Statement on the toxicological properties and maximum residue levels of acetamiprid and its metabolites

Abstract

Acetamiprid is a pesticide active substance with insecticidal action whose approval was renewed by Commission Implementing Regulation (EU) 2018/113. In January 2022, the EFSA PPR Panel published a statement following a request from the European Commission to advise on human health or the environment based on new scientific evidence presented by France during the decision-making phase. In July 2022, by means of a further mandate received from the European Commission, EFSA was requested to provide advice if new information and any other scientific evidence that has become available since the assessment conducted for the renewal in 2018 warrant re-evaluation of (i) toxicological parameters used for the risk assessment of acetamiprid during the renewal process, including toxicological endpoints; (ii) the residue definition for acetamiprid in products of plant origin; and (iii) the safety of existing maximum residue levels (MRLs). Meanwhile, the applicant of acetamiprid in the EU submitted new toxicology studies regarding the toxicological profile of the metabolite IM-2-1. Furthermore, the European Commission was made aware that several recent publications in scientific literature were made available after the literature searches conducted by EFSA. As the new data could affect the advice that EFSA was expected to deliver through the 2022 mandate, EFSA was further requested to consider this information by means of a revised mandate received in September 2023. As regards re-evaluation of point (i) in this statement, this was addressed by an EFSA Working Group integrating all the available evidence. The results of the weight of evidence indicated that there are major uncertainties in the body of evidence for the developmental neurotoxicity (DNT) properties of acetamiprid and further data are therefore needed to come to a more robust mechanistic understanding to enable appropriate hazard and risk assessment. In view of these uncertainties, the EFSA WG proposed to lower the acceptable daily intake (ADI) and acute reference dose (ARfD) from 0.025 to 0.005 mg/kg body weight (per day). A revised residue definition for risk assessment was proposed for leafy and fruit crops as sum of acetamiprid and N-desmethyl-acetamiprid (IM-2-1), expressed as acetamiprid. Regarding pulses/oilseeds, root crops and cereals, the new data received did not indicate a need to modify the existing residue definition for risk assessment, which therefore remains as parent acetamiprid. Regarding the residue definition for enforcement, the available data did not indicate a need to modify the existing definition because acetamiprid is still a sufficient marker of the residues in all crop groups. Considering the new health-based guidance values derived in the present statement, a risk for consumer has been identified for 38 MRLs currently in place in the EU Regulation. Consequently, EFSA recommended to lower the existing MRLs for 38 commodities based on the assessment of fall-back Good Agricultural Practices received within an ad hoc data call. Some fall-back MRLs proposals require further risk management considerations.

Keywords: acetamiprid; developmental neurotoxicity; insecticides; maximum residue levels; metabolite IM‐2‐1; monitoring data.

FIGURE 1

AOP‐informed IATA workflow for acetamiprid assessment.

FIGURE 2

PRISMA flow chart of the literature search process for acetamiprid, including the screening for relevance of results.

FIGURE 3

Summary of the appraisal of the endpoint categories of the in vivo, in vitro and zebrafish studies selected from the systematic literature review for acetamiprid measuring DNT endpoints.

FIGURE 4

Assays in the current DNT IVB and assays identified as high priority for development (from OECD, 2023). Assays are grouped according to the neurodevelopmental process evaluated (rows) and test system used (columns). Each assay box lists the abbreviated assay name, cell type and assay development laboratory. Assays that need further development, and not included in the current DNT IVB, are identified as data gaps. Each assay is represented as a box that lists the test method name (italics), the test system (cell type used) and the home institution of the developer (IUF,  Leibniz Research Institute for Environmental medicine – green; UKON, University of Konstanz ‐ grey; EPA, US Environmental Protection Agency – blue). Other abbreviations can be found in the abbreviations list.

FIGURE 5

Heatmap of acetamiprid, nicotine and other neonicotinoids in the US EPA DNT IVB MEA (NNF) assay, including positive and negative performance controls. Data extracted from ToXCast (invitrodb v3.5 in June, 2023). The following filters applied: ≥ 3 ToxCast flags capturing curve‐fitting behaviour such as noisy data; curve‐fits with a model top less ≤ 1.2 times the cut‐off for a positive and a resultant AC50 lower than the concentration range screened; concentrations series with fewer than four concentrations; excluded MEA NFA ‘_up’ endpoints as not validated by positive performance controls.

FIGURE 6

Heatmap of acetamiprid, nicotine and other neonicotinoids in the US EPA DNT high content image cellular event assays for assessing chemical effects on neurodevelopment processes. Data extracted from ToXCast (invitrodb v3.5 in June, 2023). Assays included proliferation in neural progenitor cells hNP1; apoptosis in neural progenitor cells hNP1; neurite initiation in human neurons; neurite initiation cortical rat primary neurons; neurite maturation in rat primary neural culture; synaptogenesis in rat primary neural culture.

FIGURE 7

Heatmap of acetamiprid, nicotine and other neonicotinoids in the EU DNT IVB. Data extracted from Blum et al. (2023) and EFSA PPR Panel (2021).

FIGURE 8

Nicotinic acetyl choline receptor (nAChR) ontogeny in rats and humans in the different brain areas. Figure extracted and adapted from OECD IATA Case Study no. 365.

FIGURE 9

Integration of the acetamiprid DNT BoE into an AOP framework including the related uncertainties. Uncertainties are shaded in grey.

FIGURE 10

PRISMA flow chart of the literature search process for acetamiprid and its metabolites, including the screening for relevance. *See list of metabolites in Table 16.

FIGURE 11

Schematic overview of interrelation of identified uncertainties related to metabolism and excretion processes of acetamiprid and IM‐2‐1 in the available PBK model for acetamiprid. The PBK model parameter values chosen for the kinetic processes related to U1, U2 and U4 impact on predicted internal and urinary acetamiprid concentrations (U6). The PBK model parameter values chosen for the kinetic processes related to U1–U5 impact on predicted internal and urinary IM‐2‐1 concentrations (U7).