission date proposed by the applicant: unknown; see section 1) Specific dermal absorption data for the formulation Pyrinex 25CS, also with particular attention to its behaviour once mixed and sprayed, to the definition of the kinetics of the release and its impact on the dermal absorption (relevant for representative uses on grapes; submission date proposed by the applicant: unknown; see section 1) Residue trials reflecting the cgap supported for Annex I inclusion under Directive 91/414/EEC (1x 245 g a.s./ha, 21 day PHI) (relevant for representative uses on grapes; submission date proposed by the applicant: unknown; see section 2) Data to confirm that the analytical methods proposed to analyse total TCP residues are efficient in analysing the TCP conjugates and all compounds containing the TCP moiety (relevant for representative uses on grapes; submission date proposed by the applicant: unknown; see section 2) A standard hydrolysis study where all fractions are unambiguously identified. The toxicological profile of all identified metabolites (e.g. desethyl chlorpyrifos) should be addressed (relevant for representative use on grapes; submission date proposed by the applicant: unknown; see section 2) Pending on the outcomes of the standard hydrolysis study requested above, new processing studies for wine grapes (heating method) might be needed (relevant for representative uses on wine grapes; submission date proposed by the applicant: unknown; see section 2) 4. Particular conditions proposed to be taken into account to manage the risk(s) identified The operator has to wear gloves, broad-brimmed headwear and RPE during M/L and gloves, RPE, coverall and sturdy footwear during application to reach exposure levels below the AOEL (in all scenarios). 5. Concerns 5.1. Issues that could not be finalised An issue is listed as an issue that could not be finalised where 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 of Annex VI to Directive 91/414/EEC and where 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). 1. No data are available to derive MRL proposals and to conduct a consumer risk assessment according to the critical GAP proposed for Annex I inclusion and defined as a single application at 245 g a.s./ha with a 21 day PHI. 2. The nature of the residue in processed commodities has not been sufficiently addressed and therefore, the presence of the desethyl chlorpyrifos metabolite in wine cannot be excluded. Additional contribution of desethyl chlorpyrifos to the consumer intakes might be expected Critical areas of concern An issue is listed as a critical area of concern where there is enough information available to perform an assessment for the representative uses in line with the Uniform Principles of Annex VI to Directive 91/414/EEC, and where this assessment does not permit to conclude that for at least one of the representative uses it may be expected that a plant protection product containing the active substance will EFSA Journal 2014;12(4):

17 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 where the assessment at a higher tier level could not be finalised due to a lack of information, and where the assessment performed at the lower tier level does not permit to conclude 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. 3. The estimated exposure for re-entry workers exceeds the AOEL in all scenarios and for all representative uses. 4. Irrespective of the PPP formulations, the use of chlorpyrifos on table grapes according to the cgap defined as a single application at 648 g a.s./ha with a 21 day PHI, leads to a significant exceedance of the ARfD (no further refinement possible) 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 4, has been evaluated as being effective, then risk identified is not indicated in this table.) Representative use Risk identified Operator risk Assessment not finalised Risk identified Worker risk Assessment not finalised Risk identified Bystander risk Assessment not finalised Risk identified Consumer risk Assessment not finalised Comments/Remarks Table grapes Wine grapes cgap 1x 245 g/ha 1x 648 g/ha 1x 648 g/ha 1x 245 g/ha 2x 360 g/ha 2x 360 g/ha Formulations EC EC, WG, CS Pyrinex 25CS EC EC, WG, CS Pyrinex 25CS X 3 X 3 X 3 X 3 X 3 X 3 X 4 X 4 X 1 X 1,2 X 2 X 2 The superscript numbers in this table relate to the numbered points indicated in sections 5.1 and 5.2. Where there is no superscript number see sections 1 to 3 for further information. EFSA Journal 2014;12(4):

18 REFERENCES EFSA (European Food Safety Authority), Conclusion regarding the peer review of the pesticide risk assessment of the active substance triclopyr. The EFSA Journal 2005, 56r, doi: /j.efsa r EFSA (European Food Safety Authority), Modification of the existing MRLs for chlorpyrifos in various crops and in products of animal origin. EFSA Journal 2012;10(1):2510, 83 pp. doi: /j.efsa EFSA (European Food Safety Authority), Peer Review Report to the conclusion regarding the peer review of the pesticide human health risk assessment of the active substance chlorpyrifos. Available online: European Commission, Guidelines for the generation of data concerning residues as provided in Annex II part A, section 6 and Annex III, part A, section 8 of Directive 91/414/EEC concerning the placing of plant protection products on the market, 1607/VI/97 rev.2, 10 June European Commission, Review Report for the active substance chlorpyrifos finalised in the Standing Committee on the Food Chain and Animal Health at its meeting on 3 June 2005 in view of the inclusion of chlorpyrifos in Annex I of Directive 91/414/EEC. SANCO/3059/99 - rev. 1.5, 3 June JMPR (Joint Meeting on Pesticide Residues), 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, September 1995, Report 1995, 246 pp. JMPR (Joint Meeting on Pesticide Residues), 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, September 2004, Report 2004, 383 pp. JMPR (Joint Meeting on Pesticide Residues), 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, September 2007, Report 2007, 164 pp. OECD (Organization for Economic Co-operation and Development), 2011a. OECD MRL Calculator: User Guide. Series of pesticides No. 56, ENV/JM/MONO(2011)2, 1 March In: Pesticide Publications/Publications on Pesticide Residues OECD (Organization for Economic Co-operation and Development), 2011b. OECD MRL Calculator: spreadsheet for single data set and spreadsheet for multiple data set, 2 March In: Pesticide Publications/Publications on Pesticide Residues. Spain, Draft Assessment Report (DAR) on the active substance chlorpyrifos, prepared by the rapporteur Member State Spain in the framework of Directive 91/414/EEC, May Spain, Addendum III B6: Residue data to Draft Assessment Report on chlorpyrifos, prepared by the rapporteur Member State Spain in the framework of Directive 91/414/EEC, March Spain, Addendum IV B6: Residue data to Draft Assessment Report on chlorpyrifos, prepared by the rapporteur Member State Spain in the framework of Directive 91/414/EEC, April Spain, 2010a. Evaluation report on the modification of MRLs for chlorpyrifos in various commodities prepared by the evaluating Member State Spain under Article 8 of Regulation (EC) No 396/2005, 25 October Spain, 2010b. Evaluation report on the modification of MRLs for chlorpyrifos in various commodities prepared by the evaluating Member State Spain under Article 8 of Regulation (EC) No 396/2005, 25 October EFSA Journal 2014;12(4):