Modification of the existing maximum residue levels for acibenzolar‐S‐methyl in beans with pods and peas with pods

Abstract

In accordance with Article 6 of Regulation (EC) No 396/2005, the applicant Syngenta France SAS submitted a request to the competent national authority in France to amend the residue definition for risk assessment and to modify the existing maximum residue levels (MRLs) for the active substance acibenzolar‐S‐methyl in beans (with pods) and peas (with pods). The toxicological data submitted in support of this MRL application were found to be sufficient to conclude that the plant metabolite 4‐OH acibenzolar acid is not genotoxic in vitro, however lacking investigation of the general toxicity, a definitive conclusion cannot be derived whether 4‐OH acibenzolar acid (free and conjugated) should be included or excluded from the residue definition for risk assessment for all commodities belonging to the groups of leafy crops and pulses/oilseeds. The data submitted in support of the request were found to be sufficient to derive MRL proposals on the basis of the current residue definition (sum of acibenzolar‐S‐methyl and acibenzolar acid (free and conjugated), expressed as acibenzolar‐S‐methyl) for the intended uses on lettuces and salad plants, beans (with pods) and peas (with pods). The available residue trials are sufficient to derive MRL proposals of 1 mg/kg for beans with pods and peas with pods. The submitted information did not provide evidence that the existing MRL has to be changed for the intended uses on lettuces and other salad plants. For herbs and edible flowers, data gaps were identified which precluded the derivation of MRL proposals. The consumer risk assessment for the current residue definition did not identify an unacceptable risk for consumers. The indicative exposure calculations performed for the metabolite 4‐OH acibenzolar indicate that exposure to this metabolite is lower than the exposure to acibenzolar‐S‐methyl and acibenzolar acid (free and conjugated). However, considering the data gaps identified, a definitive conclusion cannot be derived by EFSA on the risk for consumers related to the intake of residues of 4‐OH acibenzolar acid. The reliable end points appropriate for use in regulatory risk assessment are presented.

Summary

In accordance with Article 6 of Regulation (EC) No 396/2005, Syngenta France SAS submitted an application to the competent national authority in France (evaluating Member State, EMS) to amend the residue definition for risk assessment and modify the existing maximum residue levels (MRLs) for the active substance acibenzolar‐S‐methyl in beans with pods and peas with pods. The applicant did not request a change to the existing MRLs for acibenzolar‐S‐methyl in lettuces and salad plants, and herbs and edible flowers. 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 17 July 2019. The EMS concluded that the submitted information does not allow to modify the residue definition. To accommodate for the intended uses of acibenzolar‐S‐methyl, the EMS proposed to raise the existing MRL for beans (with pods) and peas (with pods) from the limit of quantification (LOQ) of 0.01 to 1.0 mg/kg.

EFSA assessed the application and the evaluation report as required by Article 10 of the MRL regulation. Based on the conclusions derived by EFSA in the framework of Regulation (EC) No 1107/2009, 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 toxicological data submitted in support of this MRL application were found to be sufficient to conclude that the plant metabolite 4‐OH acibenzolar acid is not genotoxic in vitro. However, as no repeated dose toxicity study has been generated to address the general toxicity of 4–OH acibenzolar acid, the information available is insufficient to conclude whether the toxicological profile of the metabolite is comparable with that of the parent compound.

The metabolism of acibenzolar‐S‐methyl following foliar application was investigated in crops belonging to the groups of fruit crops (tomato), leafy crops (tobacco, lettuce) and cereals/grass (wheat). Based on the results of metabolism studies and findings in the residue field trials, the peer review concluded that metabolism proceeds in a similar pathway in fruit crops, cereals/grass crop groups and tobacco. However, for leafy crops and other crop groups, the experts recommended that metabolite 4–OH acibenzolar acid should be considered for the inclusion in the residue definition for risk assessment, depending on residue trials data and toxicological data. In the framework of the current assessment, new metabolism studies in the relevant crop groups of leafy crops and pulses/oilseeds were not submitted. In support of the applicant's proposal to extend the residue definition for risk assessment (i.e. the residue definition that does not include metabolite 4–OH acibenzolar acid) to all crop groups (especially leafy crops and legumes (belonging to pulses/oilseeds crop group)), the applicant submitted genotoxicity studies on the metabolite 4–OH acibenzolar acid, and magnitude of residues studies (residue trials) in lettuce and beans which analysed also for the metabolite 4–OH acibenzolar acid. The residue trials data in lettuce indicate that the metabolite 4–OH acibenzolar acid is present at significant levels, confirming the data from lettuce metabolism studies. Based on the available metabolism studies and the submitted residue field trials, it cannot be concluded that metabolism proceeds in a similar pathway in all crop groups. However, for the specific proposed uses on succulent peas (with pods) and beans (with pods), EFSA concluded that the metabolic behaviour in primary crop is addressed.

Studies investigating the effect of processing on the nature of acibenzolar‐S‐methyl (hydrolysis studies) demonstrated that the active substance is stable under conditions that simulate pasteurisation and baking, brewing and boiling process; however, these studies showed that acibenzolar‐S‐methyl significantly degrades into acibenzolar acid under sterilisation conditions.

In rotational crops, the major residue identified was the metabolite acibenzolar acid. However, from the levels observed in the rotational crops study, it can be concluded that the uptake of residues from soil will not be significant in rotational crops.

The following residue definitions were proposed in the MRL Review and in the EU pesticides peer review in the framework of the renewal of approval of the active substance under Regulation (EC) No 1107/2009:

• residue for enforcement: Sum of acibenzolar‐S-methyl and acibenzolar acid (free and conjugated), expressed as acibenzolar‐S-methyl;

• residue definition for risk assessment:

  • –Sum of acibenzolar‐S-methyl and acibenzolar acid (free and conjugated), expressed as acibenzolar‐S-methyl (general residue definition proposed in the peer review, applicable to the commodities assessed in the MRL review, including leafy crops);
  • –for cereals/grass, fruit crops and tobacco: Sum of acibenzolar‐S-methyl and acibenzolar acid (free and conjugated), expressed as acibenzolar‐S-methyl;
  • –for other crops than cereal/grass and fruit crops: open, depending on residue trials data and toxicological data, the metabolite 4–OH acibenzolar acid could be considered in the residue definition for risk assessment.

These residue definitions are applicable to processed commodities. A specific residue definition for rotational crops is not deemed necessary due to the very low residue levels expected.

Based on the information submitted in the MRL application, EFSA concluded that, lacking the investigation of the general toxicity of metabolite 4–OH acibenzolar acid, a definitive conclusion cannot be derived on whether the plant metabolite 4–OH acibenzolar acid (free and conjugated) should be included or excluded from the residue definition for risk assessment for all commodities belonging to the groups of leafy crops and pulses/oilseeds. The available residue trials also did not show a coherent picture that would allow to derive a conclusion on whether 4–OH acibenzolar acid (free and conjugated) is a relevant metabolite for dietary risk assessment.

Taking into account the available information, EFSA considered the residue definition for risk assessment and enforcement for fruits and fruiting vegetables (sum of acibenzolar‐S‐methyl and acibenzolar acid (free and conjugated), expressed as acibenzolar‐S‐methyl) as appropriate for the specific uses on succulent beans (with pods) and peas (with pods) assessed in this application. As regards the residue definition for risk assessment for other crop groups than cereals/grasses and fruits (in particular for leafy vegetables), a risk management decision should be taken, considering the information provided in this assessment.

Sufficiently validated analytical methods are available to quantify residues in the crops assessed in this application according to the enforcement residue definition. The methods enable quantification of residues at or above 0.01 mg/kg in the crops assessed (LOQ).

The residue trials data submitted in support of this MRL application were found to be sufficient to calculate MRL proposals and risk assessment values on the basis of the current residue definition (sum of acibenzolar‐S‐methyl and acibenzolar acid (free and conjugated), expressed as acibenzolar‐S‐methyl) for the intended uses on lettuces and salad plants, beans (with pods) and peas (with pods). The available residue trials are sufficient to derive MRL proposals of 1 mg/kg for beans with pods and peas with pods. The submitted information did not provide evidence that the existing MRL has to be changed for the intended uses on lettuces and other salad plants. The intended uses on herbs and edible flowers are not adequately supported by residue data, and therefore, MRL proposals cannot be derived.

Specific processing studies for the crops under assessment were not submitted and are not required as they are not expected to affect the outcome of the risk assessment. However, if more robust processing factors were to be required by risk managers, in particular for enforcement purposes, additional processing studies would be needed.

Residues of acibenzolar‐S‐methyl in commodities of animal origin were not assessed since the crops under consideration in this MRL application are normally not fed to livestock.

The toxicological profile of acibenzolar‐S‐methyl was assessed in the framework of the EU pesticides peer review under Regulation (EC) No 1107/2009 and the data were sufficient to derive an acceptable daily intake (ADI) of 0.03 mg/kg body weight (bw) per day and an acute reference dose (ARfD) of 0.03 mg/kg bw. The metabolite acibenzolar acid (free and conjugated) included in the residue definition is of similar toxicity as the parent active substance.

EFSA performed a dietary risk assessment for the risk assessment residue definition ‘sum of acibenzolar‐S‐methyl and acibenzolar acid (free and conjugated), expressed as acibenzolar‐S‐methyl’ using revision 3.1 of the EFSA PRIMo. Based on these calculations, EFSA concluded that the long‐term intake resulting from the existing uses and the proposed uses of acibenzolar‐S‐methyl on lettuces and salad plants, beans (with pods) and peas (with pods) is unlikely to present a risk to consumer health with regard to residues of acibenzolar‐S‐methyl and acibenzolar acid (free and conjugated).

In order to provide risk managers additional information whether it is appropriate to include metabolite 4–OH acibenzolar acid (free and conjugated) in the residue definition for risk assessment, EFSA performed an indicative short‐term and long‐term exposure assessment for this metabolite, for which the general toxicity has not been satisfactorily addressed and for which toxicological reference values could not be derived. The EMS also performed indicative long‐term and short‐term consumer exposure assessments for the metabolite 4–OH acibenzolar acid (free and conjugated) and compared the exposure calculated for 4–OH acibenzolar acid (free and conjugated) to the Toxicological Threshold of Concern (TTC) for Cramer Class III. However, the use of the TTC approach is not an agreed practice to decide whether toxicological studies can be waived for certain metabolites.

As regards the exposure calculation for 4–OH acibenzolar acid (free and conjugated), the estimated highest short‐term exposure for 4–OH acibenzolar acid, free and conjugated (expressed as 4–OH acibenzolar acid) was 8.1 μg/kg bw for processed escaroles/broad‐leaved endives (indicative data for existing use good agricultural practices (GAPs)). The highest estimated long‐term dietary exposure was 0.36 μg/kg bw per day (NL toddler diet). The exposure calculations for 4–OH acibenzolar acid are indicative due to a lack of robust data for existing uses on leafy crops (lettuces and salad plants, spinaches and herbs and edible flowers). Overall, the indicative exposure calculations give an indication that the exposure to 4–OH acibenzolar acid is lower than the exposure to acibenzolar‐S‐methyl and acibenzolar acid (free and conjugated). However, considering the data gaps identified, a definitive conclusion cannot be derived by EFSA on the risk for consumers related to the intake of residues of 4–OH acibenzolar acid.

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

Full details of all endpoints and the consumer risk assessment can be found in Appendices Appendix B – List of end points, Appendix C – Pesticide Residue Intake Model (PRIMo)–D.

Codea	Commodity	Existing EU MRL (mg/kg)	Proposed EU MRL (mg/kg)	Comment/justification
Enforcement residue definition: Sum of acibenzolar‐S‐methyl and acibenzolar acid (free and conjugated), expressed as acibenzolar‐S‐methyl Risk assessment residue definition: Sum of acibenzolar‐S‐methyl and acibenzolar acid (free and conjugated), expressed as acibenzolar‐S‐methyl Further risk management discussions required whether the residue definition needs to be amended, taking into account the information presented in this reasoned opinion
0251010	Lamb's lettuces/corn salads	0.3	No change	The submitted information did not provide evidence that the existing MRL has to be changed for the intended uses. No risk for consumers identified for the current residue definition. Risk assessment is affected by additional non‐standard uncertainty due to the lack of data to fully characterise metabolite 4–OH acibenzolar acid which was identified in the peer review as candidate to be included in the residue definition for risk assessment for leafy crops.
0251020	Lettuces	0.4	No change	An MRL proposal of 0.3 mg/kg was calculated for the intended indoor use. The MRL proposal is lower than the existing EU MRL, which is based on the Codex MRL. No risk for consumers identified for the current residue definition. Risk assessment is affected by additional non‐standard uncertainty due to the lack of data to fully characterise metabolite 4–OH acibenzolar acid which was identified in the peer review as candidate to be included in the residue definition for risk assessment for leafy crops.
0251030	Escaroles/broad‐leaved endives	0.3	No change	The submitted information did not provide evidence that the existing MRL has to be changed for the intended uses. No risk for consumers identified for the current residue definition. Risk assessment is affected by additional non‐standard uncertainty due to the lack of data to fully characterise metabolite 4–OH acibenzolar acid which was identified in the peer review as candidate to be included in the residue definition for risk assessment for leafy crops.
0251040	Cresses and other sprouts and shoots	0.3	No change
0251050	Land cresses	0.3	No change
0251060	Roman rocket/rucola	0.3	No change
0251070	Red mustards	0.3	No change
0251080	Baby leaf crops (including brassica species)	0.3	No change
0251990	Others	0.3	No change
0256000	Herbs and edible flowers	0.3	No MRL proposal	The submitted data are not sufficient to derive an MRL proposal for the intended use. The applicant did not propose a change to the existing MRL. The existing EU MRL is based on a comparable existing SEU GAP assessed in the MRL review and supported by residue trials on spinach. No risk for consumers identified for the current residue definition. Risk assessment is affected by additional non‐standard uncertainty due to the lack of data to fully characterise metabolite 4–OH acibenzolar acid which was identified in the peer review as candidate to be included in the residue definition for risk assessment for leafy crops.
0260010	Beans (with pods)	0.01*	1.0	The submitted data are sufficient to derive an MRL proposal for the intended indoor use. No consumer health risk was identified.
0260030	Peas (with pods)	0.01*	1.0	The submitted data are sufficient to derive an MRL proposal for the intended indoor use. No consumer health risk was identified.

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

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

Assessment

The European Food Safety Authority (EFSA) received an application to amend the residue definition for risk assessment and to modify the existing maximum residue levels (MRLs) for acibenzolar‐S‐methyl in beans (with pods) and peas (with pods). The detailed description of the intended uses of acibenzolar‐S‐methyl, which are the basis for the current MRL application, is reported in Appendix A.

Acibenzolar‐S‐methyl is the ISO common name for S‐methyl benzo[1,2,3]thiadiazole‐7‐carbothioate (IUPAC). The chemical structures of the active substance and its main metabolites are reported in Appendix E.

Acibenzolar‐S‐methyl was evaluated for the renewal of approval in the framework of Regulation (EC) No 1107/20091 according to Commission Regulation (EU) No 1141/20102, as amended by Commission Implementing Regulation (EU) No 380/20133, with France designated as rapporteur Member State (RMS); the representative uses assessed were foliar treatments on pome fruits, tomato and tobacco. The renewal assessment report (RAR) prepared by the RMS has been peer reviewed by EFSA (EFSA, 2014). Acibenzolar‐S‐methyl was approved4 for the use as plant activator on 1 April 2016.

The European Union (EU) MRLs for acibenzolar‐S‐methyl are established in Annex II of Regulation (EC) No 396/20055. The review of existing MRLs according to Article 12 of Regulation (EC) No 396/2005 (MRL review) has been performed (EFSA, 2013) and the proposed modifications have been implemented in the MRL legislation.6 After completion of the MRL review, EFSA has issued three reasoned opinions on the modification of MRLs for acibenzolar‐S‐methyl. The proposals from these reasoned opinions have been considered in recent MRL regulations.7 Certain Codex maximum residue limits (CXLs) have been taken over in the EU MRL legislation by Commission Regulation (EU) 2018/6878.

In accordance with Article 6 of Regulation (EC) No 396/2005, Syngenta France SAS submitted an application to the competent national authority in France (evaluating Member State, EMS) to amend the risk assessment residue definition; the applicant proposed to simplify the residue definition for risk assessment for leafy crops and legume vegetables, excluding the metabolite 4–OH acibenzolar acid. The applicant also requested a modification of the existing maximum residue levels (MRLs) for the active substance acibenzolar‐S‐methyl in beans (with pods) and peas (with pods) from the limit of quantification (LOQ) of 0.01 to 0.9 mg/kg. The applicant did not request a change to the existing MRLs for acibenzolar‐S‐methyl in lettuces and salad plants, and herbs and edible flowers. 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 EFSA on 17 July 2019. The EMS concluded that the submitted information does not allow to modify the residue definition. To accommodate for the intended uses of acibenzolar‐S‐methyl, the EMS proposed to raise the existing MRL for beans (with pods) and peas (with pods) from the limit of quantification (LOQ) of 0.01 to 1.0 mg/kg.

EFSA assessed the application and the evaluation report as required by Article 10 of the MRL regulation. EFSA based its assessment on the evaluation report submitted by the EMS (France, 2019), the renewal assessment report (RAR) (and its addendum) (France, 2013, 2014), the European Commission review report on acibenzolar‐S‐methyl (European Commission, 2016, 2020), the conclusion on the peer review of the pesticide risk assessment of the active substance acibenzolar‐S‐methyl (EFSA, 2014), as well as the conclusions from previous EFSA opinions on acibenzolar‐S‐methyl (EFSA, 2017b, 2018b, 2019b), including the review of the existing MRLs for acibenzolar‐S‐methyl according to Article 12 of Regulation (EC) No 396/2005 (EFSA, 2013).

For this application, the data requirements established in Regulation (EU) No 544/20119 and the guidance documents applicable at the date of submission of the application to the EMS are applicable (European Commission, 1997a,b,c,d,e,f,g, 2000, 2010a,b, 2017; OECD, 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 546/201110.

The assessment of the confirmatory data following the peer review of the active substance is not yet finalised, and therefore, the conclusions reported in this reasoned opinion might need to be reconsidered in the light of the outcome of that assessment.

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 (France, 2019) 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. Mammalian toxicology

The toxicology of acibenzolar‐S‐methyl was assessed in the pesticides peer review in the framework of the renewal of approval of the active substance under Regulation (EC) No 1107/2009 (EFSA, 2014). The toxicological reference values for acibenzolar‐S‐methyl derived in the peer review (i.e. ADI and ARfD values) were established in the review report (European Commission, 2020) finalised in support of Commission Implementing Regulation (EU) No 2016/3894 concerning the renewal of approval of acibenzolar‐S‐methyl. No new toxicological studies on the parent active substance acibenzolar‐S‐methyl were submitted in the context of the present MRL application (France, 2019).

However, in the plant metabolism studies, a metabolite 4–OH acibenzolar acid was observed at significant levels in lettuce. This finding was confirmed later in the submitted residue trials. Thus, the peer review concluded that for crop groups other than fruit crops, cereals/grass and tobacco, metabolite 4–OH acibenzolar acid could be considered for the inclusion in the residue definition for risk assessment, depending on residue trials data and toxicological data (EFSA, 2014). Now, in order to address outstanding issues on the toxicity of 4–OH acibenzolar acid, the applicant submitted new toxicity studies with this metabolite (see Section 1.1).

1.1. Toxicological studies performed on metabolites

The plant metabolite acibenzolar acid (CGA 210007) is also a major rat metabolite and was shown to share the toxicity potential of the parent acibenzolar‐S‐methyl; therefore, the peer review concluded that the reference values of the parent are applicable to this metabolite (EFSA, 2014).

The plant metabolite 4–OH acibenzolar acid (CGA 323060) was assessed in the framework of the peer review on the basis of the available acute oral toxicity study and a bacterial gene mutation assay (Ames test); however, no repeated‐dose toxicity study was available and the peer review concluded that the information was insufficient to conclude on the relative toxicity of 4–OH acibenzolar acid relevant for consumer exposure (EFSA, 2014).

The toxicology of 4–OH acibenzolar acid was also assessed in the JMPR evaluation where, noting the lack of toxicological information available, JMPR considered that biotransformation of acibenzolar‐S‐methyl in the rat included hydroxylation of acibenzolar acid, leading to the minor metabolites 4–OH acibenzolar acid and 5–OH acibenzolar acid. Considering the structural similarities these minor metabolites in rats with the parent, the JMPR concluded that 4–OH acibenzolar acid and 5‐OH acibenzolar acid are unlikely to be of greater toxicity than the parent (FAO, 2016b). However, EFSA considered that insufficient toxicological information has been provided to conclude on the toxicological profile of the metabolites 4–OH acibenzolar acid and 5–OH acibenzolar acid (EFSA, 2017a).

In the context of the present MRL application, the applicant submitted two new genotoxicity studies on the metabolite 4–OH acibenzolar acid (France, 2019). The submitted in vitro micronucleus test demonstrated that 4–OH acibenzolar acid did not induce micronuclei in human lymphocytes and is therefore considered to be non‐clastogenic/aneugenic in this test. The submitted gene mutation assay in Chinese Hamster V79 cells in vitro (V79/HPRT) showed statistically significant increases of mutant colonies but without dose‐response when analysed by trend test, within the control range data and not reproduced in the second experiment, and was finally considered negative. EFSA concluded that, based on the submitted genotoxicity tests, the metabolite 4–OH acibenzolar acid is considered not genotoxic in vitro.

Overall, EFSA concluded that on the basis of the available studies, the genotoxicity potential of the plant metabolite 4–OH acibenzolar acid has been satisfactorily addressed. However, as no repeated dose toxicity study has been generated to address the general toxicity of 4–OH acibenzolar acid, the information available is insufficient to conclude whether the toxicological profile of the metabolite is comparable with that of the parent compound.

2. Residues in plants

2.1. Nature of residues and methods of analysis in plants

2.1.1. Nature of residues in primary crops

The metabolism of acibenzolar‐S‐methyl in primary crops belonging to the groups of fruit crops (tomato), leafy crops (tobacco, lettuce) and cereals/grass (wheat) has been investigated in the pesticides peer review in the framework of the renewal of approval of the active substance under Regulation (EC) No 1107/2009 (EFSA, 2014).

The metabolic pathway of acibenzolar‐S‐methyl proceeds via hydrolysis of the parent compound to acibenzolar acid followed by ester conjugation with sugars. Subsequent hydroxylation of the phenyl ring leads to 4–OH acibenzolar acid and to 5–OH acibenzolar acid (tomato, tobacco, lettuce) followed by conjugation as O‐glycoside. Acibenzolar acid (free and conjugated) was identified as the major metabolite in most plant commodities.

The plant metabolite 4–OH acibenzolar acid was observed predominantly in conjugated form, at significant levels in lettuce up to 20% total radioactive residue (TRR),11 and at lower levels in tomatoes (8.2% TRR) and tobacco leaves (7.3% TRR) (France, 1998, 2014). The occurrence of 4–OH acibenzolar acid was also investigated under field conditions in residue trials on lettuce and spinach, which indicated that significant residues of 4–OH acibenzolar acid can be expected in lettuce, but this metabolite seems a poor marker of total residue in spinach (France, 2014).

Based on the results of metabolism studies and findings in the residue field trials, the peer review concluded that metabolism proceeds in a similar pathway in fruit crops, cereals/grass crop groups and tobacco. However, for other crop groups, the experts recommended that metabolite 4–OH acibenzolar acid should be considered for the inclusion in the residue definition for risk assessment, depending on residue trials data and toxicological data (EFSA, 2014) (see Section 2.1.6).

For both crop groups under consideration in the current application – leafy crops and pulses/oilseeds – the risk assessment residue definition is currently set on a provisional basis and it could not be concluded in the EU pesticides peer review whether there is a need to include metabolite 4–OH acibenzolar acid. In the framework of the current assessment, new metabolism studies in the relevant crop groups were not submitted. In support of the applicant's proposal to extend the residue definition for risk assessment (i.e. the residue definition that does not include metabolite 4–OH acibenzolar acid) to all crop groups (especially leafy crops and legumes (belonging to pulses/oilseeds crop group)), the applicant submitted genotoxicity studies on the metabolite 4–OH acibenzolar acid (see Section 1), and magnitude of residues studies (residue trials) in lettuce and beans which analysed also for the metabolite 4–OH acibenzolar acid (see Section 2.2.1).

The residue trials data in lettuce, treated at 0.3N the lowest application rate investigated in metabolism studies, indicate that the metabolite 4–OH acibenzolar acid is present at levels up to 0.13 mg/kg, confirming the data from lettuce metabolism studies. However, pending the assessment of the general toxicity of metabolite 4–OH acibenzolar acid, EFSA cannot conclude whether the metabolite is of toxicological relevance for the inclusion in the risk assessment residue definition (see Section 2.1.6).

The residue trials on beans (with pods) indicate that residues of 4–OH acibenzolar acid were below the LOQ in all samples, except one sample with residues at the LOQ of 0.01 mg/kg. For pulses/oilseeds group crops, no metabolism studies are available to confirm these findings. However, peas and beans are leguminous vegetables formed as pod fruit from the aerial parts of the plant and, for the specific GAPs on fresh peas (with pods) and beans (with pods) harvested as succulent green seeds, the available metabolism studies conducted on fruit crops and cereal/grass crops are considered sufficiently representative to address the metabolic behaviour expected in succulent peas and beans. Therefore, the metabolic behaviour in primary crop is considered addressed for the specific proposed uses on succulent peas (with pods) and beans (with pods).

For the applicant's proposed extension of the residue definition for risk assessment to all crop groups, no further metabolism data are submitted. Based on the available metabolism studies and the submitted residue field trials, it cannot be concluded that metabolism proceeds in a similar pathway in all crop groups. Therefore, the conclusions of this reasoned opinion are restricted to leafy crops and legumes.

2.1.2. Nature of residues in rotational crops

Acibenzolar‐S‐methyl is authorised or is proposed to be used on several crops that can be grown in rotation with other crops. According to the soil degradation studies evaluated in the framework of the EU pesticides peer review, the DT₉₀ value of acibenzolar‐S‐methyl ranged from 0.6 to 3.3 days (EFSA, 2014). The DT₉₀ of main soil metabolite acibenzolar acid ranged from 31.3 to 359 days. The trigger value of 100 days was exceeded, and therefore, further studies investigating the nature and magnitude of residues in rotational crops are required.

In the rotational crop metabolism studies assessed in the frameworks of the MRL review and the EU pesticides peer review, TRR levels were equal to or below 0.001 mg eq/kg levels in lettuce, radish, winter wheat and maize when planted at 30, 113, 141 and 337 days after soil treatment with ¹⁴C–labelled acibenzolar‐S‐methyl at a rate of 0.05 kg a.s./ha (France, 1998, EFSA, 2013, 2014). Since residues in rotational crops were too low for further identification, the study does not allow comparing the metabolic patterns in rotational and primary crops. However, from the levels observed in the rotational crops study, it can be concluded that the uptake of residues from soil will not be significant in rotational crops, provided that acibenzolar‐S‐methyl is applied on the crops under consideration in compliance with the GAPs for the intended uses reported in Appendix A.

2.1.3. Nature of residues in processed commodities

The effect of processing on the nature of acibenzolar‐S‐methyl was investigated in the framework of the EU pesticides peer review (EFSA, 2014). These studies showed that acibenzolar‐S‐methyl is hydrolytically stable under conditions that simulate pasteurisation and baking, brewing and boiling process; however, these studies showed that the acibenzolar‐S‐methyl significantly degrades (50.5 % of applied radioactivity (AR)) into acibenzolar acid under sterilisation conditions. Based on this characterisation, it was concluded that the residue pattern in processed commodities is similar to the residue pattern in raw commodities (EFSA, 2013, 2014).

2.1.4. Methods of analysis in plants

Analytical methods for the determination of acibenzolar‐S‐methyl residues and of the metabolite acibenzolar acid (free and conjugated) were assessed during the EU pesticides peer review and in a previous MRL application (EFSA, 2014, 2019b). The methods are sufficiently validated for the determination of residues of acibenzolar‐S‐methyl and acibenzolar acid (free and conjugated) in the crops under consideration. The methods allow quantifying residues at or above the LOQ of 0.01 mg/kg for the total residue (sum of acibenzolar‐S‐methyl and acibenzolar acid, free and conjugated) in crops belonging to the group of high water content, high acid content, high oil content commodities and dry tobacco leaves.

2.1.5. Storage stability of residues in plants

The storage stability of acibenzolar‐S‐methyl, acibenzolar acid and 4–OH acibenzolar acid in plants stored under frozen conditions was investigated in the frameworks of the MRL review and previous MRL applications (EFSA, 2013, 2017b, 2019b). It was demonstrated that in crops assessed in the framework of this application, residues were stable for at least 12 months when stored at –18°C.

2.1.6. Proposed residue definitions

The following residue definitions were proposed in the MRL Review (EFSA, 2013) and in the EU pesticides peer review (EFSA, 2014) in the framework of the renewal of approval of the active substance under Regulation (EC) No 1107/2009:

• residue for enforcement: Sum of acibenzolar‐S-methyl and acibenzolar acid (free and conjugated), expressed as acibenzolar‐S-methyl (EFSA, 2013, 2014);

• residue definition for risk assessment:

  • – Sum of acibenzolar‐S-methyl and acibenzolar acid (free and conjugated), expressed as acibenzolar‐S-methyl (general residue definition proposed in the peer review, applicable to the commodities assessed in the MRL review, including leafy crops) (EFSA, 2013);
  • – for cereals/grass, fruit crops, and tobacco: Sum of acibenzolar‐S-methyl and acibenzolar acid (free and conjugated), expressed as acibenzolar‐S-methyl (EFSA, 2014);
  • – for other crops than cereal/grass and fruit crops: open, depending on residue trials data and toxicological data, the metabolite 4–OH acibenzolar acid could be considered in the residue definition for risk assessment (EFSA, 2014).

The residue definition for enforcement set in Regulation (EC) No 396/2005 is identical with the above‐mentioned residue definition for enforcement.

The residue definitions are applicable to processed commodities. A specific residue definition for rotational crops is not deemed necessary due to the very low residue levels expected.

It is further noted that the residue definition derived by JMPR for compliance with Codex MRLs is comparable with the EU residue definition for enforcement. However, the JMPR evaluation defined the residue definition for dietary risk assessment in plants as the sum of acibenzolar‐S‐methyl and acibenzolar acid (free and conjugated) and 4–OH acibenzolar acid (free and conjugated), expressed as acibenzolar‐S‐methyl (FAO, 2016b); as regards the toxicity of 4‐OH acibenzolar acid JMPR concluded that owing to the structural similarities of the metabolite with the parent and considering that the metabolite was also identified in rats, the meeting concluded that they are unlikely to be of greater toxicity than the parent. However, in providing support for preparation of an EU position in the 49th session of the CCPR, EFSA was of the opinion that insufficient toxicological information had been provided to conclude on the toxicological profile of the metabolite 4‐OH acibenzolar acid (EFSA, 2017a).

In the present application, the applicant requested to confirm the residue definition for risk assessment to be applicable to all crop groups, including leafy crops and legume vegetables (belonging to pulses/oilseeds crop group). To support this proposal, the applicant submitted toxicological data that addressed the genotoxicity of the metabolite 4–OH acibenzolar acid (see Section 1.1), and provided residue trials with lettuce and legumes where samples were analysed for the metabolite 4–OH acibenzolar acid (see Section 2.2.1).

EFSA concluded that, lacking the investigation of the general toxicity of metabolite 4–OH acibenzolar acid, a definitive conclusion cannot be derived on whether the plant metabolite 4–OH acibenzolar acid (free and conjugated) should be included or excluded from the residue definition for risk assessment for all commodities belonging to the groups of leafy crops and pulses/oilseeds. The available residue trials also did not show a coherent picture that would allow to derive a conclusion on whether 4–OH acibenzolar acid (free and conjugated) is a relevant metabolite for dietary risk assessment (see details in Section 2.2).

Taking into account the available information, EFSA considered the residue definition for risk assessment and enforcement for fruits and fruiting vegetables (sum of acibenzolar‐S‐methyl and acibenzolar acid (free and conjugated), expressed as acibenzolar‐S‐methyl) as appropriate for the specific uses on succulent beans (with pods) and peas (with pods) assessed in this application (see Section 2.1.1).

As regards the residue definition for risk assessment for other crop groups than cereals/grasses and fruits (in particular for leafy vegetables), a risk management decision should be taken, considering the information provided in this assessment

• on the toxicological profile of 4–OH acibenzolar acid (free and conjugated) (Section 1),

• the information on plant metabolism (Section 2.1.1),

• the information on the amount of residue of 4–OH acibenzolar acid (free and conjugated) found in different crops (Section 2.2.1),

• the results of the risk assessment for the sum of acibenzolar‐S-methyl and acibenzolar acid (free and conjugated), expressed as acibenzolar‐S-methyl (Section 4.1) and

• the exposure assessment for 4–OH acibenzolar acid (free and conjugated) (Section 4.2).

If a risk management decision is taken to formally include the metabolite 4–OH acibenzolar acid (free and conjugated) in the residue definition for risk assessment for certain crops, a review of the existing MRLs in the light of the new residue definition should be considered.

2.2. Magnitude of residues in plants

2.2.1. Magnitude of residues in primary crops

In support of the MRL application, the applicant submitted residue trials performed in lettuce and in beans with pods.

The residue trials samples were analysed for acibenzolar‐S‐methyl and acibenzolar acid (free and conjugated), expressed as acibenzolar‐S‐methyl in accordance with the residue definition for enforcement and risk assessment, and for the metabolite 4–OH acibenzolar acid (free and conjugated). The EMS applied a molecular weight conversion factor of 1.07 to express residues of 4–OH acibenzolar acid as acibenzolar‐S‐methyl equivalents.

According to the assessment of the EMS, the methods used were sufficiently validated and fit for purpose. Samples were analysed by high‐performance liquid chromatography with tandem mass spectroscopy (HPLC‐MS/MS) for acibenzolar‐S‐methyl, acibenzolar acid and its conjugates with an LOQ of 0.01 mg/kg, and by LC‐MS/MS and HPLC‐MS/MS for the metabolite 4–OH acibenzolar acid and its conjugates with an LOQ of 0.01 mg/kg (France, 2019).

The samples of these residue trials were stored under conditions for which integrity of the samples has been demonstrated. The results of the magnitude of residues studies compliant with the GAPs assessed in the present application are summarised in Appendix B.2.2.1.

Lettuces and other salad plants

Intended use GAP greenhouse application: 1‐2 × 0.016 kg/ha, PHI 3 days

Intended use SEU GAP: 1 × 0.016 kg/ha, PHI 3 days

In support of the MRL application and to provide the information on the levels of metabolite 4–OH acibenzolar acid in lettuce, the applicant submitted eight residue decline trials on protected lettuce (indoor use) and eight residue decline trials on outdoor lettuce (SEU) (France, 2019).

Residue decline trials on protected open‐leaf lettuce were performed in the United Kingdom, northern France, Germany, Spain and Italy in 2016. In total, eight trials are compliant with the intended indoor use on lettuces and salad plants. The metabolite 4–OH acibenzolar acid (free and conjugated) was below the LOQ in all lettuce samples.

Residue decline trials on outdoor open‐leaf lettuce were performed in southern France, Italy and Spain in 2016. In total, eight trials are compliant with the intended outdoor SEU use GAP on lettuces and salad plants. The metabolite 4–OH acibenzolar acid (free and conjugated) was quantified at levels above the LOQ in only one trial on outdoor lettuce (0.04 mg/kg) and was below the LOQ in all other submitted GAP compliant residue trials on outdoor lettuce.

Trials with two applications on protected lettuce were more critical with regard to residue levels of acibenzolar‐S‐methyl and acibenzolar acid (free and conjugated).

The applicant proposed to extrapolate the available residue data on lettuce to the whole group of lettuces and other salad plants. Extrapolation from trials performed on open‐leaf varieties lettuce to the whole subgroup lettuces and salad plants is possible (European Commission, 2017). The number and quality of the trials on lettuce are sufficient to calculate an MRL of 0.3 mg/kg for acibenzolar‐S‐methyl residues in the whole subgroup lettuces and salad plants (0251000), on the basis of the proposed indoor use GAP.

The calculated MRL of 0.3 mg/kg is lower than the existing EU MRL for acibenzolar‐S‐methyl in lettuces of 0.4 mg/kg, which is based on the Codex MRL and included in EU Legislation by Commission Regulation (EU) 2018/68712. The calculated MRL is identical to the existing EU MRL for acibenzolar‐S‐methyl in salad plants other than lettuces derived in the framework of the MRL review (EFSA, 2013). Thus, no modification of the existing EU MRLs is required.

Lettuces and other salad plants, herbs and edible flowers (existing use GAPs)

Existing use NEU/SEU/indoor GAPs: 3 × 0.014 kg/ha, interval 10 days, PHI 10 days (EFSA, 2013)

The applicant submitted 12 residue decline trials on outdoor head lettuce which were assessed previously in the framework of the EU pesticides peer review (France, 2014). Of which six trials were performed in accordance with the existing use SEU GAP for lettuces assessed in the MRL review (SEU: 3 × 0.014 kg a.s./ha, interval 7–10 days, PHI 10 days; EFSA, 2013) and were sufficiently independent, of which three trials analysed for 4–OH acibenzolar acid, and were assessed in order to derive indicative risk assessment values for the metabolite 4–OH acibenzolar acid (free and conjugated) for the existing use SEU GAP for lettuces (see Section 4.2). The residues of 4–OH acibenzolar acid were above the LOQ only in one independent trial and accounted for up to 0.13 mg/kg. The derived risk assessment values are indicative because there is an insufficient number of independent trials (three trials) that analysed for 4–OH acibenzolar acid (free and conjugated). The EMS applied non‐standard extrapolation from trials on head lettuce to other salad plants, herbs and edible flowers (existing SEU uses), which is not foreseen in the guidance (European Commission, 2017). However, since data on residue levels of the metabolite 4‐OH acibenzolar acid are not available for the existing use EU GAPs on other salad plants, herbs and edible flowers, EFSA applied a similar conservative approach as proposed by the EMS, and selected the higher risk assessment values for 4–OH acibenzolar acid (indicative supervised trial median residue (STMR) and highest residue (HR) values derived from three SEU trials on head lettuce), and applied non‐standard extrapolation to other salad plants, herbs and edible flowers (existing uses EU GAPs) (see Appendix D.2).

Herbs and edible flowers

Intended use SEU GAP: 1‐3 × 0.010 kg/ha, PHI 10 days

The applicant submitted 12 residue decline trials on outdoor head lettuce which were assessed previously in the framework of the EU pesticides peer review (see above) and proposed that the residue data are extrapolated to the group of herbs and edible flowers. The applicant did not propose a change to the existing MRLs for herbs and edible flowers. EFSA agrees with the EMS that the proposed extrapolation from trials on head lettuce to herbs and edible flowers is not foreseen in the guidance (European Commission, 2017), and does not allow to derive a new MRL for the intended use on herbs and edible flowers.

Beans with pods, peas with pods

Intended use GAP greenhouse application: 2 × 0.016 kg/ha, PHI 3 days

In support of the MRL application, the applicant submitted residue decline trials on protected beans (indoor use). Eight GAP compliant residue trials were performed in northern France, Germany, Spain and Italy in 2016. The metabolite 4–OH acibenzolar acid was quantified at the LOQ of 0.01 mg/kg in only one trial in beans with pods and was at levels below the LOQ in all other samples.

The applicant proposed to extrapolate the available residue data on beans (with pods) to peas (with pods). Extrapolation from trials performed on beans (with pods) to peas (with pods) is possible (European Commission, 2017). The number and quality of the trials are sufficient to derive an MRL proposal of 1 mg/kg for acibenzolar‐S‐methyl residues in beans with pods (0260010) and peas with pods (0260030), on the basis of the proposed indoor use GAP.

2.2.2. Magnitude of residues in rotational crops

The possible transfer of acibenzolar‐S‐methyl residues to crops that are grown in crop rotation has been assessed in the frameworks of the MRL review, the EU pesticides peer review and in previous reasoned opinions (EFSA, 2013, 2014, 2018b). The available studies demonstrate that no significant residues (> 0.01 mg/kg) are expected in succeeding crops (lettuce, radish winter wheat and maize) planted in soil treated at 0.05 kg a.s./ha. Since the maximum annual application rate for the crops under consideration (i.e. 0.032 kg a.s./ha per year) is lower than the application rate tested in the rotational crop study, it is concluded that no residues are expected, provided that the active substance is applied according to the proposed GAPs.

2.2.3. Magnitude of residues in processed commodities

Specific processing studies for the crops under assessment were not submitted and are not required as they are not expected to affect the outcome of the risk assessment. However, if more robust processing factors were to be required by risk managers, in particular for enforcement purposes, additional processing studies would be needed.

2.2.4. Proposed MRLs

The available data are considered sufficient to calculate MRLs proposals as well as risk assessment values for the residue definition derived in the framework of the MRL review (sum of acibenzolar‐S‐methyl and acibenzolar acid (free and conjugated), expressed as acibenzolar‐S‐methyl) based on the intended uses, except for herbs and edible flowers (see Appendix B.5).

In Section 4, EFSA assessed whether residues on these crops resulting from the intended uses are likely to pose a consumer health risk.

3. Residues in livestock

Not relevant as a specific GAP on bean vines intended for animal feeding is not included in the framework of the present application and the commodities under consideration are not used for feed purposes.

4. Consumer risk assessment

4.1. Consumer risk assessment for acibenzolar‐S‐methyl and acibenzolar acid (free and conjugated)

EFSA performed a dietary risk assessment for the risk assessment residue definition ‘sum of acibenzolar‐S‐methyl and acibenzolar acid (free and conjugated), expressed as acibenzolar‐S‐methyl’ using revision 3.1 of the EFSA PRIMo (EFSA, 2018a, 2019a). This exposure assessment model contains food consumption data for different subgroups 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, 2016a).

The toxicological reference values for acibenzolar‐S‐methyl used in the risk assessment (i.e. ADI of 0.03 mg/kg bw per day and ARfD value of 0.03 mg/kg bw) were derived in the framework of the EU pesticides peer review (European Commission, 2020). The metabolite acibenzolar acid, included in the residue definition for risk assessment in free and conjugated form, is also a major rat metabolite and was shown to share the toxicity potential of the parent acibenzolar‐S‐methyl; therefore, the reference values of the parent are applicable to this metabolite (EFSA, 2014).

Short‐term (acute) dietary risk assessment

The short‐term exposure assessment was performed for the commodities assessed in this application. The calculations were based on the HR values derived from supervised field trials or derived in the JMPR assessment, and the complete list of input values can be found in Appendix D.2.

The short‐term exposure for acibenzolar‐S‐methyl and acibenzolar acid (free and conjugated) did not exceed the ARfD for any of the crops assessed in this application (the highest exposure was calculated for lettuces: 23% of the ARfD, for more details, see Appendix B.4.1).

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 (EFSA, 2013). EFSA updated the calculation with the relevant STMR values derived from the residue trials submitted in support of this MRL application for lettuces and salad plants, beans (with pods) and peas (with pods), and the STMRs derived in the EFSA conclusion published after the MRL review (EFSA, 2014) and in subsequent EFSA opinions (EFSA, 2017b, 2018b, 2019b), as well as the STMRs derived by the JMPR for the acceptable CXLs included in Regulation (EC) No 396/2005 (FAO, 2016b). The input values used in the exposure calculations are summarised in Appendix D.2.

The estimated long‐term dietary intake for acibenzolar‐S‐methyl and acibenzolar acid (free and conjugated) accounted for up to 3% of the ADI (NL toddler diet). The contribution of residues expected in the commodities assessed in this application to the overall long‐term exposure is presented in more detail in Appendix B.4.1.

Based on these calculations, EFSA concluded that the long‐term intake resulting from the existing uses and the proposed uses of acibenzolar‐S‐methyl on lettuces and salad plants, beans (with pods) and peas (with pods) is unlikely to present a risk to consumer health with regard to residues of acibenzolar‐S‐methyl and acibenzolar acid (free and conjugated).

4.2. Indicative dietary exposure calculations for metabolite 4–OH acibenzolar acid (free and conjugated)

In order to provide risk managers additional information whether it is appropriate to include metabolite 4–OH acibenzolar acid (free and conjugated) in the residue definition for risk assessment (see Section 2.1.6), EFSA performed in Section 4.2. an indicative short‐term and long‐term exposure assessment for this metabolite, for which the general toxicity has not been satisfactorily addressed and for which toxicological reference values could not be derived (see Section 1).

The EMS also performed indicative long‐term and short‐term consumer exposure assessments for the metabolite 4–OH acibenzolar acid (free and conjugated) (France, 2019).13 The EMS compared the exposure calculated for 4–OH acibenzolar acid (free and conjugated) to the toxicological threshold of concern (TTC) for Cramer Class III (France, 2019). The EMS highest estimated short‐term exposure to 4–OH acibenzolar acid, expressed as acibenzolar‐S‐methyl equivalents, based on the existing EU GAPs (8.6 μg/kg bw and 5.2 μg/kg bw for processed and raw escaroles/broad‐leaved endives, respectively) exceeded the TTC of 5.0 μg/kg bw for Cramer Class III (France, 2019). The EMS highest estimated short‐term intake based on the intended use GAPs (2.7 μg/kg bw and 1.6 μg/kg bw for processed and raw escaroles/broad‐leaved endives, respectively) was below the TTC. The EMS estimated highest long‐term dietary exposure for metabolite 4–OH acibenzolar acid, expressed as acibenzolar‐S‐methyl equivalents, was 0.62 μg/kg bw per day (NL toddler diet, considering either the existing EU GAPs or the intended use GAPs), which is below (41%) the TTC of 1.5 μg/kg bw per day for Cramer Class III (France, 2019).

EFSA agrees with the EMS that the calculation of the exposure for metabolites can support risk managers to take an informed decision whether it is appropriate to include a metabolite in a residue definition. However, the use of the TTC approach is not an agreed practice to decide whether toxicological studies can be waived for certain metabolites. As regards the exposure calculation for 4–OH acibenzolar acid (free and conjugated), EFSA used different criteria how to derive the input values (see detailed explanations below) and expressed values as 4‐OH acibenzolar acid equivalents, which explain the different results derived by EFSA and the EMS.

Short‐term (acute) dietary risk assessment

The short‐term exposure calculation for 4–OH acibenzolar acid (free and conjugated) was performed using PRIMo revision 3.1. The assessment was performed for all crops, including all leafy crop commodities. For spinaches, the input value was derived from data assessed by JMPR, estimating the concentration of 4–OH acibenzolar acid by using a generic conversion/adjustment factor derived from metabolism studies. For the other leafy crops, the input values were derived from supervised field trials; if data for different GAPs (less critical GAP than the GAP leading to the MRL) were available, EFSA selected the most critical input value. Since information on residue levels of 4–OH acibenzolar acid is not available for the existing EU uses on herbs and edible flowers, and salad plants other than lettuces, the EMS proposed and EFSA also applied a conservative approach to extrapolate the higher indicative HR value from three SEU trials in head lettuce. The complete list of input values can be found in Appendix D.2.

The estimated highest short‐term exposure for 4–OH acibenzolar acid, free and conjugated (expressed as 4–OH acibenzolar acid) was 8.1 μg/kg bw for processed escaroles/broad‐leaved endives (indicative data for existing use GAPs), 4.9 μg/kg bw for raw escaroles/broad‐leaved endives, and was 4.6 μg/kg bw for lettuces (indicative data for existing use GAPs) (see Appendix B.4.2).

The short‐term exposure calculations are indicative due to a lack of robust data for existing uses on leafy crops (lettuces and salad plants, spinaches and herbs and edible flowers).

Compared to the exposure of acibenzolar‐S‐methyl residues in line with the current residue definition for risk assessment (sum of acibenzolar‐S‐methyl and acibenzolar acid (free and conjugated), expressed as acibenzolar‐S‐methyl), the exposure to 4–OH acibenzolar acid (free and conjugated), expressed as 4–OH acibenzolar acid, is lower (lettuces: 4.6 μg/kg bw for 4‐OH acibenzolar acid vs. 6.9 μg/kg bw for current residue definition; spinaches: 4.1 μg/kg bw for 4‐OH acibenzolar acid vs. 8.1 μg/kg bw; escaroles: 4.9 μg/kg bw for 4‐OH‐acibenzolar acid vs. 6.8 μg/kg bw).

Long‐term (chronic) dietary risk assessment

An indicative long‐term exposure calculation was performed, taking into account the proposed uses on the crops under consideration and the existing uses at EU level as reported for the MRL review (EFSA, 2013) and CXLs implemented in the EU legislation. EFSA performed the calculation with the relevant STMR values available for 4‐OH acibenzolar acid from either the residue trials submitted in support of this MRL application or derived by the JMPR. Since for existing EU uses on herbs and edible flowers, and salad plants other than lettuces, information on residue levels of 4–OH acibenzolar acid is not available, the EMS proposed and EFSA also applied a conservative approach to extrapolate the higher indicative STMR value from three SEU trials in head lettuce.

For commodities other than leafy crops, significant residues of 4–OH acibenzolar acid are not expected (EFSA, 2014). Therefore, for those crops for which a GAP was reported in the framework of the MRL review, a subsequent MRL application, or JMPR assessment, it was assumed that residues of 4–OH acibenzolar acid are present at the default MRL of 0.01 mg/kg. The input values used in the exposure calculations are summarised in Appendix D.2.

The highest estimated long‐term dietary exposure was 0.36 μg/kg bw per day (NL toddler diet) (see Appendix B.4.2). The long‐term exposure calculation is indicative due to a lack of robust data for existing use GAPs on leafy crops (lettuces and salad plants, spinaches and herbs and edible flowers).

Overall, the calculations give an indication that the exposure to 4–OH acibenzolar acid is lower than the exposure to acibenzolar‐S‐methyl and acibenzolar acid (free and conjugated). However, considering the data gaps identified in the previous sections, a definitive conclusion cannot be derived by EFSA on the risk for consumers related to the intake of residues of 4–OH acibenzolar acid.

For further details on the exposure calculations, screenshots of the report sheets of the PRIMo calculations are presented in Appendix C.

5. Conclusion and Recommendations

The toxicological data submitted in support of this MRL application were found to be sufficient to conclude that the plant metabolite 4–OH acibenzolar acid is not genotoxic in vitro. Lacking data to characterise the general toxicity of metabolite 4–OH acibenzolar acid, a definitive conclusion cannot be derived whether the plant metabolite 4–OH acibenzolar acid (free and conjugated) should be included or excluded from the residue definition for risk assessment for all commodities belonging to the groups of leafy crops and pulses/oilseeds. The available residue trials also did not show a coherent picture that would allow to derive a conclusion whether 4–OH acibenzolar acid (free and conjugated) is a relevant metabolite for dietary risk assessment for leafy crops.

For the intended uses on succulent beans (with pods) and peas (with pods), EFSA considered the current residue definition for risk assessment (sum of acibenzolar‐S‐methyl and acibenzolar acid (free and conjugated), expressed as acibenzolar‐S‐methyl) to be appropriate.

The residue trials data submitted in support of this MRL application were found to be sufficient to calculate MRL proposals and risk assessment values on the basis of the current residue definition (sum of acibenzolar‐S‐methyl and acibenzolar acid (free and conjugated), expressed as acibenzolar‐S‐methyl) for the intended uses on lettuces and salad plants, beans (with pods) and peas (with pods).

The consumer risk assessment for the current residue definition did not identify an unacceptable risk for consumers.

The indicative exposure calculations performed for the metabolite 4–OH acibenzolar acid give an indication that the exposure to this metabolite is lower than the exposure to acibenzolar‐S‐methyl and acibenzolar acid (free and conjugated). However, considering the data gaps identified in the previous sections, a definitive conclusion cannot be derived by EFSA on the risk for consumers related to the intake of residues of 4–OH acibenzolar acid. The MRL recommendations are summarised in Appendix B.5.

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

CAC

Codex Alimentarius Commission

CAS

Chemical Abstract Service

CCPR

Codex Committee on Pesticide Residues

CF

conversion factor for enforcement to risk assessment residue definition

CIRCA

(EU) Communication & Information Resource Centre Administrator

CS

capsule suspension

CV

coefficient of variation (relative standard deviation)

CXL

Codex maximum residue limit

DAR

draft assessment report

DAT

days after treatment

DM

dry matter

DT₉₀

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

EMS

evaluating Member State

eq

residue expressed as a.s. equivalent

FAO

Food and Agriculture Organization of the United Nations

GAP

Good Agricultural Practice

GR

granule

GS

growth stage

HPLC

high‐performance liquid chromatography

HPLC‐MS

high‐performance liquid chromatography with mass spectrometry

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

JMPR

Joint FAO/WHO Meeting on Pesticide Residues

LC

liquid chromatography

LOAEL

lowest observed adverse effect level

LOQ

limit of quantification

MRL

maximum residue level

MS

Member States

MS

mass spectrometry detector

MS/MS

tandem mass spectrometry detector

MW

molecular weight

NEU

northern Europe

NOAEL

no observed adverse effect level

OECD

Organisation for Economic Co‐operation and Development

PBI

plant back interval

PF

processing factor

PHI

preharvest interval

PRIMo

(EFSA) Pesticide Residues Intake Model

RA

risk assessment

RAC

raw agricultural commodity

RD

residue definition

RMS

rapporteur Member State

SANCO

Directorate‐General for Health and Consumers

SC

suspension concentrate

SEU

southern Europe

SL

soluble concentrate

SP

water‐soluble powder

STMR

supervised trials median residue

TAR

total applied radioactivity

TRR

total radioactive residue

UV

ultraviolet (detector)

WG

water‐dispersible granule

WHO

World Health Organization

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

1.

Crop and/or situation	NEU, SEU, MS or country	F G or Ia	Pests or group of pests controlled	Preparation		Application				Application rate per treatment				PHI (days)d	Remarks
				Typeb	Conc. a.s.	Method kind	Range of growth stages & seasonc	Number min–max	Interval between application (min)	g a.s./hL min–max	Water L/ha min–max	Rate	Unit
Lettuces and salad plants: lamb's lettuce/corn salads, lettuces, escaroles/broad‐leaved endives, cress and other sprouts and shoots, land cress, roman rocket/rucola, red mustards, baby leaf crops (including brassica species)	SEU (BG, CY, ES, GR, HR, IT, PT, MT)	G	Thrips (Frankliniella occidentalis). Lepidoptera (Spodoptera spp., Heliothis armigera. Chrysodeisis chalcite,. Autographa gamma), aphids (Aphis gossypii, Aphis fabae and Myzus persicae)	SC	12.5 g/L	Foliar treatment – broadcast spraying	12–49	1–2	7		250–1,000	16	g a.s./ha	3
Lettuces and salad plants: lamb's lettuce/corn salads, lettuces, escaroles/broad‐leaved endives, cress and other sprouts and shoots, land cress, roman rocket/rucola, red mustards, baby leaf crops (including brassica species)	SEU (BG, CY, ES, GR, HR, IT, PT, MT)	F	Thrips (Frankliniella occidentalis). Lepidoptera (Spodoptera spp., Heliothis armigera. Chrysodeisis chalcite,. Autographa gamma), aphids (Aphis gossypii, Aphis fabae and Myzus persicae)	SC	12.5 g/L	Foliar treatment – broadcast spraying	12–49	1	–		250–1,000	16	g a.s./ha	3
Herbs and edible flowers: chervil, chives, celery leaves, parsley, sage, rosemary, thyme, basil and edible flowers, laurel/bay leaves, tarragon, others	SEU	F	Colletotrichum spp. Phytophthora spp.	WG	40.0 g/kg	Foliar treatment – broadcast spraying	18–49	1–3	10		100–300	10	g a.s./ha	10	Countries: FR
Beans (with pods); Peas (with pods)	SEU	G	Thrips (Frankliniella occidentalis). Lepidoptera (Spodoptera spp., Heliothis armigera. Chrysodeisis chalcite,. Autographa gamma), aphids (Aphis gossypii, Aphis fabae and Myzus persicae)	SC	12.5 g/kg	Foliar treatment – broadcast spraying	18–49	1–2	7		250–1,000	16	g a.s./ha	3	Countries: BG, CY, ES, GR, HR, IT, PT, MT

MRL: maximum residue level; GAP: Good Agricultural Practice; NEU: northern European Union; SEU: southern European Union; MS: Member State; a.s.: active substance; SC: suspension concentrate; WG: water‐dispersible granule.

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

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

^cGrowth 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.

^dPHI – minimum preharvest interval.

Appendix B – List of end points

B.1. Mammalian toxicology

B.2. Residues in plants

B.2.1. Nature of residues and methods of analysis in plants

B.2.1.1. Metabolism studies, methods of analysis and residue definitions in plants

Primary crops (available studies)	Crop groups	Crop(s)	Application(s)	Sampling (DAT)	Comment/Source
	Fruit crops	Tomato	Foliar, G 3 × 0.0152 kg a.s./ha, interval 14 days; total application rate: 0.0456 kg a.s./ha	0, 30	[14C‐U‐phenyl]‐acibenzolar‐S‐methyl (France, 1998, 2014; EFSA, 2013, 2014).
	Leafy crops	Tobacco	Foliar, G 3 applications; total application rate: 0.170 kg a.s./ha	0, 17, 27, 35, 45, 52
		Lettuce	Foliar, G 4 × 0.105 kg a.s./ha; total application rate: 0.42 kg a.s./ha	0, 7
			Foliar, G 4 × 0.035 kg a.s./ha; total application rate: 0.14 kg a.s./ha (1st application 7–9 leaf stage)	0, 7
	Cereals/grass	Wheat	Foliar, F 1 × 0.05 kg a.s./ha (Application at the end of tillering)	0, 14, 28, 75
			Foliar, G 1 × 0.05 kg a.s./ha (Application at 4 leaf stage)	0, 1, 3, 7, 14

Rotational crops (available studies)	Crop groups	Crop(s)	Application(s)	PBI (DAT)	Comment/Source
	Root/tuber crops	Radish	Bare soil application, F, 0.05 kg a.s./ha	30, 113, 141, 337	Radiolabelled active substance: [14C‐U‐phenyl]‐acibenzolar‐S‐methyl (France, 1998, EFSA, 2013, 2014).
	Leafy crops	Lettuce	Bare soil application, F, 0.05 kg a.s./ha	30, 113, 141, 337
	Cereal (small grain)	Wheat	Bare soil application, F, 0.05 kg a.s./ha	30, 113, 141, 337
		Maize	Bare soil application, F, 0.05 Kg a.s./ha	30, 113, 141, 337

Processed commodities (hydrolysis study)	Conditions	Stable?	Comment/Source
	Pasteurisation (20 min, 90°C, pH 4)	Yes	EFSA (2014)
	Baking, brewing and boiling (60 min, 100°C, pH 5)	Yes	EFSA (2014)
	Sterilisation (20 min, 120°C, pH 6)	No	Degradation into acibenzolar acid accounting for 50.5% of applied radioactivity (EFSA, 2013, 2014)
	Other processing conditions	–	–

B.2.1.2. Stability of residues in plants

Plant products (available studies)	Category	Commodity	T (°C)	Stability period		Compounds covered	Comment/Source
				Value	Unit
	High water content	Tobacco, lettuce, tomato, cabbage, squash and turnips	–20	20	Months	Acibenzolar‐S‐methyl, acibenzolar acid	EFSA (2013)
	High water content	Lettuce	–20	12	Months	4‐OH acibenzolar acid	EFSA (2019b)
	High oil content	Hazelnuts	–20	197	Days	acibenzolar‐S‐methyl, acibenzolar acid	Study to continue up to 12 months (EFSA 2019b)
	High oil content	Rape seed	–20	12	Months	4‐OH acibenzolar acid	EFSA (2019b)
	High protein content	–	–	–	–	–	–
	High protein content	Dried beans	–20	12	Months	4‐OH acibenzolar acid	EFSA (2019b)
	Dry/High starch	Wheat grain	–18	24	Months	acibenzolar‐S‐methyl, acibenzolar acid	EFSA (2013)
	Dry/High starch	Wheat grain, potato tuber	–20	12	Months	4‐OH acibenzolar acid	EFSA (2019b)
	High acid content	Strawberries	–21	10	Months	acibenzolar‐S‐methyl, acibenzolar acid	EFSA (2017b, 2018b, 2019b)
	High acid content	Kiwi fruit	–20	12	Months	4‐OH acibenzolar acid	EFSA (2019b)
	Processed products	–	–	–	–	–	–
	Others	Wheat straw	–20	12	Months	4‐OH acibenzolar acid	EFSA (2019b)
		Forage	–	–	–	–	–

B.2.2. Magnitude of residues in plants

B.2.2.1. Summary of residues data from the supervised residue trials

Commodity	Region/Indoora	Residue levels observed in the supervised residue trials (mg/kg)	Comments/Source	Calculated MRL (mg/kg)	HRb (mg/kg)	STMRc (mg/kg)	CFd
Enforcement residue definition: Sum of acibenzolar‐S‐methyl and acibenzolar acid (free and conjugated), expressed as acibenzolar‐S‐methyl Risk assessment residue definition: Sum of acibenzolar‐S‐methyl and acibenzolar acid (free and conjugated), expressed as acibenzolar‐S‐methyl
Lettuce	Indoor	Trials: 2 × 14.8‐17.1 g a.s./ha, interval 7 days, BBCH 21‐49, PHI 3 days Mo: 0.04, 0.05, 0.08, 2× 0.09, 0.10, 0.15, 0.17 RA: 0.04, 0.05, 0.08, 2× 0.09, 0.10, 0.15, 0.17 4‐OH acibenzolar acid e : 8 × < 0.01	Residue trials on protected open‐leaf varieties compliant with the intended indoor GAP. Extrapolation to whole subgroup lettuces and salad plants (0251000) possible. The existing EU MRL is 0.4 mg/kg for lettuces and 0.3 mg/kg for salad plants other than lettuces.	0.3	Mo: 0.17 RA: 0.17 4‐OH acibenzolar acid e : 0.01	Mo: 0.09 RA: 0.09 4‐OH acibenzolar acid e : 0.01	–
Lettuce	SEU	Trials: 1 × 15.2‐17.1 g a.s./ha, BBCH 47‐49, PHI 3 days Mo: 0.02, 4 × 0.03, 2 × 0.04, 0.06f RA: 0.02, 4 × 0.03, 2× 0.04, 0.06f 4‐OH acibenzolar acid e : 7 × < 0.01, 0.04f	Residue trials on open‐leaf varieties compliant with SEU GAP. Extrapolation to whole subgroup lettuces and salad plants (0251000) possible. The existing EU MRLs are higher than the MRL calculated for the intended SEU use.	0.15	Mo: 0.06 RA: 0.06 4‐OH acibenzolar acid e: 0.04	Mo: 0.03 RA: 0.03 4‐OH acibenzolar acid e: 0.01	–
Lettuce	SEU	Trials: 3 × 14 g a.s./ha, interval 9‐12 days, BBCH 40‐46, PHI 10 days Mo: < 0.02, 0.02g (closed head lettuce); 3× 0.02, 0.03h (‘semi‐open’ head lettuce) RA: < 0.02, 0.02g (closed head lettuce); 3 × 0.02, 0.03h (‘semi‐open’ head lettuce) 4‐OH acibenzolar acid e : < 0.02, < 0.02g (closed head lettuce); 0.13h (‘semi‐open’ head lettuce)	Submitted residue trials on head lettuce. Trials have been assessed previously in the framework of the pesticides peer review (France, 2014). Trials performed in accordance with the existing SEU GAP on lettuces. Indicative risk assessment values are derived for 4–OH acibenzolar acid based on an insufficient number (3) of independent trials which analyse for 4–OH acibenzolar acid (free and conjugated). The metabolite 4–OH acibenzolar acid was not analysed in 3 trials.	–	Mo: 0.03 (indicative) RA: 0.03 (indicative) 4‐OH acibenzolar acid e: 0.13 (indicative)	Mo: 0.02 (indicative) RA: 0.02 (indicative) 4‐OH acibenzolar acid e: 0.02 (indicative)	–
Beans (with pods)	Indoor	Trials: 2 × 13.8‐16.8 g a.s./ha, interval 7 days, BBCH 64‐79, PHI 3 days Mo: 0.20, 2 × 0.21, 0.22, 0.33i), 0.34, 0.47, 0.48 RA: 0.20, 2 × 0.21, 0.22, 0.33i), 0.34, 0.47, 0.48 4‐OH acibenzolar acid e : 7 × < 0.01, 0.01f	Residue trials on protected beans (with pods) compliant with the intended indoor GAP. Extrapolation to peas (with pods) possible.	1	Mo: 0.48 RA: 0.48 4‐OH acibenzolar acid e: 0.01	Mo: 0.275 RA: 0.275 4‐OH acibenzolar acid e: 0.01	–

MRL: maximum residue level; GAP: Good Agricultural Practice; Mo: monitoring; RA: risk assessment.

^*Indicates that the MRL is proposed at the limit of quantification.

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

^bHighest residue. The highest residue for risk assessment refers to the whole commodity and not to the edible portion.

^cSupervised trials median residue. The median residue for risk assessment refers to the whole commodity and not to the edible portion.

^dConversion factor to recalculate residues according to the residue definition for monitoring to the residue definition for risk assessment.

^eThe EMS applied a molecular weight conversion factor of 1.07 to express residues of 4–OH acibenzolar acid as acibenzolar‐S‐methyl equivalents (France, 2019).

^fHigher residue value at later PHI selected (7 days PHI).

^gHighest value from non‐independent trials performed at same location and dates (trials 2009/99 and 2010/99).

^hHighest value from non‐independent trials performed at same location and dates on ‘semi‐open’ head lettuce varieties (trials 2043/99 and 2036/99) which analysed for acibenzolar‐S‐methyl and acibenzolar acid (free and conjugated) and 4–OH acibenzolar acid, also performed at same location and dates as trial on closed head variety (trial 2035/99) which analysed for acibenzolar‐S‐methyl and acibenzolar acid (free and conjugated) only. Residue values for 4–OH acibenzolar acid (trials 2043/99 and 2036/99): 0.05 mg/kg and 0.13 mg/kg at PHI 10 days, the latter value being the mean of two determinations of 0.04 and 0.22 mg/kg (France, 2019), noting residue values of 0.10, 0.07, 0.06 and 0.08 mg/kg in the same trial at PHIs 0, 3, 7 and 14 days, respectively, there is no clear diminution or increase of the residue levels with time (France, 2014).

ⁱHigher residue value at later PHI selected (10 days PHI).

B.2.2.2. Residues in rotational crops

B.2.2.3. Processing factors

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

B.3. Residues in livestock

Not relevant to the present MRL application.

B.4. Consumer risk assessment

B.4.1. Consumer risk assessment for acibenzolar‐S‐methyl and acibenzolar acid (free and conjugated)

B.4.2. Indicative consumer exposure calculations for metabolite 4–OH acibenzolar acid (free and conjugated)

B.5. Recommended MRLs

Codea	Commodity	Existing EU MRL (mg/kg)	Proposed EU MRL (mg/kg)	Comment/justification
Enforcement residue definition: Sum of acibenzolar‐S‐methyl and acibenzolar acid (free and conjugated), expressed as acibenzolar‐S‐methyl Risk assessment residue definition: Sum of acibenzolar‐S‐methyl and acibenzolar acid (free and conjugated), expressed as acibenzolar‐S‐methyl Further risk management discussions required whether the residue definition needs to be amended, taking into account the information presented in this reasoned opinion
0251010	Lamb's lettuces/corn salads	0.3	No change	The submitted information did not provide evidence that the existing MRL has to be changed for the intended uses. No risk for consumers identified for the current residue definition. Risk assessment is affected by additional non‐standard uncertainty due to the lack of data to fully characterise metabolite 4–OH acibenzolar acid which was identified in the peer review as candidate to be included in the residue definition for risk assessment for leafy crops.
0251020	Lettuces	0.4	No change	An MRL proposal of 0.3 mg/kg was calculated for the intended indoor use. The MRL proposal is lower than the existing EU MRL, which is based on the Codex MRL. No risk for consumers identified for the current residue definition. Risk assessment is affected by additional non‐standard uncertainty due to the lack of data to fully characterise metabolite 4–OH acibenzolar acid which was identified in the peer review as candidate to be included in the residue definition for risk assessment for leafy crops.
0251030	Escaroles/broad‐leaved endives	0.3	No change	The submitted information did not provide evidence that the existing MRL has to be changed for the intended uses. No risk for consumers identified for the current residue definition. Risk assessment is affected by additional non‐standard uncertainty due to the lack of data to fully characterise metabolite 4–OH acibenzolar acid which was identified in the peer review as candidate to be included in the residue definition for risk assessment for leafy crops.
0251040	Cresses and other sprouts and shoots	0.3	No change
0251050	Land cresses	0.3	No change
0251060	Roman rocket/rucola	0.3	No change
0251070	Red mustards	0.3	No change
0251080	Baby leaf crops (including brassica species)	0.3	No change
0251990	Others	0.3	No change
0256000	Herbs and edible flowers	0.3	No MRL proposal	The submitted data are not sufficient to derive an MRL proposal for the intended use. The applicant did not propose a change to the existing MRL. The existing EU MRL is based on a comparable existing SEU GAP assessed in the MRL review and supported by residue trials on spinach. No risk for consumers identified for the current residue definition. Risk assessment is affected by additional non‐standard uncertainty due to the lack of data to fully characterise metabolite 4–OH acibenzolar acid which was identified in the peer review as candidate to be included in the residue definition for risk assessment for leafy crops.
0260010	Beans (with pods)	0.01*	1.0	The submitted data are sufficient to derive an MRL proposal for the intended indoor use. No consumer health risk was identified.
0260030	Peas (with pods)	0.01*	1.0	The submitted data are sufficient to derive an MRL proposal for the intended indoor use. No consumer health risk was identified.

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

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

Appendix C – Pesticide Residue Intake Model (PRIMo)

1.

• Consumer risk assessment for acibenzolar‐S-methyl and acibenzolar acid (free and conjugated)

• Indicative dietary exposure calculations for metabolite 4‐OH acibenzolar acid (free and conjugated)

Appendix D – Input values for the exposure calculations

D.1. Livestock dietary burden calculations

Not relevant to the present MRL application.

D.2. Consumer risk assessment

• Consumer risk assessment for acibenzolar‐S-methyl and acibenzolar acid (free and conjugated)

Commodity	Chronic risk assessment		Acute risk assessment
	Input value (mg/kg)	Comment	Input value (mg/kg)	Comment
Residue definition for risk assessment: sum of acibenzolar‐S-methyl and acibenzolar acid (free and conjugated), expressed as acibenzolar‐S-methyl
Hazelnuts/cobnuts	0.06	STMR‐RAC (EFSA, 2019b)	0.07	HR‐RAC (EFSA, 2019b)
Apples	0.01	CXL STMR‐RAC (FAO, 2016b)	0.17	CXL HR‐RAC (FAO, 2016b)
Pears	0.02	Tentative STMR‐RAC (EFSA, 2013)	0.09	Tentative HR‐RAC (EFSA, 2013)
Quinces	0.01	STMR‐RAC (EFSA, 2014)	0.09	HR‐RAC (EFSA, 2014)
Medlar	0.01	STMR‐RAC (EFSA, 2014)	0.09	HR‐RAC (EFSA, 2014)
Loquats/Japanese medlars	0.01	STMR‐RAC (EFSA, 2014)	0.09	HR‐RAC (EFSA, 2014)
Other pome fruit	0.01	STMR‐RAC (EFSA, 2014)	0.09	HR‐RAC (EFSA, 2014)
Apricots	0.03	EU STMR‐RAC (EFSA, 2013)	0.09	EU HR‐RAC (EFSA, 2013)
Peaches	0.03	EU STMR‐RAC (EFSA, 2013)	0.09	EU HR‐RAC (EFSA, 2013)
Strawberries	0.045	CXL STMR‐RAC (FAO, 2016b)	0.08	CXL HR‐RAC (FAO, 2016b)
Cranberries	0.045	CXL STMR‐RAC (FAO, 2016b)	0.08	CXL HR‐RAC (FAO, 2016b)
Kiwi fruits (green, red, yellow)	0.05	STMR‐RAC (EFSA, 2017b, 2018b, 2019b)	0.17	HR‐RAC (EFSA, 2017b, 2018b, 2019b)
Bananas	0.02	STMR‐RAC (EFSA, 2013)	0.08	HR‐RAC (EFSA, 2013)
Mangoes	0.21	Tentative STMR‐RAC (EFSA, 2013)	0.36	Tentative HR‐RAC (EFSA, 2013)
Garlic	0.05	CXL STMR‐RAC (FAO, 2016b)	0.06	CXL HR‐RAC (FAO, 2016b)
Onions	0.05	CXL STMR‐RAC (FAO, 2016b)	0.06	CXL HR‐RAC (FAO, 2016b)
Shallots	0.05	CXL STMR‐RAC (FAO, 2016b)	0.06	CXL HR‐RAC (FAO, 2016b)
Tomatoes	0.11	EU STMR‐RAC (SEU)b (EFSA, 2014)	0.15	EU HR‐RAC (SEU)b (EFSA, 2014)
Aubergines/egg plants	0.04	STMR‐RAC (EFSA, 2018b)	0.08	HR‐RAC (EFSA, 2018b)
Cucumbers	0.12	STMR‐RAC (EFSA, 2018b)	0.26	HR‐RAC (EFSA, 2018b)
Gherkins	0.12	STMR‐RAC (EFSA, 2018b)	0.26	HR‐RAC (EFSA, 2018b)
Courgettes	0.12	STMR‐RAC (EFSA, 2018b)	0.26	HR‐RAC (EFSA, 2018b)
Other cucurbits – edible peel	0.12	STMR‐RAC (EFSA, 2018b)	0.26	HR‐RAC (EFSA, 2018b)
Melons	0.04	STMR‐RAC (EFSA, 2018b)	0.08	HR‐RAC (EFSA, 2018b)
Pumpkins	0.04	STMR‐RAC (EFSA, 2018b)	0.08	HR‐RAC (EFSA, 2018b)
Watermelons	0.04	STMR‐RAC (EFSA, 2018b)	0.08	HR‐RAC (EFSA, 2018b)
Other cucurbits – inedible peel	0.04	STMR‐RAC (EFSA, 2018b)	0.08	HR‐RAC (EFSA, 2018b)
Lamb's lettuce/corn salads	0.11	STMR‐RAC (EFSA, 2013)	0.17	HR‐RAC (France, 2019)
Lettuces	0.12	CXL STMR‐RAC (leaf lettuce)a (FAO, 2016b)	0.18	CXL HR‐RAC (leaf lettuce)a (FAO, 2016b)
Escaroles/broad‐leaved endives	0.11	STMR‐RAC (EFSA, 2013)	0.17	HR‐RAC (France, 2019)
Cress and other sprouts and shoots	0.11	STMR‐RAC (EFSA, 2013)	0.17	HR‐RAC (France, 2019)
Land cress	0.11	STMR‐RAC (EFSA, 2013)	0.17	HR‐RAC (France, 2019)
Roman rocket/rucola	0.11	STMR‐RAC (EFSA, 2013)	0.17	HR‐RAC (France, 2019)
Red mustards	0.11	STMR‐RAC (EFSA, 2013)	0.17	HR‐RAC (France, 2019)
Baby leaf crops (including brassica species)	0.11	STMR‐RAC (EFSA, 2013)	0.17	HR‐RAC (France, 2019)
Other lettuce and other salad plants	0.11	STMR‐RAC (EFSA, 2013)	0.17	HR‐RAC (France, 2019)
Spinaches	0.19	CXL STMR‐RACa (FAO, 2016b)	0.36	CXL HR‐RACa (FAO, 2016b)
Chervil	0.14	STMR‐RAC (EFSA, 2013)	0.18	HR‐RAC (EFSA, 2013)
Chives	0.14	STMR‐RAC (EFSA, 2013)	0.18	HR‐RAC (EFSA, 2013)
Celery leaves	0.14	STMR‐RAC (EFSA, 2013)	0.18	HR‐RAC (EFSA, 2013)
Parsley	0.14	STMR‐RAC (EFSA, 2013)	0.18	HR‐RAC (EFSA, 2013)
Sage	0.14	STMR‐RAC (EFSA, 2013)	0.18	HR‐RAC (EFSA, 2013)
Rosemary	0.14	STMR‐RAC (EFSA, 2013)	0.18	HR‐RAC (EFSA, 2013)
Thyme	0.14	STMR‐RAC (EFSA, 2013)	0.18	HR‐RAC (EFSA, 2013)
Basil and edible flowers	0.14	STMR‐RAC (EFSA, 2013)	0.18	HR‐RAC (EFSA, 2013)
Laurel/bay leaves	0.14	STMR‐RAC (EFSA, 2013)	0.18	HR‐RAC (EFSA, 2013)
Tarragon	0.14	STMR‐RAC (EFSA, 2013)	0.18	HR‐RAC (EFSA, 2013)
Other herbs	0.14	STMR‐RAC (EFSA, 2013)	0.18	HR‐RAC (EFSA, 2013)
Beans (with pods)	0.275	STMR‐RAC (France, 2019)	0.48	HR‐RAC (France, 2019)
Peas (with pods)	0.275	STMR‐RAC (France, 2019)	0.48	HR‐RAC (France, 2019)
Barley	0.02	STMR‐RAC (EFSA, 2013)	0.02	STMR‐RAC (EFSA, 2013)
Wheat	0.02	STMR‐RAC (EFSA, 2013)	0.02	STMR‐RAC (EFSA, 2013)
Other crops/commodities	–	The contributions of commodities where no GAP was reported in the framework of the MRL review or subsequent MRL applications were not included in the calculation.	–	The contributions of commodities where no GAP was reported in the framework of the MRL review or subsequent MRL applications were not included in the calculation.

STMR‐RAC: supervised trials median residue in raw agricultural commodity; HR‐RAC: highest residue in raw agricultural commodity; PeF: Peeling factor; CXL: codex maximum residue limit; MRL: maximum residue level; GAP: Good Agricultural Practice.

^aThe JMPR agreed that residues of 4‐OH acibenzolar acid (free and conjugated) should be included in the residue definition for risk assessment in plants, and applied an correction factor of 1.5 to residues in leafy vegetables measured according to the residue definition for monitoring to convert residues to the equivalent sum of acibenzolar‐S‐methyl, acibenzolar acid (free and conjugated) and 4‐OH acibenzolar acid (free and conjugated). For leaf lettuce, the JMPR derived adjusted risk assessment values STMR of 0.18 (= 1.5 × 0.12) and HR of 0.27 (= 1.5 × 0.18) mg/kg to account for residues of 4‐OH acibenzolar acid (free and conjugated). For spinaches, the JMPR derived adjusted risk assessment values STMR of 0.285 (= 1.5 × 0.19) and HR of 0.54 (= 1.5 × 0.36) mg/kg to account for residues of 4‐OH acibenzolar acid (free and conjugated) (FAO, 2016b).

^bEFSA assumed the EU GAP for indoor use on tomatoes assessed in the MRL review has been revoked following identification of possible exceedance of the ARfD (EFSA, 2014), and consequently, risk assessment values are derived from outdoor use (SEU).

• Indicative dietary exposure calculations for metabolite 4‐OH acibenzolar acid (free and conjugated)

Commodity	Chronic exposure assessment		Acute exposure assessment
	Input value (mg/kg)	Comment	Input value (mg/kg)	Comment
Consumer exposure calculations for 4–OH acibenzolar acid (free and conjugated), expressed as 4–OH acibenzolar acid
Hazelnuts/cobnuts	0.01	Default EU MRL. Significant residues of 4–OH acibenzolar acid are not expected (EFSA, 2014)	0.01	Default EU MRL. Significant residues of 4–OH acibenzolar acid are not expected (EFSA, 2014)
Apples	0.01		0.01
Pears	0.01		0.01
Quinces	0.01		0.01
Medlar	0.01		0.01
Loquats/Japanese medlars	0.01		0.01
Other pome fruit	0.01		0.01
Apricots	0.01		0.01
Peaches	0.01		0.01
Strawberries	0.01		0.01
Cranberries	0.01		0.01
Kiwi fruits (green, red, yellow)	0.01		0.01
Bananas	0.01		0.01
Mangoes	0.01		0.01
Garlic	0.01		0.01
Onions	0.01		0.01
Shallots	0.01		0.01
Tomatoes	0.01		0.01
Aubergines/egg plants	0.01		0.01
Cucumbers	0.01		0.01
Gherkins	0.01		0.01
Courgettes	0.01		0.01
Other cucurbits – edible peel	0.01		0.01
Melons	0.01		0.01
Pumpkins	0.01		0.01
Watermelons	0.01		0.01
Other cucurbits – inedible peel	0.01		0.01
Lamb's lettuce/corn salads	0.02	Existing use NEU/SEU/Indoor GAPsa: indicative STMR‐RACb from 3 SEU trials on head lettuce: 0.02 (France, 2019); Intended use SEU GAP STMR‐RACb: 0.01 (France, 2019)	0.13	Existing use NEU/SEU/Indoor GAPsa: indicative HR‐RACb from 3 SEU trials on head lettuce: 0.13 (France, 2019); Intended use SEU GAP HR‐RACb: 0.04 (France, 2019)
Lettuces	0.06	Adjusted CXL STMR‐RAC (leaf lettuce)c (FAO, 2016b)	0.13	Existing use NEU/SEU/Indoor GAPs: indicative HR‐RACb from 3 SEU trials on head lettuce: 0.13 (France, 2019); Adjusted CXL HR‐RAC (leaf lettuce)c: 0.09 (FAO, 2016b); Intended use SEU GAP HR‐RACb: 0.04 (France, 2019)
Escaroles/broad‐leaved endives	0.02	Existing use NEU/SEU/Indoor GAPsa: indicative STMR‐RACb from 3 SEU trials on head lettuce: 0.02 (France, 2019); Intended use SEU GAP STMR‐RACb: 0.01 (France, 2019)	0.13	Existing use NEU/SEU/Indoor GAPsa: indicative HR‐RACb from 3 SEU trials on head lettuce: 0.13 (France, 2019); Intended use SEU GAP HR‐RACb: 0.04 (France, 2019)
Cress and other sprouts and shoots
Land cress
Roman rocket/rucola
Red mustards
Baby leaf crops (including brassica species)
Other lettuce and other salad plants
Spinaches	0.095	Adjusted CXL STMR‐RACc (FAO, 2016b)	0.18	Adjusted CXL HR‐RACc (FAO, 2016b)
Chervil	0.02	Existing use NEU/SEU GAPsa: indicative STMR‐RACb from 3 SEU trials on head lettuce: 0.02 (France, 2019)	0.13	Existing use NEU/SEU GAPsa: indicative HR‐RACb from 3 SEU trials on head lettuce: 0.13 (France, 2019)
Chives
Celery leaves
Parsley
Sage
Rosemary
Thyme
Basil and edible flowers
Laurel/bay leaves
Tarragon
Other herbs
Beans (with pods)	0.01	STMR‐RACb (France, 2019)	0.01	HR‐RACb (France, 2019)
Peas (with pods)	0.01	STMR‐RACb (France, 2019)	0.01	HR‐RACb (France, 2019)
Barley	0.01	Significant residues of 4–OH acibenzolar acid above 0.01 mg/kg are not expected (EFSA, 2014)	0.01	Significant residues of 4–OH acibenzolar acid above 0.01 mg/kg are not expected (EFSA, 2014)
Wheat	0.01		0.01
Other crops/commodities	–	The contributions of commodities where no GAP was reported in the framework of the MRL review or subsequent MRL applications were not included in the calculation.	–	The contributions of commodities where no GAP was reported in the framework of the MRL review or subsequent MRL applications were not included in the calculation.

STMR‐RAC: supervised trials median residue in raw agricultural commodity; HR‐RAC: highest residue in raw agricultural commodity; PeF: Peeling factor; CXL: codex maximum residue limit; MRL: maximum residue level; GAP: Good Agricultural Practice NEU: northern Europe; SEU: southern Europe.

^aFor existing use EU GAPs on herbs and edible flowers, and salad plants other than lettuces (EFSA, 2013), data are not available on residue levels of 4‐OH acibenzolar acid, therefore, in a conservative approach similar to the approach proposed by the EMS, EFSA selected the higher indicative risk assessment value derived from an insufficient number of independent SEU trials on head lettuce, and applied non‐standard extrapolation to other salad plants, herbs and edible flowers.

^bThe submitted residue trials expressed residues of 4–OH acibenzolar acid as acibenzolar‐S‐methyl equivalents (molecular weight conversion factor of 1.07; France, 2019). EFSA recalculated residue values above the LOQ, expressed as 4–OH acibenzolar acid.

^cThe JMPR agreed that residues of 4‐OH acibenzolar acid (free and conjugated) should be included in the residue definition for risk assessment in plants, and applied an adjustment factor of 1.5 to residues in leafy vegetables measured according to the residue definition for monitoring to convert residues to the equivalent sum of acibenzolar‐S‐methyl, acibenzolar acid (free and conjugated) and 4‐OH acibenzolar acid (free and conjugated). For leaf lettuce, the JMPR derived adjusted risk assessment values total STMR of 0.18 (= 1.5 × 0.12) and total HR of 0.27 (= 1.5 × 0.18) mg/kg to account for residues of 4‐OH acibenzolar acid (free and conjugated). For spinaches, the JMPR derived adjusted risk assessment values total STMR of 0.285 (= 1.5 × 0.19) and total HR of 0.54 (= 1.5 × 0.36) mg/kg to account for residues of 4‐OH acibenzolar acid (free and conjugated) (FAO, 2016b).

Appendix E – Used compound codes

1.

Code/trivial namea	IUPAC name/SMILES notation/InChIKeyb	Structural formulac
acibenzolar‐ S ‐methyl CGA 245704 benzothiadiazole	S‐methyl benzo[1,2,3]thiadiazole‐7‐carbothioate O=C(SC)c1cccc2nnsc12 UELITFHSCLAHKR‐UHFFFAOYSA‐N
acibenzolar acid CGA 210007	1,2,3‐benzothiadiazole‐7‐carboxylic acid O=C(O)c1cccc2nnsc12 COAIOOWBEPAOFY‐UHFFFAOYSA‐N
4‐OH acibenzolar acid CGA 323060	4‐hydroxy‐1,2,3‐benzothiadiazole‐7‐carboxylic acid O=C(O)c1ccc(O)c2nnsc12 RZSJWCHAQOKSRQ‐UHFFFAOYSA‐N
5‐OH acibenzolar acid CGA 324041	5‐hydroxy‐1,2,3‐benzothiadiazole‐7‐carboxylic acid O=C(O)c1c(O)ccc2nnsc12 KFCBKGUXJXJRLM‐UHFFFAOYSA‐N

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

^aThe metabolite name in bold is the name used in the conclusion.

^bACD/Name 2019.1.3 ACD/Labs 2019 Release (File version N05E41, Build 111418, 3 September 2019).

^cACD/ChemSketch 2019.1.3 ACD/Labs 2019 Release (File version C05H41, Build 111302, 27 August 2019).

Suggested citation: European Food Safety Authority (EFSA) , Anastassiadou M, Bernasconi G, Brancato A, Carrasco Cabrera L, Ferreira L, Greco L, Jarrah S, Kazocina A, Leuschner R, Magrans JO, Miron I, Nave S, Pedersen R, Reich H, Rojas A, Sacchi A, Santos M, Scarlato AP, Theobald A, Vagenende B and Verani A, 2021. Reasoned Opinion on the modification of the existing maximum residue levels for acibenzolar‐S‐methyl in beans with pods and peas with pods. EFSA Journal 2021;19(2):6430, 44 pp. 10.2903/j.efsa.2021.6430