EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR 

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER

EPA Registration Division contact: [Jessica Rogala 703-347-0263]

TEMPLATE:

[Bayer CropScience] 

[2F8101]

EPA has received a pesticide petition ([2F8101]) from [Bayer CropScience], [2

T.W. Alexander Drive, Research Triangle Park, NC 27709] proposing, pursuant to

section 408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C.

346a(d), to amend 40 CFR part 180 by establishing a tolerance for total residues of

[flupyradifurone, 2(5H)-furanone,4-[[(6-chloro-3- pyridinyl)methyl](2,2-

difluoroethyl)amino] in or on the raw agricultural commodities [Aspirated Grains

Fractions] at [40] ppm, [Root Vegetables Except Sugar Beets (Crop Subgroup 1B)] at

[1.5] ppm, [Tuberous and Corm Vegetable, (Crop Sub-Group 1C)] at [0.5] ppm, [Onion,

bulb, subgroup, (Crop subgroup 3-07A] at [0.3] ppm, [Onion, green, subgroup, (Crop

subgroup 3-07B)] at [3] ppm, [Leafy Vegetables, Except Brassica Vegetables (Crop

Group 4)] at [40] ppm, [Taro Leaves] at [40] ppm, [Head and Stem Brassica (Crop

Subgroup 5A)] at [6] ppm, [Leafy Brassica Greens (Crop Subgroup 5B)] at [40] ppm,

[Turnip Greens] at [40] ppm, [Edible-Podded Legume Vegetables (Crop Subgroup 6A)]

at [5] ppm, [Succulent, Shelled Pea and Bean (Crop Subgroup 6B)] at [4] ppm, [Dried,

Shelled Pea and Bean (Except Soybean) (Crop Subgroups 6C)] at [6] ppm, [Foliage of

Legume vegetables, including soybeans (Crop Group 7), Forage, Green Vines] at [40]

ppm, [Foliage of Legume vegetables, including soybeans (Crop Group 7), Hay] at [50]

ppm, [Soybean, seed] at [4] ppm, [Fruiting Vegetables, Except Cucurbits (Crop Group 8-

10), Fruit] at [3] ppm, [Tomato, paste] at [4] ppm, [Cucurbit Vegetables (Crop Group 9),

Fruit] at [2] ppm, [Citrus Fruits (Crop Group 10-10), Fruit] at [3] ppm, [Citrus, pulp,

dried] at [15] ppm, [Pome Fruits (Crop Group 11-10), Fruit] at [1.5] ppm, [Bushberry

Subgroup (Crop Subgroup 13-07B)] at [4] ppm, [Small Fruit Vine Climbing Subgroup,

Except Fuzzy Kiwifruit (Crop Subgroup 13-07F)] at [3] ppm, [Grapes, raisin]
2

at [6] ppm, [Low Growing Berry Subgroup (Crop Subgroup 13-07G)] at [1.5] ppm, [Tree 

Nuts (Crop Group 14), Nutmeat] at [0.15] ppm, [Pistachio] at [0.15] ppm, [Tree Nuts 

(Crop Group 14), Hulls] at [15] ppm, [Grain, cereal, (Crop Group 15), except rice; grain] 

at [4] ppm, [Sweet Corn, kernels plus cobs with husks removed (K+CWHR)] at [0.4] 

ppm, [Wheat, bran] at [5] ppm, [Rice, grain (rotational crop)] at [4] ppm, [Grain, cereal, 

forage, fodder and straw, Group 16, forage] at [20] ppm, [Grain, cereal, forage, fodder

and straw, Group 16, hay] at [40] ppm, [Grain, cereal, forage, fodder and straw, Group

16, straw] at [30] ppm, [Grain, cereal, forage, fodder and straw, Group 16, stover] at [15] 

ppm, [Cotton, undelinted seed, (Crop Subgroup 20C)] at [0.9] ppm, [Cotton, gin byproducts] at [40] ppm, [Nongrass animal feeds, forage, (Crop Group 18)] at [20] ppm, 

[Nongrass animal feeds, hay, (Crop Group 18)] at [40] ppm, [Coffee, bean, green] at [2] 

ppm, [Coffee, bean, roasted; instant] at [3] ppm, [Hops] at [20] ppm, [Peanut, hay] at [30] 

ppm, [Peanut, nutmeat] at [0.15] ppm, [Prickly pear cactus, fruit;] at [0.5] ppm, [Pitaya, 

fruit] at [0.5] ppm, [Prickly pear cactus, pads] at [0.9] ppm, [Cattle, Goat, Hog, Horse, 

Sheep fat] at [0.5] ppm, [Cattle, Goat, Hog, Horse, Sheep meat] at [1] ppm, [Cattle, Goat, 

Hog, Horse, Sheep, meat byproducts] at [2] ppm, [Milk] at [0.3] ppm, [Poultry, eggs] at 

[0.3] ppm, [Poultry, meat] at [0.5] ppm, [Poultry, meat byproducts] at [0.5] ppm. EPA

has determined that the petition contains data or information regarding the elements set

forth in section 408 (d)(2) of FDDCA; however, EPA has not fully evaluated the 

sufficiency of the submitted data at this time or whether the data supports granting of the 

petition. Additional data may be needed before EPA rules on the petition.

A. Residue Chemistry

1. Plant metabolism. [Primary crop metabolism studies have been performed 

on apple, tomato, potato, cotton, and rice (representing five diverse crops) using 

foliar, soil, or seed treatment application with [

14C]flupyradifurone.

The flupyradifurone plant metabolism studies have shown a reasonably consistent 

metabolic profile across both foliar and soil application. The major metabolic 

pathways involved cleavage of the difluoroethylamine and pyridinylmethylamine 

bonds leading to the formation of difluoroacetic acid (DFA) and difluoroethylaminofuranone and its corresponding counterpart flupyradifurone-CHMP, which was 

either conjugated with carbohydrates or oxidized to 6-chloronicotinic acid (6-CNA). 

Hydroxylation of the furanone moiety followed by conjugation or complete 

degradation of the furanone moiety and incorporation of carbon atoms into the 

natural compound pool, e.g. into glucose/carbohydrates were also observed.

Flupyradifurone parent compound and difluoroacetic acid (DFA) were consistently 

observed at significant levels across all primary crop matrices. Thus, the residue 

definition for enforcement of flupyradifurone residues in primary crops is proposed 

as parent flupyradifurone and difluroacetic acid (DFA).

The uptake and metabolism of flupyradifurone was investigated in the rotational 

crops wheat, Swiss chard and turnips from three consecutive rotations in two 

separate experiments with [furanone-4-

14C]flupyradifurone or [pyridinylmethyl-
3

14C]flupyradifurone. Additionally, all crop matrices were analyzed for 

difluoroacetic acid (DFA) residues using LC/MS/MS. Overall the metabolism was 

very similar to primary crops and therefore the residue definition for enforcement is 

the same as primary crops.]

2. Analytical method. [Tolerances are being proposed in primary crops and 

rotational crops and animal tissues and milk for flupyradifurone and the metabolite 

difluoroacetic acid (DFA). The analytical method involves, solvent extraction, 

purification through a C-18 solid-phase extraction column, and addition of a mixture

of stable, isotopically labelled internal standards. Quantitation is by high 

performance liquid chromatography-electrospray ionization/tandem mass 

spectrometry (HPLC/MS/MS).]

3. Magnitude of residues. [A full program of magnitude of the residue trials 

was conducted in the various required regions across the United States and Canada 

in accordance with guidance for crop field trials from the US EPA and PMRA to 

support the requested tolerances. Additionally, coffee trials conducted in South 

and Central America and blueberry trials conducted in North and South America, 

Europe, Australia, and New Zealand were also submitted. Three modes of 

application, foliar (all crops), soil drench (citrus, fruiting and cucurbit vegetables, 

grapes, and coffee), and seed treatment (cereal grains, cotton, and soybean) and 

adjuvants (methylated seed oil, non-ionic surfactants, and crop oil concentrates) 

were employed in the residue studies.

Processing studies were also conducted on apple, coffee, corn, cotton, grapes, 

orange, peanut, potato, soybean, tomato, and wheat.]

B. Toxicological Profile

1. Acute toxicity. [Technical flupyradifurone (Toxicity Category II to IV) 

shows low acute toxicity via the oral, dermal and inhalation routes of exposure. 

Technical flupyradifurone is a slight eye irritant, but is not irritating to the skin 

(Toxicity Categories III and IV, respectively). The technical material is not a skin 

sensitizer. Acute neurotoxicity of flupyradifurone was assessed in the rat. 

Compound-related effects following a single oral dose of the test substance were 

observed in both sexes at the low dose tested of 50 mg/kg body weight, but were 

limited to clinical signs (i.e. dilated pupils, piloerection) in the initial acute 

neurotoxicity study. A follow-up study showed no incidences of these clinical signs 

at the highest tolerated dose of 35 mg/kg body weight, which was established as a 

clear NOAEL for acute neurotoxicity in the rat.]

2. Genotoxicty. [Genotoxicity potential was evaluated in a series of tests 

including in vitro and in vivo tests. There was no indication of gene mutation either 

in the presence or absence of metabolic activation in both the bacterial reverse 

mutation and mammalian gene mutation tests. The in vitro chromosome aberration

test and the in vivo mouse micronucleus test were also both negative. These studies
4

demonstrate that flupyradifurone has no genotoxic potential.]

3. Immunotoxicity. [The immunotoxicity potential of flupyradifurone was 

assessed in a 28-day immunotoxicity study in the female adult rat, using the Sheep 

Red Blood Cell Enzyme-Linked Immunosorbent Assay (SRBC ELISA). 

Flupyradifurone demonstrated no effect on anti-SRBC IgM concentrations in 

plasma or on spleen and thymus organ weights. Therefore, the NOAEL for 

immunotoxicity is the highest dose tested (230 mg a.i./kg body weight in females). 

Flupyradifurone is therefore not considered to be immunotoxic.]

4. Reproductive and developmental toxicity. [In both the reproductive and 

prenatal developmental toxicity studies in rats and/or rabbits, non-maternal toxicity 

was identified at equivalent or higher doses than maternal toxicity in both species.

In the rat two-generation reproduction study, decreases in body weight and body 

weight gain were observed in females (P and F1), and decreased body weight (F1),

increased liver weight (absolute and relative to body weight) associated with minimal

hepatocellular hypertrophy, and increased absolute thyroid weights in males. 

Decreases in cycle number, litter size, and the number of implants were observed in

the F1-generation only at the HDT. Decreases in pup weight and pup weight gain

were due to maternal effects leading to secondarily-mediated changes, and organ

weight changes (brain, thymus, spleen) were considered secondary to decreases in

pup weight. The findings observed in rat fetuses at the highest dose tested (slight

decrease in fetal weight and increased incidence of skeletal variations – incomplete

skull bone ossification) were minor and secondary to maternal toxicity. There was no

indication of a teratogenic effect of flupyradifurone in either the rat or the rabbit.

In the developmental neurotoxicity study, treatment-related findings in offspring 

were limited to decreased body weight and body weight gain during lactation, 

increased startle amplitude in females (PND 60), and increased motor and 

locomotor activity in males on PND 13 observed only at the highest dietary level 

tested of 1,200 ppm. Decreased body weight and body weight gain were also 

observed in maternal animals at the same dietary level.]

The reproduction and developmental toxicity studies with flupyradifurone do not 

indicate any pre- or postnatal susceptibility of offspring.

5. Subchronic toxicity. [The common target organ in rats, mice, and dogs was 

the liver. Liver findings seen in these species were increased liver weights in both 

sexes associated with centrilobular hepatocellular hypertrophy (rat), hepatocellular 

vacuolation (mouse), and brown pigments in Kupffer cells (dog). In addition to the 

liver, the thyroid, kidney, and skeletal muscle were also target organs in rats, mice, 

and dogs, respectively. In the male rat, increased relative thyroid weights were 

associated with dark coloration and follicular cell hypertrophy, but these effects 

were observed only at the highest dietary level tested and shown to be reversible. In 

the male mouse, decreased absolute and brain weight-relative kidney weights were 

associated with a loss of corticoepithelial vacuolation at the highest dietary level
5

tested. Myofiber atrophy/degeneration was observed in skeletal muscle of both 

sexes in the subchronic dog study. The dog was the most sensitive species, followed 

by the rat, with the mouse being the least sensitive.

In the subchronic neurotoxicity study, there were no treatment-related effects 

observed in either sex up to and including the highest dietary level tested of 2,500 

ppm.

In a 28-day dermal toxicity study in rats, decreased absolute and relative liver 

weights were observed in males at 500 mg/kg/day, the highest dose tested.]

6. Chronic toxicity. [Chronic toxicity and carcinogenicity of flupyradifurone 

was evaluated in the rat and mouse, and chronic toxicity in the dog. In the rat, 

treatment-related effects seen in the liver were higher mean liver to body weight 

ratios associated with centrilobular hypertrophy, centrilobular hepatocellular 

macrovacuolation, lower incidences of periportal hepatocellular vacuolation, and 

eosinophilic, mixed, and tigroid foci of altered hepatocytes. In addition, higher 

incidences of brown pigments in Kupffer cells, interstitial mononuclear cell

infiltrate and periportal hepatocellular macrovacuolation were observed in females. 

Higher incidences of follicular cell hypertrophy and of follicular cell pigment in both 

sexes at the final sacrifice and increased incidences of colloid alteration at the

interim (both sexes) and final sacrifice (males only) were observed in the thyroid. 

There was no evidence of a treatment-related increased incidence of tumors of any 

type in any organ. In the mouse, effects noted in the liver were increased liver 

weights associated with higher incidence and severity of diffuse hepatocellular 

vacuolation (mainly centrilobular) in males, while a decreased incidence of diffuse 

hepatocellular macrovacuolation (mainly periportal) was noted in females. In the 

kidney, lower weight, decreased incidence and severity of bilateral basophilic 

tubules, focal cortical mineralization, and corticoepithelial vacuolation were noted 

in males. No treatment-related neoplastic changes were observed at any dose level 

tested in either sex. In the chronic dog study, treatment-related findings were

limited to minimal to slight myofiber atrophy and/or degeneration in skeletal muscle

(gastrocnemius, biceps femoris) observed in both sexes. ]

7. Animal metabolism. [Metabolism studies conducted in the rat show that 

although >90% of the orally administered dose was absorbed following single oral 

administration of [pyridinylmethyl14C]- or [furanone-4-

14C]-flupyradifurone, 

excretion of radioactivity was very fast and nearly complete at 48 hours after 

administration.

The main route of excretion was renal, ranging from 75% to 90% of the 

administered dose. Female rats had slightly higher renal excretion rate than male 

rats. Only 0.02% to 2% of the administered dose was recovered in the expired air.

The parent compound flupyradifurone was found as a significant, if not the 

dominant constituent of the residue in milk, eggs, and edible tissues of both tested 

species in the livestock metabolism studies. Other metabolites determined in
6

comparable concentrations were the natural compound lactose in goat's milk after 

administration of [furanone-4-

14C]flupyradifurone, flupyradifurone-acetyl-AMCP 

in eggs and tissues of laying hens after administration of [pyridinylmethyl14C]flupyradifurone, and flupyradifurone-OH in eggs.

DFA (difluoroacetic acid) was determined in selected livestock samples by highresolution LC-MS subsequent to the metabolism studies, since rat studies conducted 

with [ethyl-1-

14C]flupyradifurone showed major amounts of this metabolite in 

organs and tissues. Extrapolation of rat data suggested high DFA levels in livestock 

tissues as well, which was confirmed by the non-radioactive LC/MS analyses. Based 

on these findings, it was concluded that difluoroacetic acid is a major livestock 

metabolite and should be a constituent of the residue definition for data collection.

Based on these findings, flupyradifurone, DFA, flupyradifurone-OH, and 

flupyradifurone-acetyl-AMCP, expressed as flupyradifurone equivalents, were 

included in the residue definition for data collection.

Based on the results from the livestock feeding studies, BCS proposes that 

compliance with the tolerance levels in milk, meat and meat by-products, and eggs 

should be determined by measuring only flupyradifurone and its metabolite, 

difluoroacetic acid (DFA).]

8. Metabolite toxicology. [The toxicological properties of two plant metabolites 

of flupyradifurone found at low levels in urine in the rat metabolism study, 

difluoroacetic acid (DFA) and flupyradifurone-difluoroethyl-amino-furanone ( 

flupyradifurone-DFEAF), and two additional plant metabolites common to other 

pesticides, flupyradifurone-CHMP (6-chloropyridin-3-ylmethanol) and 

flupyradifurone-6-CNA (6-chloronicotinic acid), were investigated. Study results on 

the metabolites indicate that all metabolites are less toxic than parent and that the 

parent flupyradifurone endpoints are sufficient to cover the residues of the 

metabolites in risk assessment.]

9. Endocrine disruption. [There is no evidence to suggest that flupyradifurone 

has any primary endocrine disruptive potential. Thyroid changes observed in male 

rats were observed at high dietary levels of flupyradifurone and were reversible in 

the subchronic rat study. Delays in sexual development in rat pups in the twogeneration reproduction study were observed only in the F1 generation and the 

HDT. Reproductive and developmental findings provided no evidence of an 

enhanced sensitivity of the young.]

C. Aggregate Exposure

1. Dietary exposure. [The toxicological and exposure database for 

flupyradifurone is considered complete. There was no indication of an increased
7

sensitivity of the young in any studies including the reproductive and developmental 

studies in rats and rabbits. Therefore, the special FQPA safety factor can be reduced

to 1X and an uncertainty factor of 100 is adequate to account for inter- and intraspecies variability. Acute and chronic Population Adjusted Doses (aPAD and cPAD)

are, therefore, the same as the reference doses for the populations and 

subpopulations of interest. Acute dietary exposure was expressed as a percentage of 

the aPAD of 0.35 mg/kg bw/day from a NOAEL of 35 mg/kg bw/day based on the 

acute neurotoxicity screening battery, with an uncertainty factor of 100. Chronic 

dietary exposure was expressed as a percentage of the chronic Population Adjusted 

Dose (cPAD) of 0.078 mg/kg bw/day based on a NOAEL of 7.8 mg/kg bw/day based 

on two co-critical studies, the two generation reproduction study in rats and a 

chronic toxicity study in dogs, with an uncertainty factor of 100.]

i. Food. [Tier 3 acute and chronic dietary risk assessments were conducted to 

evaluate the dietary exposure of the U.S. population and selected subpopulations to 

flupyradifurone residues. This assessment includes all proposed potential primary 

crop residues and inadvertent or rotational crop residues and secondary residues in 

animal tissues and milk. The assessments conservatively assumed the percent of all 

crops treated was equal to the maximum market leader value for that crop from the 

last three years. The Tier 3 acute and chronic assessments were conducted using 

CARES Version 3.0 software. Consumption data used in this program were taken 

from USDA’s CSFII, 1994-1996, 1998. With these conservative assumptions, acute 

exposure (99.9th percentile) for food utilizes 8.6% of the aPAD for the US 

Population and 25.8% for All Infants (< 1 yr. old), the most highly exposed 

subpopulation. Chronic exposure for food only utilizes 3.2% of the cPAD for the

US Population and 10.2% of the cPAD for Children 1-2 yrs. old, the most highly 

exposed subpopulation.]

ii. Drinking water. [Estimated Drinking Water Concentrations (EDWCs) from

ground water and surface water sources were calculated for the residues of 

flupyradifurone and the major environmental difluoroacetic acid (DFA). This 

exposure assessment was conducted using the modeling approach approved by the 

Office of Pesticide Programs of USEPA (EPA). The standard crop scenarios 

developed by the EPA were used for surface water assessment. The environmental 

fate parameters used for the surface water model PRZM/EXAMS and the ground 

water model SCI-GROW were estimated in accordance to the EPA input parameter 

guidance document. The highest ground water concentration of flupyradifurone 

plus difluroacetic acid (DFA) was 0.9 μg/L (acute and chronic) from all proposed 

uses (410 g a.i./ha) except the hop use (154 g a.i./ha). The 90

th percentile timedependent Estimated Drinking Water Concentrations (EDWCs) from surface water 

source were calculated for the proposed representative flupyradifurone crop uses.

A PCA factor of 0.91 was considered to adjust modeled EDWCs. Overall, the 

highest potential acute EDWC values were estimated from the Florida cucumber 

scenario with an acute concentration of 35.0 μg/L and the highest chronic EDWC 

values were estimated from the Nebraska corn scenario with a concentration of 8.0

μg/L
8

Drinking water did not significantly increase dietary exposure. The incorporation 

of the EDWC of 35.0 μg/L into an acute exposure assessment resulted in the U.S. 

adult population utilizing 9.1% of the aPAD (vs. 8.6% for food only) and All 

Infants, the most highly exposed subpopulation, utilizing 26.2% of the aPAD (vs.

25.8% for food only). The addition of the chronic EDWC of 8.0 μg/L resulted in the

U.S. adult population utilizing 3.4% of the cPAD (vs. 3.2% for food only) and 

Children 1-2, the most highly exposed subpopulation, utilizing 10.5% (vs. 10.2% for 

food only). In conclusion, the results of the very conservative acute and chronic 

dietary exposure analyses (including food and drinking water) demonstrates that 

flupyradifurone drinking water exposure consumes a very small percentage of the 

risk cup for all scenarios and population subgroups examined. Therefore, there is a 

reasonable certainty that no harm will result from exposure to potential residues of 

flupyradifurone in food and water.]

2. Non-dietary exposure. [Based on the use patterns non-dietary exposure to 

flupyradifurone is not anticipated.]

D. Cumulative Effects

[At this time, there is no available information to indicate that 

flupyradifurone or its metabolites have a common mechanism of human toxicity 

with other substances. Flupyradifurone is a member of the butenolide class of 

chemistry. For this class of chemistry, EPA has not yet conducted a detailed review 

of common mechanisms to determine whether it is appropriate, or how to include 

these chemicals in a cumulative risk assessment. Flupyradifurone does not appear 

to produce a toxic metabolite produced by other substances. For the purposes of 

this assessment, therefore, no common mechanism of toxicity has been considered.]

E. Safety Determination

1. U.S. population. [Risk assessments for flupyradifurone are based on a 

complete and reliable toxicity data package and conservative assumptions. Chronic 

aggregate dietary exposure (food and water) utilizes 3.4% of the cPAD for the US 

Population. Acute aggregate dietary exposure (food and water) for the U.S. adult 

population utilizes 9.1% of the aPAD. Non-dietary exposure of the U.S. population 

to flupyradifurone is not anticipated. Therefore, there is a reasonable certainty that 

no harm will occur to the US Population from aggregate exposure (food and 

drinking water) to residues of flupyradifurone.]

2. Infants and children. [The toxicological and exposure database for 

flupyradifurone is considered complete. There was no indication of an increased 

sensitivity of the young in any studies including the reproductive and developmental 

studies in rats and rabbits. Therefore, the special FQPA can be reduced to 1X and 

an uncertainty factor of 100 is adequate. Based on conservative assumptions,
9

chronic aggregate dietary exposure (food and water) utilizes 10.5% of the cPAD for 

Children 1-2 yrs. old, the most highly exposed subpopulation. Acute aggregate 

dietary exposure (food and water) utilizes 26.2% of the aPAD for All Infants, the 

most highly exposed subpopulation. Non-dietary exposure of infants and children

to flupyradifurone is not anticipated. Therefore, there is a reasonable certainty that 

no harm will occur to infants and children from aggregate exposure (food and 

drinking water) to residues of flupyradifurone.]

F. International Tolerances

[No tolerances have been established for flupyradifurone. Flupyradifurone is 

being reviewed as an OECD Joint Review among the U.S., Canada, Australia, Brazil 

and Mexico. Harmonized tolerances are being proposed to minimize trade barriers 

between the participating regions.]

August 13, 2012