Targeted review of maximum residue levels (MRLs) for azocyclotin and cyhexatin

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, two of them being azocyclotin and cyhexatin.

In accordance with the terms of reference, EFSA investigated the origin of the current EU MRLs for azocyclotin and cyhexatin, 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 MRLs for azocyclotin and cyhexatin has been established as an import tolerance. EFSA also screened the quality of the toxicological reference values (TRVs) derived at EU level and by the Joint Meeting on Pesticide residues (JMPR). As EFSA identified critical issues related to the available toxicological database, EFSA organised an expert consultation (Pesticides Peer Review Teleconference 92) to discuss the toxicological profile and the TRVs for azocyclotin and cyhexatin.

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 azocyclotin and cyhexatin in plants and animals was previously investigated in the framework of the EU evaluation (Italy, 2008a,b) as well as by JMPR (FAO, 2005a,b). According to the results of the metabolism studies assessed, the residue definition for enforcement and risk assessment, both for plant and animal products, is the sum of azocyclotin and cyhexatin, expressed as cyhexatin.

Analytical methods are available for the enforcement of the proposed residue definition in high water and high acid content matrices with an LOQ of 0.01 mg/kg, in orange dry pulp with an LOQ of 0.02 mg/kg, in apple dry pomace with an LOQ of 0.05 mg/kg and in high oil content matrices with an LOQ of 0.1 mg/kg. Azocyclotin and cyhexatin residues can be enforced in food of animal origin with an LOQ of 0.1 mg/kg in muscle and liver. No method is available for the enforcement of residues in kidney, fat, milk and eggs. According to the EURLs, a QuEChERS multi‐residue analytical method with an LOQ of 0.01 mg/kg for the routine analysis of azocyclotin and cyhexatin residues in high water, high acid and dry commodities. Based on the experience gained with these matrices, a default LOQ of 0.01 mg/kg in all commodities of animal origin except fat and a default LOQ of 0.02 mg/kg in fat and in high oil content matrices is also deemed achievable to monitor azocyclotin and cyhexatin residues.

The origin of all current MRLs set for azocyclotin and cyhexatin was investigated, and further risk management discussions are required to decide whether the existing EU MRL for apples and wine grapes should be maintained or lowered to the LOQ.

A screening of the quality of the group TRVs proposed by the RMS and of those established by the JMPR was performed, and the set of toxicological studies used to derive these TRVs was assessed according to the current standards. As critical issues were identified, a Member States experts' consultation took place. The experts concluded that the TRVs proposed by the RMS and derived by JMPR cannot be confirmed for azocyclotin and cyhexatin since the genotoxicity potential of either active substance was considered inconclusive, the data available were of insufficient reliability compared to current standards, and uncertainty factors could not be established. Accordingly, the acceptable daily intake (ADI) and acute reference dose (ARfD) used for the setting of MRLs 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:

• additional studies to conclude on the genotoxic potential of azocyclotin and cyhexatin;
• assessment of the validity of analytical methods used in feed, body fluids and tissues, air and any additional matrices used in support of the toxicological studies;
• literature search;
• additional toxicological data to perform an ED assessment;
• comparative in vitro metabolism study on animal species used in pivotal studies and on human material;
• full re‐evaluation of the toxicological data package and reporting relevant details on the studies and the results in accordance with the current guidelines.

Chronic and acute exposure calculations were performed using revision 3.1 of PRIMo, considering commodities for which the existing EU MRLs were found to be sufficiently substantiated, while all CXLs/MRLs that could be no longer substantiated (upon risk managers’ decision) were proposed to be lowered to the appropriate LOQ, as well as all other commodities for which no GAP was reported under this review. Comparing to the EU TRVs, no exceedances were observed, and the highest chronic exposure represented 51% of the ADI (NL toddler). The highest acute exposure amounted to 86% of the ARfD (apples). Nevertheless, EFSA emphasises that as the toxicological assessment revealed deficiencies regarding the toxicological studies available for azocyclotin and cyhexatin and considering that EU 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.

Due to the deficiencies identified regarding the toxicological studies available for azocyclotin and cyhexatin, none of the existing EU MRLs listed in the summary table below are recommended for inclusion in Annex II to the Regulation. If a decision on the withdrawing of TRVs is taken, EFSA recommends that risk managers discuss whether all MRLs currently implemented in EU Regulation should be lowered to the respective LOQs.

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 product, 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 396/2005 ¹ .

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 2021, ³ and February 2022 ⁴ ). The SCoPAFF agreed that ten active substances, for which potential consumer risks were identified, should be assessed by EFSA as a priority. Two of the substances identified for being assessed with high priority are azocyclotin and cyhexatin.

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 azocyclotin and cyhexatin.

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 azocyclotin and cyhexatin. 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 justified ⁵ 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 2009 ⁶ 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 Regulation ⁸ 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 azocyclotin and cyhexatin, by 22 May 2023.

Assessment

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

• In Section 1 (Regulatory background information on azocyclotin and cyhexatin), 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).
• 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 residues analysis is reported (ToR 4). In addition, EFSA summarised the information on the analytical methods assessed previously by EFSA and/or JMPR.
• 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 in the EU and by JMPR are assessed (ToR 7).
• In Section 4 (Consumer risk assessment), an indicative screening of the chronic and acute consumer exposure is presented (ToRs 5 and 6). The dietary exposure assessment 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 at EU and JMPR level). However, noting that following the experts' meeting on mammalian toxicology EFSA does not support the EU 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).

EFSA has based its assessment on the following documents:

• the Draft Assessment Reports (DAR) (Italy, 2008a,b);
• the Reports and Evaluations of the JMPR (FAO, 2005a,b);
• the reports of the Codex Committee on Pesticide residues (CCPR, 2006);

As requested in the ToR 2, Member States were invited to submit by 18 October 2022 the 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 azocyclotin and cyhexatin 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. In addition, an expert consultation in mammalian toxicology was conducted in January 2023; the peer review meeting report TC 97 (EFSA, 2023a) is also considered as main supporting document.

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 the current standards, EFSA prepared a draft reasoned opinion, which was circulated to Member States and EURLs for consultation via a written procedure in March 2023. Comments received by 4 April 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, 2023b). 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 azocyclotin and cyhexatin

The key events concerning the regulatory history of azocyclotin and cyhexatin, 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 in order to screen the quality of the 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).

Taking into account the quick conversion of azocyclotin to cyhexatin in aqueous solution, the RMS and JMPR considered appropriate to derive a group ADI and a group ARfD covering the toxicity of both compounds. The group TRVs for cyhexatin and azocyclotin reported in Table 6 were derived by the RMS Italy, in the DARs from 2006 (Italy, 2008a,b); the TRVs were not peer reviewed as the application was withdrawn. In 2005, the JMPR derived a group ADI and ARfD which can be found in Table 7; these values were retained by the EC for the derivation of MRLs.

The different ARfD and ADI values derived by the RMS and JMPR can be explained by a different interpretation of the same available studies and of the adversity of the same findings. The critical no observed adverse effect level (NOAEL) used by the JMPR to derive the ADI was considered as the lowest observable adverse effect level (LOAEL) by the RMS. Regarding the NOAELs relevant to derive the ARfD, the RMS also concluded on lower values compared to the JMPR assessment.

EFSA screened the completeness and the quality of the toxicological studies that were used to derive the group TRVs by the RMS and the JMPR, focussing on the question as to whether the studies meet the current scientific standards. EFSA did not undertake a full review of the original studies; the basis of the TRVs derivation was scrutinised mainly based on the data reported in the original DARs (Italy, 2008a,b).

During this scrutiny, EFSA identified critical issues related to the available toxicological database which were discussed with Member State experts in mammalian toxicology during the Pesticides Peer Review Teleconference 97 in January 2023 (EFSA, 2023a).

The discussions with the Member State experts focussed on the following two critical points:

• the genotoxicity data set;
• the robustness of the available data to derive toxicological reference values, i.e. the ADI, the ARfD and respective UF.

The genotoxicity data packages for azocyclotin and cyhexatin contain studies assessing the three endpoints, i.e. gene mutation in bacterial and mammalian cells (in vitro), clastogenicity (in vitro and in vivo) and aneugenicity (in vivo).

For cyhexatin, ⁹ the studies for gene mutation showed negative (in bacterial and mammalian cells), positive and equivocal results (in mammalian cells). The in vitro clastogenicity study was positive with and without metabolic activation, while in vivo studies for clastogenicity and aneugenicity showed negative results. The studies were conducted in the 1980s and 1990s according to the OECD test guidelines in place at the time, or prior to their publication. One test guideline was deleted in the meantime, the in vitro unscheduled DNA synthesis assay TG 482 (OECD, 1986) that was considered relevant and reliable at the time of the evaluation in a weight of evidence assessment of the gene mutation potential of the test substance but is not considered relevant anymore.

Deviations with regards to current test guidelines (or concurrent test guidelines in case none were followed) could not be assessed, and the results of the in vitro studies could not be independently reviewed due to the lack of reporting details (e.g. tabulated results). With regards to in vivo studies (mammalian erythrocyte micronucleus tests in mice), proof of bone marrow exposure was shown when the test substance was administered by intraperitoneal injection (statistically significant reductions of the polychromatic/normochromatic erythrocytes (PCE/NCE) ratio compared to control animals), but not when the test substance was administered by oral gavage (no information on general toxicity induced by treatment, no change in the PCE/NCE ratio and plasma analysis was not performed), but taken together, the experts agreed that cyhexatin is unlikely to present clastogenicity or aneugenicity potential considering current standards (EFSA Scientific Committee, 2017).

It was noted that, according to the current scientific standards, if a substance is tested positive in an in vitro gene mutation test, a suitable in vivo follow‐up test (e.g. in vivo Comet assay TG 489 (OECD, 2016) or transgenic rodent somatic and germ cell gene mutation assay TG 488 (OECD, 2022)) would be requested (EFSA Scientific Committee, 2011). The experts agreed that no conclusion can be reached on the genotoxic potential of cyhexatin due to the positive results observed in vitro in an AS52/XPRT mammalian cell forward gene mutation assay.

For azocyclotin, ¹⁰ the experts noted that the data base is poor when compared with current standards (old studies from the 1970s and 1980s, not performed according to GLP or OECD test guidelines, no report of the potential deviations with regards to OECD TG). Although the overall outcome of the various tests is reported as negative or equivocal, the quality of the available studies and reporting is not sufficient to conclude on the genotoxicity potential of azocyclotin according to current standards.

Overall, the genotoxicity data packages available for or cyhexatin or azocyclotin are not considered reliable. It is therefore not possible to conclude on their genotoxicity potential, in particular regarding the gene mutation potential of cyhexatin that presented positive results in vitro.

With regards to the toxicological data package needed to derive a group ADI and a group ARfD for cyhexatin and azocyclotin according to the current data requirements, ¹¹ the experts identified major limitations and missing data. Due to the deficiencies listed below, the experts concluded that the derivation of toxicological reference values according to current scientific standards is not possible ¹² :

• The genotoxic potential of cyhexatin and azocyclotin was found to be inconclusive.
• The assessment of the validity of the toxicological studies and reliability of their results is limited by the lack of details on the toxicological studies reported in the DARs (Italy, 2008a,b) (e.g. that do not allow to verify the compliance of these studies with the current or older versions of the test guidelines), and the unknown validity of the analytical methods used in feed, body fluids and tissues, air and any additional matrices used in support of the toxicity studies. These limitations imply, for instance, that it is not possible to understand the difference in NOAELs derived by the EU and the JMPR assessments, as is the case of the maternal and embryotoxicity NOAELs of the developmental and 2‐generation reproductive toxicity studies in rats and developmental toxicity in rabbits (critical to the risk assessment).
• A search for published literature has not been conducted.
• The endocrine disruptive potential of azocyclotin and cyhexatin 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.
• A comparative in vitro metabolism study performed on animal species used in pivotal studies and on human material is not available to determine the relevance of the toxicological animal data to humans and whether additional testing of potential unique human metabolites would be required.

The use of an additional uncertainty factor could not be established on the basis of deficiencies and uncertainties identified.

The JMPR values suffer from the same limitations as they appear to be based on the same toxicological studies, at least with regards to the genotoxicity data package.

It was concluded that the existing toxicological reference values proposed by the RMS or established by the JMPR cannot be confirmed for azocyclotin and cyhexatin since their genotoxicity potential is inconclusive, the data available are considered insufficient when compared to current standards, and uncertainty factors cannot be established.

Accordingly, considering that the ADI and ARfD used to establish the EU MRLs do not comply with the current scientific standards, EFSA would recommend their withdrawal.

4. Consumer risk assessment

In order to address ToR 5 (a) (Scenario 1), and (b) (Scenario 2) ToR 6 and ToR 11, EFSA calculated the chronic and acute dietary exposure, based on the current residue definition for risk assessment, i.e. sum of azocyclotin and cyhexatin, expressed as cyhexatin. 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.

As for some commodities, EFSA suggested two risk management options (i.e. for apples and wine grapes; see Table 5 and Appendix C), the following two sub‐scenarios were calculated:

• Scenario 1A:

  • ○
    All CXLs and EU MRLs that are sufficiently substantiated or which were recommended for further risk management discussion (labelled as ‘to be discussed’ in Table 5) were considered for the exposure assessment, using the relevant risk assessment values for the current MRL. For the chronic exposure assessment, the calculation is based on the supervised trials median residue levels (STMR) derived for raw agricultural commodities (noting that for oranges, a peeling factor was applied). For the acute exposure assessment, the calculation is based on the highest residue levels (HR) expected in raw agricultural commodities. For oranges, the peeling factor was also included in the acute exposure assessment.
  • ○
    All other commodities where no GAP was reported in the framework of the MRL review were included in the calculation with the appropriate LOQ.
• Scenario 1B:

  • ○
    Same input values as in scenario 1A, except for the CXL/MRLs labelled as ‘to be discussed’ in Table 5, for which the appropriate LOQ was used, assuming that a risk management decision on the lowering of these MRLs would be taken.
• Scenario 2:

  • ○
    Like scenario 1A, but lowering all CXLs that were set before 2009 and never evaluated by EFSA to the appropriate LOQ.

The acute and chronic exposure calculations were compared to current EU TRVs (FAO, 2005a,b), noting that during the experts' meeting on mammalian toxicology held in January 2023, the experts concluded that these TRVs do not comply with the current scientific standards and therefore 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 sheets of the indicative PRIMo calculations for scenarios 1A, 1B and 2 are presented in Appendix B.

In scenarios 1A, 1B and 2, the highest chronic exposure was calculated for NL toddler, representing respectively 51%, 44% and 42% of the ADI. The contribution of the MRLs set at the LOQ to the exposure represents 38% of the ADI for scenario 1A and 42% of the ADI for both scenarios 1B and scenario 2.

The highest acute exposure was calculated for apples in scenario 1A, representing 86% of the ARfD.

The toxicological assessment revealed deficiencies regarding the toxicological studies available for azocyclotin and cyhexatin (EFSA, 2023a) which do not fully comply with the current scientific standards. Considering the high level of uncertainty affecting the TRVs derived in 2005, EFSA did not confirm the previously derived TRVs. Therefore, the risk assessment cannot be finalised.

Conclusions and recommendations

The metabolism of azocyclotin and cyhexatin in plants and animals was previously investigated in the framework of the EU evaluation (Italy, 2008a,b) as well as by JMPR (FAO, 2005a,b). According to the results of the metabolism studies assessed, the residue definition for enforcement and risk assessment, both for plant and animal products, is the sum of azocyclotin and cyhexatin, expressed as cyhexatin.

Analytical methods are available for the enforcement of the proposed residue definition in high water and high acid content matrices with an LOQ of 0.01 mg/kg, in orange dry pulp with an LOQ of 0.02 mg/kg, in apple dry pomace with an LOQ of 0.05 mg/kg and in high oil content matrices with an LOQ of 0.1 mg/kg. Azocyclotin and cyhexatin residues can be enforced in food of animal origin with an LOQ of 0.1 mg/kg in muscle and liver. No method is available for the enforcement of residues in kidney, fat, milk and eggs. According to the EURLs, a QuEChERS multi‐residue analytical method with an LOQ of 0.01 mg/kg for the routine analysis of azocyclotin and cyhexatin residues in high water, high acid and dry commodities. Based on the experience gained with these matrices, a default LOQ of 0.01 mg/kg in all commodities of animal origin except fat and a default LOQ of 0.02 mg/kg in fat and in high oil content matrices is also deemed achievable to monitor azocyclotin and cyhexatin residues.

The origin of all current MRLs set for azocyclotin and cyhexatin was investigated, and further risk management discussions are required to decide whether the existing EU MRL for apples and wine grapes should be maintained or lowered to the LOQ.

A screening of the quality of the group TRVs proposed by the RMS and of those established by the JMPR was performed, and the set of toxicological studies used to derive these TRVs was assessed according to the current standards. As critical issues were identified, a Member States experts' consultation took place. The experts concluded that the TRVs proposed by the RMS and derived by JMPR cannot be confirmed for azocyclotin and cyhexatin since the genotoxicity potential of either active substance was considered inconclusive, the data available were of insufficient reliability compared to current standards, and uncertainty factors could not be established. Accordingly, the ADI and ARfD used for the setting of MRLs 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:

• additional studies to conclude on the genotoxic potential of azocyclotin and cyhexatin;
• assessment of the validity of analytical methods used in feed, body fluids and tissues, air and any additional matrices used in support of the toxicological studies;
• literature search;
• additional toxicological data to perform an ED assessment;
• comparative in vitro metabolism study on animal species used in pivotal studies and on human material;
• full re‐evaluation of the toxicological data package and reporting relevant details on the studies and the results in accordance with the current guidelines.

Chronic and acute exposure calculations were performed using revision 3.1 of PRIMo, considering commodities for which the existing EU MRLs were found to be sufficiently substantiated, while all CXLs/MRLs that could be no longer substantiated (upon risk managers’ decision) were proposed to be lowered to the appropriate LOQ, as well as all other commodities for which no GAP was reported under this review. Comparing to the EU TRVs, no exceedances were observed, and the highest chronic exposure represented 51% of the ADI (NL toddler). The highest acute exposure amounted to 86% of the ARfD (apples). Nevertheless, EFSA emphasises that as the toxicological assessment revealed deficiencies regarding the toxicological studies available for azocyclotin and cyhexatin and considering that EU 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.

Due to the deficiencies identified regarding the toxicological studies available for azocyclotin and cyhexatin, none of the existing EU MRLs listed in the table below (Table 8) are recommended for inclusion in Annex II to the Regulation. If a decision on the withdrawing of TRVs is taken, EFSA recommends that risk managers discuss whether all MRLs currently implemented in EU Regulation should be lowered to the respective LOQs.

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

Appendix B – Pesticide Residue Intake Model (PRIMo)

1.

• PRIMo_(Sc. 1A)

• PRIMo_(Sc. 1B)

• PRIMo_(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, Carrasco Cabrera L, Castellan I, Castoldi A, Chiusolo A, Crivellente F, Del Aguila M, Ferreira L, Giner Santonja G, 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 azocyclotin and cyhexatin. EFSA Journal 2023;21(6):8038, 30 pp. 10.2903/j.efsa.2023.8038 [CrossRef] [Google Scholar]

Requestor: European Commission

Question numbers: EFSA‐Q‐2022‐00442; EFSA‐Q‐2022‐00445

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.

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Approved: 10 May 2023

Notes

References