EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR 

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER 

EPA Registration Division contact: [insert name and telephone number with area 

code] 

INSTRUCTIONS: Please utilize this outline in preparing the pesticide petition. In 

cases where the outline element does not apply, please insert “NA-Remove” and 

maintain the outline. Please do not change the margins, font, or format in your 

pesticide petition. Simply replace the instructions that appear in green, i.e., “[insert 

company name],” with the information specific to your action.

TEMPLATE: 

[Bayer CropScience]

[Insert petition number]

 EPA has received a pesticide petition ([5F8404]) 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 residues of 

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

difluoroethyl)amino] in or on the raw agricultural commodities [Kava, Roots] at [0.9]

ppm, [Cilantro, Fresh Leaves] at [30] ppm, [Kava, Fresh Leaves] at [40] ppm, [Stone 

Fruits (Crop Group 12-12), Fruit] at [1.5] ppm, [Caneberry (Crop Subgroup 13-07A), 

Fruit] at [5] ppm, [Quinoa] at [3] ppm, [Abiu, Fruit] at [0.6] ppm, [Akee Apple, Fruit] at 

[0.6] ppm, [Avocado, Fruit] at [0.6] ppm, [Bacury, Fruit] at [0.6] ppm, [Banana, Fruit] at 

[0.6] ppm, [Binjai, Fruit] at [0.6] ppm, [Canistel, Fruit] at [0.6] ppm, [Cupuacú, Fruit] at 

[0.6] ppm, [Etambe, Fruit] at [0.6] ppm, [Jatobá, Fruit] at [0.6] ppm, [Kei Apple, Fruit] at 

[0.6] ppm, [Langstat, Fruit] at [0.6] ppm, [Lanjut, Fruit] at [0.6] ppm, [Lucuma, Fruit] at 

[0.6] ppm, [Mabolo, Fruit] at [0.6] ppm, [Mango, Fruit] at [0.6] ppm, [Mangosteen, Fruit]

at [0.6] ppm, [Paho, Fruit] at [0.6] ppm, [Papaya, Fruit] at [0.6] ppm, [Pawpaw, 

Common, Fruit] at [0.6] ppm, [Pelipisan, Fruit] at [0.6] ppm, [Pequi, Fruit] at [0.6] ppm, 

[Pequia, Fruit] at [0.6] ppm, [Persimmon, American, Fruit] at [0.6] ppm, [Plantain, Fruit]

at [0.6] ppm, [Pomegranate, Fruit] at [0.6] ppm, [Poshte, Fruit] at [0.6] ppm, [Quandong, 

Fruit] at [0.6] ppm, [Sapote, Fruit] at [0.6] ppm, [Sataw, Fruit] at [0.6] ppm, [Screw-pine, 

Fruit] at [0.6] ppm, [Star apple, Fruit] at [0.6] ppm, [Tamarind-of-the-Indies, Fruit] at 

[0.6] ppm, [Wild Loquat, Fruit] at [0.6] 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 
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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 EPA has 

determined the residue definition for enforcement of flupyradifurone residues in 

primary crops as parent flupyradifurone. 

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 [pyridinylmethyl14C]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. 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 chromatographyelectrospray 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. 

A processing study was also conducted on plum.] 
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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 

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 
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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 

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 
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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 [pyridinylmethyl-14C]- 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 

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, the EPA has determined that 

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

should be determined by measuring the parent flupyradifurone only.] 

 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 
6

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 

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 

intra- species 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. [Unrefined 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 registered 

and proposed potential primary crop residues and inadvertent or rotational crop 

residues and secondary residues in animal tissues and milk. The assessments 

conservatively assumed 100% of all crops were treated. The unrefined acute and 

chronic assessments were conducted using DEEM-FCID Version 4.02 software. 

Consumption data used in this program were from the NHANES/WWEIA 2005-

2010 surveys. With these conservative assumptions, acute exposure (95th percentile) 

for food utilizes 20.9% of the aPAD for the US Population and 36.7% for Children 

1-2 years, the most highly exposed subpopulation. Chronic exposure for food only 

utilizes 31.6% of the cPAD for the US Population and 75.2% of the cPAD for 

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

 ii. Drinking water. [Estimated Drinking Water Concentrations (EDWCs) 
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from ground water and surface water sources were calculated. The total toxic 

residues are defined by EPA as parent plus two photo-degradates (flupyradifuronesuccinamide and flupyradifurone-azabicyclosuccinamide) plus unextracted 

residues. The modeling approach approved by the Office of Pesticide Programs of 

EPA, the standard crop scenarios developed by the EPA and the surface water 

model PRZM/EXAMS and the ground water model PRZM-GW were used to 

estimate the values. The highest ground water concentration was 352 μg/L (acute) 

and 307 μg/L (chronic) from all proposed uses. The 90th percentile time-dependent 

Estimated Drinking Water Concentrations (EDWCs) from surface water sources 

were calculated for the proposed representative flupyradifurone crop uses. 

Overall, the highest potential acute EDWC value was 52.5 μg/L and the highest 

chronic EDWC was 22.3 μg/L. The PRZM-GW ground water EDWCs were used in 

the dietary assessments. 

Drinking water did not significantly increase dietary exposure. The incorporation 

of the EDWC of 352 μg/L into the acute exposure assessment resulted in the U.S. 

adult population utilizing 24.1% of the aPAD (vs. 20.9% for food only), and 

Children 1-2, the most highly exposed subpopulation, utilizing 40.7% of the aPAD 

(vs. 36.7% for food only). The addition of the chronic EDWC of 307 μg/L resulted 

in the U.S. adult population utilizing 39.6% of the cPAD (vs. 31.6% for food only) 

and Children 1-2, the most highly exposed subpopulation, utilizing 86.1% (vs. 

75.2% 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 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. [Bayer CropScience is proposing to register 

flupyradifurone for professional use for foliar or soil application to landscape and 

production ornamental plants, greenhouse vegetables and transplants, fruits, and 

nut trees. Consumer uses proposed are homeowner application to garden 

vegetables, fruits, ornamental flowers, ornamentals, shrubs and outdoor 

houseplants. Risk assessments, as required by EPA for all appropriate scenarios and 

populations (Adults 20-49 and Children 6-12), were conducted. Professional 

application, homeowner application and post application to adults and children 

exposure scenarios are above the level of concern for flupyradifurone (MOE>100).] 

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 
8

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 

dietary exposure (food and water) utilizes 39.6% of the cPAD for the US Population. 

Acute dietary exposure (food and water) for the U.S. population utilizes 24.1% of 

the aPAD. Potential residential exposure of the U.S. population to flupyradifurone 

(from professional and homeowner applications) is above levels of concern 

(MOE>100). FQPA requires aggregation of all potential sources of exposure from 

food, drinking water and residential exposures. An aggregate assessment including 

these sources for Adults (20-49) results in a combined MOE of 330, well above the 

level of concern. Therefore, there is a reasonable certainty that no harm will occur 

to the US Population from aggregate exposure (food, drinking water and residential 

sources) 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 factor can be reduced to 

1X and an uncertainty factor of 100 is adequate. Based on conservative 

assumptions, chronic aggregate dietary exposure (food and water) utilizes 86.1% of 

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

aggregate dietary exposure (food and water) utilizes 40.7% of the aPAD for 

Children 1-2, the most highly exposed subpopulation. A non-dietary assessment was 

conducted for Children 6-12, the appropriate population of concern for the 

proposed residential uses (resulting in potential post application exposure). The 

aggregate assessment including food, drinking water and non-dietary exposure for 

this population resulted in an MOE of 290 (LOC=100). Therefore, there is a 

reasonable certainty that no harm will occur to infants and children from aggregate 

exposure to residues of flupyradifurone.]

F. International Tolerances

 [No international tolerances have been established for flupyradifurone. The 

initial registration application dossier for flupyradifurone was evaluated under 

global joint review among Australia, Brazil, Canada, Mexico and the United States. 

Flupyradifurone is currently under review for proposed domestic uses and import 

MRLs in the EU, Japan, Korea and Taiwan. It is also being reviewed by JMPR for 

Codex MRLs. Harmonized tolerances are being proposed to minimize trade 

barriers between the participating regions.] 
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