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. 2025 Sep 30;23(9):e9639. doi: 10.2903/j.efsa.2025.9639

Statement on the testing strategy and timelines for the assessment of developmental neurotoxicity and endocrine disruption properties of acetamiprid in the context of the review of the approval of the active substance

European Food Safety Authority (EFSA)✉
PMCID: PMC12481163  PMID: 41036495

Abstract

On 29 January 2021, the EFSA Panel on Plant Protection Products and their Residues adopted a Statement on acetamiprid in response to a mandate from the Commission following a notification under Article 69 of Regulation (EC) No 1107/2009 in which, among others, it was recommended to conduct an assessment of the endocrine disrupting (ED) properties of acetamiprid in line with the criteria established by Commission Regulation (EU) No 2018/605. On 27 March 2024, EFSA issued a Statement on the toxicological properties and maximum residue levels of acetamiprid and its metabolites, following a mandate from the Commission pursuant to Article 31 of Regulation (EC) No 178/2002. EFSA concluded that there are data gaps in the in vivo body of evidence, including the lack of an acceptable measurement of learning and memory, motor activity and morphometric evaluation in the available developmental neurotoxicity (DNT) studies. To account for the identified gaps, EFSA proposed to include an additional uncertainty factor of 5 in the derivation of the Health‐Based Guidance Values: as a consequence, it could not be fully established that acetamiprid still meets the approval criteria laid down in Article 4 of Regulation (EC) No 1107/2009 with respect to its DNT, as well as for the ED properties for which an assessment is not available. Therefore, the European Commission decided to launch a review of the existing approval in accordance with Article 21 of that Regulation and invited the applicant to submit a comprehensive list of existing or planned studies, along with any relevant information, for re‐assessing the ED and DNT properties of acetamiprid. On 21 May 2025, pursuant to Article 21(2) of Regulation (EC) No 1107/2009, the Commission requested EFSA to assess the proposal, as submitted by the applicant, on the testing strategy and associated timelines for the generation of additional data for the assessment of the DNT and ED properties of acetamiprid. The current statement contains EFSA's considerations whether the proposed studies are considered sufficient and realistic to complete the assessment of the ED properties of the active substance in line with Commission Regulation (EU) 2018/605 and to conduct an evaluation of DNT properties in line with the recommendations given in the EFSA statement issued in 2024.

Keywords: acetamiprid, developmental neurotoxicity, endocrine disrupting properties, insecticide, peer review, pesticide, risk assessment

SUMMARY

The approval of acetamiprid was renewed by Commission Implementing Regulation (EU) 2018/113 until 28 February 2033.

On 29 November 2021, the European Food Safety Authority (EFSA) Panel on Plant Protection Products and their Residues (PPR Panel) adopted a statement in response to a mandate triggered by a notification by a Member State under Article 69 of Regulation (EC) No 1107/2009. EFSA concluded that there was no new evidence of higher hazards compared to its 2016 assessment for genotoxicity, developmental toxicity, neurotoxicity, including developmental neurotoxicity (DNT), immunotoxicity and risks to birds, aquatic organisms, bees and soil organisms. In this statement, EFSA recommended that an assessment of the endocrine disrupting (ED) properties of acetamiprid be conducted in line with the criteria established by Commission Regulation (EU) 2018/605.

Subsequently, on 27 March 2024, EFSA issued a second statement under Article 31 of Regulation (EC) No 178/2002, focusing on the toxicological properties and maximum residue levels of acetamiprid and its metabolites. This assessment employed an evidence‐based adverse outcome pathway (AOP)‐informed integrated approaches to testing and assessment (IATA) to evaluate the DNT properties of acetamiprid. EFSA concluded that possible molecular and cellular effects of the substance could lead to an adverse outcome at organism level, and therefore represent a DNT concern. However, EFSA also noted that there are data gaps in the in vivo body of evidence, including the lack of an acceptable measurement of learning and memory, motor activity and morphometrics evaluation in the available DNT studies. These gaps should be filled to allow a more robust mechanistic understanding, to identify all DNT effects of acetamiprid and to obtain concordant dose–response relationships enabling hazard and risk assessment. Consequently, EFSA recommended adding an additional uncertainty factor of 5 to the acceptable daily intake (ADI) and acute reference dose (ARfD) compared to the previous EU agreed reference values due to uncertainties with respect to the ability of acetamiprid to affect neural development.

Given these findings, the European Commission determined that it could no longer confirm whether acetamiprid still satisfies the approval criteria laid down in Article 4 of Regulation (EC) No 1107/2009, particularly concerning its DNT and ED properties. Therefore, a review of the substance's existing approval was initiated in accordance with Article 21 of that Regulation. As part of the review, on 15 October 2024, the Commission requested the applicant to submit a complete list of studies that exist (including those not yet submitted or evaluated), or that it intends to perform relevant to the assessment of ED and DNT properties. In response, the applicant submitted a study proposal and timeline on 13 January 2025 (Ref. ARES(2025)258519).

Following this, on 21 May 2025, EFSA received a further mandate from the Commission to evaluate, in consultation with the rapporteur Member State (RMS) the Netherlands (responsible for the previous renewal), Germany (for the forthcoming renewal) and co‐RMS Spain (for both renewals), whether the applicant's proposed studies and associated timeline are sufficient and realistic. EFSA was requested to provide its opinion within 3 months of accepting the mandate, by 5 September 2025. Specifically, EFSA is expected to assess whether the proposed plan enables a complete evaluation of the endocrine‐disrupting properties of acetamiprid for both human health and non‐target organisms, in line with Regulation (EC) No 1107/2009 as amended by Commission Regulation (EU) 2018/605; and supports a robust assessment of the developmental neurotoxicity (DNT) properties of acetamiprid, consistent with EFSA's 2024 statement, including considerations of study reliability.

For the evaluation of DNT properties of acetamiprid, the proposed test is deemed appropriate provided that it is conducted in accordance with OECD TG 426 and the recommendations as outlined in the EFSA statement issued in 2024.

EFSA agrees with the proposed testing strategy and associated timelines for the assessment of the endocrine‐disrupting properties of the substance with respect to human health in line with Commission Regulation (EU) 2018/605. Nevertheless, some uncertainties were raised considering the completeness of the data set.

For non‐target organisms, other than mammals, the testing strategy proposed by the applicant only covers a test to sufficiently investigate the endocrine activity through the oestrogen, androgen and steroidogenesis (EAS)‐modalities. Concerns were raised regarding the appropriateness of that test to cover e.g. possible anti‐androgenic mode of action. In addition, no tests have been proposed for investigating the endocrine disrupting potential through the T‐modality.

1. INTRODUCTION

Acetamiprid is an insecticide active substance covered by the third batch of the renewal programme for pesticides (‘AIR3’) in accordance with Commission Implementing Regulation (EU) No 844/2012. 1 The active substance was first approved by Commission Directive 2004/99/EC 2 and its approval was renewed by Commission Implementing Regulation (EU) 2018/113 3 until 28 February 2033 following the EFSA renewal peer review (EFSA, 2016).

On 29 November 2021, the European Food Safety Authority (EFSA) Panel on Plant Protection Products and their Residues (PPR Panel) adopted a statement (EFSA PPR Panel, 2021) in response to a mandate from the Commission following a notification under Article 69 of Regulation (EC) No 1107/2009 from one Member State. EFSA stated that no conclusive evidence of higher hazards had been found compared to the previous assessment (i.e. EFSA Conclusion (EFSA, 2016) for genotoxicity, developmental toxicity, neurotoxicity, including developmental neurotoxicity (DNT) and immunotoxicity nor evidence of higher hazards compared to the previous assessment for birds, aquatic organisms, bees and soil organisms. In this Statement, EFSA recommended conducting an assessment of the endocrine‐disrupting (ED) properties of acetamiprid in line with the criteria established by Commission Regulation (EU) 2018/605. 4

On 27 March 2024, EFSA issued a Statement on the toxicological properties and maximum residue levels of acetamiprid and its metabolites (EFSA, 2024), following a mandate from the Commission pursuant to Article 31 of Regulation (EC) No 178/2002. 5 This Statement summarised an assessment of DNT properties of acetamiprid based on an evidence‐based AOP‐informed IATA, 6 which concluded that possible molecular and cellular effects of the substance could lead to an adverse outcome at organism level, therefore representing a DNT concern. EFSA also noted that there are data gaps in the in vivo body of evidence, including the lack of an acceptable measurement of learning and memory, motor activity and morphometrics evaluation in the available DNT studies. These gaps should be filled to allow a more robust mechanistic understanding, to identify all DNT effects of acetamiprid and to obtain concordant dose–response relationships enabling hazard and risk assessment. Consequently, EFSA recommended in its Statement to include an additional uncertainty factor of 5 to the ADI and ARfD compared to the previous EU agreed reference values based on uncertainties with respect to the ability of acetamiprid to affect neural development.

EFSA prepared a draft statement in July 2025 which was circulated to the rapporteur Member State, Germany, and to all Member States for commenting via a written procedure before finalisation. A key supporting document to this statement is the peer review report (EFSA, 2025), which contains the comments received on the draft statement, in which all views including minority views, where applicable, can be found. The report is considered a background document to this statement and thus is made publicly available.

1.1. Background and Terms of Reference as provided by the requestor

Given the results of the EFSA evaluations referred to in the previous sections, it cannot be fully established that acetamiprid still satisfies the approval criteria laid down in Article 4 of Regulation (EC) No 1107/2009 with respect to its DNT and ED properties. Therefore, the European Commission initiated a review of the existing approval in accordance with Article 21 of that Regulation and requested, on 15 October 2024, the applicant (Nisso Chemical Europe GmbH) to submit a complete list of studies that exist (including those not yet submitted or evaluated), or that it intends to perform and submit in the context of assessing the ED and DNT properties of acetamiprid.

On 13 January 2025 the applicant submitted a proposal for studies to be provided with associated time schedule for data generation (Ref. ARES(2025)258519, enclosed to the mandate). 7

On 21 May 2025, pursuant to Article 21(2) of Regulation (EC) No 1107/2009, EFSA was asked by the European Commission to consider ‐ in consultation with the RMS, the Netherlands (for the previous renewal) and Germany (for the forthcoming renewal), and co‐RMS Spain (for both renewals) ‐ the proposal as submitted by the applicant and to confirm whether the proposed studies are considered sufficient and realistic to:

  1. complete the assessment of the endocrine disrupting properties of acetamiprid to human health and non‐target organisms as provided in Regulation (EC) No 1107/2009 amended by Commission Regulation (EU) 2018/605 and;

  2. to conduct an evaluation of DNT properties of acetamiprid in line with the recommendation given in the EFSA Statement on the toxicological properties and maximum residue levels of acetamiprid and its metabolite issued in 2024, including with respect to the reliability of studies.

If relevant, EFSA was requested to also identify which additional studies would be required and to specify the timeframe needed for conducting each of the planned (or additional) studies.

For this purpose, a statement has been elaborated by EFSA within 3 months following the acceptance of the request (on 5 June 2025).

2. DATA AND ASSESSMENT

EFSA has elaborated the considerations presented in the following sections on the basis of the proposed studies and associated timelines as submitted by the applicant and by using the pertinent in place guidance documents and the current scientific and technical knowledge on the topics in subject.

2.1. Testing strategy as submitted by the applicant

A summary of the intended DNT and ED studies relevant to the review of approval of acetamiprid under Article 21 is presented below, along with the estimates for the completion of the studies as provided by the applicant (Table 1). However, as noted by the applicant, additional time may be needed if there are delays with the testing facilities. Also, it is noted that pending the results of the ED studies specified in Table 1, it is not possible to predict whether additional testing may be triggered in line with the ECHA/EFSA Guidance for the identification of endocrine disruptors in the context of Regulations (EU) No 528/2012 and (EC) No 1107/2009 (ECHA and EFSA, 2018). It is therefore expected, in line with the procedure established in Commission Implementing Regulation (EU) No 2018/1659, 8 that up to 30 months may be required if such circumstances arise, according to the applicant's argumentation. The applicant proposed 3 months for the delivery of the summary dossier following the completion of the studies. As also requested, a summary of all relevant evidence from the scientific peer‐reviewed open literature on DNT and ED properties of acetamiprid, its metabolites and breakdown or reaction products published after the renewal of the approval will also be provided at the same time by the applicant.

TABLE 1.

Summary of data generation plan as provided by the applicant (enclosed to the mandate7).

Study Expected final report date*
Analytical methods
Analytical validation and stability study of acetamiprid in suspension formulations December 2024
Stability test and analytical method validation of the acetamiprid contents in diet and solvent Report Finalised
Analytical method validation of the acetamiprid contents in solvent Q3 2025
Analytical method validation of the acetamiprid contents in water Q3 2025
ED properties for human health and non‐target organisms
H295R steroidogenesis assay Q3 2025
The uterotrophic assay of acetamiprid in rats Report available
Hershberger bioassay in rats Q4 2025
Fish short‐term reproduction assay March 2026
DNT properties
An oral (gavage) developmental neurotoxicity study of acetamiprid in CD® (Sprague Dawley) IGS rats December 2025
Scientific peer‐reviewed open literature
Summary of all relevant data from the scientific peer‐reviewed open literature on DNT and ED properties of acetamiprid, its metabolites and breakdown or reaction products published after the renewal of the approval Q4 2025
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*

Estimates as provided by Nisso Chemical Europe GmbH.

2.2. EFSA considerations on the proposed testing strategy and associated timelines

The proposed analytical methods may be appropriate to address the regulatory requirements, provided that validation data according to European Commission (2021) are submitted for all matrices used in support of the proposed toxicology studies (e.g. feed, body fluids and tissues, air and any additional matrices) and ecotoxicological studies (e.g. soil, water, sediment, feed and any additional matrices).

The applicant proposes to summarise all relevant data from scientific peer‐reviewed open literature and databases (e.g. ToxCast) on ED properties of acetamiprid, its metabolites and breakdown or reaction products published after the renewal of the approval. Therefore, a systematic literature review, i.e. the literature should be extended by covering the period the applicant is granted to provide the additional data, including a search of existing databases as outlined in Appendix D of the ECHA/EFSA ED guidance, should be updated and all studies retrieved should be assessed for relevance and reliability and included in the lines of evidence and weight of evidence for the ED assessment of both humans and non‐target organisms, as needed.

2.2.1. Data generation for the ED assessment for humans

Regarding the testing strategy proposed by the applicant for the ED assessment of acetamiprid for humans, EFSA agrees with the studies proposed following the relevant guidances and with the associated timelines. EFSA noted that the applicant proposed a series of additional (levels 2 and 3) studies to address the EAS‐modalities and complete the ED assessment. Nevertheless, EFSA would like to raise the following concerns regarding the completeness of the assessment of the EATS‐modalities:

  • –

    In accordance with ECHA/EFSA ED guidance, in order to consider the assessment of the A‐ and S‐modalities complete, the substance should also be tested in the ARTA (androgen receptor transactivation assay, OECD Test Guideline No. 458) and the Aromatase assay (US EPA, EDSP Test Guideline, OPPTS 890.1200).

  • –

    No reference is made regarding studies to address ED effects related to the T‐modality. EFSA has noticed that the available studies providing information on the thyroid are few and performed more than 20 years ago (from the late 90s and beginning of 2000s). EFSA recommends that the applicant should confirm that all data necessary to follow the ED strategy in accordance with the ECHA/EFSA ED guidance to ensure that T parameters are sufficiently investigated.

If a positive result is found for an endocrine activity, in line with ECHA/EFSA guidance, a mode of action (MoA) should be postulated and additional information on adversity might be needed, e.g. level 5 tests should be performed.

2.2.2. Data generation for the ED assessment for non‐target organisms

For assessing the endocrine‐disrupting properties in non‐target organisms, a Fish Short‐Term Reproduction Assay (FSTRA) is proposed (OECD TG 229, 2012). This test, categorised at level 3 of the OECD conceptual framework (OECD, 2018), is considered suitable for thoroughly investigating the endocrine activity through EAS‐modalities. However, the following considerations should be taken into account before initiating the test, such as:

  • The FSTRA is not considered suitable if there is positive evidence that the substance may act as an anti‐androgen. A recent review on the detection of anti‐androgenic activity of chemicals in fish studies (Panter et al., 2023) concluded that the performance of the FSTRA in detecting anti‐androgens is not worse than other fish tests. However, the same review indicated that the most reliable tests for identifying anti‐androgens are tests involving co‐exposure with an androgen. For substances potentially showing a low anti‐androgenic potential, a response may not be observed in studies without co‐exposure. Therefore, in line with Arena et al. (2019), EFSA maintains that the FSTRA is not the most suitable fish test for those cases and it should be complemented by a RADAR (OECD TG 251, 2022) or a test in line with OECD guidance 148 (OECD GD 148, 2017).

  • The FSTRA should also include an evaluation of the gonad histopathology in both sexes.

EFSA notes that no studies are proposed to investigate the ED potential of acetamiprid through the T‐modality. However, a full ED assessment allowing to conclude on EATS‐modalities for non‐mammalian species should be conducted. To this aim, in line with ECHA/EFSA ED guidance, an Amphibian Metamorphosis Assay (AMA) should be performed (OECD TG 231, 2009). The Annex A of the ECHA/EFSA ED guidance (2018) could be consulted to determine whether a Xenopus Eleutheroembryonic Thyroid Assay (XETA) (OECD TG 248) can be performed instead, provided that the conditions outlined in the Annex are met.

If the level 3 tests, as discussed above (FSTRA and RADAR or a test in line with OECD GD 148 for EAS‐modalities and an AMA or a XETA for the T‐modality), show positive evidence, an MoA analysis followed by additional tests to further investigate adversity should be conducted, e.g. Medaka Extended One Generation Test (MEOGRT) in line with OECD 240 (OECD TG 240, 2023) and/or The Larval Amphibian Growth and Development Assay (LAGDA) in line with OECD 241. In the absence of an MoA analysis and of additional studies, as needed, it might not be possible to conclude on the endocrine‐disrupting properties of acetamiprid.

It is also noted that an assessment for concluding on the endocrine‐disrupting properties of acetamiprid in wild mammals should also be available. Based on the conclusion reached on the ED assessment for humans, an assessment of the relevance at the level of population of any adverse effect should be conducted, as needed.

2.3. EFSA considerations on the testing strategy and timelines for data generation to conduct an evaluation DNT properties

An Oral (Gavage) Developmental Neurotoxicity Study of Acetamiprid in CD® (Sprague Dawley) IGS Rats is proposed for the purpose of evaluating the developmental neurotoxicity (DNT) properties of acetamiprid. The test is deemed appropriate to conduct an evaluation of the DNT properties of acetamiprid provided that:

  • –

    It is conducted in accordance with OECD TG 426;

  • –

    It is addressing the uncertainties identified in EFSA statement issued in 2024 (EFSA, 2024); and

  • –

    it is conducted following the recommendations outlined therein, i.e. consider appropriate historical control data (HCD) and positive control data (PCD) from the performing laboratory as part of the DNT data package.

In addition, the applicant is proposing to summarise all relevant data from the scientific peer‐reviewed open literature on DNT properties of acetamiprid, its metabolites and breakdown or reaction products published after the renewal of the approval, i.e. the literature should be extended by covering the period the applicant is granted to provide the additional data. It should be noted that some evidence of DNT concern for acetamiprid are available in the EFSA statement issued in 2024 (EFSA, 2024). Overall, all evidence retrieved through a systematic literature review should be assessed for relevance and reliability and included in the weight of evidence, as needed (EFSA, 2021). In addition, the requested historical control data should consider the methodology proposed in the PPR Panel Scientific Opinion on the ‘Use and reporting of historical control data for regulatory studies covering the HCD collation, evaluation and use for the index study under assessment (EFSA PPR Panel, 2025).

3. CONCLUSIONS

EFSA agrees with the testing strategy and associated timelines proposed by the applicant to perform the ED assessment of acetamiprid for humans; however, some uncertainties were raised considering the completeness of the data set.

EFSA agrees that a Fish Short‐Term Reproduction Assay (FSTRA) is generally the recommended test for sufficiently investigating endocrine activity in non‐mammalian species through the EAS‐modalities. However, the appropriateness of that assay should be fully considered, particularly if there is a potential concern that acetamiprid may act as an anti‐androgen. In such cases, the FSTRA should be complemented by additional tests, i.e. a test in line with OECD TG 251 or with OECD GD 148. Moreover, no proposals have been made to investigate the endocrine‐disrupting potential of acetamiprid in non‐mammalian species through the T‐modality. If available studies provide positive evidence for endocrine activity, in line with ECHA/EFSA ED guidance, a mode of action should be postulated, and additional information on adversity might be needed, e.g. level 5 tests should be performed.

For wild mammals, based on the conclusion reached on the ED assessment for humans, an assessment of the relevance at the population level of any adverse effect should be conducted, as needed.

A systematic literature review, including a search of existing databases, should also be performed followed by a proper evaluation for relevance and reliability of the retrieved studies and appropriate consideration in the weight of evidence for the ED assessment of both humans and non‐target organisms, as needed.

For evaluating the DNT properties of acetamiprid, the proposed test is deemed appropriate, provided that it is conducted in accordance with OECD TG 426 and the recommendations outlined in the EFSA statement issued in 2024 (EFSA, 2024) and in the PPR Panel Scientific Opinion on HCD (EFSA PPR Panel, 2025). Relevant scientific peer‐review open literature published after the renewal of approval should be summarised and assessed for relevance and reliability and included in the weight of evidence, as needed.

ABBREVIATIONS

ADI

acceptable daily intake

AOP

adverse outcome pathway

DNT

developmental neurotoxicity

ECHA

European Chemicals Agency

ED

endocrine disrupting

IATA

integrated approaches to testing and assessment

OECD

Organisation for Economic Co‐operation and Development

PPR

Plant Protection Products and their Residues

RMS

rapporteur Member State

REQUESTOR

European Commission

QUESTION NUMBER

EFSA‐Q‐2025‐00364

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MAP DISCLAIMER

The designations employed and the presentation of material on any maps included in this scientific output do not imply the expression of any opinion whatsoever on the part of the European Food Safety Authority concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries.

EFSA (European Food Safety Authority) , (2025). Statement on the testing strategy and timelines for the assessment of developmental neurotoxicity and endocrine disruption properties of acetamiprid in the context of the review of the approval of the active substance. EFSA Journal, 23(9), e9639. 10.2903/j.efsa.2025.9639

Adopted: 5 September 2025

The declarations of interest of all scientific experts active in EFSA's work are available at https://open.efsa.europa.eu/experts.

Notes

1

Commission Implementing Regulation (EU) No 844/2012 of 18 September 2012 setting out the provisions necessary for the implementation of the renewal procedure for active substances, as provided for in Regulation (EC) No 1107/2009 of the European Parliament and of the Council concerning the placing of plant protection products on the market. OJ L 252, 19.9.2012, p. 26–32.

2

Commission Directive 2004/99/EC of 1 October 2004 amending Council Directive 91/414/EEC to include acetamiprid and thiacloprid as active substances. OJ L 309, 6.10.2004, p. 6–8.

3

Commission Implementing Regulation (EU) 2018/113 of 24 January 2018 renewing the approval of the active substance acetamiprid in accordance with Regulation (EC) No 1107/2009 of the European Parliament and of the Council concerning the placing of plant protection products on the market, and amending the Annex to Commission Implementing Regulation (EU) No 540/2011. OJ L 20, 25.1.2018, p. 7–10.

4

Commission Regulation (EU) 2018/605 amending Annex II to Regulation (EC) No 1107/2009 by setting out scientific criteria for the determination of endocrine disrupting properties, OJ L 101, 20.4.2018, p. 33, ELI: https://data.europa.eu/eli/reg/2018/605/oj.

5

Regulation (EC) No 178/2002 of the European Parliament and of the Council of 28 January 2002 laying down the general principles and requirements of food law, establishing the European Food Safety Authority and laying down procedures in matters of food safety, OJ L 31, 1.2.2002, p. 1, ELI: http://data.europa.eu/eli/reg/2002/178/oj.

6

Integrated Approaches to Testing and Assessment supported by Adverse Outcome Pathway, see e.g. https://www.oecd.org/en/topics/sub‐issues/assessment‐of‐chemicals/integrated‐approaches‐to‐testing‐and‐assessment.html.

8

Commission Implementing Regulation (EU) 2018/1659 of 7 November 2018 amending Implementing Regulation (EU) No 844/2012 in view of the scientific criteria for the determination of endocrine‐disrupting properties introduced by Regulation (EU) 2018/605. OJ L 278, 8.11.2018, pp. 3–6.

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