Review of the existing maximum residue levels (MRLs) for chlorpropham according to Article 12 of Regulation (EC) No 396/2005 1

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1 EFSA Journal 2012;10(2):2584 REASONED OPINION Review of the existing maximum residue levels (MRLs) for chlorpropham according to Article 12 of Regulation (EC) No 396/ European Food Safety Authority 2, 3 European Food Safety Authority (EFSA), Parma, Italy SUMMARY Chlorpropham was included in Annex I to Directive 91/414/EEC on 01 February 2005, which is before the entry into force of Regulation (EC) No 396/2005 on 02 September EFSA is therefore required to provide a reasoned opinion on the review of the existing MRLs for that active substance in compliance with Article 12(2) of afore mentioned regulation. In order to collect the relevant pesticide residues data, EFSA asked The Netherlands, as the designated rapporteur Member State (RMS), to complete the Pesticide Residues Overview File (PROFile). The requested information was submitted to EFSA on 02 September 2008 and, after having considered several comments made by EFSA, the RMS provided on 29 October 2009 a revised PROFile. Based on the conclusions derived in the framework of Directive 91/414/EEC, under the supervision of the European Commission, and the additional information provided by the RMS, EFSA issued on 17 May 2011 a draft reasoned opinion that was circulated to Member State experts for consultation. Comments received by 22 July 2011 were discussed in a meeting of experts, which took place on 18 November 2011, and the outcome of that meeting was considered for finalisation of this reasoned opinion. The following conclusions are derived. The toxicological profile of chlorpropham was evaluated in the framework of Directive 91/414/EEC, which resulted in an ADI of 0.05 mg/kg bw/d and an ARfD of 0.50 mg/kg bw. Primary crop metabolism of chlorpropham was investigated considering a post-harvest treatment application on potato and a pre-emergence application for herbicide uses in leafy and, root and tuber vegetables, hereby covering two different crop groups. Considering all residue data available on chlorpropham, the residue definition for enforcement and for risk assessment is proposed as chlorpropham only. However, this residue definition is considered tentative because further information on the toxicological properties of 3-chloroaniline are still required, in particular regarding its potential genotoxicity and carcinogenicity. In addition, a detailed evaluation report for the two metabolism studies and additional data on storage stability of 3-chloroaniline or with analysis performed right after harvest are still recommended to confirm the absence of the 3-chloroaniline metabolite in treated crops. A validated analytical method for enforcement of the proposed residue 1 On request from EFSA, Question No EFSA-Q , approved on 13 February Correspondence: pesticides.mrl@efsa.europa.eu 3 Acknowledgement: EFSA wishes to thank the rapporteur Member State The Netherlands for the preparatory work on this scientific output. Suggested citation: European Food Safety Authority; Review of the existing maximum residue levels (MRLs) for chlorpropham according to Article 12 of Regulation (EC) No 396/2005. EFSA Journal 2012;10(2):2584. [53 pp.] doi: /j.efsa Available online: European Food Safety Authority, 2012

2 definition in plant commodities is available, with an LOQ of at least 0.05 mg/kg in dry, acidic and high water content commodities. Regarding the magnitude of residues in primary crops, the available residues data are only considered sufficient to derive tentative MRL proposals as well as risk assessment values for most commodities under evaluation due to the data gaps identified for 3-chloroaniline. For cardoons, herbal infusions (flowers), spices (fruits and berries) and grass (for seed production), the available data (residue trials, analytical methods and/or plant metabolism) were insufficient to derive tentative MRLs and risk assessment values. The effect of processing on the nature of chlorpropham was not investigated in the framework of the peer review. Considering the high contribution of potatoes to the overall chronic exposure, a hydrolysis study is however still required. Studies investigating the magnitude of residues in some processed products are available for potatoes but they only allowed EFSA to derive indicative processing factors because nature of residues in processed commodities was not adequately investigated. As DT 90 values of chlorpropham are expected to be lower than 90 days, investigation of residues in rotational crops is not required and relevant residues in these crops are not expected. Based on the uses reported by the RMS, significant intakes were calculated for dairy ruminant, meat ruminants, pigs and poultry. Metabolism in lactating ruminants and poultry was sufficiently investigated and findings can be extrapolated to pigs as well. The relevant residue definition for both enforcement and risk assessment in pigs and ruminants was defined as the sum of chlorpropham and 4'-hydroxy-chlorpropham-O-sulphonic acid (4-HSA), expressed as chlorpropham. Available studies also demonstrated that residues of chlorpropham and 4-HSA are not expected in significant amounts and MRLs in pigs and ruminants can be set at the LOQ, except for kidney. A validated analytical method for enforcement of the proposed MRLs ruminants and pigs is also available, with an LOQ of 0.05 mg/kg for milk, meat, fat, liver and kidney. In hens, the relevant residue definition for both enforcement and risk assessment was tentatively defined as the sum of chlorpropham and 3-chloro-4-hydroxyaniline conjugates expressed as chlorpropham. In particular, 3-chloro-4-hydroxyaniline could be considered as having a higher toxicological potential than parent and further information on the toxicity of this compound is therefore required. As no feeding study for poultry was available, EFSA was only able to derive for poultry products tentative MRLs at the LOQ of 0.05 mg/kg. These tentative MRLs still need to be confirmed by a feeding study on laying hen and a validated analytical method for enforcement. Both chronic and acute consumer exposure resulting from the uses reported in the framework of this review were calculated using revision 2 of the EFSA PRIMo and no exceedance of the ADI or ARfD was identified. The highest chronic exposure represented 32.3 % of the ADI (Dutch child) and the highest acute exposure amounted to 66 % of the ARfD (potatoes). However, EFSA highlights the high degree of uncertainty related to this calculation because a processing factor was used for parent chlorpropham in boiled unpeeled potatoes while nature of residues in heated commodities was not investigated. According to EFSA, CXLs of chlorpropham (incl. the MRL for potato) are not adequate because the impact of potato consumption on MRLs for commodities of animal origin was not appropriately taken into account by JMPR. Nevertheless, both chronic and acute consumer exposure resulting from the reported uses and the CXL on potato were calculated. The highest chronic exposure was calculated for Dutch child, representing 77.5 % of the ADI. With regard to the acute exposure, an exceedance of the ARfD was also identified for potato, representing % of the ARfD. Based on the above calculations and the fact that occurrence of residues in commodities of animal origin was not properly EFSA Journal 2012;10(2):2584 2

3 assessed by the JMPR, EFSA concludes that all CXLs for chlorpropham are expected to be of concern for European consumers. Based on the above assessment, EFSA does not recommend inclusion of this active substance in Annex IV to Regulation (EC) No 396/2005. MRL recommendations were derived in compliance with the decision tree reported in Appendix D (see table below for a summary). All MRL values listed as Recommended in the table are sufficiently supported by data and therefore proposed for inclusion in Annex II to the Regulation. The remaining MRL values listed in the table are not recommended for inclusion in Annex II because they require further consideration by risk managers (see table footnotes for details). In particular, certain tentative MRLs or existing EU MRLs still need to be confirmed by the following data: a validated analytical method (including ILV and confirmatory method) for enforcement of chlorpropham residues in herbal infusions and spices; further data on the toxicological properties of 3-chloroaniline; a detailed evaluation of the primary crop metabolism studies on root and tuber vegetables group and on leafy vegetables group with additional data on storage stability or analysis performed right after harvest; 8 residue trials on open-leaf lettuce varieties to support the indoor GAP on lettuce and scarole; 4 residue trials to support the French GAP on cardoons; 4 residue trials to support the French GAP on herbal infusions (dried flowers); 4 residue trials to support the French GAP on spices (fruits and berries); 4 residue trials to support the northern outdoor GAP on grass (for seed production); a hydrolysis study investigating the effect of processing on residue nature; a validated analytical method (including ILV and confirmatory method) for enforcement of chlorpropham residues in foods of poultry origin; further information on the toxicity of 3-chloro-4-hydroxyaniline; a feeding study on laying hen. If the above reported data gaps are not addressed in the future, Member States are recommended to withdraw or modify the relevant authorisations at national level. Minor deficiencies were also identified in the assessment but these deficiencies are not expected to impact either on the validity of the Recommended MRLs or on the national authorisations. The following data are therefore considered desirable but not essential: a detailed evaluation report for the GC-MS analytical method on ruminants commodities reported by the RMS. EFSA Journal 2012;10(2):2584 3

4 Code number Commodity Existing EU MRL Existing CXL Tentative enforcement residue definition: chlorpropham MRL Outcome of the review Comment Potatoes Further consideration needed (a) Celeriac 0.05* * Further consideration needed (b) Onions 0.05* * Further consideration needed (b) Shallots 0.05* * Further consideration needed (b) Lettuce 0.05* * Further consideration needed (b) Scarole (broad-leaf endive) 0.05* * Further consideration needed (b) Rocket, rucola 0.05* * Further consideration needed (b) Spinach 0.05* * Further consideration needed (b) Witloof 0.05* * Further consideration needed (b) Cardoons 0.05* * Further consideration needed (f) Celery 0.05* * Further consideration needed (b) Fennel 0.05* * Further consideration needed (b) Herbal infusions (dried flowers) Spices (fruits and berries) 0.1* - 0.1* Further consideration needed (f) 0.1* - 0.1* Further consideration needed (f) Chicory roots 0.05* * Further consideration needed (b) - Other products of plant origin See App. C - - Further consideration needed (c) Enforcement residue definition: chlorpropham and 4 -hydroxychlorpropham-o-sulphonic acid (4-HSA), expressed as chlorpropham Swine meat 0.05* * (F) Recommended (d) Swine fat (free of lean meat) 0.05* * Recommended (d) Swine liver 0.05* * Recommended (d) Swine kidney Recommended (d) Bovine meat 0.05* * (F) Recommended (e) Bovine fat 0.05* * Recommended (d) Bovine liver 0.05* 0.01* 0.05* Recommended (e) Bovine kidney * 0.2 Recommended (e) Sheep meat 0.05* * (F) Recommended (d) Sheep fat 0.05* * Recommended (d) Sheep liver 0.05* * Recommended (d) Sheep kidney Recommended (d) Goat meat 0.05* * (F) Recommended (d) Goat fat 0.05* * Recommended (d) EFSA Journal 2012;10(2):2584 4

5 Code number Commodity Existing EU MRL Existing CXL MRL Outcome of the review Comment Goat liver 0.05* * Recommended (d) Goat kidney Recommended (d) Cattle milk * 0.05* Recommended (e) Sheep milk * Recommended (d) Goat milk * Recommended (d) Other products of animal origin See App. C Further consideration needed (c) Tentative enforcement residue definition: chlorpropham and 3-chloro-4-hydroxyaniline conjugates expressed as chlorpropham Poultry meat 0.05* * (F) Further consideration needed (b) Poultry fat 0.05* * Further consideration needed (b) Poultry liver 0.05* * Further consideration needed (b) Bird s eggs * Further consideration needed (b) (*): Indicates that the MRL is set at the limit of analytical quantification. (F): MRL is expressed as mg/kg of fat contained in the whole product. (a): Tentative MRL is derived from a GAP evaluated at EU level, which is not fully supported by data but for which no risk to consumers could be identified (assuming the existing residue definition); CXL is higher but it is also not sufficiently supported by data and a risk to consumers cannot be excluded (combination E-IV in Appendix D). (b): Tentative MRL is derived from a GAP evaluated at EU level, which is not fully supported by data but for which no risk to consumers could be identified (assuming the existing residue definition); no CXL is available (combination E-I in Appendix D). (c): There are no relevant authorisations or import tolerances reported at EU level; no CXL is available. Either the specific LOQ or the default MRL of 0.01 mg/kg may be considered (combination A-I in Appendix D). (d): MRL is derived from a GAP evaluated at EU level, which is fully supported by data and for which no risk to consumers is identified; no CXL is available (combination G-I in Appendix D). (e): MRL is derived from a GAP evaluated at EU level, which is fully supported by data and for which no risk to consumers is identified; CXL is not compatible with EU residue definitions (combination G-II in Appendix D). (f): GAP evaluated at EU level is not supported by data but no risk to consumers could be identified for the existing EU MRL (assuming the existing residue definition); no CXL is available (combination C-I in Appendix D). KEY WORDS chlorpropham, MRL review, Regulation (EC) No 396/2005, consumer risk assessment, carbamate, herbicide, plant growth regulator, 3-chloroaniline, 4 -hydroxychlorpropham-o-sulphonic acid (4-HSA), 3-chloro-4- hydroxy-aniline. EFSA Journal 2012;10(2):2584 5

6 TABLE OF CONTENTS Summary... 1 Table of contents... 6 Background... 7 Terms of reference... 8 The active substance and its use pattern... 8 Assessment Methods of analysis Methods for enforcement of residues in food of plant origin Methods for enforcement of residues in food of animal origin Mammalian toxicology Residues Nature and magnitude of residues in plant Primary crops Rotational crops Nature and magnitude of residues in livestock Dietary burden of livestock Nature of residues Magnitude of residues Consumer risk assessment Consumer risk assessment without the CXLs Consumer risk assessment with consideration of the existing CXLs Conclusions and recommendations Documentation provided to EFSA References Appendix A Good Agricultural Practices (GAPs) Appendix B Pesticide Residues Intake Model (PRIMo) Appendix C Existing EU maximum residue limits (MRLs) and Codex Limits (CXLs) Appendix D Decision tree for deriving MRL recommendations Appendix E List of metabolites and related structural formula Abbreviations EFSA Journal 2012;10(2):2584 6

7 BACKGROUND Regulation (EC) No 396/ establishes the rules governing the setting as well as the review of pesticide MRLs at European level. Article 12(2) of that regulation lays down that EFSA shall provide by 01 September 2009 a reasoned opinion on the review of the existing MRLs for all active substances included in Annex I to Directive 91/414/EEC 5 before 02 September As chlorpropham was included in Annex I to the above mentioned directive on 01 February 2005, EFSA initiated the review of all existing MRLs for that active substance and a task with the reference number EFSA-Q was included in the EFSA Register of Questions. According to the legal provisions, EFSA shall base its reasoned opinion in particular on the relevant assessment report prepared under Directive 91/414/EEC. It should be noted, however, that in the framework of Directive 91/414/EEC only a few representative uses are evaluated while MRLs set out in Regulation (EC) No 396/2005 should accommodate for all uses authorised within the EU as well as uses authorised in third countries having a significant impact on international trade. The information included in the assessment report prepared under Directive 91/414/EEC is therefore insufficient for the assessment of all existing MRLs for a given active substance. In order to have an overview on the pesticide residues data that have been considered for the setting of the existing MRLs, EFSA developed the Pesticide Residue Overview File (PROFile). The PROFile is an electronic inventory of all pesticide residues data relevant to the risk assessment as well as the MRL setting for a given active substance. This includes data on: the nature and magnitude of residues in primary crops; the nature and magnitude of residues in processed commodities; the nature and magnitude of residues in rotational crops; the nature and magnitude of residues in livestock commodities and; the analytical methods for enforcement of the proposed MRLs. The Netherlands, the designated rapporteur Member State (RMS) in the framework of Directive 91/414/EEC, was asked to complete the PROFile for chlorpropham. The requested information was submitted to EFSA on 02 September 2008 and subsequently checked for completeness. On 29 October 2009, after having clarified some issues with EFSA, the RMS provided a revised PROFile. A draft reasoned opinion was issued by EFSA on 17 May 2011 and submitted to Member States (MS) for commenting. All MS comments received by 22 July 2011 were evaluated by EFSA. As further discussion on some unresolved issues was required, a meeting with MS experts took place on 18 November The conclusions of this meeting were considered by EFSA for finalization of the reasoned opinion. 4 Commission Regulation (EC) No 396/2005 of 23 February OJ L 70, , p Council Directive 91/414/EEC of 15 July 1991, OJ L 230, , p EFSA Journal 2012;10(2):2584 7

8 TERMS OF REFERENCE According to Article 12 of Regulation (EC) No 396/2005, EFSA shall provide a reasoned opinion on: the inclusion of the active substance in Annex IV to the Regulation, when appropriate; the necessity of setting new MRLs for the active substance or deleting/modifying existing MRLs set out O in Annex II or III of the Regulation; CH 3 the HN inclusion O CHof 2 OH the recommended MRLs in Annex II or III to the Regulation; Conjugate to oligosaccharide the setting of specific processing factors as referred to in Article 20(2) of the Regulation. Cl 1-hydroxychlorpropham THE ACTIVE SUBSTANCE AND ITS USE PATTERN Chlorpropham is the ISO common name for isopropyl 3-chlorophenylcarbamate (IUPAC). O CH 3 HN O CH 3 Cl und residues chlorpropham Chlorpropham belongs to the group of carbamate compounds which are used as plant growth regulator or herbicide. Chlorpropham is a systemic substance, absorbed predominately by roots. It inhibits root and epicotyl growth, normal cell division, protein and RNA synthesis, suppresses transpiration and respiration, interferes with oxidative phosphorylation and photosynthesis and inhibits the activity of beta-amylase. Chlorpropham is used as sprouting inhibitor for potatoes, and O CH 3 can be use as a herbicide against annual weeds. HN O CH 3 Conjugate to amino acid Chlorpropham was evaluated in the framework and oligosaccharide of Directive 91/414/EEC with The Netherlands being the designated rapporteur Member State (RMS). The representative uses supported for the peer review process Cl were a post-harvest treatment for sprout suppression on stored potatoes in northern OH and southern Europe, and a pre-emergence treatment on flower bulbs, ornamentals and nursery stocks in 4'-hydroxychlorpropham northern Europe. Following the peer review, a decision on inclusion of the active substance in Annex I to Directive 91/414/EEC was published by means of Commission Directive 2004/20/EC 6, entering into force on 01 February According to Regulation (EU) No 540/2011 7, chlorpropham is deemed to have been approved under Regulation (EC) No 1107/ This approval is restricted to uses as herbicide and sprout suppressor only. As EFSA was not yet involved in the peer review of HN O CH 3 chlorpropham, a conclusion of EFSA on this active substance is not available. O CH 3 The EU MRLs for chlorpropham are established in Annexes II and IIIB of Regulation (EC) No 396/ All existing EU MRLs, which are established for the chlorpropham only for potato, sum of chlorpropham and 3-chloroaniline, Cl expressed as chlorpropham for all other plant commodities, and sum of chlorpropham and OCH 4 -hydroxychlorpropham-o-sulphonic 3 acid (4-HSA), expressed as chlorpropham for animal commodities, are summarized in Appendix C.1 to this document. CXLs for p-methoxychlorpropham chlorpropham were also established by the Codex Alimentarius Commission and are reported in 6 Commission Directive 2004/20/EC of 2 March 2004, OJ L 70, , p Regulation (EU) No 540/2011 of 25 May 2011, OJ L 153, , p Regulation (EC) No 1107/2009 of 21 October 2009, OJ 309, , p EFSA Journal 2012;10(2):2584 8

9 Appendix C.2 to this reasoned opinion. These CXLs refer to chlorpropham for plant and for animal commodities. For the purpose of this MRL review, the critical uses of chlorpropham currently authorized within the EU have been collected by the RMS and reported in the PROFile. The additional GAPs reported during the Member States consultation were also considered, except for the GAP on kiwi that was notified by France (see Appendix A). In fact, France informed EFSA after the consultation that the GAP is no longer supported by the authorisation holder. It was therefore disregarded for the finalisation of this review. Chlorpropham is mainly applied indoor as a post-harvest treatment for potato, and outdoor as a foliar treatment on celeriac, onions, shallots, lettuce, scarole, spinach, celery and chicory roots in northern Europe. The RMS did not report any use authorised in third countries that might have a significant impact on international trade. ASSESSMENT EFSA bases its assessment on the PROFile submitted the RMS, the Draft Assessment Report (DAR) and its addenda prepared under Council Directive 91/414/EEC (The Netherlands, 1999, 2002, 2003), the Review Report on chlorpropham (EC, 2003), the JMPR Evaluation reports (FAO, 2001, 2008) and several evaluation reports submitted during the Member States consultation (Belgium, 2011; France, 2011; The Netherlands, 2011). Evaluation reports submitted by United Kingdom during the Member States consultation were not further considered in the framework of this review as they only provided information that was already covered by the other evaluation reports. The assessment is performed in accordance with the legal provisions of the Uniform Principles for the Evaluation of the Authorization of Plant Protection Products adopted by Commission Regulation (EU) No 546/ and the currently applicable guidance documents relevant for the consumer risk assessment of pesticide residues (EC, 1996, 1997a, 1997b, 1997c, 1997d, 1997e, 1997f, 1997g, 2000, 2010a, 2010b, 2011). 1. Methods of analysis 1.1. Methods for enforcement of residues in food of plant origin During the peer review under Directive 91/414/EEC, analytical methods using GC-ECD or GC-NPD and their ILVs were evaluated and validated for the determination of parent chlorpropham in plant matrices with an LOQ of 0.02 mg/kg in high water content (potatoes) commodities. Others analytical methods using GC-NPD were evaluated and validated with an LOQ of mg/kg for determination of parent chlorpropham and its three metabolites 3-chloroaniline, para-hydroxychlorpropham and para-methoxy-chlorpropham in potato and potato products (FAO, 2001; The Netherlands, 1999). This method can be used as confirmatory method for the previous method. After Annex I inclusion, the RMS also evaluated applicability of the multi-residue method DFG S19 using HPLC-MS/MS and, according to the RMS, this method is validated with an LOQ of 0.05 mg/kg for high water content commodities (reported in the PROFile). Moreover, the multi-residue QuEChERS method, in combination with HPLC-MS/MS and GC-MS, are also available to dose parent chlorpropham in high water content, acidic and dry commodities (CEN, 2008). Recovery data for this analytical method are summarised in Table 1-1 below. 9 Regulation (EU) No 546/2011 of 10 June OJ L 155, , p EFSA Journal 2012;10(2):2584 9

10 Hence, based on the overall availability of data, EFSA concludes that parent chlorpropham can be enforced in food of plant origin with an LOQ of at least 0.05 mg/kg in dry, acidic and high water content commodities. Table 1-1: Recovery data for the analysis of chlorpropham in different crop groups using the QuEChERS method in combination with LC-MS/MS and GC-MS (CEN, 2008) Commodity group Chromatography Spiking levels Recoveries Min. Max. Mean (%) RSD (%) n No of labs Acidic GC Dry (cereals, pulses) GC Watery GC Acidic LC Dry (cereals, pulses) LC Watery LC Methods for enforcement of residues in food of animal origin During the peer review under Directive 91/414/EEC, an analytical method using HPLC-UV for determination of the sum of chlorpropham and its metabolite 4-HSA 10 expressed as chlorpropham was evaluated and validated in food of animal origin with an LOQ of 0.05 mg/kg in milk for each compound. A confirmatory method and an ILV are not available for this method (The Netherlands, 2002; FAO, 2001). Analytical methods for liver, kidney, muscle were also submitted but they were not fully validated. After Annex I inclusion, the RMS also evaluated a GC-MS method, reported in the PROFile, which according to the RMS, is validated with an LOQ of 0.05 mg/kg for milk, meat, fat, liver and kidney. However, this method was not reported in detail and a detailed evaluation report for this method is therefore still desirable. The residue definition in poultry also includes conjugates of 3-chloro-4-hydroxyaniline but no analytical method is available for enforcement of this metabolite; a method should therefore be provided. Hence, EFSA concludes that the sum of chlorpropham and its metabolite 4-HSA expressed as chlorpropham, can be enforced with an LOQ of 0.05 mg/kg in swine and ruminants tissues as well as in ruminants milk. 2. Mammalian toxicology The toxicological assessment of chlorpropham was peer reviewed under Directive 91/414/EEC and toxicological reference values were established by the European Commission (2003). These toxicological reference values are summarized in Table '-hydroxychlorpropham-O-sulfonic acid. See Appendix E. EFSA Journal 2012;10(2):

11 Table 2-1: Overview of the toxicological reference values Chlorpropham Source Year Value Study relied upon Safety factor ADI EC mg/kg bw/d 60 wks dog 100 ARfD EC mg/kg bw 90 d dog Residues 3.1. Nature and magnitude of residues in plant Primary crops Nature of residues Metabolism of chlorpropham was studied in potato tuber following post harvest treatment, using isopropyl-labelled or Cl-labelled chlorpropham. Data are summarized in Table 3-1. Other studies on post-harvest treatment and herbicide uses with foliar or root treatment were not considered relevant for the application methods supported in the framework of this review. In addition, most of the studies dated from the early 1970 s and showed various deficiencies; they were therefore considered as supporting information only. Table 3-1: Summary of available metabolism studies in plants Group Crop Label position Application and sampling details Root and tuber vegetables washed potato [ 14 C-ring] chlorpropham (1.5%) Method, F or G (a) G rolled in emulsion (a): Outdoor/field application (F) or glasshouse/protected/indoor application (G) Rate 15 ml with a concentration of 26.23% of chlorpropham No Sampling (DAT) 1 0, 2, 7, 21, 42, 63, 84, 112, 140, 168, 196, 224, 252, 280, 308, 336, 364 Remarks Considering the post-harvest use, chlorpropham is metabolised in potato tuber via hydroxylation and subsequent methylation or conjugation with glucose, oligosaccharides or amino acids of hydroxychlorpropham 11. Chlorpropham is the main recovered compound with a total radioactive residue (TRR) of 84.6% (16.94 mg eq/kg) in potato peel, and a TRR of 41.7% (0.52 mg eq/kg) in potato pulp. Besides chlorpropham, hydroxy-chlorpropham conjugates, represent 8.4% (1.69 mg eq/kg) of the in the potato peel, and a TRR of 35.1% (0.44 mg eq/kg) in the potato pulp. 3-chloroaniline 12 represents 11 hydroxy-chlorpropham. See Appendix E chloroaniline. See Appendix E EFSA Journal 2012;10(2):

12 3.6 % of the TRR (0.7 mg eq/kg) in potato peel and 6 % of the TRR under conjugated form in pulp (0.075 mg eq/kg). Considering the herbicide use, a study shows that 3-chloroaniline can be found at high level in some vegetables with a short vegetative cycle (Rouchaud et al., 1987; The Netherlands, 1999): after an application of 1.6 kg/ha on soil before planting lettuce, 0.13 mg/kg of chlorpropham and 0.14 mg/kg of 3-chloroaniline were found in lettuce at harvest (PHI 61days), after a second treatment following the harvest, residue levels in the succeeding lettuce were estimated at 0.22 mg/kg and 0.19 mg/kg respectively (PHI 35 days), and after a third treatment at 0.21 mg/kg and 0.23 mg/kg respectively (PHI 42 days). As 3-chloroaniline was identified in minor amounts in the rat metabolism as well, the RMS considered the toxicity of 3-chloroaniline to be covered by the toxicological reference values of the parent compound. On this basis, the residue of concern for risk assessment and enforcement in plants was defined during the peer review as the sum of chlorpropham and 3-chloroaniline expressed as chlorpropham, except for potato, where the residue was defined as chlorpropham only due to the low contribution of 3-chloroaniline to the total residue following a post-harvest use (The Netherlands, 1999). After the annex I inclusion, new representative metabolism studies were submitted and evaluated by the RMS for herbicide uses with foliar treatments in root and tuber vegetables and leafy vegetables. EFSA considers that these studies, conducted at pre-emergence growth stage, can also support treatments performed early at post-emergence or post-planting stage. These studies pointed out low residue levels of 3-chloroaniline. Despite low levels of radioactive residues, the RMS considered these results sufficient to propose a modification of the residue definition for enforcement and risk assessment in all plants as the parent compound only. EFSA notes that the Rouchaud et al. study is old, not GLP compliant and conducted without radiolabelled compounds while the new metabolism studies were performed according to the latest guidelines. Considering all residue data available on chlorpropham, EFSA agrees with the RMS that there are good indications that 3-chloroaniline will not be present in significant amounts following early herbicide uses. In particular, the metabolism study in onion is considered reliable as 3- chloroaniline residues showed no degradation for this period. However, the storage stability of 3- chloroaniline in lettuce was limited and a degradation of 3-chloroaniline residues cannot be excluded in lettuce samples analyzed 3 months after harvest. Furthermore the presence of 3-chloroaniline in commodities that can be put on the market right after harvest (e.g. lettuce) is not excluded. It was therefore agreed during the expert meeting (organised in the framework of this review) that additional data on storage stability or analysis performed right after harvest are required to conclude on the presence of 3-chloroaniline in lettuce and on the reliability of the lettuce metabolism study. EFSA is also of the opinion that 3-chloroaniline might have a more severe toxicity than the parent compound because 3-chloroaniline belongs to the group of chloroaniline compounds, several of which (e.g. 4-chloroaniline and 4,6-dichloroaniline) are suspected to be carcinogenic (EFSA, 2009; US EPA, 1998, 2000). According to Regulation (EC) No 1272/ , 4-chloroaniline is even classified as a carcinogenic 1B. The minor amounts of 3-chloroaniline identified in rat metabolism are not sufficient to exclude the potential carcinogenicity of this compound. Further information on the toxicity of 3- chloroaniline is therefore required, in particular with regard to its genotoxicity and carcinogenicity. If this compound would prove to be carcinogenic, the amounts of 3-chloroaniline identified in potatoes, although significantly lower than the parent compound, would require a separate risk assessment. This. 13 Commission Regulation (EC) No 1272/2008 of 16 December OJ L 353, , p EFSA Journal 2012;10(2):

13 issue was discussed during the meeting of experts (organised in the framework of this review) and agreed upon by all experts. Considering the above reported data gaps, a tentative residue definition for enforcement and risk assessment is proposed as chlorpropham only. A valid analytical method for enforcement of the proposed residue definition is available, except for herbal infusions and spices (see section 1.1). Chlorpropham is also authorized for foliar treatment in spices (fruits and berries), for which no representative metabolism study is available. As they are very minor crops and as metabolism was investigated in leafy vegetables, a representative metabolism study for fruits and fruiting vegetables is not deemed necessary. Nevertheless, if other fruit and berry crops would be supported in the future, an additional metabolism study would be required Magnitude of residues According to the RMS, the active substance chlorpropham is authorised for post-harvest treatment in potato and for foliar treatment in several crops in northern Europe at pre-emergence/pre-planting or at post emergence/post-planting (see Appendix A). To assess the magnitude of chlorpropham residues resulting from these GAPs, EFSA considered all residues trials reported in the PROFile and additional data submitted during the Member States consultation (Belgium, 2011; France, 2011; The Netherlands, 2011). All available residues trials that comply with the authorised GAPs, are summarized in Table 3-2. The number of residues trials and extrapolations were evaluated in view of the European guidelines on comparability, extrapolation, group tolerances and data requirements for setting MRLs (EC, 2011). A sufficient number of trials complying with the GAP was reported by the RMS for all crops under assessment, except in the following cases: Potatoes: several formulations (EC, HN, DP) and types of applications were reported by MS during the Member States consultation. Formulations EC and HN are the most critical one and results of both formulations are detailed in Table 3-2. It was agreed during the meeting of experts (organised in the framework of this review) that the mean residue values for each treated lot were more representative than the highest residue values. As the results are comparable, all the data were used to derive MRL and risk assessment values. Onions: The number of residues trials supporting the northern outdoor GAP is not compliant with the data requirements for this crop. However, the reduced number was considered sufficient by EFSA because all available trial results were below the LOQ, indicating a no residues situation; further residues trials are not required. Lettuce, scarole: no residue trials complying with the indoor GAP are available. Although tentative MRL and risk assessment values can be derived from the northern data, slower degradation under indoor conditions may lead to higher uptakes by plants. In these particular conditions, a potential uptake of 3-chloroaniline cannot be disregarded. Therefore, 8 trials on open-leaf lettuce complying with the indoor GAP are still required. Rocket, rucola: The number of residues trials supporting the northern outdoor GAP is not compliant with the data requirements for this crop. However, the reduced number was considered sufficient by EFSA because all available trial results were below the LOQ, indicating a no residues situation; further residues trials are not required. Moreover, no residue trials supporting the southern outdoor GAP are required as it is only grown in France. EFSA Journal 2012;10(2):

14 Cardoons, herbal infusions (flowers), spices (fruits and berries): no residue trials are available to support the northern and southern outdoor uses. Considering that they are minor crops in northern and southern Europe and only grown in France, 4 residue trials complying with the northern outdoor or southern outdoor GAP are required for each crop. Consequently, neither MRLs nor risk assessment values can be derived. There is also no metabolism study on fruits and fruiting vegetables to support the use on spices. Grass (for seed production): no residue trials are available to support the northern outdoor use. Considering that this crop is not intended for direct human consumption, 4 residue trials complying with the northern outdoor GAP are required. Consequently, neither MRLs nor risk assessment values can be derived. Kiwi: France notified during the Member States consultation the use of chlorpropham on kiwi. However, France informed EFSA after the consultation that the GAP is no longer supported by the authorisation holder. It was therefore disregarded for the finalisation of this review. The potential degradation of residues during storage of the samples was also assessed. In the framework of the peer review, storage stability of chlorpropham was demonstrated for a period of 13 months at -20 C in commodities with high water (potato) (The Netherlands, 1999). According to the RMS, all residues trial samples reported in the PROFile were stored in compliance with the above reported storage conditions. Considering the data gaps reported for 3-chloroaniline in sections , the available residues data are only considered sufficient to derive tentative MRL proposals as well as risk assessment values for all commodities under evaluation except for cardoons, herbal infusions (flowers), spices (fruits and berries) and grass (for seed production) where the available data (residue trials, analytical methods and/or plant metabolism) were insufficient to derive tentative MRLs (see also Table 3-2). EFSA Journal 2012;10(2):

15 Table 3-2: Overview of the available residues trials data Commodity Region (a) Outdoor /Indoor Individual trial results Enforcement Risk assessment Median residue (b) Highest residue (c) MRL proposal Median CF (d) Comments Tentative residue definition for enforcement and risk assessment: chlorpropham Potato EU Indoor EC 18g/t, PHI 60d: 0.93; 1.6; 1.9; 2.75; 3.35; 3.59; 4.27; 2x4.3; 4.43; 4.67; 4.8; 4.9; 5.3; 5.6; 5.77; 6.8; 7.23; 8 HN x8 g/t; PHI 1-30d: 0.39; 0.65; 0.75; 1.3; 1.37; 1.43; 1.5; 2.24; 2.46; 3.2; 3.45; 3.9; 2x4.4; 4.74 ; 5.34 ; 8.33 ; 8.79 EC 18g/t, PHI 60d: 0.93; 1.6; 1.9; 2.75; 3.35; 3.59; 4.27; 2x4.3; 4.43; 4.67; 4.8; 4.9; 5.3; 5.6; 5.77; 6.8; 7.23; 8 HN x8 g/t; PHI 1-30d: 0.39; 0.65; 0.75; 1.3; 1.37; 1.43; 1.5; 2.24; 2.46; 3.2; 3.45; 3.9; 2x4.4; 4.74 ; 5.34 ; 8.33 ; Celeriac NEU Outdoor 4 x < x < * Onions Shallots Lettuce Scarole (broad-leaf endive) NEU Outdoor 6 x < x < * NEU Outdoor 12 x < x < * NEU/ SEU 1 Dataset results from trials with fogging, or with spraying at different GAPs. Results comparable. Highest value not necessarily after latest application. R ber = 10.2 R max = Trials compliant with the GAP. 1 Trials on onions compliant with the GAP. 1 Trials on lettuce compliant with the GAP. Indoor No residue trials available (Belgium, 2011; The Netherlands, 2011). EFSA Journal 2012;10(2):

16 Commodity Region (a) Outdoor /Indoor Individual trial results Enforcement Risk assessment Median residue (b) Highest residue (c) MRL proposal Median CF (d) Comments Rocket, rucola NEU Outdoor 6 x < x < * SEU Outdoor * Spinach NEU Outdoor 3 x < x < * Witloof NEU Outdoor 6 x < x < * 1 Trials on lettuce compliant with the GAP on rocket, rucola (France, 2011). 1 Trials are not requested as it is grown in France only and as residue trials were conducted in NEU (France, 2011). 1 Trials compliant with the GAP. 1 Trials compliant with the GAP (application on the field for production of witloof roots prior to forcing the witloof). Cardoon NEU Outdoor No residue trials available (France, 2011). Celery Fennel Herbal infusions (flowers) SEU Outdoor No residue trials available (France, 2011). NEU Outdoor 4 x < x < * 1 Trials on celery compliant with the GAP; extrapolation to fennel is possible (Belgium, 2011).. NEU Outdoor No residue trials available (France, 2011). SEU Outdoor No residue trials available (France, 2011). EFSA Journal 2012;10(2):

17 Commodity Region (a) Outdoor /Indoor Individual trial results Enforcement Risk assessment Median residue (b) Highest residue (c) MRL proposal Median CF (d) Comments Spices (fruits and berries) NEU Outdoor No residue trials available (France, 2011). SEU Outdoor No residue trials available (France, 2011). Chicory roots NEU Outdoor 6 x < x < * Grass (for seed production) 1 Trials compliant with the GAP. NEU Outdoor No residue trials available (The Netherlands, 2011). (a): NEU, SEU, EU or Import (country code). In the case of indoor uses there is no necessity to differentiate between NEU and SEU. (b): Median value of the individual trial results according to the enforcement residue definition. (c): Highest value of the individual trial results according to the enforcement residue definition. (d): The median conversion factor for enforcement to risk assessment is obtained by calculating the median of the individual conversion factors for each residues trial. (*): Indicates that the MRL is set at the limit of analytical quantification. EFSA Journal 2012;10(2):

18 Effect of industrial processing and/or household preparation The effect of processing on the nature of chlorpropham was not investigated in the framework of the peer review. As quantifiable residues of chlorpropham are not expected in celeriac, onions, shallots, lettuce, scarole, spinach, witloof, celery and chicory roots, there is no need to investigate the effect of industrial and/or household processing for these crops. For potatoes however, a hydrolysis study investigating the effect of processing is required considering the high contribution of potatoes to the chronic exposure. In particular, the potential hydrolysis of chlorpropham to 3-chloroaniline should be further considered as this compound might be of higher toxicity than the parent compound. Studies investigating the magnitude of residues in processed commodities of potato were also reported in the framework of the peer review (The Netherlands, 1999). An overview of all available processing studies is available in Table 3-3. These processing factors are however considered as indicative only considering that nature of residues in potatoes was not investigated. Table 3-3: Overview of the available processing studies Processed commodity Number of studies Median PF (a) Median CF (b) Comments Indicative processing factors (no residue can be defined in processed commodities) Potatoes, peeled and boiled DAR (The Netherlands, 1999). Potatoes, unpeeled and boiled DAR (The Netherlands, 1999). (a): The median processing factor is obtained by calculating the median of the individual processing factors of each processing study. (b): The median conversion factor for enforcement to risk assessment is obtained by calculating the median of the individual conversion factors of each processing study Rotational crops All crops under consideration, except for the post-harvest use on potato, may be grown in rotation but according to the soil laboratory degradation studies evaluated in the framework of the peer review, the DT 90 value of chlorpropham (calculated from DT 50 value), is expected to be lower than 90 days, which is below the trigger value of 100 days (The Netherlands, 1999). According to the European guidelines on rotational crops (EC, 1997b), further investigation of residues in rotational crops is not required and relevant residues in these crops are not expected Nature and magnitude of residues in livestock Dietary burden of livestock Chlorpropham is authorised for use on one main crop that might be fed to livestock. The median and maximum dietary burdens were therefore calculated for different groups of livestock using the agreed European methodology (EC, 1996). The input values for all relevant commodities have been selected according to the recommendations of JMPR (FAO, 2009) and are summarized in Table 3-4. EFSA Journal 2012;10(2):

19 Table 3-4: Input values for the dietary burden calculation Commodity Median dietary burden Maximum dietary burden Input value Comment Tentative risk assessment residue definition: chlorpropham Input value Comment Potato 4.27 Median residue 8.79 Highest residue The results of the calculations are reported in Table 3-5. The calculated dietary burdens for all groups of livestock were found to exceed the trigger value of 0.1 mg/kg DM. Further investigation of residues is therefore required in all commodities of animal origin. Table 3-5: Results of the dietary burden calculation Maximum dietary burden (mg/kg bw/d) Median dietary burden (mg/kg bw/d) Tentative risk assessment residue definition: chlorpropham Highest contributing commodity Max dietary burden (mg/kg DM) Trigger exceeded (Y/N) Dairy ruminants Potatoes Yes Meat ruminants Potatoes Yes Poultry Potatoes Yes Pigs Potatoes Yes Nature of residues The nature of chlorpropham residues in commodities of animal origin was investigated in the framework of Directive 91/414/EEC (The Netherlands, 1999). Reported metabolism studies included one study in lactating goats and one study in laying hens using 14 C-phenyl labelled chlorpropham. Lactating goats were dosed with 1.6 and 1.9 mg/kg bw/d of 14 C-phenyl labelled chlorpropham, corresponding to the 1.1N and 1.3N exposure of meat ruminants. Laying hens were treated from 3.3 to 4.2 mg/kg bw/d of 14 C- phenyl labelled chlorpropham, corresponding to the 4.5N to 5.7N exposure of poultry. These studies demonstrated that the parent compound is readily metabolised, initially by hydrolysis and hydroxylation, and then converted to conjugated metabolites and endogenously matrix bound residues related to both parent compound and 3-chloroaniline. A difference in the residue composition in the edible products was observed between goat and hen. In the goat, the main residue in milk and kidney is the metabolite 4 -hydroxychlorpropham-o-sulphonic acid 14 (4-HSA) representing 81 % (0.36 mg eq/kg) and 16 % (< 0.01 mg eq/kg) of the total radioactive residue respectively. In fat tissues, the main residue is chlorpropham representing 88 % (<0.03 mg eq/kg) of total radioactive residue. In liver, although the total radioactive residue reaches 0.32 mg eq/kg, any individual compounds does not exceed 5 %. Since 4-HSA is a major residue in ruminant tissues and products, it should be included in the residue definition hydroxychlorpropham-o-sulphonic. See Appendix E. EFSA Journal 2012;10(2):

20 In hens, the main residue in fat and skin is chlorpropham representing 92 % (0.17 mg eq/kg) and 68 % (0.10 mg eq/kg) of the total radioactive residue, respectively. In other tissues and in eggs, the main residue is composed of 3-chloro-4-hydroxyaniline 15 conjugates ranging from 22 % (0.039 mg eq/kg) to 70 % (0.468 mg eq/kg) of total radioactive residue. However, it cannot be excluded that this metabolite has a higher toxicological potential than the parent compound. In fact, it is closely related to the group of chloroaniline compounds, some of which (e.g. 4-chloroaniline and 4,6-dichloroaniline) are suspected to be carcinogenic (EFSA, 2009; US EPA, 1998, 2000); according to Regulation (EC) No 1272/2008, 4-chloroaniline is classified as carcinogenic 1B. Further information on the toxicity of 3-chloro-4-hydroxyaniline is therefore required. Table 3-6: Summary of available metabolism studies in livestock Group Species Label position Lactating ruminants Laying poultry Goat Hens 14 C- phenyl 14 C- phenyl No of animal 2 animals + 1 control 10 laying hens + 2 controls Application details Rate (mg/kg bw/d) Sample details Duration Commodity Time days Milk Twice daily Urine and faeces Tissues Daily After sacrifice (24h after last dose) days Eggs Twice daily Excreta Tissues Daily After sacrifice (8h after last dose) Since metabolism in rats and ruminants were considered as similar, the findings in ruminants can also be extrapolated to pigs. Although residue definitions for enforcement should be restricted to the parent compound as much as possible, based on the study reported in the DAR (The Netherlands, 1999), inclusion of the metabolites is required because the parent compound alone is not a good indicator for all matrices. So the relevant residue for both enforcement and risk assessment in pigs and ruminants is defined as the sum of chlorpropham and 4'-hydroxychlor-propham-O-sulphonic acid (4-HSA) expressed as chlorpropham. For poultry, considering that further information on the toxicological properties of 3- chloro-4-hydroxyaniline are still required, the relevant residue for both enforcement and risk assessment is tentatively defined as the sum of chlorpropham and 3-chloro-4-hydroxy-aniline conjugates expressed as chlorpropham. A valid analytical method for enforcement of the proposed residue definitions is available, except for all poultry tissues and products (see section 1.1) chloro-4-hydroxyaniline. See Appendix E. EFSA Journal 2012;10(2):