Targeted review of maximum residue levels (MRLs) for fenpropathrin

Abstract

Summary

The European Commission submitted a request to EFSA for a targeted review of maximum residue limits (MRLs) for 10 active substances no longer approved in the EU, but for which MRLs greater than the limit of quantification (LOQ) are still in place and for which Member States have identified potential consumer health risks. Separate reasoned opinions should be provided in accordance with Article 43 of Regulation (EC) 396/2005, for each of the substances included in this mandate, one of them being fenpropathrin.

In accordance with the terms of reference, EFSA investigated the origin of the current EU MRLs for fenpropathrin, and whether they are sufficiently substantiated. An EU MRL is considered substantiated if it is sufficiently supported by data and established for uses still authorised or based on Codex Maximum Residue Limit (CXL) or import tolerance that are still in place and relevant. Accordingly, MRLs that were derived for previously authorised EU uses are obsolete and should be lowered to the LOQ. For those commodities for which the existing EU MRLs are based on a CXL, EFSA investigated whether the CXLs are still in place and whether they are sufficiently supported by data. Obsolete or insufficiently supported Codex MRLs are also candidates for being lowered to the LOQ. To identify possible import tolerances, EFSA consulted Member States on Good Agricultural Practices authorised in third countries that were evaluated at national level which might justify maintaining certain MRLs as import tolerances. Following this Member State consultation, EFSA concluded that none of the existing EU MRL for fenpropathrin has been established as an import tolerance. EFSA also screened the appropriateness of the toxicological reference values (TRVs) derived by the Joint Meeting on Pesticide residues (JMPR) according to the current data requirements and standards.

EFSA prepared a draft reasoned opinion that was shared with Member States and the European Reference Laboratories (EURLs) for consultation via a written procedure. Comments received were considered during the finalisation of this reasoned opinion. The following conclusions are derived.

The metabolism of fenpropathrin in plant and animal was previously investigated by JMPR. According to the results of the metabolism studies assessed, the residue definition for enforcement and risk assessment, both for plant and animal products, is fenpropathrin. The residue is fat soluble.

Analytical methods are available for the enforcement of the proposed residue definition in high water content, high oil content and high acid content commodities, as well as in coffee with an LOQ of 0.01 mg/kg and in tea with an LOQ of 0.05 mg/kg. Fenpropathrin can be enforced in food of animal origin with an LOQ of 0.01 mg/kg in muscle, fat, milk and eggs. According to the EURLs, a QuEChERS multi‐residue analytical method is available with an LOQ of 0.01 mg/kg for the routine analysis of fenpropathrin in high water content, high acid content, high oil content and dry commodities, as well as in commodities of animal origin (egg, muscle and liver). Based on the experience gained with these matrices, an LOQ of 0.01 mg/kg is deemed achievable also for animal fat and kidney.

The origin of all current MRLs set for fenpropathrin (based on formerly approved uses or on CXLs) was investigated, and it was concluded that none of the existing MRLs were sufficiently substantiated. No fall‐back MRLs were identified for any of the crops under assessment (citrus fruits, strawberries, melon, tea).

A screening of the appropriateness of the TRVs set by the JMPR was performed, and the set of toxicological studies used to derive these TRVs was assessed according to the current data requirements and standards. It was concluded that the TRVs cannot be confirmed for fenpropathrin since the data available were insufficient compared to current standards, and uncertainty factors could not be established. Accordingly, the acceptable daily intake (ADI) and acute reference dose (ARfD) derived in 2012 do not comply with the current scientific standards. Therefore, EFSA recommends withdrawing these TRVs. The following data would be required to finalise the toxicological assessment which is a pre‐requisite to derive robust TRVs:

• submission of the available studies with a full evaluation of the toxicological data package and reporting relevant details on the studies and the results in accordance with the current guidelines, including an assessment of the reliability and relevance of each individual study and assessment of the validity of the analytical methods used in feed, body fluids and tissues, air and any additional matrices used in support of the toxicological studies;
• an interspecies comparative in vitro metabolism study on animal species used in pivotal studies and on human material;
• additional toxicological data to perform an ED assessment;
• an up‐to‐date search for published literature;
• an assessment of the toxicological relevance of impurities potentially present in the technical specification.

Chronic and acute exposure calculations were performed using revision 3.1 of PRIMo, considering all CXLs/MRLs no longer substantiated at the appropriate LOQ, as well as all other commodities for which no GAP was reported under this review. Comparing to the current TRVs, no exceedances were observed, and the highest chronic exposure represented 4% of the ADI (Dutch toddler) and the highest acute exposure amounted to 5% of the ARfD (potatoes). Nevertheless, EFSA emphasises that as the toxicological assessment revealed deficiencies regarding the toxicological studies available for fenpropathrin and considering that the TRVs do not meet the current scientific standards, the indicative risk assessment cannot be finalised, and results presented under the current review are indicative only.

It is concluded that none of the existing EU MRLs/CXLs listed in the table below are recommended for inclusion in Annex II to the Regulation.

Summary table

Background

In March 2021, a Member State submitted to the European Commission the results of a screening performed on all maximum residue levels (MRLs) of active substances used in plant protection products that are not approved in the EU. The list contained 904 substances; for 297 of them, at least one MRL was set at a level above the limit of quantification (LOQ).

For 219 of these substances, the MRLs are not related to the uses of the substances in plant protection products (e.g. MRLs reflect the use of biocides or veterinary medical products, or MRLs are set to account for their occurrence in certain food due to environmental persistence, or their natural occurrence). For the other 78 substances, the MRLs were established either based on formerly approved uses in the EU, on import tolerance requests, or on Codex maximum residue limits (CXLs).

Some of these substances were never approved in the EU, or their approval was withdrawn before 2008, and therefore they did not fall within the scope of the systematic review of all existing MRLs under Article 12 of Regulation (EC) No 396/2005¹.

A second Member State conducted additional analysis, identifying potential consumer risk for some of the MRLs set for these active substances.

Based on these analyses, the European Commission conducted a prioritisation exercise to identify substances for which existing MRLs should be reviewed with high priority. The prioritisation was also discussed and agreed with Member States during several meetings of the Standing Committee on Plants, Animals, Food and Feed (SCoPAFF), section Phytopharmaceuticals – Pesticides residues (September 2021,² November 2021³ and February 2022⁴). The SCoPAFF agreed that ten active substances, for which potential consumer risks were identified, should be assessed by EFSA as a priority. One of the substances identified for being assessed with high priority is fenpropathrin.

The European Commission proposed to mandate EFSA to provide a targeted review of MRLs for the substances concerned without delay. Due to the urgency of the subject, EFSA was invited to consider, if appropriate, delivering a separate reasoned opinion for each of the substances included in this mandate, as to be able to start providing outcomes to the Commission as soon as possible and successively. In this reasoned opinion, EFSA covered the targeted review of the MRLs for fenpropathrin.

Terms of Reference (as provided by the requestor)

EFSA was requested by the European Commission, according to Article 43 of Regulation (EC) No 396/2005, to prepare a reasoned opinion on fenpropathrin. In particular, the following tasks should be performed:

1. to investigate the origin of the current EU MRLs (e.g. MRL based on formerly approved uses in the EU, on import tolerance requests, or on CXLs). This analysis should allow to verify if the CXLs/import tolerances are still justified⁵ and to identify MRLs that do not correspond to import tolerances or currently established CXLs (non‐verified CXL/import tolerances);
2. to consult Member States on information about Good Agricultural Practices authorised in third countries and already evaluated at MS level, which might support maintaining the existing import tolerances or setting of new (lowered) import tolerances, if this is necessary in view of consumer protection;
3. to identify fall‐back MRLs for MRLs that do not correspond to a verified CXLs/import tolerance; these fall‐back MRLs could be either a lower import tolerance or a lower CXL established more recently. If no fall‐back MRL can be identified, the MRL should be considered for lowering to the appropriate LOQ;
4. to consult the EU Reference Laboratories (EURLs) on the LOQs achievable during routine analyses for all commodities;
5. to perform an indicative screening of the chronic and acute consumer exposure related to the existing EU MRLs reflecting the verified CXLs/import tolerances, fall‐back MRLs and/or proposed revised LOQ MRLs, using the newest version of the Pesticide Residues Intake Model (PRIMo) based on the available residue definitions for risk assessment and, if not available, residue definitions for enforcement derived at EU level or by JMPR. The following scenarios should be calculated:

   1. Scenario 1:

      1. Values at the appropriate LOQ: all MRLs that are based on former EU uses and all CXLs that were revoked by the Codex Committee on Pesticide Residues (CCPR) should be lowered to the appropriate LOQ;
      2. Non‐LOQ values to be considered: CXLs that were previously taken over in EU legislation, CXLs that were covered by still existing (higher) EU MRLs to be considered at the value of the CXL, MRLs based on existing import tolerances.
   2. Scenario 2:

      1. Like scenario 1, but lowering all CXLs that were evaluated by EFSA before and including 2009⁶ and all import tolerances established before and including 2007,⁷ respectively, to the appropriate LOQ.
6. to derive the input values for commodities of animal origin for the consumer exposure calculation from the relevant assessment where the MRLs for animal products were derived. However, if the respective risk assessment values (HR/STMR) cannot be retrieved from the available sources, the exposure shall be calculated with the existing MRL. If the existing MRL is no longer justified and no fall‐back MRL can be retrieved, the existing MRL should be considered for being lowered to the LOQ; in this case the risk assessment screening should be performed with the LOQ;
7. to examine the available information in order to screen the quality of the toxicological reference values (TRVs) set at EU level and of those established by JMPR. This screening should also consider the completeness of the set of toxicological studies used to derive the TRVs, as to assess if it would be acceptable according to the current standards. In case deficiencies are identified, these should be highlighted along with the resulting uncertainties;
8. to examine the available information in order to screen the quality of the residue definitions for risk assessment set at EU level and of those established by JMPR. In case deficiencies are identified, these should be highlighted along with the resulting uncertainties;
9. to compare the indicative chronic and acute dietary exposure to the toxicological reference values derived at EU level or, if not available, to the toxicological reference values derived by JMPR;
10. to report information on the classification of the substance under the CLP Regulation⁸ and whether the active substance meets the criteria for endocrine disruptors;
11. to assess, in all cases, the contribution of MRLs at the LOQ to the exposure in all exposure scenarios;
12. to recommend MRLs that do not pose an unacceptable risk to consumers, where possible, and advise risk managers on alternative options. Where relevant, EFSA should indicate whether the achievable LOQs are sufficiently protective for consumers;
13. to share its draft reasoned opinion for consultation with Member States (MSs) and EURLs before finalising it.

EFSA accepted the mandate and to deliver its assessment by finalising separate reasoned opinions for each of the substances included in this mandate, including fenpropathrin, by 22 May 2023.

Assessment

To address the complex Terms of Reference (ToR), EFSA used the following approach:

• In Section 1 (Regulatory background information on fenpropathrin), information on classification of the active substance under CLP regulation and on endocrine properties is reported (addressing ToR 10).
• In Section 2.1 (Nature of residues and residue definitions), a screening of the quality of residue definitions is reported (addressing ToR 8). Since no studies are available at EU level, EFSA summarises the available data from JMPR reports.
• In Section 2.2 (Analytical methods for MRLs enforcement), information on analytical methods for MRLs enforcement provided by the EURLs on the LOQs achievable during routine residue analysis is reported (ToR 4). In addition, EFSA summarised the information on the analytical methods available from JMPR reports.
• In Section 2.3 (Existing MRLs), information on the origin of the current MRLs is reported in tabular format (ToR 1). In the same section, information provided by MSs on good agricultural practices (GAPs) authorised in third countries and previously evaluated in view of setting import tolerances can be found (ToR 2). This information, together with information on existing CXLs, is used to derive possible fall‐back MRLs (ToR 3) that are also reported in the table if available.
• In Section 3 (Toxicological reference values), the quality of the TRVs set by the JMPR are assessed (ToR 7).
• In Section 4 (Consumer risk assessment), an indicative screening of the chronic and acute consumer exposure is presented (ToR 5 and 6). The dietary exposure assessment Scenario 1 and 2 is performed as requested in ToR 5 (a) and (b). This section also addresses ToR 11 (contribution of MRLs at the LOQ to the total exposure) and ToR 9 (comparison of the dietary exposure with the TRVs derived by the JMPR, however, noting that EFSA proposes to withdraw the TRVs currently in place).
• In the Conclusions and recommendations section, EFSA presents the MRL proposals that are unlikely to pose an unacceptable risk to consumers, where possible, and the ones for which further consideration is required (ToR 12).

No draft assessment report (DAR) and no EFSA conclusion are available. Therefore, EFSA has based its assessment on the following documents:

• Scientific support for preparing an EU position in the 45th and 47th Sessions of the Codex Committee on Pesticide Residues (CCPR) (EFSA, 2013, 2015);
• the reports and evaluations of the JMPR (FAO, 1993, 2006, 2012, 2014);
• the reports of the Codex Committee on Pesticide residues (CCPR, 2007, 2015).

As requested by the terms of reference (ToR 2), Member States were invited to submit by 18 October 2022 the Good Agricultural Practices (GAPs) that are authorised in third countries and already evaluated at national level, in the format of specific GAP forms, as well as the supporting residue data, in the format of an evaluation report. In the framework of this consultation, seven Member States (CZ, DE, ES, FR, IT, NL and SE) provided feedback regarding fenpropathrin and notified that no import tolerances were in place. The EU Reference Laboratories (EURLs) were also consulted (ToR 4) to provide an evaluation report on the availability of analytical methods for enforcement and the LOQs achievable during routine analysis in plants and animal commodities. The EURLs report on analytical methods (EURLs, 2022) submitted during the collection of data is considered as main supporting document to this reasoned opinion and, thus, made publicly available.

On the basis of the data submitted by the MSs, the EURLs, the data available in the Joint Meeting on Pesticide residues (JMPR) Evaluation reports and taking into account the screening of the available toxicological data with regards to their completeness and quality according to current standards, EFSA prepared a draft reasoned opinion, which was circulated to Member States and EURLs for consultation via a written procedure in April 2023. Comments received by 2 May 2023 were considered during the finalisation of this reasoned opinion (ToR 13).

Further supporting document to this reasoned opinion is the Member States consultation report (EFSA, 2023). The exposure calculations for all crops reported in the framework of this review performed using the EFSA Pesticide Residues Intake Model (PRIMo) are also key supporting documents made publicly available as background document to this reasoned opinion.

1. Regulatory background information on fenpropathrin

The key events concerning the regulatory history of fenpropathrin, the background information, together with the relevant published documents are summarised in Table 1.

2. Residue definitions and existing EU MRLs

3. Toxicological reference values

EFSA was mandated to examine the available information to screen the quality of the toxicological reference values (TRVs) set at EU level and of those established by the JMPR, and to assess the completeness of the set of toxicological studies used to derive the TRVs according to the current standards (ToR 7). EFSA assessed the appropriateness of these TRVs in the light of the currently available information and of the completeness of the underlying toxicological dataset according to the current standards.

The TRVs for fenpropathrin reported in Table 6 were derived by the JMPR in 2012, the active substance was never peer reviewed at the EU level. The JMPR values were used for a tentative assessment for the Codex MRL proposals (EFSA, 2013, 2015). EFSA noted then that no firm conclusion could be made on the appropriateness of the TRVs, in particular with regards to the unknown stereo‐composition of the tested material assessed by the JMPR.

EFSA screened the completeness and the appropriateness of the toxicological data reported in the JMPR monograph (FAO, 2012) used to derive the TRVs, focusing on the question whether the information is sufficient to assess whether they meet current quality (i.e. reliability and reporting) standards and the EU data requirements.⁹ The original studies are not available to EFSA.

The JMPR reports that most of the studies do not comply with good laboratory practice (GLP) as they were conducted before the implementation of GLP.

With regards to the toxicological data package needed to derive an ADI and ARfD, the following data gaps were identified according to the current data requirements:

• an assessment of the validity of the analytical methods used in feed, body fluids and tissues, air and any additional matrices used in support of the toxicological studies;
• toxicological relevance of impurities potentially present in the technical specification;
• an interspecies comparative in vitro metabolism study performed on animal species used in pivotal studies and on human material, to determine the relevance of the toxicological animal data to humans and whether additional testing of potential unique human metabolites would be required;
• an up‐to‐date search for published literature;
• the endocrine disruptive potential of fenpropathrin was not assessed according to the current ECHA/EFSA Guidance (ECHA and EFSA, 2018). It is expected that additional toxicological information would be needed to perform such an assessment.

With regards to the JMPR report, it is noted that the JMPR evaluation in 2012 was not a complete re‐evaluation, but an amendment of a previous one from 1993. In 2012, only a small number of new studies were reviewed and an ARfD established; the ADI, as derived in 1993 was then confirmed. The 1993 evaluation report is not considered a reliable source of information due to the lack of reporting of details on the methods and results of the toxicological studies, such as the presentation of the tabulated results, that does not allow an independent review; the same applies to the 2012 report. An assessment of the relevance and reliability of each study when compared to the current OECD test guidelines would also be needed. For instance, in the JMPR assessment a developmental neurotoxicity (DNT) study is reported. It is noted that the DNT study is critical for the risk assessment of fenpropathrin due to the neurotoxic mode of action of the active substance and substantiated by the effects triggering the ADI. DNT studies are complex to interpret and with the information reported in the JMPR it cannot be concluded a no observed adverse effect level/lowest observable adverse effect level (NOAEL/LOAEL) for the study with an acceptable uncertainty, also considering that lower mean absolute brain weight and length were noted in pups but dismissed and no clear incidence, severity and starting dose‐related effect can be retrieved.

Considering the data gaps and uncertainties identified, it is concluded that the data available are insufficient to assess the strength of the toxicological reference values compared to current standards, and uncertainty factors could not be established. Accordingly, considering that the ADI and ARfD derived by the JMPR in 2012 do not comply with the current scientific standards, EFSA would recommend their withdrawal.

4. Consumer risk assessment

In order to address ToR 5, ToR 6 and ToR 11, EFSA calculated the chronic and acute dietary exposure, based on the residue definition for risk assessment derived by JMPR, i.e. fenpropathrin. Chronic and acute exposure calculations for all crops reported in the framework of this review were performed using revision 3.1 of the EFSA PRIMo (EFSA, 2018, 2019). All input values included in the exposure calculations are summarised in Appendix C.

The following scenario was calculated (Scenario 1):

• For commodities for which the CXLs/MRLs are no longer substantiated, the appropriate LOQ was used as input value for the exposure calculation.
• All other commodities where no GAP was reported in the framework of the MRL review were included in the calculation with the appropriate LOQ.

The risk assessment scenario as described in ToR 5 (b) (Scenario 2) is relevant for the assessment of fenpropathrin as all CXLs set in EU Regulation were implemented before and including 2009. However, as the CXLs are not substantiated, the scenario 2 would be identical to scenario 1.

The acute and chronic exposure calculations were compared to current EU TRVs (FAO, 2012), noting that EFSA concluded that these TRVs do not comply with the current scientific standards and recommended to withdraw the existing EU TRVs (see Section 3). Thus, the risk assessment requested in ToR 5 and presented in this review is indicative only.

Screenshots of the report sheet of the PRIMo calculations for scenario 1 are presented in Appendix B.

The highest chronic exposure was calculated for Dutch toddler, representing 4% of the ADI. The contribution of the MRLs set at the LOQ to the exposure represents 4% of the ADI. The highest acute exposure was calculated for potatoes, representing 5% of the ARfD.

The toxicological assessment revealed deficiencies regarding the toxicological studies available for fenpropathrin. Considering the high level of uncertainty affecting the TRVs derived by JMPR in 2012, EFSA did not confirm these TRVs, and the risk assessment cannot be finalised.

Conclusions and recommendations

The metabolism of fenpropathrin in plant and animal was previously investigated by the JMPR. According to the results of the metabolism studies assessed, the residue definition for enforcement and risk assessment, both for plant and animal products, is fenpropathrin. The residue is fat soluble.

Analytical methods are available for the enforcement of the proposed residue definition in high water content, high oil content and high acid content, as well as in coffee with an LOQ of 0.01 mg/kg and in tea with an LOQ of 0.05 mg/kg. Fenpropathrin can be enforced in food of animal origin with an LOQ of 0.01 mg/kg in muscle, fat, milk and eggs. According to the EURLs, a QuEChERS multi‐residue analytical method is available with an LOQ of 0.01 mg/kg for the routine analysis of fenpropathrin in high water content, high acid content, high oil content and dry commodities, as well as in commodities of animal origin (egg, muscle and liver). Based on the experience gained with these matrices, an LOQ of 0.01 mg/kg is deemed achievable also for animal fat and kidney.

The origin of all current MRLs set for fenpropathrin (based on formerly approved uses or on CXLs) was investigated, and it was concluded that none of the existing MRLs were sufficiently substantiated. No fall‐back MRLs were identified for any of the crops under assessment (citrus fruits, strawberries, melon, tea).

A screening of the appropriateness of the TRVs set by the JMPR was performed, and the set of toxicological studies used to derive these TRVs was assessed according to the current data requirements and standards. It was concluded that the TRVs cannot be confirmed for fenpropathrin since the data available were insufficient compared to current standards, and uncertainty factors could not be established. Accordingly, the ADI and ARfD derived in 2012 do not comply with the current scientific standards. Therefore, EFSA recommends withdrawing these TRVs. The following data would be required to finalise the toxicological assessment which is a pre‐requisite to derive robust TRVs:

• submission of the available studies with a full evaluation of the toxicological data package and reporting relevant details on the studies and the results in accordance with the current guidelines, including an assessment of the reliability and relevance of each individual study and assessment of the validity of the analytical methods used in feed, body fluids and tissues, air and any additional matrices used in support of the toxicological studies;
• an interspecies comparative in vitro metabolism study on animal species used in pivotal studies and on human material;
• additional toxicological data to perform an ED assessment;
• an up‐to‐date search for published literature;
• an assessment of the toxicological relevance of impurities potentially present in the technical specification.

Chronic and acute exposure calculations were performed using revision 3.1 of PRIMo, considering all CXLs/MRLs no longer substantiated at the appropriate LOQ, as well as all other commodities for which no GAP was reported under this review. Comparing to the current TRVs, no exceedances were observed, and the highest chronic exposure represented 4% of the ADI (Dutch toddler) and the highest acute exposure amounted to 5% of the ARfD (potatoes). Nevertheless, EFSA emphasises that as the toxicological assessment revealed deficiencies regarding the toxicological studies available for fenpropathrin and considering that the TRVs do not meet the current scientific standards, the indicative risk assessment cannot be finalised, and results presented under the current review are indicative only.

It is concluded that none of the existing EU MRLs/CXLs listed in the Table 7 are recommended for inclusion in Annex II to the Regulation.

Appendix A – Summary of the fall‐back GAPs collected from Member States

Appendix B – Pesticide Residue Intake Model (PRIMo)

1.

• PRIMo_EU_(Sc. 1 and Sc.2)

Appendix C – Input values for the exposure calculations

Notes

Suggested citation: EFSA (European Food Safety Authority) , Bellisai G, Bernasconi G, Binaglia M, Brancato A, Cabrera LC, Castellan I, Castoldi AF, Chiusolo A, Crivellente F, Del Aguila M, Ferreira L, Santonja GG, Greco L, Istace F, Jarrah S, Lanzoni A, Leuschner R, Mangas I, Miron I, Nave S, Panzarea M, Parra Morte JM, Pedersen R, Reich H, Ruocco S, Santos M, Scarlato AP, Terron A, Theobald A, Tiramani M and Verani A, 2023. Reasoned Opinion on the targeted review of maximum residue limits (MRLs) for fenpropathrin. EFSA Journal 2023;21(6):8057, 24 pp. 10.2903/j.efsa.2023.8057 [CrossRef] [Google Scholar]

Requestor: European Commission

Question number: EFSA‐Q‐2022‐00450

Declarations of interest: If you wish to access the declaration of interests of any expert contributing to an EFSA scientific assessment, please contact ue.aporue.asfe@tnemeganamtseretni.

EFSA may include images or other content for which it does not hold copyright. In such cases, EFSA indicates the copyright holder and users should seek permission to reproduce the content from the original source.

Approved: 17 May 2023

Notes

References