Posted on February 5, 2015 · Posted in Bees, New Pesticides

The US Environmental Protection Agency (US EPA) recently announced registration of the new insecticide flupyradifurone, with claims of being “safer for bees” than many of the established insecticides, including organophosphates, pyrethroids and neonicotinoids.

Manufactured by Bayer CropScience, Flupyradifurone is proposed as an alternative insecticide for controlling sucking pest species—aphids, psyllids, stink bugs, and white flies—which are becoming increasingly resistant to currently available pesticide chemistries. Foliar applications, chemigation (pesticide application in irrigation water) and soil drenches of the end-use product, SivantoTM 200 SL, are approved for use on a large number of crops, including fruits and vegetables frequented by honey bees and native pollinators. Despite the safety claims in the registration notice, the available data suggest that flupyradifurone may possess many of the undesirable attributes associated with neonicotinoids and other conventional insecticides.

Flupyradifurone Chemically Similar to Neonicotinoids

Although flupyradifurone is chemically classified as a butenolide, many scientists and even the casual observer might consider the insecticide to be a neonicotinoid. Both flupyradifurone and neonicotinoids have the same mode of action involving activation of the nicotinic acetylcholine receptor (i.e., nAChR agonist) and very similar chemical structures (see structural comparison below). In addition, both are systemic insecticides intended for uptake and distribution throughout various plant parts—from stems and leaves to pollen and nectar stores in flowering plants. Like the neonicotinoids, flupyradifurone is also highly soluble in water (3,200 mg dissolves in one liter of water at 20 ºC) and moderately persistent in the environment with an average field dissipation half-life of five months.


Considering the hazards associated with neonicotinoids, it’s worth taking a closer look at flupyradifurone in the context of available honey bee toxicity data.

A review of US EPA’s Environmental Fate and Ecological Risk Assessment for the flupyradifurone technical grade active ingredient (TGAI) revealed that “flupyradifurone TGAI is practically non-toxic to young adult honeybees (Apis mellifera) on an acute contact basis; however, the compound is highly toxic to young adult bees on an acute oral exposure basis.” Further, the acute oral toxicity test provided a “steep dose response relationship in which 0 and 100 percent mortality were observed at 0.34 and 2.8 μg ai/bee, respectively.” Comparison with the acute oral LD50 values for five common neonicotinoids derived from the US EPA Ecotox database shows that flupyradifurone is not as toxic as clothianidin or imidacloprid, but more than an order of magnitude more toxic than acetamiprid (see Table 1). The steep dose-response curve is highly problematic and serves as evidence that even a small change in exposure could pose serious problems to bees.

Table 1. Comparison Data for Flupyradifurone and Several Neonicotinoids

Chemical Oral LD50 (ug/bee) Water Solubility (mg/L) Average Aerobic Soil Half-life (days)
Imidacloprid 0.004 514 997
Clothianidin 0.004 259 214
Thiamethoxam 0.005 4,100 229
Dinotefuran 0.02 39,800 51
Flupyradifurone 1.2 3,200 144
Acetamiprid 14.5 3,600 10

LD50 = dose lethal to 50% of test bees; ug/bee = micrograms per bee

Field Studies Leave Unanswered Questions

US EPA counters the concerns indicated in the laboratory-based acute oral toxicity tests with evidence from semi-field and full field exposure studies showing minimal impacts on bees. In these “higher tier” studies, bees were either confined in gauze tunnels containing flupyradifurone-treated flowering Phacelia or allowed to forage freely near fields of flowering canola treated with a commercial flupyradifurone formulation.

The semi-field tunnel studies involved exposure of confined honey bees for approximately two weeks and generally showed only transient treatment-related effects on mortality and flight intensity. However, the inclusion of too few replicates and large disparities in starting colony sizes (e.g., the treatment colonies were more than three times larger than the control colonies at the start of the test) limited the ability to draw statistically defensible conclusions. In general, semi-field studies have serious limitations that have not yet been addressed by regulatory guidelines.


Full field studies provided more realistic exposure durations and conditions—experimental colonies were exposed during bloom (late spring/early summer) and monitored through the overwintering period until the next spring. Hive pollen analyses during the full field study indicated that bees were actively foraging on alternative food sources, which certainly affected the level of exposure during the study and may explain the lack of colony-wide impacts observed.

Synergistic Interactions Amplify Flupyradifurone Toxicity

One must keep in mind that higher tier semi-field and full field studies only take into account the toxicity associated with the flypyradifurone commercial formulation. Absent from risk management decisions is consideration of pesticide mixtures commonly encountered in the field, specifically the potential for synergistic effects and chemical transformation that may amplify the toxicity of a given insecticide to pollinators.

A registrant-submitted study included in the Ecological Risk Assessment provides evidence that tebuconazole, an azole fungicide, enhances the acute contact and oral toxicities of the commercial flupyradifurone formulations by 116-fold and 6.1-fold, respectively, when mixed together. Earlier work by Pilling et al. and recent work by Reed Johnson and co-workers shows that ergosterol biosynthesis-inhibiting fungicides such as tebuconazole, propiconazole and prochloraz synergize the toxicity of insecticides through inhibition of detoxicative cytochrome P450 monooxygenase activity. Indeed, the strategy of combining an insecticide with a synergist is so effective at increasing its toxicity that it is a primary tool used in insecticide resistance management.

In response to public commenters on this regulatory action, US EPA acknowledged the difficulty in testing every possible combination of a new active ingredient with the multitude of other chemicals used in modern crop production, but also noted that the Sivanto label does not permit tank mixing of the product with azole fungicides. This may help protect pollinators in the field being sprayed, but doesn’t preclude bees from being exposed to multiple pesticides, since they forage widely.

Looking Ahead

Only after the chemical becomes widely used in agriculture and independent scientists probe the nuances of flupyradifurone toxicity will we begin to understand the scope of impacts on honey bees associated with US EPA’s regulatory decision. But when you consider the similarity of flupyradifurone to established neonicotinoid insecticides, it begs the question: was the registration of this “new” insecticide really necessary?

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