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Evaluation of confirmatory data following the Article 12 MRL review for dimethenamid‐P

Abstract The applicant BASF SE submitted a request to the competent national authority in Germany to evaluate the confirmatory data that were identified for dimethenamid‐P in the framework of the maximum residue level (MRL) review under Article 12 of Regulation (EC) No 396/2005 as not available. The data gap refers to the submission of a plant metabolism study investigating the fate of dimethenamid‐P following foliar treatment with a short preharvest interval (PHI) in a leafy or bulb vegetable crop. The confirmatory data requirement is considered sufficiently addressed according to the conclusions of the peer review, which, based on available metabolism studies, proposed to modify the existing enforcement and risk assessment residue definitions in all plant commodities, by including additional dimethenamid‐P metabolites ((2RS)‐3‐(2‐{(2,4‐dimethylthiophen‐3‐yl)[(2S)‐1‐methoxypropan‐2‐yl]amino}‐2‐oxoethanesulfinyl)‐2‐hydroxypropanoic acid (M30) and (2RS)‐3‐[(2‐{(2,4‐dimethylthiophen‐3‐yl)[(2S)‐1‐methoxypropan‐2‐yl]amino}‐2‐oxoethyl)sulfanyl]‐2‐hydroxypropanoic acid (M26). The residue data of metabolites M26 and M30 are currently not available for all authorised uses assessed in the MRL review. Should risk managers decide amending residue definitions, the existing EU MRLs would need to be revised accordingly. The consumer exposure as calculated by the MRL review was updated in two scenarios, using the existing and the new toxicological reference values as derived by the peer review. For the crops under consideration (spring onions, lettuce, escarole and herbs), indicative conversion factors were applied to account for possible metabolite burden. No consumer intake concerns were identified.


Summary
In 2013, when the European Food Safety Authority (EFSA) reviewed the existing maximum residue levels (MRLs) for dimethenamid-P according to Article 12 of Regulation (EC) No 396/2005, EFSA identified some information as unavailable (data gaps) and derived tentative MRLs for those uses which were not fully supported by data but for which no risk to consumers was identified. A plant metabolism study investigating the fate of dimethenamid-P following a foliar treatment with a short preharvest interval (PHI) in a crop belonging to the class of leafy or bulb vegetables was requested as confirmatory data.
The tentative MRL proposals for the crops affected by the data gap have been implemented in the MRL legislation by Commission Regulation (EU) No 2015/552, including a footnote that indicated the type of confirmatory data that should be provided by a party having an interest in maintaining the proposed tentative MRL by 8 April 2017.
In accordance with the agreed procedure set out in the working document SANTE/10235/2016, BASF SE submitted a formal application to the competent national authority in Germany (rapporteur Member State (RMS)) to evaluate the confirmatory data identified during the MRL review. In order to address the data gap, the applicant revised the Good Agricultural Practices (GAPs) for the crops for which tentative MRLs have been established: lettuce, spring onions and herbs. A new GAP on escarole was also reported. Furthermore, the applicant referred to new metabolism studies that have been assessed in the framework of the process of renewal of the approval for dimethenamid-P (in the following referred to as peer review process).
The evaluation report prepared by the RMS summarised the information submitted by the applicant. The application was submitted to the European Commission and forwarded to EFSA on 25 September 2018.
The table below summarises the conclusions and recommendations derived on the basis of the assessment of confirmatory data submitted by the applicant. The data gap identified by EFSA regarding metabolism study is considered addressed. Based on the new and previously available metabolism studies, the peer review proposed to modify the existing residue definitions for enforcement and risk assessment as 'dimethenamid (sum of stereoisomers) and metabolites M26 and M30, expressed as dimethenamid-P'.
Since the modification of the residue definition will have an impact not only on the crops for which confirmatory data were requested, but for a wide range of crops with approved uses, further risk management discussions are required on the implementation of the new residue definitions. If the existing residue definition for enforcement is maintained, the MRLs for the crops under consideration are confirmed. The residue data on lettuce is acceptable to propose a new MRL in escarole, provided that the NEU use of dimethenamid-P on escarole is confirmed. The risk assessment performed in the framework of the MRL review was updated, taking into account the presence of M26 and M30 in leafy crops (lacking residue trials for the proposed new residue definition, indicative conversion factors were used to recalculate the input values for spring onions, lettuce, escarole and herbs). EFSA calculated two scenarios: while in scenario 1 the current ADI/ARfD was used, in scenario 2 an indicative risk assessment was performed, using new toxicological reference values derived in the peer review (not yet formally adopted

Assessment
The review of existing maximum residue levels (MRLs) for the active substance dimethenamid-P according to Article 12 of Regulation (EC) No 396/2005 1 (MRL review) has been performed in 2013 (EFSA, 2013). The European Food Safety Authority (EFSA) identified some information as unavailable (data gaps) and derived tentative MRLs for those uses not fully supported by data but for which no risk to consumers was identified.
Following the MRL review, the existing MRLs have been modified in the MRL legislation by Commission Regulation (EU) No 2015/552 2 , including a footnote that specified the type of information that was identified as missing for the tentative MRLs. Any party having an interest in maintaining the proposed tentative MRL was requested to address the confirmatory data by 8 April 2017.
In accordance with the specific provisions set out in the working document of the European Commission SANTE/10235/2016(European Commission, 2016, the applicant BASF SE submitted an application to the competent national authority in Germany (designated rapporteur Member State (RMS)) to evaluate the confirmatory data identified during the MRL review. To address the data gaps identified by EFSA, the applicant has amended the authorised Good Agricultural Practices (GAPs) for spring onions, lettuce and herbs by deleting the preharvest interval (PHI) since the active substance must be applied at an early development stage of the crop (BBCH 10-18) which does not require to specify a PHI. In Appendix A, the previously assessed GAPs and the adjusted GAPs are reported. Furthermore, the applicant referred to metabolism studies that have been assessed in the framework of the renewal of the approval of dimethenamid-P.
In addition, a GAP on escarole was reported, for which the existing MRL should be modified. The evaluating Member State (EMS) clarified that the applicant (BASF SE) is not the authorisation holder for escarole, but there might be a minor use registration in the northern Europe (NEU) requiring the MRL for escarole.
The RMS assessed the information and the arguments provided by the applicant in an evaluation report, which was submitted to the European Commission and forwarded to EFSA on 25 September 2018 (Germany, 2018). EFSA assessed the application as requested by the European Commission in accordance with Article 9 of Regulation (EC) No 396/2005. EFSA based its assessment on the evaluation report submitted by the RMS (Germany, 2018), the reasoned opinion on the MRL review according to Article 12 of Regulation (EC) No 396/2005 (EFSA, 2013) and the EFSA conclusion on the peer review of the pesticide risk assessment of the active substance dimethenamid-P (EFSA, 2018).
For this application, the data requirements established in Regulation (EU) No 544/2011 3 and the relevant guidance documents at the date of implementation of the confirmatory data requirements by Regulation (EU) No 2015/552 are applicable. 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 546/2011. 4 An updated list of end points, including the end points of relevant studies assessed previously and the confirmatory data evaluated in this application, is presented in Appendix B.
The evaluation report submitted by the RMS (Germany, 2018) is considered a supporting document to this reasoned opinion and, thus, is made publicly available as a background document to this reasoned opinion.
Nature of residues and methods of analysis in plants 1.1.1. Nature of residues in primary crops The applicant did not submit a plant metabolism study investigating the fate of dimethenamid-P following a foliar treatment with a short PHI in a leafy or bulb vegetable crop as requested as confirmatory data.
According to the applicant, the results in maize forage following foliar treatment provide information on the metabolic profile expected in leafy parts of the crop treated close to harvesting. This proposal is in line with the conclusions of the peer review, where, on the basis of available metabolism studies with maize (foliar and soil treatment), sugar beet (foliar application) and soybean (soil application), a comparable metabolic pathway for all plant commodities was concluded.
Overall, the available plant metabolism studies demonstrate that residues of parent dimethenamid-P and its metabolites are all below 0.01 mg/kg in soybeans, sugar beet roots and maize grain; in soybean leaves and maize forage metabolites M26 (soybean leaves) and M30 (maize forage, DAT 30), accounted for more than 10% TRR. The presence of these metabolites was confirmed by certain residue trials submitted under the peer review, i.e. in spring onions (PHI 28-43), Chinese cabbage and curly kale (PHI 26-65) residues of metabolite M30 were above the limit of quantification (LOQ).
The peer review concluded that these metabolites are relevant plant metabolites to be included in the risk assessment and enforcement residue definitions for all plant commodities (EFSA, 2018).
EFSA concluded that the available maize metabolism study is sufficient to address the data gap for spring onions, herbs and lettuce as identified by the MRL review.

Nature of residues in rotational crops
New studies were not submitted and are not relevant.

Nature of residues in processed commodities
Not relevant for the current assessment.

Methods of analysis in plants
Not relevant for the current assessment.

Stability of residues in plants
Not relevant for the current assessment. 5 The MRL review assessed metabolism of dimethenamid-P in maize and soybean following soil treatment and in sugar beet following foliar treatment (EFSA, 2013).

Proposed residue definitions
In the framework of the MRL review, the following residue definition for the risk assessment and enforcement was derived: 'dimethenamid, including other mixtures of constituent isomers including dimethenamid-P (sum of isomers)' (EFSA, 2013). The residue definition was considered tentative for some of the authorised uses in Europe (spring onions, lettuce and herbs) where consumable parts are harvested after foliar treatment with a short PHI.
The same residue definition is currently implemented in Regulation (EC) No 396/2005. Based on the metabolism studies described under Section 1.1.1, and taking into account, the toxicological relevance of metabolites, the experts performing the peer review of dimethenamid-P recently proposed to modify the residue definitions (enforcement and risk assessment) for plant commodities as 'dimethenamid (sum of stereoisomers) and metabolites (2RS These residue definitions are not yet formally adopted. The peer review also concluded that, based on structure similarity, the toxicological reference values of dimethenamid-P are applicable to metabolites M26 and M30, which are considered unlikely to be genotoxic. If a decision is taken by risk managers to follow the recommendations of the peer review (EFSA, 2018) and to modify the residue definitions, a comprehensive revision of the existing MRLs would be required.

Magnitude of residues in plants
In the framework of the current assessment, the applicant proposed to modify the authorised GAPs for lettuce, chives and spring onions by deleting PHI intervals. For chives, in addition, another NEU GAP, involving split application, was reported (see Appendix A). The EMS also reported a new GAP on escarole which was not assessed previously.

Spring onions, chives
The deletion of the PHI interval and splitting of the application rate (only for chives) in the authorised GAP on spring onions and chives is not expected to affect the validity of trials assessed in the MRL review (no residue situation was observed). Thus, the adjusted GAPs are considered sufficiently supported by residue data. The available studies confirm that residues of parent dimethenamid-P above the LOQ are not expected in spring onions and chives.

Lettuce, fresh herbs (except chives), escarole
The adjusted GAP on lettuce is less critical than the authorised GAP assessed in the MRL review. The new reported GAP on escarole, which, according to the information from the EMS would support minor uses in the NEU, is identical to the GAP on lettuce reported in the framework of the current assessment.
New residue trials matching the adjusted GAP or the new GAP on escarole, have not been submitted. However, as residues of parent dimethenamid-P were below the LOQ of 0.01 mg/kg for a more critical GAP on lettuce assessed by the MRL review, it is concluded that available lettuce trials are valid to support the adjusted GAP on lettuce, the existing authorised GAP on herbs and the new GAP on escarole. The MRL of 0.01 mg/kg (at the LOQ) is thus confirmed for the existing residue definition in lettuce, herbs (except chives) and escarole.
It is noted that new metabolism studies confirm that in the crops under consideration metabolites are present at higher levels than parent, and thus shall be considered in the risk assessment. For spring onions, the residue trials assessed by the peer review support the adjusted GAP and provide information on metabolite levels. A conversion factor of 2.7 is derived for spring onions (extrapolated to chives) from the existing to the new risk assessment residue definition. For lettuce, herbs (except chives) and escarole in the absence of specific residue data, a conversion factor of 2.6 can be derived from the peer review residue trials on leafy brassica (Chinese cabbage, curly kale; GAP involving early treatment) to account for metabolites of M30 and M26.

Consumer risk assessment
New toxicological reference values were derived in the framework of the renewal of the approval of dimethenamid-P (EFSA, 2018). The new ADI and ARfD have not yet been adopted. Moreover, new information available from metabolism studies would require consideration of dimethenamid-P metabolites M26 and M30 in the exposure assessment. The residue data on metabolites are currently not available for all crops on which the use of dimethenamid-P is authorised, but since the available residue trials assessed in the peer review indicate no residue situation in all crops, with exception of spring onions and leafy brassica, the lack of this information is not expected to underestimate the actual consumer exposure.
In the framework of the current assessment, EFSA updated the consumer exposure calculated in the MRL review with data on metabolites in the crops under consideration (scenario 1). In order to estimate the consumer exposure for the toxicological reference values proposed by the peer review, a second exposure scenario (scenario 2) was calculated, using new acceptable daily intake (ADI) and acute reference dose (ARfD) values. The scenario 2 is considered indicative as the new toxicological reference values are not yet enforced.
For lettuce, herbs, escarole and spring onions, indicative conversion factors of 2.6 and 2.7, derived from the peer review residue trials on leafy brassica and spring onions, respectively, were applied to the input values. For the remaining commodities, the input values for the chronic and acute exposure assessment were as reported in the MRL review. Those crops, on which the authorised uses have not been reported under the MRL review, were excluded from the exposure calculation.

Scenario 1
The calculated exposure was compared with the currently applicable toxicological reference values: ADI of 0.02 mg/kg body weight (bw) day and an ARfD of 0.25 mg/kg bw (European Commission, 2003). The highest calculated chronic exposure accounted for 1.5% of the ADI (UK toddler diet). No acute consumer intake concerns were identified for any of the crops, with a maximum individual highest exposure calculated from residues in escarole (0.9% of the ARfD) and lettuce (0.3% of the ARfD).

Scenario 2 (indicative)
The calculated exposure was compared with the toxicological reference values as derived by the recent EFSA peer review: ADI of 0.04 mg/kg bw day and the ARfD value of 0.08 mg/kg bw (EFSA, 2018). The toxicological reference values are not enforced yet. The calculated indicative chronic exposure accounted for a maximum 0.8% of the ADI (UK Toddler) and the highest acute exposure was calculated from the intake of escarole (2.8% of the ARfD) and lettuce (0.9% of the ARfD).
Although the contribution of dimethenamid metabolites in all crops from all authorised uses could not be assessed, given the wide margin of safety, it can be concluded that currently no risk of consumers is associated with the intake of crops containing dimethenamid-P residues when treated according to the authorised use patterns.

Conclusion and Recommendations
To address the data gaps, the applicant and the RMS referred to a new metabolism study on maize (foliar treatment), which was assessed for the renewal of the approval of dimethenamid-P, but not available for the MRL review. Along with other available metabolism studies, the peer review proposed to modify the existing enforcement and risk assessment residue definitions in all plant commodities, by including metabolites M26 and M30, and derived new toxicological reference values.
The residue data on metabolites M26 and M30 are currently not available for the authorised uses assessed in the MRL review. Since the modification of the residue definition will have an impact not only on the crops for which confirmatory data were requested, but for a wide range of crops with approved uses, further risk management discussions are required on the implementation of new residue definitions. It is noted that in the peer review a wide range of residue trials were assessed confirming the presence of metabolite M30 only in spring onions and leafy brassica, whereas for the remaining crops residues of dimethenamid-P and its metabolites M26 and M30 were below the LOQ.
If the existing residue definition is maintained, the tentative MRLs in spring onions, lettuce and herbs and a new MRL of 0.01 mg/kg (LOQ) in escarole, are confirmed.
New information available from metabolism studies requires consideration of dimethenamid-P metabolites M26 and M30 in the exposure assessment. The consumer exposure calculated by the MRL review was updated in two scenarios, using the existing and the new toxicological reference values. For the input values of spring onions, lettuce, escarole and herbs, indicative conversion factors as derived from available peer review trials were applied to account for the metabolite burden. No consumer intake concerns were identified.
Although the contribution of dimethenamid metabolites in all crops from all authorised uses could not be assessed, given the wide margin of safety, it can be concluded that no risk of consumers is currently associated with the intake of crops containing residues when treated according to the authorised use patterns.
The overview of the assessment of confirmatory data and the recommended MRL modifications are summarised in Appendix A.4.    247, 30.9.2003, p. 20-25. 7 Not enforced yet. 8 Not enforced yet.
The calculations are based on the median residue levels expected in raw agricultural commodities from the authorised uses assessed in the MRL review (EFSA, 2013) and for the new use reported for escarole (Germany, 2018) The following conversion factors for risk assessment were applied: 2.7 for spring onions and chives and 2.6 for lettuce, escarole and herbs (except chives) to account for metabolites M26 and M30 The calculation for Scenario 2 is indicative since a formal decision on the toxicological reference values has not yet been taken The data gap identified by EFSA regarding metabolism study is considered addressed. Based on the new and previously available metabolism studies, the peer review proposed to modify the existing residue definitions for enforcement and risk assessment as "dimethenamid (sum of stereoisomers) and metabolites M26 and M30, expressed as dimethenamid-P". Since the modification of the residue definition will have an impact not only on the crops for which confirmatory data were requested, but for a wide range of crops with approved uses, further risk management discussions are required on the implementation of the new residue definitions. If the existing residue definition for enforcement is maintained, the MRLs for the crops under consideration are confirmed. The residue data on lettuce is acceptable to propose a new MRL in escarole, provided that the NEU use of dimethenamid-P on escarole is confirmed. The risk assessment performed in the framework of the MRL review was updated, taking into account the presence of M26 and M30 in leafy crops (lacking residue trials for the proposed new residue definition, indicative conversion factors were used to recalculate the input values for spring onions, lettuce, escarole and herbs). EFSA calculated two scenarios: while in scenario 1 the current ADI/ARfD was used, in scenario 2 an indicative risk assessment was performed, using new toxicological reference values derived in the peer review (not yet formally adopted).
No consumer health concerns were identified (scenario 1: 1.5% of the ADI, max. 0.9% of ARfD for escarole and 0.3% of ARfD for lettuce scenario 2: 0.8% of the ADI, max. 2.8% of ARfD for escarole and 0.9% of ARfD for lettuce). Given the wide margin of safety, it can be concluded that the existing uses of dimethenamid-P do not pose a risk to consumers

Conclusion:
The estimated Theoretical Maximum Daily Intakes (TMDI), based on pTMRLs were below the ADI. A long-term intake of residues of Dimethenamid-P is unlikely to present a public health concern.
Dimethenamid-P The acute risk assessment is based on the ARfD.

Unprocessed commodities
*) The results of the IESTI calculations are reported for at least 5 commodities. If the ARfD is exceeded for more than 5 commodities, all IESTI values > 90% of ARfD are reported. **) pTMRL: provisional temporary MRL. ***) pTMRL: provisional temporary MRL for unprocessed commodity.
No exceedance of the ARfD/ADI was identified for any unprocessed commodity.

Conclusion:
For Dimethenamid-P, IESTI 1 and IESTI 2 were calculated for food commodities for which pTMRLs were submitted and for which consumption data are available.
In the IESTI 1 calculation, the variability factors were 10, 7 or 5 (according to JMPR manual 2002); for lettuce, a variability factor of 5 was used.
In the IESTI 2 calculations, the variability factors of 10 and 7 were replaced by 5. For lettuce, the calculation was performed with a variabilty factor of 3.

No of commodities for which ARfD/ADI is exceeded (IESTI 2):
For each commodity, the calculation is based on the highest reported MS consumption per kg bw and the corresponding unit weight from the MS with the critical consumption. If no data on the unit weight was available from that MS, an average European unit weight was used for the IESTI calculation.

No of commodities for which ARfD/ADI is exceeded:
No of commodities for which ARfD/ADI is exceeded: Threshold MRL is the calculated residue level which would leads to an exposure equivalent to 100% of the ARfD.

Conclusion:
The estimated Theoretical Maximum Daily Intakes (TMDI), based on pTMRLs were below the ADI. A long-term intake of residues of Dimethenamid-P is unlikely to present a public health concern.
Dimethenamid-P Evaluation of confirmatory data for dimethenamid-P to address data gaps identified in the MRL review The acute risk assessment is based on the ARfD.

Unprocessed commodities
*) The results of the IESTI calculations are reported for at least 5 commodities. If the ARfD is exceeded for more than 5 commodities, all IESTI values > 90% of ARfD are reported. **) pTMRL: provisional temporary MRL. ***) pTMRL: provisional temporary MRL for unprocessed commodity.
No exceedance of the ARfD/ADI was identified for any unprocessed commodity.

Conclusion:
For Dimethenamid-P, IESTI 1 and IESTI 2 were calculated for food commodities for which pTMRLs were submitted and for which consumption data are available.
In the IESTI 1 calculation, the variability factors were 10, 7 or 5 (according to JMPR manual 2002); for lettuce, a variability factor of 5 was used.
In the IESTI 2 calculations, the variability factors of 10 and 7 were replaced by 5. For lettuce, the calculation was performed with a variabilty factor of 3.

No of commodities for which ARfD/ADI is exceeded (IESTI 2):
For each commodity, the calculation is based on the highest reported MS consumption per kg bw and the corresponding unit weight from the MS with the critical consumption. If no data on the unit weight was available from that MS, an average European unit weight was used for the IESTI calculation.

No of commodities for which ARfD/ADI is exceeded:
No of commodities for which ARfD/ADI is exceeded: Threshold MRL is the calculated residue level which would leads to an exposure equivalent to 100% of the ARfD.
No of commodities for which ARfD/ADI is exceeded (IESTI 1):