EFSA assesses potential link between two neonicotinoids and developmental neurotoxicity

Two neonicotinoid insecticides - acetamiprid and imidacloprid - may affect the developing human nervous system, said the European Food Safety Authority (EFSA). Experts from the Authority propose that some guidance levels for acceptable exposure to the two neonicotinoids be lowered while further research is carried out to provide more reliable data on so-called developmental neurotoxicity (DNT). EFSA’s Panel on Plant Protection Products and their Residues (PPR) calls for the definition of criteria at EU level to trigger submission of mandatory DNT studies as part of the pesticide authorisation process. This could include the development of a comprehensive testing strategy to evaluate the DNT-potential of substances, including all neonicotinoids.

EFSA has delivered its scientific opinion at the request of the European Commission by considering recent research by Kimura-Kuroda[1] and existing data on the potential of acetamiprid and imidacloprid to damage the developing human nervous system - in particular the brain.

The PPR Panel found that acetamiprid and imidacloprid may adversely affect the development of neurons and brain structures associated with functions such as learning and memory. It concluded that some current guidance levels for acceptable exposure to acetamiprid and imidacloprid may not be protective enough to safeguard against developmental neurotoxicity and should be reduced.  These so-called toxicological reference values provide clear guidance on the level of a substance that consumers can be exposed to in the short- and long-term without an appreciable health risk. Examples include the acute reference dose (ARfD), the acceptable daily intake (ADI) and the acceptable operator exposure level (AOEL). (See Notes to editors for more detail on how these reference values are designed to protect consumers and operators.)

Based on its review, EFSA proposes changes to the following toxicological reference values for acetamiprid and imidacloprid:

  • For acetamiprid – the current ADI and AOEL of 0.07 mg/kg bw/per day and the ARfD of 0.1 mg/kg bw should be lowered to 0.025 mg/kg bw (per day);
  • For imidacloprid, the current AOEL and ARfD of 0.08mg/kg/bw/day should be lowered to 0.06 mg/kg bw/per day. The current ADI for imidacloprid is considered to provide adequate protection against potential developmental neurotoxic effects.

EFSA recognises the available evidence has limitations and recommends further research be carried out to provide more robust data. However, the PPR Panel said health concerns raised in the review of the existing data are legitimate. EFSA therefore supports the establishment of clear and consistent criteria to trigger the mandatory submission of DNT studies as part of the authorisation process in the EU. This could include the development of an integrated DNT testing strategy consisting of a stepped approach that uses laboratory tests on cells (so-called in vitro) in the first instance and progresses to tests on animals (in vivo) if the initial results raise concerns over the DNT-potential of a substance. The PPR Panel advises that all neonicotinoid substances be evaluated as part of this testing strategy.

1. What is developmental neurotoxicity (DNT)?

Developmental neurotoxicity is any adverse effect on the chemistry, structure or function of the nervous system caused by chemical or physical influence that occurs during development i.e. to a foetus or a young child.

2. What was EFSA asked to do?

Following a request from the European Commission, EFSA’s Panel on Plant Protection Products and their Residues (PPR) assessed the developmental neurotoxicity potential of acetamiprid and imidacloprid.

3. Why was this request made now?

The European Commission made this request after a recently published scientific paper by Kimura and Kuroda[1]  suggested that a type of receptor in the brain - known as the nicotinic acetylcholine receptors (nAChRs) - interacts with acetamiprid and imidacloprid. The research concluded exposure to these two compounds may affect the developing mammalian nervous system as is known to occur with nicotine.

4. How did EFSA carry out this evaluation?

The PPR Panel looked at all relevant available data on acetamiprid and imidacloprid contained in the open scientific literature - including the Kimura-Kuroda study. In light of these findings, EFSA also reviewed  data previously submitted in applications to Member States as part of EU authorisation of the two pesticides.

5. What are EFSA’s main conclusions on whether acetamiprid and imidacloprid exhibit DNT effects?

The PPR Panel concludes that both acetamiprid and imidacloprid show some indications of DNT potential. Acetamiprid and imidacloprid may adversely affect the development of neurons – the building blocks of the nervous system and the cells that carry messages from the brain to other parts of the body. Consequently, the PPR Panel concluded that exposure to the two neonicotinoids could have the potential to affect some brain functions such as learning and memory.

6. How conclusive is the evidence to support this finding?

EFSA recognises the evidence has limitations and recommends further research be carried out to provide more robust data. However, the PPR Panel said health concerns raised in the review are legitimate.

7. What is a toxicological reference value?

A toxicological reference value provides clear guidance on the level of a substance that all population groups – including pregnant women, infants and children - and operators can be exposed to in the short- or long-term without an appreciable risk to their health. An initial benchmark value is established on the basis of toxicological data showing the absence of an adverse effect. This value is then scaled by an uncertainty factor, conventionally of 100, to account for the differences between test animals and humans (factor of 10) and possible differences in sensitivity between humans (another factor of 10). It serves as a reference for comparison with exposures occurring under realistic conditions over the short-or long-term.
In its risk assessment of the developmental neurotoxicity potential of acetamiprid and imidacloprid, the PPR Panel identified three such values for consideration:
  • Acute reference dose (ARfD) - the estimated level of a substance that can be ingested over a short time - usually one day – without an appreciable health risk.
  • Acceptable daily intake (ADI) - the amount of a specific substance in food or drinking water that can be ingested daily over a lifetime without an appreciable health risk.
  • Acceptable operator exposure level (AOEL) - the maximum amount of an active substance to which a worker or ‘operator’ may be exposed to - either through inhalation or by absorption through their skin - without any adverse health effects.

These values are expressed by body weight, usually in milligrams (of the substance) per kilograms of body weight, and per day in the case of repeated exposure.

8. Do the existing toxicological reference values provide adequate protection against any potential developmental neurotoxicity of acetamiprid and imidacloprid?

EFSA concludes that the toxicological reference values for acetamiprid and imidacloprid may not be protective enough and should be reduced to safeguard against developmental neurotoxicity.  As a result of its review, EFSA proposes the following changes:

  • For aceptamiprid – the current ADI and AOEL of 0.07 mg/kg bw per day and the ARfD of 0.1 mg/kg bw should be lowered to 0.025 mg/kg bw (per day);
  • For imidacloprid, the current AOEL and ARfD of 0.08mg/kg/bw per day should be lowered to 0.06 mg/kg bw per day. The current ADI for imidacloprid is considered to provide adequate protection against potential developmental neurotoxic effects.

9. Does EFSA make other recommendations?

Yes, the Authority also advises that criteria for the mandatory submission of DNT studies be established as part of the authorisation process in the EU. This could include the development of an integrated DNT testing strategy consisting of a stepped approach that uses laboratory tests on cells (so-called in vitro) in the first instance and progresses to tests on animals (in vivo) if the initial results raised concerns over the DNT- potential of a substance. The PPR Panel advises that all neonicotinoid substances be evaluated as part of this testing strategy.
Notes to editors

Scientists have developed a range of toxicological reference values designed to set guidance levels for acceptable exposure to a substance in food. They are expressed by body weight, usually in milligrams (of the substance) per kilogram of body weight, and per day in the case of repeated exposure.

  • Acute reference dose (ARfD) - the estimated level of a substance that can be ingested over a short time - usually one day – without an appreciable health risk.
  • Acceptable daily intake (ADI) - the amount of a specific substance in food or drinking water that can be ingested daily over a lifetime without an appreciable health risk.
  • Acceptable operator exposure level (AOEL) the maximum amount of an active substance to which a worker or ‘operator’ may be exposed by all routes without any adverse health effects.
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E-mail: Press@efsa.europa.eu

[1] Kimura-Kuroda J, Komuta Y, Kuroda Y, Hayashi Kawano H. Nicotine-like effects of the neonicotinoid insecticides acetamiprid and imidacloprid on cerebellar neurons from neonatal rats. PloS ONE 2012; 7 (2): e32432. doi: 10.1371/journal.pone.0032432