Neonicotinoids: The Science and Regulatory Complexity
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The document provides an overview of neonicotinoids (neonics), a class of insecticides similar to nicotine. It discusses the history and rationale for their use in agriculture, their chemical properties and modes of action. It also reviews concerns about their effects on bees and other pollinators. The regulatory review process of neonics in the European Union is examined, including risk assessments by the European Food Safety Authority that led to restrictions on the use of imidacloprid, clothianidin and thiamethoxam due to risks to bees. The limitations and timeline of the regulatory process in the EU are outlined.
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NEONICOTINOIDS
It is clear from the
scientific research that
neonicotinoids produce
sub-lethal toxic effects in
bees. It is also clear that
the risk is related to the
way neonics are used.
Summary
However, the consequences of
a blanket ban on their use may,
inadvertently, lead to other negative
ecological effects through the frequent
application of less potent, but more
toxic, insecticides. The reality is that
bees are under multiple stressors in
addition to neonicotinoids and it is
only by addressing those multiple
factors that bee health, at a colony and
population level, will be improved.
This multifactorial challenge needs
multifactorial solutions which requires
the collaboration of a wide range
of different stakeholders including
farmers, bee keepers, regulators,
ecologists, scientists and producers.
However, the debate on neonicotinoids
in Europe has been polarized, which
has made balanced, reasoned debate
difficult. It has also made it difficult
to generate solutions that focus
on working out what insecticide
options are safest to use in a given
scenario and how best to support the
responsible use of those insecticides.
For such solutions to be achieved,
it is important that all stakeholder
are ‘mindful of the nuances at the
intersection [of] science, economics,
and society.’25](https://image.slidesharecdn.com/neonicotinoids-ebkcpc005-200219175747/85/Neonicotinoids-The-Science-and-Regulatory-Complexity-19-320.jpg)
Neonicotinoids: The Science and Regulatory Complexity
- 2. 2 NEONICOTINOIDS Introduction 3 The History and Rationale of Neonicotinoid Use 4 Chemistry of Neonicotinoids 6 Agricultural Uses of Neonicotinoids 8 Concerns Over Neonicotinoid Safety 10 Bee and Pollinator Health 11 Observed Effects of Neonicotinoid on Bees 12 Regulatory Review of Neonicotinoids 13 What’s Been Happening on a Member State Level? 16 Summary of Regulatory Status in Other Jurisdictions 17 Consequence of the Restriction/Bans on Neonicotinoid Use in the EU 18 Summary 19 References 20 Contents
- 3. 3 NEONICOTINOIDS It is, therefore, slightly ironic that neonicotinoids, which were trumpeted as safer and more effective alternatives to chlorinated hydrocarbons, organophosphates, carbamates and pyrethroids, are now regarded as toxic to bees and other pollinators, as well as a wider group of species – with some neonicotinoids now banned in the European Union (EU). The agricultural and environmental consequences of neonicotinoid use, and the recent EU regulatory restriction, has made this topic one of the most controversial involving science and policy.2 Growth in the agrochemical industry has been driven by the need to produce enough food to feed a rapidly growing global population. During the last century, global food production has doubled, driven initially by the introduction of mineral phosphate fertilizers in the early 20th century and then, in the 1940s, by the introduction of synthetic crop protection products (CPPs).1 However, despite the increased crop yields resulting from synthetic pesticide use, concerns over toxicity have also been highlighted, so the development of pesticides has proceeded with the aim of creating more effective and safer active ingredients to overcome the problems of the past. Introduction The e-book provides an overview; introducing neonicotinoids, explaining the science behind their use, the reasons for safety concerns and reviewing their regulatory status across the globe.
- 4. 4 NEONICOTINOIDS Neonicotinoids, also known as neonics or NNIs, are a class of active substance used in CPPs. Neonicotinoid essentially means new ‘nicotine-like insecticide’ and, as the name suggests, they are chemically similar to nicotine.3 The History and Rationale of Neonicotinoid Use Neonicotinoids in Context of Insecticide Development Neonicotinoids offered advantages over existing insecticides, such as, better selective toxicity to arthropods over vertebrates; high persistence; a systemic activity; versatility in application, which could reduce the exposure risks to operators; and high water solubility, leading to the assumption of lower bioaccumulation and thus less impact on fish and other vertebrates.4 However, the panacea that they appeared to offer, like previous generations of insecticides, gave way to concerns over pollinator safety; leading to restrictions in their use and bans in some jurisdictions because of their impact on bees. Types of Neonicotinoids The first neonicotinoid to be developed was imidacloprid which, appeared on the market in 1991.4 Further neonicotinoids followed on the heels of imidacloprid (Figure 1) and, as a class, neonics soon became the insecticide of choice, dominating the global market in the 1990s and 2000s.5 Neonicotinoids are systemic insecticides that are taken up by the roots, or via the leaves, and then translocated to other parts of the plant, making the plants toxic to herbivorous insects. This provides direct protection from herbivorous pests, which are mainly sap sucking insects, and indirect protection from plant viruses that are transmitted by insects.4
- 5. 5 NEONICOTINOIDS Figure 1. Sub-groups and Molecular Structures of the Most Widely Used Neonicotinoids4,6 Cl N S N NO2 CH3 N H N H Clothianidin Cl N S N NO2 CH3 N O N Thiamethoxam N NO2 CH3 NO H N H Dinotefuran NO2 Cl N N N NH Imidacloprid Cl N N NO2 CH3 N N H Nitenpyram Cl N N CN CH3 CH3 N Acetamiprid Nitroguanidine Neonics Nitromethylene NeonicsPyridyl Methylamine Neonics
- 6. 6 NEONICOTINOIDS Neonics are water soluble and this enables their translocation throughout the plant into stems, leaves, flowers, fruit, pollen, nectar and guttation fluid (sap exuded through the tips of leaves in some plants). However, it is estimated that given this water solubility, only 5% of the active neonic ingredient is taken up by crops, with most dispersing into the wider environment.5 Neonicotinoids are persistent, with half-lives in soil measured in months or years, which means that they offer the potential for long-term crop protection.4 Although these characteristics are attractive for efficient pest control, they also mean that neonics can spread beyond the target crop and they have been found in nearby crops, wild plants, water ways and honey.7 Chemistry of Neonicotinoids Mode of Action Neonics act by binding to nicotinic acetylcholine receptors (nAChRs) on nerve cells in the central nervous system (CNS) of insects. Neonics act as agonists to nAChRs, activating continuous nerve activity which eventually leads to a block of nerve transmission and subsequent paralysis (Figure 2).8 In insects, nAChRs are confined to the CNS, whereas in mammals they can be found throughout the central and peripheral nervous system and in skeletal muscle.8 There are multiple subtypes of nAChRs, each with a varying sensitivity to different neonics.4 Differences in sub-unit structure between nAChRs in insects and mammals predicts higher neonic selectivity for arthropods over vertebrates.4
- 7. 7 NEONICOTINOIDS Figure 2. Mode of Action of Neonicotinoids Nerve impulse Acetylcholine nAChR Neonic Synapse Pre-synaptic cell Post-synaptic cell Continuous nerve activation Acetylchlorine is released from the pre-synaptic cell in response to a nerve impulse. 01 Acetylchlorine is broken down by the enzyme acetylcholinesertase and transported back into the pre-synaptic cell. Neonics are not broken down in this way and remain in the synapse. 02 Binding of neonics to nAChRs on the post-synaptic cell produces continuous nerve activation. 03
- 8. 8 NEONICOTINOIDS As well as being used in agriculture, horticulture, tree nursery and forestry settings, neonicotinoids are also used for pest control in urban areas (e.g., to combat cockroaches), for veterinary applications (e.g., flea treatments) and in fish farming.4 From an agricultural standpoint, two characteristics of neonics that make them attractive is their effect on a broad-spectrum of pests that target economically important crops and their mode of application (Table 1).4 By far the most common application method used for neonics is seed dressing, where it is applied prophylactically to the seeds and then translocated through the plant as it grows.4 Neonicotinoid seed treatment can provide protection to seedlings for up to ten weeks and can also reduce the need for subsequent multiple pesticide sprays to the growing crop.7 Agricultural Uses of Neonicotinoids In developed countries, seed application has often been routine and used regardless of the presence or absence of pests.4 In fact, in North America, untreated maize seeds are difficult to obtain, as insurers will not pay out on claims for crop losses unless farmers can demonstrate they have followed usual agricultural practice such as sowing treated seeds.4 Interestingly, in Italy in 2012, insurance systems were in place to reduce the use of neonics where pest levels were low. In this scenario because the risk of crop damage was small, no control was needed and compensation was available if the crop failed.9
- 9. 9 NEONICOTINOIDS Table 1. Examples of Pests Targeted, and Crops Protected, by Neonicotinoids4,10 PESTS TARGETED CROPS PROTECTED METHODS OF APPLICATION Hemipteran sap-feeding insects: ▶ Aphidae (aphids) ▶ Aleyrodidae (whitefly) ▶ Cicadellidae (leafhoppers) ▶ Fulgoroidea (planthoppers) ▶ Pseudococcidae (mealybugs) ▶ Cereals including maize ▶ Oilseed rape ▶ Rice ▶ Potato ▶ Sugar beet ▶ Sunflower ▶ Fruit, like citrus and apple ▶ Vegetables ▶ Soy ▶ Ornamental plants ▶ Cotton ▶ Foliar spraying ▶ Seed dressing ▶ Seed pilling ▶ Soil treatment ▶ Granular application ▶ Dipping of seedlings ▶ Chemigation ▶ Soil drenching ▶ Furrow application ▶ Trunk injections in trees ▶ Mixing with irrigation water ▶ Drenching of flower bulbs ▶ Brush application to stems of fruit trees Foliar feeding insects: ▶ Leptinotarsae (Colorado potato beetle) ▶ Lepidoptera Plutellidae (diamond backed moth) ▶ Phytophagous mites (various species) Soil pests: ▶ Chrysomelidae (western corn rootworm, among others) ▶ Elateridae (wireworms) ▶ Coleoptera: Scarabaeidae (white grubs)
- 10. 10 NEONICOTINOIDS One of the benefits of neonics – their broad-spectrum of activity against multiple pests – is also a drawback, as non-target arthropod species are also affected. Initial concerns over neonic safety related to their impact on bees and other pollinators, however wider concern has grown regarding their effect on terrestrial and aquatic invertebrates and vertebrates, including humans.11 The primary concern of regulators has been the impact of neonics on bees, given their importance on ecosystems and their commercial value to crop yields. Pollinators are estimated to provide or stabilize yields of approximately 75% of global crop species.12 The main crop pollinators in Europe and North America are the honeybee (Apis mellifera) and bumble bees (Bombus).13 Concerns Over Neonicotinoid Safety
- 11. 11 NEONICOTINOIDS Figure 3. Multiple Pressures Impact Pollinator Health12 Bee and Pollinator Health The health of bee and pollinator populations is threatened by multiple factors, not just neonics (Figure 3). Complex interactions drive pollinator decline There are multiple interrelated stressors that negatively impact pollinators at the level of the individual, colony and wider populations. Pesticides (including neonicotinods) Pesticides used in intensive crop management can harm pollinators. Sublethal doses of neonics have been shown to alter pollinator performance and behavior. Pests and pathogens The varroa destructor mite is the main vector of many viruses that cause honey bee colony loss. Other pest threats may come from alien bee species spreading geographically. Loss/fragmentation of habitat Urbanization and intensification of farming have fragmented and reduced the areas used for nesting and foraging. Climate change This can impact the normal range of plants and pollinators, shifting them to new locations or causing a mismatch in their distribution and the synchronization of flowering and pollinator flight periods. Reduced nutritional quality of forage Reductions in flowering plant diversity and abundance reduces food variety and availability, disrupting the optimum nutrient intake needed to support growth and reproduction. Poor nutrition also reduces honey bee immunity.
- 12. 12 NEONICOTINOIDS Neonics, at sublethal doses, have been shown to impact bee behavior and performance; however, the risk of exposure is dependent on neonic application rate, application type and crop type.5 The impact of neonics on pollinators has been most extensively studied in individual honey bees and bumble bees.2,14 Neonics have been observed to alter a number of bee behaviors including:5,13 ▶ Memory ▶ Foraging efficiency ▶ Flight ability ▶ Initial flower preference ▶ Navigation ▶ Survival ▶ Colony development ▶ Queen production Observed Effects of Neonicotinoid on Bees
- 13. 13 NEONICOTINOIDS European Regulation Regulators across the globe have been concerned about the impact of neonicotinoids on bee health, as a reduction in bee numbers was observed at about the same time neonics were introduced in some countries, although this pattern is not consistent worldwide. Regulatory Review of Neonicotinoids In 2012, the European Commission (EC) commissioned the European Food Safety Authority (EFSA) to produce a risk assessment on the impact of three neonicotinoids – imidacloprid, clothianidin and thiamethoxam – as seed dressing or granules on honey bees, bumble bees and solitary bees. This kicked off a six-year review process involving EC, EFSA, member states (MSs), producers and non-governmental organizations (NGOs) – see Figure 4.
- 14. 14 NEONICOTINOIDS Figure 4. EU Review Process for Imidacloprid, Clothianidin and Thiamethoxam6 2012 2013 2015 2016 2018 EC commissions EFSA to produce a risk assessment on the impact of imidacloprid, clothianidin and thiamethoxam, as seed dressings or granules, on pollinators. Summary of Limitations Regulation 485/2013 prescribes: Use by private individuals is banned Seed treatment is restricted MSs had to adapt their national authorizations by September 30, 2013. Additional request for more information from producers on areas of uncertainty. Review of scientific information relevant for the risk assessment to be reviewed in 2 years. Based on additional data supplied by producers and the MS review, EFSA publishes conclusions for: Imidacloprid Clothianidin Insufficient information provided for thiamethoxam EFSA publishes a new set of conclusions from the 2-year review, including evaluation of data supplied by MSs, producers and NGOs as part of the data-call in. This leads to strengthening of the conditions for approval and EC adopting regulations: 2018/783 (imidacloprid) 2018/784 (clothianidin) 2018/785 (thiamethoxam) Strengthened Limitations PPPs containing ≥1 of the three neonicos may only be applied to crops which, during their entire life cycle, remain in a permanent greenhouse, or on seeds that are exclusively intended for use in permanent greenhouses (the plant obtained remains in this greenhouse throughout its life cycle) MSs needed to adjust authorizations by September 19, 2018 to reflect this Farmers needed to comply with restrictions by December 19, 2018 EFSA publishes risk assessment for the three neonics on application types other than as seed dressings or granules. Previous limitations upheld. EFSA publishes report. EC and MSs adopt regulation 485/2013 which limits the use of the three neonics. Additional data requested from producers to provide additional information to address uncertainties identified in the risk assessment. Review in 2 years requested. Foliar treatment of most cereals is banned For a whole range of listed crops use is restricted (only to greenhouses or for use after flowering)
- 15. 15 NEONICOTINOIDS EFSA’s decision, and the subsequent EC legislation restricting/banning the use of these three neonics, was widely criticized by producers and farmers and it was out of step with other regulators globally. Some of the key aspects driving the EC/EFSA decision making and the views of opponents are captured below. There are two other neonicotinoids currently approved in the EU – acetamiprid and thiacloprid. Acetamiprid was assessed as being of low risk and thiacloprid is a candidate for substitution because of its endocrine disrupting properties (Table 2). EFSA VIEWPOINT ON RISK ASSESSMENTS OPPONENT VIEWPOINT ON RISK ASSESSMENTS EFSA used the Guidance Document on the risk assessment of plant protection products on bees otherwise known as the Bee Risk Guidance Document (BRGD) as the basis for their risk assessment.15 This risk assessment was designed to overcome concerns regarding the appropriateness of existing risk assessments and to provide a consistent and level playing field for assessment and interpretation of bee data. The BRGD is a draft guidance document; however, the EC recommended its use by EFSA in the risk assessment for neonicotinoids, despite many MSs being opposed to it. The MSs felt it set the bar for risk at an unrealistic level that could result in substances that are not of concern to bees being wrongly identified as posing a risk to them.6 The BRGD allowed for a tiered testing approach and considered data from three bee species, in eight different exposure scenarios, for 17 different crops, taking into account application approach and timing of harvesting; making it a wide ranging and comprehensive review of likely sources of risk that could occur under normal agricultural conditions. Assessment was carried out at three different levels or tiers: ▶ Tier I: screening assessments ▶ Tier II: partly field-based and partly caged studies ▶ Tier III: full field studies The assessment was hugely complex with multiple variables and, of over 1,700 assessments considered, only a small fraction reflected higher tier studies (Tiers II and III). However, for most of EFSA’s assessments, Tier II or Tier III data was absent, especially for treated crop scenarios where neonicotinoid-treated seeds are used. Therefore, the evidence basis EFSA used to interpret risk may have been scientifically inappropriate. EFSA rated the risk to each bee type (honey, bumble and solitary) separately for specific exposure scenarios for different crops. EFSA took the overall risk across all the species. For example, for imidacloprid use on oilseed rape (winter and spring), although the exposure risk for honey bees was low from residues in nectar and pollen, the risk for bumble bees was high. Furthermore, the exposure risk was high for honey bees for exposure via dust drift in the same crop. Therefore the overall risk assessment was high.17 Opponents disagreed with the interpretation of overall risk, stating that ‘high risk was reached for only 5% of more than 500 scenarios’ and that in ‘70% of the cases where a final risk conclusion could be reached, EFSA concluded a low risk; in 25% of cases a conclusion of uncertain risk was reached.’18 Therefore interpretation of overall risk were overly conservative.
- 16. 16 NEONICOTINOIDS A number of MSs have been using emergency authorizations, which are valid for 120 days, in situations where it is deemed that there is no other reasonable protection against a pest other than neonics.6 In 2017, Bulgaria, Estonia, Finland, Hungary, Latvia, Lithuania and Romania applied such emergency authorizations.19 EFSA, at the request of the EC, have now developed a methodology for evaluating the data supporting the use of emergency authorizations.20 What’s Been Happening on a Member State (MS) Level? An Example of the Rationale for Emergency Authorizations21 Belgium have also approved the use of an emergency 120-day authorization of thiametoxam and clothianidin seed treatment for sugar beets, carrots and lettuce grown in the open for the 2019 growing season. Belgium’s rationale was that use of low quantities of these neonics, applied to seeds, avoids later foliar application of broad-spectrum pyrethroids, which are more hazardous to all beneficial arthropods. Risk to bees is minimized because the seed treatment does not cause dust drift and the crops do not flower or show guttation, so exposure is limited. To add further protection, the authorization includes a restriction of the full crop rotation to the planting of non-flowering or non-bee-attractive successive crops.
- 17. 17 NEONICOTINOIDS The EU view on the risk posed to bees by neonicotinoid-treated seed is out of step with many other regulators globally; with the US Environmental Protection Agency (EPA), US Department of Agriculture and agencies in Canada and Australia all stating that neonics, as seed treatment, are not a major health threat to honey bees.16 Other jurisdictions do asses risks to bees – for example in 2014, the US and Canadian governments published their ‘Guidance for Assessing Pesticide Risks to Bees’.23 The EPA has also issued a bee advisory box on labels to highlight its strengthened pollinator protection. However, no other jurisdiction round the globe has yet followed Europe’s ban on neonics. Summary of Regulatory Status in Other Jurisdictions Table 2. Regulatory Status of the Main Neonicotinoid Active Substances Used in Cpps in Europe and America ACTIVE SUBSTANCE REGULATORY STATUS EPA22 EFSA3 Imidacloprid Updated pollinator risk assessment and a proposed interim decision will be issued for public comment in spring 2019. The use in bee-attractive crops (including maize, oilseed rape and sunflower) is prohibited, with the exception of uses: ▶ in greenhouses ▶ of treatment of some crops after flowering ▶ of winter cereals Applicants are obliged to provide ‘confirmatory information’ in order to confirm the safety of the uses still allowed. Clothianidin Thiamethoxam Acetamiprid A proposed interim decision will be issued for public comment in spring 2019. EFSA established a low risk to bees so there is no ban or further restrictions. Acetamiprid has been renewed until 2033. Thiacloprid Registration review voluntarily cancelled by registrant. Case closure issued Nov 2014. Is a candidate for substitution because of its endocrine disrupting properties. National authorities need to carry out comparative assessment to establish if more favorable alternative plant protection processes exist. The current approval expires on April 30, 2019 but a renewal application is ongoing. Dinotefuran Updated pollinator risk assessment and a proposed interim decision will be issued for public comment in spring 2019. Not licensed in the EU.
- 18. 18 NEONICOTINOIDS The consequences of the neonic ban, although designed to reduce one of the multiple stressors which bees are exposed to, may lead to other negative ecological and economic effects. Figure 5 shows one assessment of the ecological and economic impact, estimated from data for the 2013 neonic ban, looking specifically at the impact related to oilseed rape.24 Consequence of the Restriction/Bans on Neonicotinoid Use in the EU CO2 release from new agricultural land use 4% in annual yield of oilseed rape quality of oilseed rape leads to price 0.73 applications per hectare of foliar sprays pest resistance €120 million of production costs for oilseed rape annually in EU €880 million in annual GDP in the EU net water usage due to less efficient water management in third countries biodiversity in other countriesagricultural land needed for production > 500,000 hectares of grass/health land converted to oilseed rape production outside EU
- 19. 19 NEONICOTINOIDS It is clear from the scientific research that neonicotinoids produce sub-lethal toxic effects in bees. It is also clear that the risk is related to the way neonics are used. Summary However, the consequences of a blanket ban on their use may, inadvertently, lead to other negative ecological effects through the frequent application of less potent, but more toxic, insecticides. The reality is that bees are under multiple stressors in addition to neonicotinoids and it is only by addressing those multiple factors that bee health, at a colony and population level, will be improved. This multifactorial challenge needs multifactorial solutions which requires the collaboration of a wide range of different stakeholders including farmers, bee keepers, regulators, ecologists, scientists and producers. However, the debate on neonicotinoids in Europe has been polarized, which has made balanced, reasoned debate difficult. It has also made it difficult to generate solutions that focus on working out what insecticide options are safest to use in a given scenario and how best to support the responsible use of those insecticides. For such solutions to be achieved, it is important that all stakeholder are ‘mindful of the nuances at the intersection [of] science, economics, and society.’25
- 20. 20 NEONICOTINOIDS 1 Carvalho, F. P. Pesticides, environment, and food safety. Food Energy Secur. 6, 48–60 (2017). 2 Godfray, H. C. J. et al. A restatement of the natural science evidence base concerning neonicotinoid insecticides and insect pollinators. Proc. R. Soc. B Biol. Sci. 281, 20140558 (2014). 3 European Commission. Neonicotinoids. EC website Available at: https://ec.europa. eu/food/plant/pesticides/approval_active_ substances/approval_renewal/ neonicotinoids_en. 4 Simon-Delso, N. et al. Systemic insecticides (Neonicotinoids and fipronil): Trends, uses, mode of action and metabolites. Environ. Sci. Pollut. Res. 22, 5–34 (2015). 5 Wood, T. J. & Goulson, D. The environmental risks of neonicotinoid pesticides: a review of the evidence post 2013. Environ. Sci. Pollut. Res. Int. 24, 17285–17325 (2017). 6 Phytoweb. Neonicotinoids. Available at: https://fytoweb.be/en/plant-protection- products/use/neonicotinoids. 7 King, A. What you need to know about neonicotinoids. Chemistry World (2018). Available at: https://www.chemistryworld. com/news/what-you-need-to-know-about- neonicotinoids/3008816.article. 8 Gupta, R. & Milatovic, D. Chapter 23: Insecticides. in Biomarkers in Toxicology 389–407 (2014). References 9 Allema, B., Hoogendoorn, M., van Beek, J. & Leendertse, P. Neonicotinoids in European agriculture: Main applications, main crops and scope for alternatives. (2017). 10 Crossthwaite, A. J. et al. The invertebrate pharmacology of insecticides acting at nicotinic acetylcholine receptors. J. Pestic. Sci. 42, 67–83 (2017). 11 Mitchell, E. A. D. et al. A worldwide survey of neonicotinoids in honey. Science 358, 109–111 (2017). 12 Vanbergen, A. J. & Initiative, the I. P. Threats to an ecosystem service: pressures on pollinators. Front. Ecol. Environ. 11, 251–259 (2013). 13 Lamsa, J., Kuusella, E., Tuomi, J., Juntunen, S. & Watts, P. Low dose of neonicotinoid insecticide reduces foraging motivation of bumblebees. Proc. R. Soc. B Biol. Sci. 285, (2018). 14 Lundin, O., Rundlöf, M., Smith, H. G., Fries, I. & Bommarco, R. Neonicotinoid insecticides and their impacts on bees: A systematic review of research approaches and identification of knowledge gaps. PLoS One 10, 1–20 (2015). 15 EFSA. EFSA Guidance Document on the risk assessment of plant protection products on bees (Apis mellifera, Bombus spp. and solitary bees). (2013). 16 Entine, J. Global consensus finds neonicotinoids not driving honeybee health problems—Why is Europe so determined to ban them? Genetic Literacy Project (2018). 17 EFSA. Q&A: Conclusions on neonicotinoids 2018. (2018). Available at: https://www.efsa. europa.eu/sites/default/files/news/180228- QA-Neonics.pdf. 18 Bayer. Making sense of the recent EFSA reports on neonicotinoids: What do they really say? (2018). 19 EFSA. Neonicotinoids: EFSA evaluates emergency uses. (2018). Available at: https://www.efsa.europa.eu/en/press/ news/180621. 20 Grégoire, J. et al. Protocol for the evaluation of data concerning the necessity of the application of insecticide† active substances to control a serious danger to plant health which cannot be contained by other available means, including non-chemical methods. EFSA Support. Publ. 14, 1–26 (2017). 21 Trybou, M. Neonics to save bee(t)s! (2018). Available at: https://www.linkedin.com/pulse/ neonics-save-beets-maarten-trybou/. 22 Environmental Protection Agency (EPA). Schedule for Review of Neonicotinoid Pesticides. Available at: https://www.epa. gov/pollinator-protection/schedule-review- neonicotinoid-pesticides. 23 USEPA. Guidance for Assessing Pesticide Risks to Bees. 59 (2014). 24 Noleppa, S. Banning neonicotinoids in the European Union: An ex-post assessment of economic and environmental costs. (2017). 25 Mcafee, A. A brief history of pesticides. Am. Bee J. 157, 781–783 (2017).
- 21. 21 NEONICOTINOIDS Learn more about our crop protection solutions at www.covance.com/crop-protection Covance is the drug, medical device and diagnostics business segment of LabCorp, a leading global life sciences company. COVANCE is a registered trademark and the marketing name for Covance Inc. and its subsidiaries around the world. The Americas +1.888.COVANCE (+1.888.268.2623) +1.609.452.4440 Europe/Africa +00.800.2682.2682 +44.1423.500888 Asia Pacific +800.6568.3000 +65.6.5686588 © Copyright 2019 Covance Inc. EBKCPC005-1219