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1. Summary 

The U.S. Environmental Protection Agency, referred to hereafter as EPA, is proposing to grant 

the unconditional registration under section 3(c)(5) of the Federal Insecticide, Fungicide, and 

Rodenticide Act (FIFRA) for the new active ingredient, flupyradifurone, 2(5H)-furanone,4-[[(6-

chloro-3- pyridinyl)methyl](2,2-difluoroethyl)amino. Flupyradifurone is formulated as a 

technical and two end use products. It is a new butenolide insecticide that targets piercing, 

sucking insects such as aphids and whiteflies. The proposed uses for this new chemical include 

Bushberry, Except Cranberry (Crop Subgroup 13-07B); Low Growing Berry Except Cranberry 

(Crop Subgroup 13-07G); Bulb Vegetables (Crop Group 3-07); Cereal Grains Except Rice (Crop 

Group 15); Citrus Fruits (Crop Group 10-10); Cottonseed (Crop Subgroup 20C); Cucurbit 

Vegetables (Crop Group 9); Edible Podded Legume Vegetables (Crop Subgroup 6A); Succulent 

Shelled Pea and Bean (Crop Subgroup 6B); Dried Shelled Pea and Bean (except Soybean); 

Foliage of Legume Vegetables (except Soybean) (Crop Subgroup 7A); Non-grass Animal Feeds 

(Alfalfa and Clover only); Forage, Fodder, and Straw of Cereal Grains (Crop Group 16); Fruiting 

Vegetables (Crop Group 8-10); Hops; Head and Stem Brassica Vegetables (Crop Subgroup 5A); 

Leafy Brassica Greens (Crop Subgroup 5B); Leafy Vegetables (Except Brassica) (Crop Group 

4); Peanuts; Pitaya; Pome Fruits (Crop Group 11-10); Prickly Pear Cactus; Root Vegetables 

Except Sugar Beet (Crop Subgroup 1B); Small Fruit Vine Climbing (Except Fuzzy Kiwifruit) 

(Crop Subgroup 13-07F); Soybean (Seed); Taro Leaves; Tree nuts (Crop Group 14-12); Turnip 

Greens; and Tuberous and Corm Vegetables (Crop Subgroup 1C). 

The Agency is not granting uses proposed for Crop Group 18, the non-grass animal feeds (forage 

fodder, straw and hay) group. Uses of flupyradifurone for non-grass animal feeds will only be 

granted for clover exclusively in Washington, Oregon, and Idaho, and for alfalfa nationally; an 

insufficient number of clover trials was submitted to support the entire crop group. 

The end use product formulations are SivantoTM 200 SL and BYI 02960 480 FS. Proposed 

methods of application include seed treatment (soybean only), soil drench, and foliar. The 

maximum annual application rate is 0.365 lb a.i./A/year. 

The database submitted to support the Human Health Risk assessment is complete with the 

exception of insufficient field-trial data to support a Crop Group 18 tolerance (see Section 7.2.3 

for additional details). There are no aggregate or occupational risks of concern for human health. 

The screening-level Ecological Risk Assessment identified potential risk concerns for direct 

effects to several taxonomic categories (outlined in Section 5.4). To address the risks identified 

in the screening-level assessment, the draft labeling has been updated to minimize potential 

exposure thus effectively reducing risk. Labeling updates include a requirement for vegetative 

buffer strips, limitations on the number of crop cycles, and the updated label language for 

pollinator stewardship and best management practices that will minimize the exposure to 

terrestrial invertebrates. While flupyradifurone is toxic to honeybees (Apis mellifera) on an acute 

oral exposure basis, the compound is practically nontoxic to adult bees on an acute contact 

exposure basis and to honeybee larvae on an acute exposure basis. Therefore, the primary 

exposure route of concern is through ingestion of residues in pollen/nectar rather than direct 

contact. However, honey bee colonies exposed to flupyradifurone did not exhibit any detectable 
Page 3 of 22

long-term effects1

. Further, overwinter success was not adversely affected in field studies. The 

incorporation of label language for best practice stewardship is directed at protecting food 

resources for pollinating insects to further reduce exposure and thereby reduce potential risk. For 

example, the label includes language that advises foliar sprays be performed late in the 

afternoon/evening/night hours, outside of peak foraging periods. Additional details on risk 

mitigation labeling language are included in Section 7.2.3. 

EPA’s Reduced Risk Committee approved flupyradifurone as a reduced risk candidate for the 

proposed uses. Based on the committee's evaluation of the information provided, the human 

health and ecological hazard profiles for flupyradifurone are favorable compared to currently 

registered alternatives. Currently registered pesticides, such as those containing neonicontinoids, 

organophosphates, pyrethroids, and one compound belonging to the mectin family, are labeled 

for similar uses; comparatively, flupyradifurone presents a less hazardous ecological and human 

health profile. 

2. Requested Action 

On October 5, 2012, EPA received an application from Bayer CropScience to register products 

containing the insecticide flupyradifurone, a new active ingredient, for use on: Bushberry, 

Except Cranberry (Subgroup 13-07B); Cereal Grains Except Rice (Group 15); Citrus Fruits 

(Group 10-10); Cottonseed (Subgroup 20C); Cucurbit Vegetables (Group 9); Edible Podded 

Legume Vegetables (Subgroup 6A); Succulent Shelled Pea and Bean (Subgroup 6B); Dried 

Shelled Pea and Bean (except Soybean); Non-grass Animal Feeds (Forage, Fodder, Straw and 

Hay (Group 18); Forage, Fodder, and Straw of Cereal Grains (Group 16); Fruiting Vegetables 

Group 8-10); Hops; Head and Stem Brassica Vegetables (Subgroup 5A); Leafy Brassica Greens 

(Subgroup 5B); Leafy Vegetables (Except Brassica) (Group 4); Taro Leaves; Turnip Greens; 

Low Growing Berry Except Cranberry (Subgroup 13-07G); Peanuts; Pome Fruits (Group 11-10); 

Prickly Pear Cactus; Root Vegetables Except Sugar Beet (Subgroup 1B); Small Fruit Vine 

Climbing (Except Fuzzy Kiwifruit) (Subgroup 13-07F); Soybean (Seed); Tree nuts (Group 14-

12); Bulb Vegetables (Group 3-07); Foliage of Legume Vegetables (except Soybean) (Subgroup 

7A); Pitaya; and Tuberous and Corm Vegetables (Subgroup 1C). Reduced risk classification was 

requested for cereal grains, cotton, non-grass animal feeds, peanuts, tree nuts, vine and berry 

crops, citrus, pome fruits, prickly pear cacti, root and tuberous corm vegetables, leafy brassica, 

legumes, fruiting vegetables, and cucurbit vegetables. 

3. Chemical Information 

Chemical Name: Flupyradifurone, 2(5H)-furanone,4-[[(6-chloro-3- pyridinyl)methyl](2,2-

difluoroethyl)amino 

EPA PC Code: 122304 

 

1

 Data generated from semi-field studies (e.g., tunnel studies using whole colonies and a single nutrition/forage 

source), where applications were made at maximum foliar rates while bees were actively foraging at full bloom, 

only identified relatively transient increases in adult bee mortality hours to several days following treatment. 
Page 4 of 22

Chemical Abstracts Service (CAS) Number: 951659-40-8 

IRAC MoA Classification: Group 4D - Butenolide Insecticide 

Mode of Action: Flupyradifurone is the first chemical that belongs to the Insecticide Resistance 

Action Committee (IRAC) Mode of Action Classification Group 4D (Butenolide Insecticide). 

The butenolide insecticide has a mode of action similar to nicotine and neonicotinoid insecticides 

in that it is an agonist binding to nicotinic acetylcholine receptors (nAchR), blocking the receptor 

causing insect death; however, its chemical structure differs from the nitroguanidine 

neonicotinoids thus is a separate sub-class of IRAC Group 4. The compound is systemic in plants 

and targets piercing, sucking insects such as aphids and whiteflies. Flupyradifurone is expected 

to be an important tool in IPM programs, as it has a different mechanism of action than 

nitroguanidine neonicotinoids. 

4. Human Health Risk Assessment 

A summary of the human health risks of flupyradifurone is provided below. 

4.1 Hazard Characterization 

The acute toxicity of flupyradifurone was low for all routes of exposure (oral, dermal, and 

inhalation). The oral LD50 for rats was estimated to be >2,000 mg/kg bw, with some mortalities 

reported at 2,000 mg/kg bw but none at 300 mg/kg bw (Toxicity Category III). The acute dermal 

LD50 for rats was >2,000 mg/kg (Toxicity Category III). The acute inhalation LC50 for rats was

>4,671 mg/m3 (4.67 mg/L), which was the highest achievable concentration (Toxicity Category 

IV). Flupyradifurone was not irritating to rabbit skin and caused only slight ocular irritation 

(redness of the conjunctivae) which was reversed within 48 hours. 

The most sensitive effect seen in mammals was skeletal muscle atrophy/degeneration in dogs. 

With dietary administration, reductions in body weight and food consumption were commonly 

seen in all test animal species (rats, mice, dogs, and rabbits). The liver and thyroid were also 

common targets of flupyradifurone toxicity. The liver effects often consisted of increased liver 

weight, hepatocellular hypertrophy, liver enzyme increases (cytochrome P450 upregulation), and 

decreases in total cholesterol. Some of the liver effects were judged to be adaptive responses 

while others were correlated with vacuolations and changes in clinical chemistry parameters (i.e., 

increases in alkaline phosphatase (ALP) and alanine aminotransferase (ALT), and cholesterollevel changes indicative of liver effects which extended beyond the adaptive stage). The thyroid 

effects consisted of thyroid follicular cell hypertrophy and were observed mainly in rats. In 

addition, the thyroid effects were generally found in conjunction with liver effects. 

The developmental toxicity data in rats and rabbits showed that flupyradifurone caused delayed 

bone ossification in fetal rats and increased incidence of fetal death in rabbits. These effects were 

observed in the rat developmental study at the maternal lowest observed adverse effect level 

(LOAEL, 150 mg/kg/day). No adverse maternal effects were observed at the highest dose tested 
Page 5 of 22

(80 mg/kg/day) in the main and range finding rabbit developmental studies. The increased 

incidence of fetal death in rabbits was considered to be a quantitative increase in susceptibility in 

the developing fetuses. However, clear no observed adverse effect levels (NOAELs) were 

established for both rat and rabbit developmental toxicity studies. 

The results of a 2-generation reproduction study showed that flupyradifurone reduced the 

number of estrus cycles, decreased the number of implantations in P2 dams, and reduced the litter 

size in the presence of decreased body weight and food consumption in maternal animals. In 

addition, the body weight of F2 pups was decreased at a dose (37.8 mg/kg/day) where no effect 

was seen in the parental animals; this finding suggests a quantitative increase in susceptibility in 

the young rat. 

Carcinogenicity studies in rats and mice did not yield a compound-related increase in tumor 

incidence, and the genotoxicity battery did not show flupyradifurone to produce any 

genotoxicity. 

The acute neurotoxicity study showed that oral administration of flupyradifurone caused 

increases in the incidence of piloerection and dilated pupils at 50 mg/kg bw. At the next higher 

dose level (200 mg/kg bw) and above, it produced a large number of clinical signs that are 

indicative of neurotoxicity; these included lower muscle tone, rapid respiration, low arousal, 

tremors, myoclonic jerks, chewing, repetitive licking of lips, gait incoordination, flattened or 

hunched posture, dilated pupils, impaired (uncoordinated or slow) righting reflex, impaired 

flexor and tail pinch responses, and reduced rectal temperature. However, none of these clinical 

signs were found in the dietary feeding studies, including the 90-day neurotoxicity study. The 

effects seen in the acute neurotoxicity study are likely related to stimulation of the nicotinic 

acetylcholine receptors (nAchRs), however there is limited additional evidence in mammalian 

studies that the pesticidal mode of action is important to mammals. The differences in the 

findings between the acute oral neurotoxicity study and other studies using subacute dietary 

administration might be explained by the rapid absorption and excretion of flupyradifurone. 

Flupyradifurone was absorbed rapidly in the metabolism study where rats were dosed by gavage. 

Peak plasma levels were reached within 1-4 hours of dosing depending on the dose, and 

flupyradifurone was almost completely eliminated approximately 24 hours after administration. 

With subacute dietary administration, the rodent test animal consumed the compound mostly 

during the entire night, and the internal flupyradifurone concentration required to produce 

clinical signs of toxicity was probably seldom reached due to metabolism and rapid elimination 

from the body. As a result, clinical signs were not reported. No neurotoxicity or other adverse 

effects were seen in 90-day dietary neurotoxicity study in rats at dose levels as high as 174 

mg/kg bw/day. 

No immunotoxicity was found in rats tested at the highest dose of 230 mg/kg bw/day. 

Several metabolites were found in plants and rat metabolism studies; some of these metabolites 

were tested in mutagenicity studies and subchronic oral toxicity studies. The results showed that 

most of the flupyradifurone metabolites had lower toxicity than the parent compound, except for 

difluoroacetic acid (DFA). DFA may be found in food and drinking water as a result of the 

proposed uses; dermal and inhalation exposures to DFA are not expected. DFA was found in the 
Page 6 of 22

rat metabolism study at approximately 6% of the administered dose. The registrant provided 

limited toxicity data on DFA so the Agency screened the literature and databases of similar 

chemicals to identify any additional toxicity concerns resulting from exposure to DFA. A 

literature search did not identify any studies that demonstrated that DFA was more toxic than the 

parent compound at any duration of exposure. Furthermore, a structure-activity relationship 

analysis did not reveal any new concerns for DFA. 

The most sensitive flupyradifurone effects seen in the database were skeletal muscle myofiber 

atrophy/degeneration, decreases in body weight, and decreases in body weight gain at the 

LOAEL of 33 mg/kg/day in the 90-day dog oral toxicity study (NOAEL = 12 mg/kg/day). 

However, in a 90-day oral feeding study in rats DFA produced a different effect (black foci in 

the glandular part of the stomach with correlated histopathology findings of focal glandular 

erosion/necrosis at 66.2/78.8 mg/kg/day). These dose levels and effects confirm that DFA and 

flupyradifurone produce different effects on target different tissues. Although these effects 

occurred at similar potencies (similar comparable NOAELs and LOAELs on a molar basis2

), the 

effects are different. Therefore, the toxicity to DFA should be evaluated separately from 

flupyradifurone. 

4.1.1 Food Quality Protection Act (FQPA) Safety Factor 

Based on the currently available toxicity and exposure data, EPA has concluded that the FQPA 

Safety Factor for flupyradifurone can be reduced to 1X. Flupyradifurone is supported by a 

complete toxicological database. Although there are clinical signs which indicated neurotoxicity 

in adult rats, quantitative increases in susceptibility demonstrated by decreased body weights in 

F2 rat pups, and quantitative and qualitative susceptibility demonstrated by increased incidence 

of dead rabbit fetuses, there are clear NOAELs for these effects. The NOAEL for offspring 

toxicity in the 2-generation reproduction study is equivalent to the point of departure (POD) 

selected for risk assessment while the NOAELs for neurotoxicity (clinical signs) and rabbit 

development toxicity are greater than the NOAEL selected as the POD for risk assessment. 

Therefore, the POD is protective of the effects which are indicative of neurotoxicity and 

susceptibility in rats and rabbits. Overall, the data support the determination that an additional 

safety factor is not needed. 

The flupyradifurone toxicology database is adequate to characterize any potential for prenatal or 

postnatal risk for infants and children, and includes acceptable rat and rabbit developmental 

toxicity studies and a rat reproductive toxicity study, as well as acute and subchronic 

neurotoxicity studies. EPA waived the required subchronic inhalation toxicity study for the 

following reasons: flupyradifurone has a low vapor pressure, low acute inhalation toxicity 

(Toxicity Category IV). Further, based on a screening level risk assessment using a conservative 

chronic oral POD, margins of exposure (MOEs) do not exceed the target MOE 10 times the level 

of concern (LOC). 

 

2

 Calculation of Equivalent Dose Between DFA and the Parent Compound: MW flupyradifurone = 289 g/mol 

MW DFA = 97 g/mol. 289 g/mol ÷ 97 g/mol = ~ 3 g/mol. NOAEL in 90 day rat oral toxicity study with 

flupyradifurone = 30/38 (M/F) mg/kg/day. NOAEL in 14 day rat oral toxicity study with DFA = 12.7/15.6 (M/F) 

mg/kg/day. 30 mg/kg/day ÷ 3 = ~10 mg/kg/day (which is similar on a molar basis to the DFA NOAEL of 12.7 

mg/kg/day). 
Page 7 of 22

4.1.2 Cumulative Effects 

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a 

common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding for 

flupyradifurone and any other substances. Therefore, for the purposes of this action EPA has 

assumed that flupyradifurone does not have a common mechanism of toxicity with other 

substances. 

4.1.3 Toxicological Endpoints 

Table 1. Summary of Toxicity Endpoints and Points of Departure for Use in Dietary, NonOccupational, and Occupational Human Health Risk Assessments. 

Exposure/ Scenario Point of 

Departure 

Uncertainty/ 

FQPA Safety 

Factors 

RfD, PAD, 

Level of 

Concern for 

Risk 

Assessment 

Study and Toxicological Effects

Acute Dietary (All 

populations) 

NOAEL = 

35 

mg/kg/day 

UFA= 10x 

UFH=10x 

FQPA SF= 1x 

aRfD =0.35 

mg/kg/day 

Acute neurotoxicity study –rat 

LOAEL = 50 mg/kg/day. At the next higher dose 

level (200 mg/kg) or above, lower muscle tone, 

rapid respiration, low arousal, tremors, myoclonic 

jerks, chewing, repetitive licking of lips, gait 

incoordination, flattened or hunched posture, 

dilated pupils, impaired righting reflex, impaired 

flexor and tail pinch responses and reduced rectal 

temperature. Automated measures of motor 

activity were also reduced in both sexes, 

compared to controls.

Chronic Dietary (All 

Populations) 

NOAEL = 

7.8 

mg/kg/day 

UFA= 10x 

UFH=10x 

FQPA SF= 1x 

cRfD = 0.078 

mg/kg/day 

cPAD = 0.078 

mg/kg/day 

1-year oral toxicity study-dog 

LOAEL= 28 mg/kg/day based on minimal to 

slight, focal to multifocal areas of skeletal muscle 

degeneration in gastrocnemius and/or biceps 

femoris muscle. 

Dermal 

Short-(1-30 days) 

and Intermediateterms (1-6 months) 

NOAEL = 

12 

mg/kg/day 

DAF = 

7.42%a

UFA= 10x 

UFH=10x LOC = 100 

90-day oral toxicity study-dog 

LOAEL= 33 mg/kg/day based skeletal muscle 

atrophy/degeneration. 

2-generation reproduction study- rat as a cocritical study. 

NOAEL= 7.7 mg/kg/day 

Offspring LOAEL=38.7 mg/kg/day based on pup 

body weight decrease.

Inhalation Short-(1-

30 days) and 

Intermediate-terms 

(1-6 months) 

NOAEL = 

12 

mg/kg/day 

UFA= 10x 

UFH=10x LOC = 100 

90-day oral toxicity study-dog 

LOAEL= 33 mg/kg/day based on skeletal muscle 

atrophy/degeneration 

2-generation reproduction study- rat as a cocritical study. 

NOAEL= 7.7 mg/kg/day 

Offspring LOAEL=38.7 mg/kg/day based on pup 

body weight decrease.

Cancer (oral, dermal, 

inhalation) 

Classification: “Not likely to be Carcinogenic to Humans” based on data showing no treatment-related 

increase in tumors incidence in rat and mouse carcinogenicity studies. No mutagenic concern was 

reported in the genotoxicity studies. 

Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and used to 

mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL 

= no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UFA = extrapolation 
Page 8 of 22

from animal to human (interspecies). UFH = potential variation in sensitivity among members of the human population 

(intraspecies). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (c = chronic). RfD = reference dose. LOC = 

level of concern. Dermal Absorption Factor = DAF. Toxicity via the inhalation route of exposure is assumed to be equivalent to 

toxicity via the oral route. a

: This DAF was calculated based on the dermal absorption values from the 24 hours measurements of 

the most dilute test formulation used in the in vivo rat and in vitro human and rat skin dermal penetration studies. To estimate the 

human dermal absorption factor (DAF), the following equation is used: 

 Human DAF = (in vitro human % absorption) x [(in vivo rat % absorption/ (in vitro rat % absorption)]. 

4.2 Exposure and Risk Characterization 

4.2.1 Dietary Exposure and Risk 

For dietary exposure and risk assessment, unrefined acute and chronic dietary analyses were 

conducted for flupyradifurone. The assessments incorporated recommended tolerance-level 

residues, default or empirical processing factors, and conservative drinking water estimates, and 

assumed that 100% of the proposed crops were treated. 

 

4.2.1.1 Acute Dietary Risk 

The acute dietary (food and drinking water) exposure and risk estimates do not exceed the 

Agency’s LOC (i.e., <100% acute population adjusted dose (aPAD)) for the U.S. population and 

all population subgroups. At the 95th percentile of exposure, the resulting acute dietary risk 

estimates represented 24% of the aPAD for the general U.S. population and 38% of the aPAD for 

children 1-2 years old, the most highly exposed population subgroup. 

4.2.1.2 Chronic Dietary Risk 

The chronic dietary (food and drinking water) exposure and risk estimates do not exceed the 

Agency’s LOC (i.e., <100% chronic population adjusted dose (cPAD)) for the U.S. population or 

any population subgroups. The resulting chronic dietary risk estimates represented 39% of the 

cPAD for the general U.S. population and represented 84% of the cPAD for children 1-2 years 

old, the most highly exposed population subgroup. Based on the lack of refinement in the 

assessment, actual dietary exposure is expected to be significantly lower. 

4.2.1.3 Cancer Dietary Risk 

Flupyradifurone is classified as “not likely to be carcinogenic to humans.” Therefore, a cancer 

dietary exposure assessment was not performed. 

4.2.1.4 Dietary Exposure Evaluation - DFA 

Exposure to DFA as a result of flupyradifurone application is expected in food (plant- and 

animal- based) and drinking water. DFA was not a major metabolite in most plant commodities, 

but was significant for the following uses: seed treatment (soybean), soil drench (tomato), and 
Page 9 of 22

foliar (succulent legume vegetables, especially green beans and lima beans, and cucurbits). DFA 

was a major degradate on a relative basis in poultry commodities; but on an absolute basis, only 

very small concentrations of DFA and parent are anticipated at the calculated livestock feeding 

(exposure) levels. Therefore, dietary exposure to DFA is expected to be relatively low compared 

to exposure to parent flupyradifurone. 

Additionally, the Agency conducted a conservative screening-level dietary exposure evaluation. 

This evaluation assumed conservative drinking water concentrations, that 100% of the crops 

contained DFA based on measured residue data found in crop field trials. The screening 

exposure evaluation of DFA showed 5-7X less exposure to DFA than to flupyradifurone from 

the proposed uses. Since there is similar potency (albeit with different toxic effects) between 

flupyradifurone and DFA but less exposure expected to DFA than flupyradifurone, and there are 

no risk concerns from exposure to flupyradifurone, there should also be no concerns from 

exposure to DFA. 

 

4.2.2 Residential Exposure and Risk 

There are no proposed residential uses of flupyradifurone; therefore, a residential exposure 

assessment has not been conducted. 

4.2.3 Aggregate Exposure and Risk 

In accordance with the FQPA, the Agency must consider aggregate pesticide exposures and risks 

from three major sources: food, drinking water, and residential exposures. In an aggregate 

assessment, exposures from relevant sources are added together and compared to quantitative 

estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated. When 

aggregating exposures and risks from various sources, EPA considers both the route and duration 

of exposure. There are no residential uses of flupyradifurone; therefore, the aggregate risk 

includes only exposure from food and drinking water. Acute and chronic dietary risks do not 

exceed EPA’s LOC for the U.S. population or any population subgroups. 

4.2.4 Occupational Exposure and Risk 

There is potential for short- and intermediate-term occupational exposure to flupyradifurone 

during both handler (mixing, loading, and application via the dermal and inhalation routes) and 

post-application activities (via the dermal route) based on the proposed uses. 

For both dermal and inhalation exposures, the PODs selected are considered protective of both 

short- and intermediate-term durations. 

The quantitative exposure/risk assessment developed for occupational handlers is based on the 

following scenarios: 
Page 10 of 22

 mixing/loading liquid formulations for aerial, airblast, chemigation, and ground boom 

application; 

 applying sprays with aerial, airblast, and ground boom equipment; 

 flagging for aerial applications; 

 mixing/loading/applying using a backpack sprayer and mechanically pressurized 

handgun; 

 primary handling for seed treatment (loading/applying, sewing, bagging treated seed; 

multiple activities); and 

 secondary handling for seed treatment (planters). 

The proposed BYI 02960 480 FS label (seed treatment for soybean only) requires seed treaters 

and workers cleaning the treatment facilities to wear long-sleeved shirts, long pants, shoes, 

socks, and chemical resistant gloves. Baggers and others involved in the packaging of treated 

seed are required to wear long-sleeved shirts, long pants, shoes, and socks. The proposed 

SivantoTM label requires occupational handlers to wear long-sleeved shirts, long pants, shoes, 

socks, and chemical resistant gloves. 

There are no risk estimates of concern at baseline PPE (long-sleeved shirts, long pants, shoes, 

and socks). For the agricultural uses of flupyradifurone, the short- and intermediate-term 

combined (dermal + inhalation) occupational handler MOEs ranged from 260 to 17,000 with 

baseline PPE. With the addition of chemical-resistant gloves, as required on the flupyradifurone 

label, the short- and intermediate-term combined (dermal + inhalation) occupational handler 

MOEs ranged from 800 to 57,000. For the proposed seed treatment use of flupyradifurone, the 

combined (dermal + inhalation) short- and intermediate-term MOEs ranged from 2,000 to 

14,000. 

There was no dislodgeable foliar residue (DFR) study submitted with the application. Since the 

Day zero target MOE3

 for a DFR study waiver was exceeded for certain activities following 

foliar applications in grapes, the restricted entry interval (REI) was increased to 48 hours for 

girdling or cane turning activities to achieve an MOE >200. Since the increased REI for specific 

activities in grapes addresses the MOE exceedance, the DFR study requirement was waived 

since all other proposed uses resulted in MOEs greater than 200. Section 7.2.3 includes specific 

label language to address the REI for girdling and cane turning activities in grapes. 

5. Ecological Risk Assessment 

The environmental fate and ecological risk assessment is summarized below. 

5.1 Environmental Fate 

Flupyradifurone is characterized as being persistent to very persistent and is moderately mobile 

to mobile depending on soil conditions. Therefore, it has the potential to reach aquatic 

environments, including surface and groundwater, for several months or more following 

 

3

 An MOE of at least 200 is required in absence of the required DFR study. 
Page 11 of 22

application. Flupyradifurone is nonvolatile, and thus movement through air will not constitute a 

major transport pathway. The available fate data suggest that flupyradifurone is likely to 

dissipate from the point of application through various transport mechanisms, including runoff, 

erosion, and leaching to groundwater. Times to 50% dissipation of pesticide mass (DT50) in 12 

terrestrial field dissipation studies ranged from 8.3 to 310 days,with DT50 being less than 56 

days in eight of the studies. Times to 90% decline of pesticide mass (DT90) from surface soils in 

terrestrial field dissipation studies also show a wide range in persistence from <3 months to one 

year, highlighting the variability in the persistence of flupyradifurone under certain conditions. 

Since flupyradifurone is mobile to moderately mobile and persistent in the aquatic environment, 

there is the potential for both short-term and long-term exposure to aquatic organisms. 

5.2 Ecological Exposure 

Measures of exposure are based on aquatic and terrestrial models that calculate estimated 

environmental concentrations (EECs) using proposed application rates and methods. 

5.2.1 Exposure to Aquatic Life 

The environmental fate properties of flupyradifurone indicate that for foliar applications, spray 

drift, runoff, and leaching are potential transport mechanisms to aquatic habitats where nontarget organisms may be exposed. A sensitivity analysis was completed to determine the 

contribution of each route of exposure. When the contribution from spray drift is removed from 

aquatic exposure estimates, many proposed uses still exceeded the acute risk to federally listed 

threatened/endangered species (hereafter referred to as “listed” species) and chronic risk LOCs. 

This indicates that exposure exceedances in most cases are driven by residues in runoff. The 

requirement for a maintained vegetative buffer intercepting runoff before entering water bodies 

neighboring application sites is expected to reduce the potential exposure in aquatic systems. 

While any setback buffer between an aquatic waterbody and the treated field is expected to 

reduce exposure, methodologies are not available to determine the specific distance that is 

needed to eliminate the risk concern from transport in runoff. 

Compounds with a log octanol-water partition coefficient (Kow) of three and above are generally 

considered to have the potential to bioconcentrate in aquatic organisms. The partition coefficient 

for flupyradifurone (log Kow =0.08) falls well below this threshold and therefore the compound is 

not expected to bioconcentrate in aquatic organisms. 

For surface water, the highest peak EEC was derived for the use on alfalfa and clover (0.18 lbs 

a.i./A, 2 applications, 7-day retreatment interval, foliar and aerial application) where 1-in-10 year 

peak, 21-day, and 60-day average flupyradifurone EECs are 25.2, 24.0, and 22.1 μg/L, 

respectively, and are not substantially different from one another in terms of the magnitude of 

residues in water. 
Page 12 of 22

5.2.2 Exposure to Terrestrial Wildlife, Plants, and Beneficial Invertebrates 

It is expected that non-target terrestrial organisms can be exposed to foliar applications of 

flupyradifurone through consumption of exposed plants and invertebrates on the treated field. 

Additionally, flupyradifurone may reach terrestrial environments off the field via spray drift, and 

via application of irrigation water containing residues of flupyradifurone. With regard to the seed 

treatment, flupyradifurone may reach aquatic habitats via leaching of the chemical from the seed 

coat, and subsequent transport via runoff and/or infiltration. It is expected that non-target 

terrestrial organisms can be exposed to flupyradifurone through consumption of treated seeds 

which may remain on the surface. Standard conservative, unrefined exposure modeling was used 

to estimate exposure to non-target terrestrial organisms, with the exception of the honeybee 

where refined modeling approaches were used because screening-level LOCs were exceeded. 

5.3 Ecological Effects 

5.3.1 Aquatic Organisms 

Flupyradifurone is slightly to practically non-toxic to aquatic vertebrates (fish and aquatic-phase 

amphibians for which fish serve as surrogates) on an acute exposure basis. Acute toxicity values 

for freshwater and estuarine/marine fish are non-definitive (i.e., LC50 values are greater than the 

highest concentration tested). Estimated peak exposure concentrations in surface water for all 

proposed uses are several orders of magnitude lower than the highest concentration tested in 

available fish acute toxicity studies; therefore, the likelihood of acute mortality in freshwater or 

estuarine/marine fish following exposure to flupyradifurone from any of the uses evaluated is 

presumed to be low. 

Flupyradifurone is very highly toxic to both freshwater insects and estuarine/marine crustaceans 

on an acute exposure basis. Flupyradifurone is slightly toxic to water fleas (Daphnia magna) and 

the Eastern oyster (Crassostrea virginica) with non-definitive acute toxicity estimates; however, 

the compound is very highly toxic to non-biting midges (Chironomus riparius) and highly toxic 

to mysid shrimp (Americamysis bahia) on an acute exposure basis. Based on toxicity tests for 

several transformation products of flupyradifurone using the most sensitive freshwater 

invertebrate, C. riparius, M47, M48, and 6-CNA degradates are less toxic than the parent 

compound by several orders of magnitude. 

The NOAEC of flupyradifurone on freshwater vascular plants and nonvascular plants was 

determined to be 34.2 mg a.i./L (frond number) and 80 mg a.i./L, respectively. It should be noted 

that 80 mg a.i./L was the highest concentration tested for growth of freshwater green algae 

(Pseudokirchneriella subcapitata) and was reported to be at the practical limit of solubility for 

flupyradifurone. The effects of several transformation products of flupyradifurone were also 

tested on green algae; none of the studies showed adverse effects at any of the concentrations 

tested. 
Page 13 of 22

5.3.2 Terrestrial Wildlife, Plants and Beneficial Invertebrates 

Based on the available data, flupyradifurone is moderately toxic to birds (and to terrestrial-phase 

amphibians and reptiles for which birds serve as surrogates) on an acute oral exposure basis and 

slightly toxic to birds on a subacute dietary exposure basis. Several of the acute oral and 

subacute dietary toxicity studies indicate effects on feed consumption, body weight, or body 

weight gain, suggesting that the chemical can affect either the willingness of birds to consume 

diets containing elevated levels of flupyradifurone (i.e., palatability) or to consume food (i.e., 

anorexia). 

Flupyradifurone is classified as practically nontoxic to mammals on an acute oral exposure basis. 

No mortality was observed at the limit dose (2000 mg/kg bw) in an acute oral toxicity study with 

the rat, which was the most sensitive mammalian species tested; therefore, the 96-hr LD50 is nondefinitive (i.e., LD50>2,000 mg a.i./kg bw). As indicated above, EPA has concluded that 

flupyradifurone exhibits low acute toxicity to mammals by all exposure routes (EPA Toxicity 

Category III or IV). 

Flupyradifurone is practically non-toxic to young adult honeybees on an acute contact basis; 

however, the compound is highly toxic to young adult bees on an acute oral exposure basis. 

Flupyradifurone is practically non-toxic to larval bees following repeat oral exposure. In the 

acute contact toxicity test, some bees showed movement coordination problems or lethargy at the 

two highest concentrations (100 and 200 μg a.i./bee) starting at 48 hours of exposure. In the 

acute oral toxicity test, behavioral abnormalities (e.g., movement coordination problems and 

lethargy) were observed in bees at doses >0.34 μg a.i./bee within only the first four hours of 

dosing. In addition, the acute oral toxicity test resulted in a steep dose-response relationship in 

which 0 and 100 percent mortality were observed at 0.34 and 2.8 μg a.i./bee, respectively. 

For terrestrial plants there were no adverse effects on survival in any of the eleven species tested 

in the vegetative vigor study. Slight phytotoxicity was observed in tomato, oat, and corn, and 

moderate effects were observed in soybean. Similarly, effects on emergence, survival, and shoot 

length did not exceed 25% in any of the eleven species tested in the seedling emergence study; 

therefore, a definitive endpoint was not established at the maximum proposed application rate for 

flupyradifurone. 

5.4 Ecological Risk

5.4.1 Aquatic Organisms 

Fish and Aquatic-Phase Amphibians 

Flupyradifurone is slightly to practically non-toxic to aquatic vertebrates (fish and aquatic-phase 

amphibians). Since acute toxicity values for freshwater and estuarine/marine fish are nondefinitive (i.e., greater than the highest concentration tested), RQ values could not be calculated. 

However, estimated peak exposure concentrations in surface water for all proposed uses are 

several orders of magnitude lower than the highest concentration tested in available fish acute 
Page 14 of 22

toxicity studies; therefore, the likelihood of acute mortality in freshwater or estuarine/marine fish 

following exposure to flupyradifurone from any of the uses evaluated is presumed to be low.

Chronic RQ values for freshwater fish for all proposed uses are ≤0.01, and therefore do not 

exceed the chronic risk LOC (RQ≥1) for fish.

Invertebrates 

Acute and chronic RQ values were derived for freshwater and estuarine/marine invertebrates 

inhabiting both water column and benthic aquatic environments using surface water and 

sediment pore water EECs, respectively. For freshwater invertebrates inhabiting surface waters, 

all proposed uses exceed the acute risk to listed species LOC (RQ = ≥0.05), while the acute risk 

to non-listed species LOC (RQ ≥0.5) is only exceeded for foliar applications when there are ≥2 

crop cycles per season. For estuarine/marine invertebrates inhabiting surface waters, most 

proposed uses exceed the acute risk to listed species LOC (RQ range: 0.01-0.26), but none 

exceed the LOC for risk to non-listed species. Chronic RQ values for freshwater invertebrates 

(RQ range: 0.27- 5.9) and estuarine/marine invertebrates (RQ range: 0.22-4.70) inhabiting 

surface waters exceed the chronic risk LOC (RQ ≥1.0) for the majority of uses. For most uses, 

exceedances are driven by the contribution of runoff as compared to spray drift. For some uses 

(legume vegetables, pome fruit, low growing berries, hops) when the contribution of spray drift 

to exposure levels is removed or when ground spray is modeled as compared to aerial spray, 

acute risk to listed species and/or chronic LOCs are no longer exceeded for freshwater and/or 

estuarine/marine invertebrates. 

For sediment-dwelling (benthic) freshwater invertebrates, represented by non-biting midges, all 

proposed uses except for prickly pears exceed the acute risk to listed species and chronic risk 

LOCs, while the acute risk to non-listed species LOC is only exceeded for foliar applications 

when there are ≥2 crop cycles per season. For sediment-dwelling estuarine/marine invertebrates, 

represented by mysid shrimp, the majority of proposed uses exceed the acute risk to listed 

species LOC, and approximately half of the proposed uses exceed the chronic risk LOC; all of 

the uses are below the LOC for non-listed species. 

Aquatic Plants 

For both vascular aquatic plants and algae, there are no exceedances of the Agency’s LOC for 

listed species. Risk to non-listed species RQ values could not be calculated since available values 

are non-definitive (i.e., greater than the highest concentrations tested); however, EC50 values for 

both vascular and nonvascular plants are at least two orders of magnitude higher than peak 

surface water EECs. Therefore, the likelihood for adverse effects to non-listed aquatic plants 

from the proposed uses of flupyradifurone is presumed to be low. 

5.4.2 Terrestrial Organisms 

Birds, Reptiles, and Terrestrial-Phase Amphibians 

For all foliar or drench uses of flupyradifurone evaluated, the acute dose-based RQ values for 

birds exceed the Agency’s LOC for acute risk to listed species (RQ≥0.1) for three or more types 
Page 15 of 22

of dietary items. In addition, for all foliar or drench uses except for hops, the acute dose-based 

RQ values for birds exceed the Agency’s LOC for acute risk to non-listed species (RQ≥0.5) for 

the smallest size class of birds (20 g) feeding on short grasses. The modeling of multiple crop 

cycles generally increases the number of dietary items for which the acute risk to non-listed 

species are exceeded. The chronic risk LOC (RQ≥1) is not exceeded for birds, and by extension 

to reptiles or terrestrial-phase amphibians for which birds serve as surrogates, for any proposed 

use, including when multiple crop cycles are taken into account. 

Mammals 

Chronic, dietary-based RQ values for mammals only exceed the chronic risk LOC for those 

mammals foraging on short grass (i.e., a single food item) when flupyradifurone is applied in two 

or more crop cycles; see Section 7.2.3 for specific label language to address potential risks 

identified in the risk assessment. Conversely, dose-based chronic RQs exceed the chronic risk 

LOC for multiple dietary items and size classes for all proposed uses evaluated. These risk 

quotients were conservatively calculated by assuming 100% of the animal’s diet comes from the 

treated site. Proximity of home range of the mammalian species to the treated site drives the 

exposure that an individual organism would receive. For those mammals where the treated site 

does not represent 100% of their diet, the exposure is reduced and thereby the potential for risk is 

reduced as well. RQ values were not calculated for acute risk to mammals because the toxicity 

endpoints were greater than the highest concentration/dose tested in each study. 

Terrestrial Plants 

For terrestrial plants, all RQs are below the risk to listed and non-listed terrestrial plants LOC 

(RQ≥1). 

Terrestrial Invertebrates 

On a conservative, unrefined dietary exposure basis (Tier I), all proposed foliar uses exceed the 

honeybee acute risk and chronic risk LOCs of 0.4 and 1.0, respectively. However, neither acute 

nor chronic LOCs are exceeded for foliar uses on a contact exposure basis or for soil drench or 

soybean seed treatment uses on an oral exposure basis. 

Since LOCs are exceeded at the Tier I screening level using model-generated exposure estimates, 

a refinement was conducted using empirical residue data from pollen and nectar from multiple 

crop types. Refined EECs were generated based on measured residues in pollen and nectar using 

known food consumption rates for bees. The data indicate that residues for most crops were at 

their daily maximum immediately following the bloom application and declined thereafter. 

Residues taken from whole flowers were substantially higher than residues in nectar obtained 

from flowers or honeybee stomachs and therefore may overestimate actual exposure values. 

Although flower residue data for most crops exceed the LOC threshold for acute risk to 

honeybees (RQ≥0.4), nectar-specific residues are below the LOC. 

The incorporation of label language for pesticide applicators best practice stewardship is directed 

at protecting food resources for pollinating insects to further reduce exposure and thereby reduce 
Page 16 of 22

potential risk. For example, the label includes language recommending that foliar sprays be 

made late in the afternoon/evening/night hours outside of peak foraging periods. 

6. Benefits and Alternatives 

Flupyradifurone demonstrates efficacy against a variety of piercing, sucking insects, including 

species that are challenging to control (e.g., scales, whiteflies) and/or transmit disease (Asian 

citrus psyllid). It is a member of a new subclass of chemicals in the IRAC Group 4D and has a 

new mechanism of action. Registration of flupyradifurone can provide growers with a new pest 

management tool that meets the criteria for EPA’s Reduced Risk Classification. It poses lower 

risk to agricultural workers relative to other currently registered pesticides with similar uses. The 

two end use products are classified as Toxicity Category III with Caution as the signal word. The 

REI for early entry into treated areas is set at the minimum time frame of 4 hours (12 hours in 

California), except when girdling and cane turning in grapes (48 hours). 

Flupyradifurone is proposed for use on a wide variety of crops, including cereal grains, cotton, 

peanuts, radish, carrot, brassica, legumes, fruiting vegetables cucurbit vegetables, hops, citrus 

fruits, bushberries, low growing berries, small climbing vine fruits, tree nuts, and prickly pears. 

The main alternative insecticides include chemicals in the organophosphate class (chlorpyrifos, 

acephate), IRAC Group 4A of the neonicotinoid class (acetamiprid, imidacloprid, 

thiamethoxam), and the pyrethroid class (bifenthrin, fenpropathrin, zeta-cypermethrin), as well 

as abamectin. 

Organophosphates, such as acephate and chlorpyrifos, pose a greater risk to applicators than 

flupyradifurone and are currently undergoing a cumulative assessment for dietary risk. These 

alternatives are classified as Toxicity Category II, requiring additional PPE and longer REIs. 

These chemicals are also more toxic to birds, terrestrial-phase amphibians, reptiles, and 

mammals than flupyradifurone. Abamectin also poses a greater human health risk through both 

worker and dietary exposure. 

As is typical with most insecticides, flupyradifurone may pose a risk to aquatic invertebrates. 

The pyrethroids, however, are significantly more toxic to these organisms. The cyano-substituted 

neonicotinoid acetamiprid is three times as toxic as flupyradifurone to freshwater invertebrates, 

and the nitroguanidine-substituted neonicotinoid thiamethoxam is approximately twice as toxic. 

As an insecticide, flupyradifurone is unusual in that it demonstrates little to no acute contact 

toxicity to honeybees. A comparison of LD50 values is shown below in Table 2 for the above 

noted compounds and several other alternatives. 
Page 17 of 22

Table 2. Honeybee acute 96-hr contact LD50 values 

Chemical LD50 

μg a.i./bee 

Bifenthrin 0.015 

Zeta-cypermethrin 0.023 

Thiamethoxam 0.024 

Spinetoram 0.024 

Chlorpyrifos 0.059 

Imidacloprid 0.078 

Abamectin 0.54 

Acephate 1.2 

Acetamiprid <12.5 

Flupyradifurone 122 

Pyriproxyfen >100 

Spirotetramat >100 

Fenpropathrin N/A 

 N/A = Data are Not Available 

7. Proposed Regulatory Decision 

Under Section 3(c)(5) of the Federal Insecticide, Fungicide and Rodenticide Act (FIFRA), the 

Agency is proposing to unconditionally register the new active ingredient flupyradifurone for use 

on Bushberry, Except Cranberry (Subgroup 13-07B); Cereal Grains Except Rice (Group 15); 

Citrus Fruits (Group 10-10); Cotton seed (Subgroup 20C) Cucurbit Vegetables (Group 9); 

Legume Vegetables (succulent or dried) (Group 6); Forage, Fodder and Straw of Cereal Grains 

(Group 16); Fruiting Vegetables (Group 8-10); Hops; Brassica (Cole) Leafy Vegetables (Group 

5); Leafy Vegetables (Except Brassica) (Group 4); Low Growing Berry Except Cranberry 

(Subgroup 13-07G);Alfalfa; Clover; Peanuts; Pome Fruits (Group 11-10); Prickly Pear Cactus; 

Root Vegetables (Subgroup 1B); Small Fruit Vine Climbing (Except Fuzzy Kiwifruit) (Subgroup 

13-07F); Soybean (Seed); Bulb Onion (Subgroup 3-07A); Green Onion (Subgroup 3-07B); Tree 

Nuts (Group 14-12); Foliage of Legume Vegetables (Group 7); Pitaya; Turnip Greens; Taro 

Leaves; and Tuberous and Corm Vegetables (Subgroup 1C). The end-use products under 

consideration for the new uses are SivantoTM and BYI 02960 480 FS . Methods of application 

include seed treatment, soil drench, and foliar. 

The Agency is not granting all of the uses proposed for Crop Group 18, the non-grass animal 

feeds (forage fodder, straw and hay) group. Uses will only be granted for clover in Washington, 

Oregon, and Idaho, and for alfalfa nationally; an insufficient number of clover trials were 

submitted to support a tolerance for the entire crop group. 

For the food uses, Canadian Maximum Residue Levels (MRLs) and U.S. tolerances are 

harmonized for primary crop commodities. 

7.1 Public Comments 

On May 29, 2013, EPA published a Notice of Receipt in the Federal Register of an application 

for registration of flupyradifurone and announced a public comment period of 30 days. Two 
Page 18 of 22

comments were received. The first expressed concern that neonicotinoid chemicals and other 

toxic substances are poisoning the environment, specifically citing concerns over cancer 

(generally) and concerns regarding pollinator exposure to toxic substances. This comment was 

not specifically addressing the application to register flupyradifurone but generally directed at 

the registration of pesticides. 

The second comment was from The City of Sacramento Department of Utilities. They expressed 

concern that registering the chemical flupyradifurone for use on rice will affect drinking water 

quality in Sacramento. 

In regard to the second comment, the applicant did not apply for a use on rice and a rotation crop 

interval for rice was not adequately supported. In response to the first comment, flupyradifurone 

is not classified as a carcinogen. As an insecticide, flupyradifurone is unusual in that it 

demonstrates little to no acute contact toxicity to honeybees. While the compound does show 

acute oral toxicity, it is comparatively better than the available registered alternatives, 

specifically the nitroguanidine-neonicotinoids which are members of a different sub-class of 

chemicals as defined by IRAC thathave a different mechanism of action. 

On June 5, 2013, EPA published a Notice of Filing in the Federal Register announcing the 

receipt of the initial filing of the flupyradifurone petition requesting the establishment of 

regulations for residues of flupyradifurone on various commodities. This publication also 

announced a public comment period of 30 days; no comments were received on the Notice of 

Filing. 

7.2 Regulatory Rationale 

Flupyradifurone is classified as a Reduced Risk chemical and the risk profile is favorable for 

both human health and non-target organisms compared to the main alternative compounds. 

Further, there were no human health risks identified for dietary or occupational worker exposures 

resulting from the proposed use patterns. There are no proposed residential uses of 

flupyradifurone. 

The screening-level Ecological Risk Assessment identified potential risk concerns for direct 

effects to several taxonomic categories (outlined above in Section 5.4). EPA believes the label 

changes made after the initial risk assessment minimizes potential exposure to non-target 

organisms thus effectively reduces potential risk. Specific label changes imposed by the Agency 

to address identified risk are included in Section 7.2.3. 

Consistent with the chemical’s mode of action (blocking the nicotinic acetylcholine receptors 

causing insect death), there are risks of concern for terrestrial invertebrates. However, relative to 

the alternative registered products (neonicontinoids and abamectin), flupyradifurone has a lower 

toxicity profile. Further, semi-field/tunnel studies only identified relatively transient increases in 

adult bee mortality. Colonies exposed to flupyradifurone did not exhibit any detectable long-term 

effects, and field studies examining colonies through overwintering did not demonstrate any 

adverse effects in the treated colonies. Currently registered alternatives such as neonicotinoid 

class chemicals for the same uses are more acutely toxic to bees than flupyradifurone. 
Page 19 of 22

Flupyradifurone is practically non-toxic to adult bees on an acute contact exposure basis and it is 

practically non-toxic to larval bees on an acute contact/oral exposure basis. Currently registered 

pesticides such as organophosphates, for which this chemical is an alternative, pose a greater risk 

to non-target organisms (birds and mammals) than flupyradifurone. 

7.2.1 Endangered Species Act Considerations 

The NAS report, available at http://www.nap.edu/catalog.php?record_id=18344, outlines 

recommendations on specific scientific and technical issues related to the development of 

pesticide risk assessments that are compliant with the Endangered Species Act and the Federal 

Insecticide, Fungicide, and Rodenticide Act. In November 2013, the EPA, along with the U.S. 

Fish & Wildlife Service (USFWS), the National Marine Fisheries Service (NMFS) (collectively, 

the Services), and the U.S. Department of Agriculture (USDA), released a summary of their 

joint Interim Approaches for assessing risks to listed species from pesticides. The Interim 

Approaches were developed jointly by the Agencies in response to the NAS’s recommendations 

and reflect a common approach to risk assessment shared by the Agencies as a way of addressing 

scientific differences between EPA and the Services. The joint Interim Approaches were released 

prior to the stakeholder workshop held on November 15, 2013 

(http://www.epa.gov/espp/2013/interagency.pdf). EPA presented the joint Interim Approaches at 

the December 2013 PPDC (Pesticide Program Dialogue Committee; 

http://www.epa.gov/pesticides/ppdc/2013/december/dec2013-mtg.html) and SFIREG (State 

FIFRA Issues Research and Evaluation Group) meetings, allowing additional opportunities for 

stakeholders to comment on the Interim Approaches. As discussed at the November 2013 

workshop, and consistent with the March 2013 stakeholder engagement process for FIFRA-ESA 

consultations, the Agencies have invited comment on the Interim Approaches as preparations are 

made to apply these new approaches in the context of upcoming registration review decisions. 

The Agencies intend to jointly implement these approaches as part of a phased iterative process 

that takes account of the input received and the lessons learned from the initial efforts to work 

with the Interim Approaches. 

It is important to understand that the development of the Interim Approaches does not by its 

terms suggest that existing or recently developed risk assessments using the criteria articulated in 

OPP’s 2004 Overview document (http://www.epa.gov/espp/consultation/ecorisk-overview.pdf) 

are necessarily “under-protective.” The Interim Approaches are intended to identify interim 

thresholds for interagency review as the Agencies jointly work to implement the 

recommendations of the NAS on certain specific registration review actions. The Agencies have 

made no determination that these thresholds are necessary to prevent take and preclude likely 

jeopardy and, in any case, the Interim Approaches do not establish legally binding thresholds for 

consultation under the Services’ implementing regulations. As EPA and the Services work 

through the initial actions that are being reviewed under the Interim Approaches, the Agencies 

will determine whether these thresholds should be modified before they are extended more 

broadly to additional regulatory actions. The details of the joint Interim Approaches are 

contained in the white paper “Interim Approaches for National-Level Pesticide Endangered 

Species Act Assessments Based on the Recommendations of the National Academy of Sciences 

April 2013 Report,” dated November 1, 2013, available at 

http://www.epa.gov/espp/2013/nas.html. 
Page 20 of 22

As the Agency has emphasized in multiple forums, EPA is focusing most of its resources for 

assessing impacts to listed species on its registration review program for currently registered 

pesticides. EPA believes that, as a general matter, currently registered pesticides present a greater 

degree of risk to listed species than most new chemistries coming to market, including 

flupyradifurone, and that it is therefore environmentally preferable in most circumstances for 

EPA to assess the impacts of existing pesticides sooner in the process than newer pesticides that 

are designed to compete with more risky alternatives. As a result, EPA does not believe the 

environment or the public would be best served by delaying the registration of flupyradifurone to 

complete consultation. Focusing EPA’s and the Services’ limited resources on completing a 

consultation on the effects of flupyradifurone would by necessity come at the expense of putting 

more resources into evaluating – and consequently regulating, where appropriate – what EPA 

believes to be more toxic compounds, that, among other things, pose greater risk to endangered 

species than does flupyradifurone. With respect to the evaluation of flupyradifurone specifically, 

it is important to understand that under any internal or interagency review, the ecological risk 

evaluation will continue to rely on the body of information used in the current EPA ecological 

assessment. 

For the reasons explained above, EPA is not consulting with the Services on the issuance of the 

flupyradifurone registration. However, EPA is currently working to prioritize its consultation 

activities with Services and will evaluate the appropriate timing and scope of consultation on 

flupyradifurone in connection with those efforts. In addition, to the extent EPA receives new 

information indicating that flupyradifurone may pose a greater risk to listed species than 

indicated by the existing scientific database for this pesticide, EPA will re-evaluate the terms of 

registration and determine whether additional use restrictions to protect listed species are 

necessary 

7.2.2 Data Requirements 

There are no outstanding data requirements for flupyradifurone. 

7.2.3 Mitigation and Labeling Requirements 

In order to address risks that were identified in the human health and ecological risk assessments, 

the following labeling language has been updated following the completion of the risk 

assessments. The updated labeling is intended to reduce the potential risk by minimizing the 

potential for exposure to flupyradifurone residues and/or or reduce exposure to humans. 

General Label Requirements

 The draft labeling has been updated to include a restriction for uses in greenhouses. Use 

in greenhouses is not permitted because there is no supporting field trial data. 
Page 21 of 22

Label changes related to establishing tolerances 

 A rotational crop interval of 30 days for rice is not adequately supported by adequate 

rotational crop data. The appropriate interval is 12-months. The exception for rice has 

been removed from the label. 

 The original petition requested a tolerance on Crop Group 18 (non-grass animal feeds). 

EPA is unable to establish the Crop Group 18 tolerances at this time for forage and hay 

because the registrant submitted an insufficient number of field trials for clover, one of 

the representative commodity crops. Based on the available data, EPA is establishing 

tolerances for alfalfa forage and hay, in addition to tolerances for clover; however, 

registration for flupyradifurone use on clover is restricted to use in Washington, Oregon, 

and Idaho, the areas where the field trials were conducted. A crop group tolerance could 

be considered if additional field trials for clover from diverse areas of the US are 

supplied. The draft labeling has been updated to remove the uses on Crop Group 18. 

 The draft labeling has been updated to specify flupyradifurone use on alfalfa grown for 

seed in Washington, Idaho, Oregon, Nevada, and Montana only where state restrictions 

on alfalfa seed production prevent the release of alfalfa seed into the food and feed 

commodity markets. No tolerance was established for alfalfa grown for seed because 

residue studies were only conducted on forage and hay. 

 The proposed label pre-harvest interval (PHI) for prickly pear is 14 days, but the crop 

trials were conducted with a 21- day PHI. Therefore the draft labeling has been updated 

to include a PHI of 21 days. 

Worker Exposure Risk 

Since the day 0 MOE was exceeded for certain activities following foliar applications in grapes, 

the restricted entry interval (REI) was increased to achieve an MOE >200 (required in the 

absence of dislodgeable foliar residue data). The draft labeling has been updated to include the 

following statement for girdling or cane turning activities in grapes following application of 

flupyradifurone: 

Do not enter or allow worker entry into treated areas during the restricted entry 

interval (REI) of 4 hours with the following exceptions: 1) the REI is 48 hours when 

girdling or cane turning in grapes; 2) in California the REI is 12 hours.

This change adequately reflects that all post-application MOEs, including cane turning and 

girdling in grapes, are not of concern and are therefore acceptable. 

Ecological Risk 

The draft labeling has been updated to address risks identified in the screening-level assessment 

by minimizing potential exposure thus effectively reducing risk. Labeling updates occurring after 

risk assessment include a requirement for vegetative buffer strips, and limitations on the number 

of crop cycles. Risks were identified for a number of crop uses where multiple crop cycles per 
Page 22 of 22

season were permitted. Exceedances are addressed by limiting the number of crop cycles to a 

single cycle per field per year. These changes have been incorporated on the proposed label. 

Environmental Hazard Statements: These are required based on the physical-chemical properties 

of flupyradifurone. 

The following Groundwater Advisory has been included on the label: 

 This chemical has properties and characteristics associated with chemicals detected in 

groundwater. This chemical may leach into groundwater if used in areas where soils are 

permeable, particularly where the water table is shallow. 

The following Surface Water Advisory statement is triggered because the proposed uses are 

outdoor uses. The following two statements were updated on the label: 

 This product may impact surface water quality due to runoff of rain water. This is 

especially true for poorly draining soils and soils with shallow groundwater. 

 This product is classified as having high potential for reaching surface water via runoff 

for several months or more after application. A level, well-maintained vegetative buffer 

strip between areas to which this product is applied and surface water features such as 

ponds, streams, and springs will reduce the potential loading of flupyradifurone and 

difluoroacetic acid (a residue of concern of flupyradifurone). Runoff of this product will 

be reduced by avoiding applications when rainfall or irrigation is expected to occur 

within 48 hours. 

The following environmental hazard statement and best management practice statement have 

been included on the label in response to the effects (or lack thereof) of flupyradifurone on 

pollinators: 

 Flupyradifurone is practically non-toxic to adult bees on an acute contact exposure basis 

and it is practically non-toxic to larval bees on an acute contact/oral exposure basis. 

Flupyradifurone is classified as toxic to adult bees on an acute oral exposure basis in 

laboratory studies. Field studies with this product, Sivanto, when used at the maximum 

labeled rates, show no long-term impact to bee colonies. 

 General Pollinator Best Management Practice: In order to minimize exposure to 

pollinators, it is recommended that foliar insecticides are applied late in the afternoon, 

evening, or at night outside of daily peak foraging periods.