Modification of the existing maximum residue level for folpet in lettuces

Abstract

In accordance with Article 6 of Regulation (EC) No 396/2005, the applicant Probelte SA submitted a request to the competent national authority in Spain to modify the existing maximum residue levels (MRLs) for the active substance folpet in lettuces. The data submitted in support of the request were found to be sufficient to derive an MRL proposal for lettuces. Adequate analytical methods for enforcement are available to control the residues of folpet and phthalimide in high water content commodities at the validated LOQ values of 0.05 mg/kg for folpet and 0.01 mg/kg for phthalimide. Based on the risk assessment results, EFSA concluded that the short‐term and long‐term intake of residues resulting from the use of folpet according to the reported agricultural practice is unlikely to present a risk to consumer health.

Summary

In accordance with Article 6 of Regulation (EC) No 396/2005, Probelte S.A. submitted an application to the competent national authority in Spain (evaluating Member State, EMS) to modify the existing maximum residue level (MRL) for the active substance folpet in lettuces. The EMS drafted an evaluation report in accordance with Article 8 of Regulation (EC) No 396/2005, which was submitted to the European Commission and forwarded to the European Food Safety Authority (EFSA) on 31 October 2017. To accommodate for the intended use of folpet on lettuces, the EMS proposed to raise the existing MRL from the limit of quantification (LOQ) of 0.03 to 1.5 mg/kg and also proposed to extrapolate the MRL to the whole group of lettuces and salad plants.

EFSA assessed the application and the evaluation report as required by Article 10 of the MRL regulation. EFSA identified data gaps which needed further clarification, which were requested from the EMS. On 15 February 2022 the EMS submitted a revised evaluation report, which replaced the previously submitted evaluation report.

Based on the conclusions derived by EFSA in the framework of Directive 91/414/EEC, the data evaluated under previous MRL assessments, and the additional data provided by the EMS in the framework of this application, the following conclusions are derived.

The metabolism of folpet following foliar application was investigated in crops belonging to the groups of fruit crops (grapes, avocados, tomatoes), root crops (potatoes) and cereals/grass (wheat) showing a similar metabolic pattern in all these three crop groups with folpet and the metabolite phthalimide being the relevant residues. Studies investigating the effect of processing on the nature of folpet (hydrolysis studies) demonstrated that the active substance degrades completely into phthalimide and phthalic acid under processing conditions representative for pasteurisation, boiling/brewing/baking and sterilisation. Investigation on the nature and magnitude of residues in rotational crops is not required since according to the soil degradation studies evaluated in the framework of the peer review, the DT₉₀ values of folpet, phthalimide and the soil metabolites phthalic acid and phthalamic acid are all below the trigger value of 100 days. Therefore, residues in rotational crops are not expected.

Based on the metabolic pattern identified in metabolism studies, hydrolysis studies, the toxicological significance of metabolites and degradation products, the residue definitions for plant products were proposed as ‘sum of folpet and phthalimide, expressed as folpet’ for both enforcement and risk assessment. These residue definitions are applicable to primary crops, rotational crops and processed products.

EFSA concluded that for the crop assessed in this application, the metabolism of folpet in primary crops and the possible degradation in processed products has been sufficiently addressed and that the previously derived residue definitions are applicable.

Sufficiently validated analytical methods are available to quantify residues according to the enforcement residue definition at or above the LOQs of 0.05 mg/kg for folpet and 0.01 mg/kg for phthalimide in high water content commodities, to which the crop under assessment belongs.

The available residue trials are sufficient to derive an MRL proposal of 1.5 mg/kg for lettuces. Regarding the salad plants different than lettuces, the applicant has neither requested a modification of the existing MRL nor provided the intended use of folpet on these crops (GAP). In any case, according to EFSA, extrapolation to salad plants different than lettuces is not supported by a sufficient number of valid residue trials on open leaf lettuce variety.

Specific studies investigating the magnitude of folpet residues in processed commodities are not required, as lettuces are not a crop expected to undergo further processing.

Residues of folpet in commodities of animal origin were not assessed since the crop under consideration in this MRL application is normally not fed to livestock.

The toxicological profile of folpet was assessed in the framework of the EU pesticides peer review under Directive 91/414/EEC and the data were sufficient to derive an acceptable daily intake (ADI) of 0.1 mg/kg body weight (bw) per day and an acute reference dose (ARfD) of 0.2 mg/kg bw. The metabolite phthalimide, included in the residue definition for risk assessment, has similar toxicity t? the parent active substance.

The consumer risk assessment was performed with revision 3.1 of the EFSA Pesticide Residues Intake Model (PRIMo). The short‐term exposure assessment was performed for the commodity assessed in this application and did not exceed the ARfD, accounting for up to 16% of the ARfD. In the framework of the MRL review, a comprehensive long‐term exposure assessment was performed, taking into account the existing uses at EU level and the acceptable Codex MRLs (CXLs). EFSA updated the calculation with the STMR value derived from the residue trials submitted in support of this MRL application and with the STMR values derived in the EFSA opinions published after the MRL review. The estimated long‐term dietary intake is up to 8% of the ADI (NL toddler diet) with the contribution of residues expected in lettuces to the overall long‐term exposure accounting for up to 0.08% of the ADI.

EFSA concluded that the proposed use of folpet on lettuces will not result in a consumer exposure exceeding the toxicological reference values and therefore is unlikely to pose a risk to consumers’ health. The chronic exposure calculation shall be regarded as indicative since for certain crops only tentative MRLs could be derived during the MRL review. Nevertheless, the safety margin for chronic exposure is sufficiently large to cover this lack of the requested information.

The EU pesticides peer review for the renewal of approval of folpet in accordance with Regulation (EC) No 1107/2009 is ongoing and, therefore, the conclusions reported in this reasoned opinion might need to be reconsidered in the light of the outcome of the peer review.

EFSA proposes to amend the existing MRLs as reported in the summary table below.

Full details of all end points and the consumer risk assessment can be found in Appendices B–D.

Code( a )	Commodity	Existing EU MRL (mg/kg)	Proposed EU MRL (mg/kg)	Comment/justification
Enforcement residue definition: Folpet (sum of folpet and phthalimide, expressed as folpet)
0251020	Lettuces	0.03*	1.5	The submitted data on lettuces are sufficient to derive an MRL proposal for the SEU use on lettuces. Risk for consumers unlikely.

MRL: maximum residue level; SEU: southern Europe.

^(a)Commodity code number according to Annex I of Regulation (EC) No 396/2005.

^*Indicates that the MRL is set at the limit of analytical quantification (LOQ).

It is noted that the newly submitted confirmatory method of analysis in a high‐water content commodity (lettuces) and its independent laboratory validation (ILV) for phthalimide address the data gap identified in the framework of the MRL review with regard to missing information on the analytical methods. Therefore, risk managers may consider deleting the footnotes in Regulation (EC) No 396/2005 only related to missing analytical methods in high water content commodities and amending footnotes where missing analytical methods in high water content commodities were reported in the same footnotes together with other missing information.

Assessment

The European Food Safety Authority (EFSA) received an application to modify the existing maximum residue levels (MRLs) for folpet in lettuces. The detailed description of the intended use of folpet, which is the basis for the current MRL application, is reported in Appendix A.

Folpet is the ISO common name for N‐(trichloromethylthio)phthalimide (IUPAC). The chemical structures of the active substance and its main metabolites are reported in Appendix E.

Folpet was evaluated in the framework of Directive 91/414/EEC1 with Italy designated as rapporteur Member State (RMS) for the representative uses as a foliar application to winter wheat, tomatoes and wine grapes. The draft assessment report (DAR) prepared by the RMS has been peer reviewed by EFSA (EFSA, 2009). Folpet was approved2 for the use as fungicide on 1 October 2007.

The process of renewal of the first approval is currently ongoing.

The EU MRLs for folpet are established in Annex II of Regulation (EC) No 396/20053. The review of existing MRLs according to Article 12 of Regulation (EC) No 396/2005 (MRL review) has been performed (EFSA, 2014) and the proposed modifications have been implemented in the MRL legislation. After completion of the MRL review, EFSA has issued two reasoned opinions on the modification of MRLs for folpet (EFSA, 2017, 2021). The proposals from these reasoned opinions have been considered in recent MRL regulations.4

In accordance with Article 6 of Regulation (EC) No 396/2005, Probelte S.A. submitted an application to the competent national authority in Spain (evaluating Member State, EMS) to modify the existing maximum residue level (MRL) for the active substance folpet in lettuces. The EMS drafted an evaluation report in accordance with Article 8 of Regulation (EC) No 396/2005, which was submitted to the European Commission and forwarded to EFSA on 31 October 2017. To accommodate for the intended use of folpet on lettuces, the EMS proposed to raise the existing MRL from the limit of quantification (LOQ) of 0.03 to 1.5 mg/kg and also proposed to extrapolate the MRL to the whole group of lettuces and salad plants.

EFSA assessed the application and the evaluation report as required by Article 10 of the MRL regulation. EFSA identified data gaps which needed further clarification, which were requested from the EMS. On 15 February 2022, the EMS submitted a revised evaluation report (Spain, 2020), which replaced the previously submitted evaluation report.

EFSA based its assessment on the evaluation report submitted by the EMS (Spain, 2020), the DAR and its addenda (Italy, 2004,2005,2008) prepared under Directive 91/414/EEC, the Commission review report on folpet (European Commission, 2000, 2008, 2011), the conclusion on the peer review of the pesticide risk assessment of the active substance folpet (EFSA, 2009), the reasoned opinion on the MRL review according to Article 12 of Regulation (EC) No 396/2005 (EFSA, 2014) as well as the conclusions from previous EFSA opinions on folpet (EFSA, 2011, 2017, 2021).

For this application, the data requirements established in Regulation (EU) No 544/20115 and the guidance documents applicable at the date of submission of the application to the EMS are applicable (European Commission, 1997a–g, 2000, 2010a,b, 2017; OECD, 2000, 2008, 2011). The assessment is performed in accordance with the legal provisions of the Uniform Principles for the Evaluation and the Authorisation of Plant Protection Products adopted by Commission Regulation (EU) No 546/20116.

As the EU pesticides peer review for the renewal of approval of folpet in accordance with Regulation (EC) No 1107/2009 is not yet finalised, the conclusions reported in this reasoned opinion may need to be reconsidered in the light of the outcome of the peer review.

A selected list of end points of the studies assessed by EFSA in the framework of this MRL application including the end points of relevant studies assessed previously, is presented in Appendix B.

The evaluation report submitted by the EMS (Spain, 2020) and the exposure calculations using the EFSA Pesticide Residues Intake Model (PRIMo) are considered as supporting documents to this reasoned opinion and, thus, are made publicly available as background documents to this reasoned opinion.

1. Residues in plants

1.1. Nature of residues and methods of analysis in plants

1.1.1. Nature of residues in primary crops

The metabolism of folpet following foliar application in primary crops belonging to the group of fruit crops (grapes, avocados and tomatoes), root crops (potatoes) and cereals/grass (wheat) has been investigated in the framework of the EU pesticides peer review and MRL review (EFSA, 2009, 2014). No additional studies were submitted in support of the current MRL application.

A similar metabolic pattern following foliar application was observed in all three crop groups tested. The parent compound is degraded to phthalimide which is further hydrolysed to phthalamic acid, phthalic acid and related conjugates. The peer review concluded that phthalamic acid and phthalic acid can naturally occur in the environment and cannot be considered specific to folpet.

For the intended use in lettuces, the metabolic behaviour in primary crops is sufficiently addressed.

1.1.2. Nature of residues in rotational crops

Lettuces can be grown in rotation with other crops. According to the soil degradation studies evaluated in the framework of the peer review, the DT₉₀ value of folpet, phthalimide and the soil metabolites phthalic acid and phthalamic acid are expected to range under laboratory conditions between 1 and 94 days, so below the trigger value of 100 days (EFSA, 2009). Additionally, the half‐lives of folpet and phthalimide are lower than 3 days under field conditions (EFSA, 2009, 2014).

Therefore, according to the European guidelines on rotational crops (European Commission, 1997c), further investigation of residues in rotational crops is not required as relevant residues in rotational crops are not expected.

1.1.3. Nature of residues in processed commodities

The effect of processing on the nature of folpet residues was investigated in the framework of a previous MRL application (EFSA, 2011) and the EU MRL review (EFSA, 2014). These studies showed that folpet degrades completely into phthalimide and phthalic acid under processing conditions representative for pasteurisation, boiling/brewing/baking and sterilisation. After processing, folpet residues are therefore composed of the same metabolites already identified in plant metabolism studies, with phthalimide being the only metabolite of toxicological relevance.

1.1.4. Analytical methods for enforcement purposes in plant commodities

Analytical methods for the determination of folpet and phthalimide residues in plants were assessed during the EU MRL review (EFSA, 2014) and in subsequent MRL applications (EFSA, 2017, 2021). A gas chromatography with mass spectrometry (GC–MS) method was developed for the determination of folpet and phthalimide in high water content commodities with LOQ values of 0.05 mg/kg for folpet and 0.02 mg/kg for phthalimide. A confirmatory method and an independent laboratory validation (ILV) are available (EFSA, 2014, 2017).

Additionally, it was reported during the MRL review that phthalimide could be enforced with an LOQ of 0.01 mg/kg in high water content matrices but a confirmatory method and an ILV were required (EFSA, 2014). A confirmatory method and its ILV were submitted and assessed with the current application (Spain, 2020).

A primary analytical method (GLP‐STUDY‐18‐000037) based on gas chromatography with tandem mass spectrometry (GC–MS/MS) for the analysis of the phthalimide in lettuces samples was validated according to the guidance document on pesticide analytical methods (European Commission, 2010b). Linearity, accuracy, precision and selectivity of the analytical method were analysed and found compliant with the requirements of the analytical method guidance confirming that phthalimide could be enforced with an LOQ of 0.01 mg/kg in lettuces samples (Spain, 2020).

An independent laboratory validation study (CH‐628/2018) in the same high‐water content commodity (lettuces) with the same number of samples and fortification levels used in the primary method was performed to validate the primary analytical method. This ILV demonstrated that the primary analytical method (GLP‐STUDY‐18‐000037) is a reliable and accurate procedure for the determination of phthalimide in lettuces (high‐water content commodity) able to achieve a limit of quantification of 0.01 mg/kg (Spain, 2020).

EFSA concludes that sufficiently validated methods of analysis are available for the determination of residues of folpet and phthalimide in high water content commodities (lettuces) and allow quantifying residues at or above the LOQ values of 0.05 mg/kg for folpet and 0.01 mg/kg for phthalimide. The methods address the data gap identified in the MRL review with regard to a missing confirmatory method and ILV for phthalimide in high water content commodities. Therefore, risk managers may consider deleting the footnote in Regulation (EC) No 396/2005 only related to missing analytical methods in high water content commodities and amending footnotes where missing analytical methods in high water content commodities were reported in the same footnotes together with other missing information.

1.1.5. Storage stability of residues in plants

The storage stability of folpet and phthalimide were assessed in the framework of the MRL review (EFSA, 2014) and in more recent MRL applications (EFSA, 2017, 2021).

Folpet and phthalimide were reported to be stable in high water, high acid and dry/high starch content commodities for at least 12 months when stored under frozen conditions. However, to confirm the storage stability of phthalimide, the MRL review requested the detailed evaluation report of the storage stability study for phthalimide in high water, high acid and dry/high starch content commodities (EFSA, 2014). Meanwhile, the detailed evaluation and further data have been provided and assessed by EFSA in a previous MRL application (EFSA, 2021). EFSA concluded that residues of phthalimide are stable at –18°C when stored for up to 12 months in high water content commodities, up to 13 months in high acid content commodities and up to 18 months in dry commodities (EFSA, 2017, 2021).

A new storage stability study with phthalimide was submitted in the framework of the present MRL application (Spain, 2020). The study was performed in lettuces under deep‐frozen conditions stored for 11 months according to the EC guidance 7032/VI/95 (Appendix H) on storage stability of residue samples and to the OECD Guidance 506 on the stability of pesticide residues in stored commodities (European Commission, 1997f; OECD, 2007). The analytical method applied for the storage stability study was sufficiently validated. For phthalimide, the mean recovery for control samples extracted without any storage was 86% for lettuces (with a relative standard deviation < 20%). Recoveries of the stored samples were all above 70% (71–76%) so the storage stability can be considered as sufficiently demonstrated.

For high water content commodities, both folpet and phthalimide residues are stable for at least 12 months when stored under deep frozen conditions (≤ −18°C).

1.1.6. Proposed residue definitions

Based on the metabolic pattern identified in metabolism studies, the results of hydrolysis studies, the toxicological significance of metabolites and degradation products, the capabilities of enforcement analytical methods, the same residue definition in all plant commodities was proposed for enforcement and risk assessment in the framework of the peer review (EFSA, 2009) and confirmed in the MRL review (EFSA, 2014).

• residue definition for enforcement and risk assessment: sum of folpet and phthalimide, expressed as folpet.

The same residue definitions are applicable to rotational crops and processed products. The residue definition for enforcement set in Regulation (EC) No 396/2005 is identical with the above‐mentioned residue definition ‘Folpet (sum of folpet and phthalimide, expressed as folpet)’.

EFSA concluded that for the intended use these residue definitions are appropriate and applicable.

1.2. Magnitude of residues in plants

1.2.1. Magnitude of residues in primary crops

In support of this MRL application, the applicant submitted supervised residue trials performed in lettuces. The samples were analysed for the parent compound and phthalimide, the metabolite included in the residue definitions for enforcement and risk assessment. According to the assessment of the EMS, the methods used were sufficiently validated and fit for purpose (Spain, 2020).

The samples of these residue trials were stored under conditions for which integrity of the samples has been demonstrated for both folpet and phthalimide.

Lettuces intended GAP (SEU): 3 × 750 g a.s./ha, 15 days interval, PHI = 21 days

The applicant initially provided eight supervised residue trials on lettuces conducted in Spain over three different growing seasons (2007, 2008 and 2009) and considered all these trials performed according to the GAP (within the ± 25% tolerance rule). According to the EMS, seven of these eight trials were on open leaf lettuce varieties.

EFSA considered one trial on an open leaf variety (trial code RNE0124‐01) as not acceptable since it was conducted with a longer PHI (24 days), a shorter time interval between applications (8 days) and a higher application rate per treatment (809‐821 g/ha) than requested. Although both PHI and application rate were within the 25% rule, EFSA highlighted that deviations of more than one parameter simultaneously are not in line with the relevant guidance document (GD SANCO 7525/VI/95 Rev.10.3; European Commission, 2017). Therefore, this residue trial could not be considered fully compliant with the GAP and, as a major crop in SEU, an additional trial was requested to the applicant to complete the residue dataset on lettuces. EFSA noted that all trials were performed with a shorter time interval than requested (mainly 8 days instead of 15 days) but evidence from decline residue studies showed that folpet and phthalimide residues are expected to degrade rapidly and therefore this deviation was considered minor and acceptable for the available residue trials.

The applicant provided the requested additional residue trial on open leaf lettuces (trial code S18‐05505) which was performed in Spain in 2018 in compliance with the intended GAP to complete the residue dataset which was assessed by the EMS in the updated evaluation report (Spain, 2020). EFSA considered this new trial valid and compliant with the GAP, so a sufficient number of supervised residue trials is now available to derive an MRL proposal for this crop.

Finally, the EMS proposed to extrapolate the MRL derived from the supervised residue trials on lettuces to the whole group of lettuces and salad plants. The EMS considered the result of seven residues trials on open leaf lettuce variety, one trial on closed leaf variety and the trial on open leaf variety (trial code RNE0124‐01) disregarded by EFSA. However, the applicant has neither requested a modification of the existing MRLs nor provided the intended use of folpet on these crops (GAP). Therefore, EFSA has not considered–the data package for extrapolation purpose and MRL setting.

Furthermore, excluding the disregarded trial, EFSA notes that the data package is not in line with the Technical Guidelines on data requirements for setting and extrapolation of MRLs (GD SANCO 7525/VI/95 Rev.10.3; European Commission, 2017) requesting a minimum of 8 trials on open leaf lettuce variety for such extrapolation.

1.2.2. Magnitude of residues in rotational crops

Studies on the magnitude of residues in rotational crops were not performed and are not required since significant residues in rotational crops are not expected (see Section 1.1.2).

1.2.3. Magnitude of residues in processed commodities

Specific processing studies for the crop under assessment are not available and not deemed necessary as lettuces is not a crop expected to undergo further processing.

1.2.4. Proposed MRLs

The available data are considered sufficient to derive an MRL proposal as well as risk assessment values for lettuces in support of the intended SEU use of folpet. In Section 3, EFSA assessed whether residues on crops resulting from the intended uses are likely to pose a consumer health risk.

2. Residues in livestock

Not relevant as lettuces are not used for feed purposes.

3. Consumer risk assessment

EFSA performed a dietary risk assessment using revision 3.1 of the EFSA PRIMo (EFSA, 2018, 2019). This exposure assessment model contains food consumption data for different sub‐groups of the EU population and allows the acute and chronic exposure assessment to be performed in accordance with the internationally agreed methodology for pesticide residues (FAO, 2016).

The toxicological reference values for folpet used in the risk assessment were derived in the framework of the EU pesticides peer review and the data were sufficient to derive an acceptable daily intake (ADI) of 0.1 mg/kg body weight (bw) per day and an acute reference dose (ARfD) of 0.2 mg/kg bw (European Commission, 2000, 2008, 2011). The metabolite included in the risk assessment residue definition, phthalimide, was considered to be of similar toxicity than the parent compound.

Short‐term (acute) dietary risk assessment

The short‐term exposure assessment was performed only for lettuces, the commodity assessed in this application, in accordance with the internationally agreed methodology (FAO, 2016). The calculations were based on the highest residue (HR) derived from supervised residues field trials on lettuces and the complete list of input values can be found in Appendix D.1.

The short‐term exposure did not exceed the ARfD, accounting for up to 16% of the ARfD for lettuces. For the commodities not assessed in this MRL application, EFSA reiterates the previous observation regarding an exceedance of the ARfD (104%, children) for table grapes (EFSA, 2021).

Long‐term (chronic) dietary risk assessment

In the framework of the MRL review a comprehensive long‐term exposure assessment was performed, taking into account the existing uses at EU level and the acceptable CXLs (EFSA, 2014). EFSA updated the calculation with the relevant STMR value derived from the residue trials submitted in support of this MRL application. In addition, STMRs derived in EFSA opinions published after the MRL review (EFSA, 2017, 2021) were used. The crops on which no uses were reported in the MRL review and the following EFSA opinions on folpet were excluded from the exposure calculation. The input values used in the exposure calculations are summarised in Appendix D.1.

The estimated long‐term dietary intake accounted for a maximum of 8% of the ADI (NL toddler diet). The contribution of residues expected in lettuces to the overall long‐term exposure accounted for up to 0.08% of the ADI.

EFSA concluded that the short‐term and long‐term intake of residues of folpet resulting from the existing and the intended uses is unlikely to present a risk to consumer health. The calculation shall be regarded as indicative since for certain crops only tentative MRLs could be derived during the MRL review (EFSA, 2014). Nevertheless, the safety margin for chronic exposure is sufficiently large to cover this lack of requested information.

For further details on the exposure calculations, a screenshot of the report sheet of the PRIMo is presented in Appendix C.

4. Conclusion and Recommendations

The data submitted in support of this MRL application were found to be sufficient to derive an MRL proposal for lettuces.

EFSA concluded that the proposed use of folpet on lettuces will not result in a consumer exposure exceeding the toxicological reference values and therefore is unlikely to pose a risk to consumers’ health. However, the chronic exposure calculation shall be regarded as indicative since for certain crops only tentative MRLs could be derived during the MRL review (EFSA, 2014). Nevertheless, the safety margin for chronic exposure is sufficiently large to cover this lack of the requested information.

The EU pesticides peer review for the renewal of approval of folpet in accordance with Regulation (EC) No 1107/2009 is ongoing and, therefore, the conclusions reported in this reasoned opinion might need to be reconsidered in the light of the outcome of the peer review.

The MRL recommendations are summarised in Appendix B.4.

Abbreviations

a.s.

active substance

ADI

acceptable daily intake

AR

applied radioactivity

ARfD

acute reference dose

BBCH

growth stages of mono‐ and dicotyledonous plants

Bw

body weight

CF

conversion factor for enforcement to risk assessment residue definition

CV

coefficient of variation (relative standard deviation)

CXL

Codex maximum residue limit

DALA

days after last application

DAR

draft assessment report

DAT

days after treatment

DT₉₀

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

EMS

evaluating Member State

FAO

Food and Agriculture Organization of the United Nations

GAP

Good Agricultural Practice

GC‐MS

gas chromatography with mass spectrometry

GC‐MS/MS

gas chromatography with tandem mass spectrometry

GLP

Good Laboratory Practice

HPLC‐MS/MS

high‐performance liquid chromatography with tandem mass spectrometry

HR

highest residue

IEDI

international estimated daily intake

IESTI

international estimated short‐term intake

ILV

independent laboratory validation

ISO

International Organisation for Standardisation

IUPAC

International Union of Pure and Applied Chemistry

LOQ

limit of quantification

MRL

maximum residue level

MS

Member States

MW

molecular weight

NEU

northern Europe

OECD

Organisation for Economic Co‐operation and Development

PBI

plant‐back interval

PF

processing factor

PHI

preharvest interval

PRIMo

(EFSA) Pesticide Residues Intake Model

QuEChERS

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

RA

risk assessment

RAC

raw agricultural commodity

RD

residue definition

RMS

rapporteur Member State

SANCO

Directorate‐General for Health and Consumers

SEU

southern Europe

STMR

supervised trials median residue

WHO

World Health Organization

WP

wettable powder

Appendix A – Summary of intended GAP triggering the amendment of existing EU MRLs

Crop and/or situation	NEU, SEU, MS or country	F G or I ( a )	Pests or group of pests controlled	Preparation		Application				Application rate per treatment				PHI (days) ( d )	Remarks
				Type ( b )	Conc. a.s. (g/kg)	Method kind	Range of growth stages & season( c )	Number min–max	Interval between application (days) max	g a.s./hL max	Water (L/ha) min–max	Rate min–max	Unit
Lettuce	SEU	F	Bremia lactucae	WP	250	Foliar treatment – broadcast spraying	First applications after planting and two applications more separated 15 days	1–3	15	0.075	600–1,000	0.45–0.75	kg a.i./ha	21	–

MRL: maximum residue level; GAP: Good Agricultural Practice; NEU: northern European Union; SEU: southern European Union; MS: Member State; a.s.: active substance; WP: Wettable powder.

^(a)Outdoor or field use (F), greenhouse application (G) or indoor application (I).

^(b)CropLife International Technical Monograph no 2, 7th Edition. Revised March 2017. Catalogue of pesticide formulation types and international coding system.

^(c)Growth stage range from first to last treatment (BBCH Monograph, Growth Stages of Plants, 1997, Blackwell, ISBN 3‐8263‐3152‐4), including, where relevant, information on season at time of application.

^(d)PHI: minimum preharvest interval.

Appendix B – List of end points

B.1 Residues in plants

B.1.1 Nature of residues and analytical methods for enforcement purposes in plant commodities

B.1.1.1 Metabolism studies, analytical methods and residue definitions in plants

Primary crops (available studies)	Crop groups	Crops	Applications	Sampling	Comment/Source
	Fruit crops	Grapes	Foliar, 3 × 1.5 kg/ha, interval 30 days	23 DALA	Active radiolabelled substance: Phenyl‐UL‐14C (foliar); Carbonyl‐14C (soil) folpet (EFSA, 2009, 2014)
		Avocados	Foliar, 3 × 3.36 kg/ha, interval 21 days	21, 97 DALA
		Tomatoes	Soil, 1 × 0.1 mg/plant	1, 4, 7, 11 DAT
	Root crops	Potatoes	Foliar, 5 × 2 kg/ha, interval not reported	2‐4 h after 1st, 3rd and 5th appl.; 3, 7 DALA
	Cereals/grass	Wheat	Foliar, 2 × 1.6 kg/ha, interval 24 days	1 DAT1; 1, 43, 81 DALA
Rotational crops (available studies)	Crop groups	Crop(s)	Application(s)	PBI (DAT)	Comment/Source
	Root/tuber crops	–	–	–	Not available and not required (EFSA, 2009, 2014)
	Leafy crops	–	–	–
	Cereal (small grain)	–	–	–
	Other	–	–	–
Processed commodities (hydrolysis study)	Conditions		Stable?		Comment/Source
	Pasteurisation (20 min, 90°C, pH 4)		No		Active radiolabelled substance: Phenyl‐U‐14C‐folpet. Folpet completely degraded predominantly to phthalimide, (pasteurisation: 92% AR; baking, brewing/boiling: 58% AR) with levels of phthalic acid increasing with temperature and pH (pasteurisation: 8%, baking, brewing/boiling: 42% AR; sterilisation 81% AR). (EFSA, 2011, 2014)
	Baking, brewing and boiling (60 min, 100°C, pH 5)		No
	Sterilisation (20 min, 120°C, pH 6)		No
	Other processing conditions		–

B.1.1.2 Stability of residues in plants

Plant products (available studies)	Category	Commodity	T (°C)	Stability period		Compounds covered	Comment/Source
				Value	Unit
	High water content	Tomatoes	–18	18	Months	Folpet	EFSA (2014)
			–18	12	Months	Phthalimide	EFSA (2014, 2021)
		Lettuces	–18	11	Months	Phthalimide	Spain (2020)
		Apples	–18	12	Months	Folpet	EFSA (2014)
			–18	12	Months	Phthalimide	EFSA (2014, 2021)
		Bulb onions	–18	12	Months	Folpet	EFSA (2021)
			–18	12	Months	Phthalimide	EFSA (2021)
	High acid content	Grapes	–18	15	Months	Folpet	EFSA (2014)
			–18	13	Months	Phthalimide	EFSA (2014, 2021)
	Dry/High starch content	Wheat grain	–20	12	Months	Folpet	EFSA (2014)
			–18	18	Months	Phthalimide	EFSA (2014, 2021)
	Others	Wheat straw	–20	12	Months	Folpet	EFSA (2014)
			–18	18	Months	Phthalimide	EFSA (2014, 2021)

B.1.2 Magnitude of residues in plants

B.1.2.1 Summary of residues data from the supervised residue trials

Commodity	Region/( a )	Residue levels observed in the supervised residue trials (mg/kg)	Comments/Source	Calculated MRL (mg/kg)	HR( b ) (mg/kg)	STMR( c ) (mg/kg)	CF( d )
Lettuces	SEU	Open leaf: < 0.02, 2 × < 0.10, 0.26, 0.41, 0.57, 0.86 Closed leaf: 0.11	Residue trials on open leaf (7) and head forming (1) lettuces compliant with SEU GAP.	1.5	0.86	0.19	n/a

MRL: maximum residue level; GAP: Good Agricultural Practice

NEU: Outdoor trials conducted in northern Europe, SEU: Outdoor trials conducted in southern Europe, EU: indoor EU trials or Country code: if non‐EU trials.

^(a)A conversion factor of 2 was used to express the concentrations of phthalimide as folpet equivalents (MW folpet/MW phthalimide = 296.546/147.133) prior to be summed up, except when residues were at or below the LOQ of the method of the trial. In this case residues of phthalimide were summed without conversion.

^(b)Highest residue. The highest residue for risk assessment refers to the whole commodity and not to the edible portion.

^(c)Supervised trials median residue. The median residue for risk assessment refers to the whole commodity and not to the edible portion.

^(d)Conversion factor to recalculate residues according to the residue definition for monitoring to the residue definition for risk assessment. n/a: not applicable

B.1.2.2 Residues in rotational crops

B.1.2.3 Processing factors

No processing studies were submitted in the framework of the present MRL application.

B.2 Residues in livestock

Not relevant.

B.3 Consumer risk assessment

B.4 Recommended MRLs

Code( a )	Commodity	Existing EU MRL (mg/kg)	Proposed EU MRL (mg/kg)	Comment/justification
Enforcement residue definition: Folpet (sum of folpet and phthalimide, expressed as folpet)
0251020	Lettuces	0.03*	1.5	The submitted data on lettuces are sufficient to derive an MRL proposal for the SEU use on lettuces. Risk for consumers unlikely.

MRL: maximum residue level; SEU: southern Europe; GAP: Good Agricultural Practice.

^(a)Commodity code number according to Annex I of Regulation (EC) No 396/2005.

^*Indicates that the MRL is set at the limit of analytical quantification (LOQ).

Appendix C – Pesticide Residue Intake Model (PRIMo)

Appendix D – Input values for the exposure calculations

D.1 Consumer risk assessment

Commodity	Existing/proposed MRL( a ) (mg/kg)	Source	Chronic risk assessment		Acute risk assessment
			Input value (mg/kg)	Comment	Input value (mg/kg)	Comment( b )
Risk assessment residue definition Sum of folpet and phthalimide, expressed as folpet
Lettuces	1.5	Proposed MRL	0.19	STMR	0.86	HR
Apples	0.3	EFSA (2017)	0.06	STMR	0.19	HR
Pears	0.3	EFSA (2017)	0.06	STMR	0.19	HR
Table grapes	6	EFSA (2014)	1.18	STMR	2.85	HR
Wine grapes	20	EFSA (2014)	1.66	STMR × PF × YF( c )	2.80	HR × PF × YF( c )
Strawberries	5	EFSA (2014)	1.3	STMR (tentative)	2.2	HR (tentative)
Table olives	0.15	EFSA (2014)	0.15	STMR (LOQ) (tentative)	0.15	HR (LOQ) (tentative)
Potatoes	0.06	EFSA (2014)	0.1	STMR (LOQ) (tentative)	0.1	HR (LOQ) (tentative)
Radishes	0.04	EFSA (2014)	0.04	STMR (LOQ) (tentative)	0.04	HR (LOQ) (tentative)
Salsifies	0.04	EFSA (2014)	0.04	STMR (LOQ) (tentative)	0.04	HR (LOQ) (tentative)
Tomatoes	5	EFSA (2014)	0.7	STMR (tentative)	2.8	HR (tentative)
Melons	0.4	EFSA (2014)	0.03	STMR (tentative)	0.17	HR (tentative)
Olives for oil production	0.15	EFSA (2014)	0.15	STMR (LOQ) (tentative)	0.15	HR (LOQ) (tentative)
Barley	2	EFSA (2021)	0.18	STMR	0.18	STMR
Oat	2	EFSA (2021)	0.18	STMR	0.18	STMR
Rye	0.3	EFSA (2021)	0.12	STMR	0.12	STMR
Wheat	0.4	EFSA (2021)	0.12	STMR (tentative)	0.12	STMR (tentative)
Hops (dried)	400	EFSA (2014)	82	STMR (tentative)	192	HR (tentative)
Tissues from terrestrial animals( d )	0.05	EFSA (2014)	0.05	STMR (LOQ) (tentative)	0.05	HR (LOQ) (tentative)
Milk( d )	0.05	EFSA (2014)	0.05	STMR (LOQ) (tentative)	0.05	HR (LOQ) (tentative)
Birds eggs( d )	0.05	EFSA (2014)	0.05	STMR (LOQ) (tentative)	0.05	HR (LOQ) (tentative)

STMR‐RAC: supervised trials median residue in raw agricultural commodity; HR‐RAC: highest residue in raw agricultural commodity; PeF: Peeling factor.

^(a)The MRL derived in 2014 are to be considered as tentative since not fully supported by data but for which no risk to consumers was identified in the framework of the MRL review for folpet according to Article 12 of Regulation (EC) No 396/2005 (EFSA, 2014).

^(b)Input values for the commodities which are not under consideration for the acute risk assessment are reported in grey.

^(c)Highest residue value for RAC leaded to an exceedance of the ARfD in this commodity; a refined risk assessment value was used for a second‐tier exposure calculation considering that the consumption of wine grapes by adults and children exclusively refers to wine ad applying the PF of 0.45 and a yield factor of 0.70 (EFSA, 2014).

^(d)The risk assessment residue definition in animal matrices is phthalimide, expressed as folpet.

Appendix E – Used compound codes

Code/trivial name( a )	IUPAC name/SMILES notation/InChiKey( b )	Structural formula( c )
Folpet	N‐(trichloromethylthio)phthalimide ClC(Cl)(Cl)SN2C(=O)c1ccccc1C2=O HKIOYBQGHSTUDB‐UHFFFAOYSA‐N
Phthalimide	1H‐isoindole‐1,3(2H)‐dione O=C1NC(=O)c2ccccc12 XKJCHHZQLQNZHY‐UHFFFAOYSA‐N
Phthalamic acid	2‐carbamoylbenzoic acid OC(=O)c1ccccc1C(N)=O CYMRPDYINXWJFU‐UHFFFAOYSA‐N
Phthalic acid	benzene‐1,2‐dicarboxylic acid OC(=O)c1ccccc1C(=O)O XNGIFLGASWRNHJ‐UHFFFAOYSA‐N
Phthalic anhydride	2‐benzofuran‐1,3‐dione O=C1OC(=O)c2ccccc12 LGRFSURHDFAFJT‐UHFFFAOYSA‐N
Thiazolidine	1,3‐thiazolidine C1CNCS1 OGYGFUAIIOPWQD‐UHFFFAOYSA‐N
Thiophosgene	carbonothioyl dichloride ClC(Cl)=S ZWZVWGITAAIFPS‐UHFFFAOYSA‐N

IUPAC: International Union of Pure and Applied Chemistry; SMILES: simplified molecular‐input line‐entry system; InChiKey: International Chemical Identifier Key.

^(a)The metabolite name in bold is the name used in the conclusion.

^(b)ACD/Name 2020.2.1 ACD/Labs 2020 Release (File version N15E41, Build 116563, 15 June 2020).

^(c)ACD/ChemSketch 2020.2.1 ACD/Labs 2020 Release (File version C25H41, Build 121153, 22 March 2021).

Suggested citation: EFSA (European Food Safety Authority) , Bellisai G, Bernasconi G, Brancato A, Cabrera LC, Castellan I, Ferreira L, Giner G, Greco L, Jarrah S, Leuschner R, Magrans JO, Miron I, Nave S, Pedersen R, Reich H, Robinson T, Ruocco S, Santos M, Scarlato AP, Theobald A and Verani A, 2022. Reasoned Opinion on the modification of the existing maximum residue level for folpet in lettuces. EFSA Journal 2022;20(4):7309, 24 pp. 10.2903/j.efsa.2022.7309