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 ([insert petition number]) 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 [penflufen, (1H-Pyrazole-4-carboxamide, N-[2-(1,3-

dimethylbutyl)phenyl]-5-fluoro-1,3-dimethyl-)] in or on the raw agricultural 

commodities [sugar beet, root ] at [0.01] parts per million (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. [Plant metabolism studies with penflufen were performed 

in wheat, soybeans and potatoes after seed treatments and on rice after soil 

treatment in the planting hole. In addition, metabolism studies were performed on 

corn, canola, cotton, sunflowers, succulent peas and beans, alfalfa and sugar beets to 

determine the total radioactive residue (TRR) uptake of penflufen after seed 

treatment. Metabolism studies with penflufen in rotational crops were performed in 

wheat, soybeans, turnips and Swiss chard. The metabolism in all plants was very 

similar. The main reactions involved were hydroxylation at the 3-position and 

conjugation of the hydroxyl group with glucose and malonic acid; conjugation with 

homoglutathione or glutathione via substitution of the fluorine atom followed by 
2

metabolic degradation of the glutathione moiety; cleavage of the N-phenyl bond and 

of the carboxamide bond; and N-demethylation and oxidation of the methyl group 

in the pyrazole moiety.]

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

for penflufen. The analytical method involves solvent extraction, filtration, and 

addition of an isotopically labeled internal standard followed by acid hydrolysis. 

Quantitation is by high performance liquid chromatography-electrospray 

ionization/tandem mass spectrometry (LC/MS/MS).]

 3. Magnitude of residues. [Based on the results from the TRR study in sugar 

beets, residue field trials were not required in accordance with guidance for crop 

field trials under OPPTS 860.1500 and DIR2003-02 (Harmonization of Regulation 

of Pesticide Seed Treatment in Canada and the United States) to support the 

requested tolerance.]

B. Toxicological Profile

 1. Acute toxicity. [Penflufen has very low acute toxicity to mammals 

irrespective of the route of exposure (oral, percutaneous or inhalation exposure). It 

is not a skin sensitizer, it is non-irritating to skin (Magnusson and Kligmann assay) 

and causes only a minimal reversible redness of the conjunctivae in the rabbit eye. 

Overall, it is classified as Toxicity Classification III. The oral LD50 in rats is greater 

than 2000 mg/kg. The dermal LD50 value in rats is greater than 2000 mg/kg. The 

inhalation LC50 for a four-hour exposure (nose only) is greater than 2022.5 g/m3. No 

clinical signs nor body weight changes or necropsy findings were observed in the 

acute oral and dermal toxicity studies conducted in rats. In the acute inhalation 

toxicity study, clinical signs were occasionally observed with recovery within four 

days after exposure. In acute neurotoxicity studies, a NOAEL of 100 mg/kg and 50 

mg/kg was established for males and females, respectively based on slight effects in 

measures of motor and locomotor activity.]

 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 penflufen has no genotoxic potential.] 

3. Immunotoxicity. [Immunotoxicity potential was evaluated in a four week 

study in rats. Determination of cell counts in the spleen and performance of the 

plaque forming assay showed no evidence for treatment-related effects at any dose. 

The high dose of 7000 ppm (755.6 mg /kg bw/day in males and of 960.5 mg /kg 

bw/day in females) was determined to be the NOEL for immunotoxicity for both 

males and females. Penflufen is therefore, not considered to be immunotoxic] 
3

 4. Reproductive and developmental toxicity. [In the rat two-generation 

reproduction study, the parental systemic NOAEL was 1000 ppm (64.1 mg/kg/day 

in males, 75.9 mg/kg/day in females) based on decreased body weight, decreased 

body weight gain, alterations in food consumption, increased liver weight with 

associated hepatocellular hypertrophy, and decreased thymus weight in both 

genders, as well as, decreased terminal body weight and spleen weights in females. 

The reproductive NOAEL was 1000 ppm for the females (73.4 mg /kg bw/day) based 

on a slight decrease in litter size in both the P and F1-generations. For males the 

NOAEL was greater than 4000 ppm in males (>338.6 mg /kg bw/day) based on no 

reproductive findings observed at the highest dose tested. The offspring NOAEL 

was 1000 ppm (72.5 mg /kg bw/day) based on maternal effects leading to 

secondarily-mediated effects on pup weight, pup weight gain, delayed vaginal 

patency and balanopreputial separation and organ weight changes (brain and 

spleen). In a rat developmental toxicity study, the maternal NOAEL was 30 

mg/kg/day, based on reduced body weight gain, and liver changes. The fetal 

NOAEL was 300 mg/kg/day based on no findings observed at the highest dose 

tested. In a rabbit developmental toxicity study, the NOAEL was 100 mg/kg/day 

both in the dam (decreased body weight gain and reduced food consumption) and in 

terms of fetal development (decreased fetal body weight) in the New Zealand White 

rabbit.] 

 5. Subchronic toxicity. [Subchronic studies showed that the liver is the major 

target organ in rats and dogs. In addition to the liver, the kidney (males) was also a 

target organ in rats. In the male rat, specific nephropathy (hyaline droplet 

nephropathy) was observed. In mice, no effects were observed at the highest dose 

tested. The dog was the most sensitive species followed by the rat with the mouse 

being the least sensitive. Overall, the lowest NOAEL was observed in the 

subchronic dog study. In this study, the NOAEL for the dog was established at 5.6 

and 6.1 mg/kg bw/day in males and females, respectively. However, the NOAEL in 

the dog was based on doses which each varied by an order of magnitude. The 

LOAELs established in the subchronic dog and chronic dog studies were both based 

on the same endpoints of increased liver weights and hepatocellular hypertrophy 

and the NOAEL of 1000 ppm established in the chronic dog toxicity study was 

between the doses for establishing the NOAEL of 180 ppm and the LOAEL of 1800 

ppm in the subchronic dog study. Therefore, relevant subchronic NOAEL of 32 

mg/kg/day was established from the chronic dog toxicity study. This NOAEL is also 

comparable with the maternal NOAEL of 30 mg/kg/day in the rat developmental 

toxicity study. 

In a 90-day neurotoxicity study at 0, 250, 2000 and 8000 ppm, no evidence of 

neurotoxicity was observed at any treatment level. Treatment-related findings of 

general toxicity at the high-dose consisted of decreased body weight, total body 

weight gain and food consumption in males and females and decreased terminal 

body weight in females. Also, liver weights were increased in high-dose males and 

females. Treatment-related findings in mid-dose males and females included 

increases in liver weights (absolute and/or relative) and decreased food consumption 
4

in females, with no corresponding effect on body weight. Based on neurotoxicology 

endpoints, a NOAEL of 8000 ppm was established for males and females (516.0 and 

608.8 mg/kg for male and female rats, respectively). 

In a four week dermal toxicity study in rats, a NOAEL of 300 mg/kg/day was 

established based on increased lymphocyte debris within the thymic cortices of the 

1000 mg/kg males and females.] 

 6. Chronic toxicity. [In the rat, at the end of the combined chronic toxicity and 

carcinogenicity study, treatment-related macroscopic findings consisted of enlarged 

liver and white focus in the liver in females only. At the microscopic examination, in 

the liver, a higher incidence of centrilobular to panlobular hepatocellular 

hypertrophy and of centrilobular hepatocellular macrovacuolation was observed in 

both sexes. In females, a higher incidence of hepatocellular brown pigments was 

also noted. A higher incidence of colloid alteration in the thyroid gland was 

observed in females only. There was no evidence of a treatment-related increased 

incidence of tumors of any type in any organ. Penflufen is thus considered not to be 

carcinogenic in the rat after a 104 week treatment period. The NOAEL over a 

carcinogenic (24 month) period of dietary administration of penflufen to the rat was 

100 ppm in both sexes (equivalent to 4.0 mg/kg/day weight/day in males and 5.6 

mg/kg body weight/day in females). 

In a mouse carcinogenicity study, the target organs were the liver and thyroid 

gland. The principal changes noted in the liver were increased liver weights 

associated with higher incidence and/or severity of diffuse centrilobular 

hepatocellular hypertrophy in both sexes. In females a higher severity of 

hepatocellular vacuolation and higher incidence and severity of diffuse mainly 

periportal hepatocellular macrovacuolation was also observed. In addition, a higher 

incidence and severity of follicular cell hyperplasia in the thyroid gland was noted in 

38/50 females compared to 23/50 females in the control group. No treatment-related 

neoplastic changes were observed at any dose level tested in either sex. The NOAEL 

in the mouse was established at 1000 ppm in both sexes (equating approximately to 

146 mg/kg body weight/day for males and 182 mg/kg body weight/day).] 

 7. Animal metabolism. [In the rat, penflufen is rapidly and almost completely 

absorbed (>96% of the dose in a bile fistulation experiment) following oral 

administration by gavage. Penflufen was extensively metabolized with unchanged 

parent compound found only in low percentages of the recovered dose. The 

metabolism of penflufen in male and female rats was similar and included Ndemethylation in the pyrazole ring, hydroxylation and extensive oxidation. Some 

cleavage of the rings was observed as was conjugation of several hydroxylated 

metabolites with glucuronic acid and cysteine. In ruminants and poultry, penflufen 

was also extensively metabolized. Penflufen residues do not accumulate in animal 

tissues, milk or eggs. ]
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 8. Metabolite toxicology. [Not applicable as parent is the compound of 

concern.] 

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

any primary endocrine disruptive potential. Reproductive and developmental 

findings provided no evidence of an enhanced sensitivity of the young. Bayer 

CropScience will conduct any studies that may be required under EPA’s Endocrine 

Disrupter Screening Program.]

C. Aggregate Exposure

 1. Dietary exposure. [The toxicological and exposure database for penflufen 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 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 0.5 mg/kg bw/day 

from a NOAEL of 50 mg/kg bw/day established for females, based on slight effects 

on measures of motor and locomotor activity in the acute neurotoxicity study in 

rats, with an uncertainty factor of 100. Chronic dietary exposure was expressed as a 

percentage of the chronic Population Adjusted Dose (cPAD) of 0.04 mg/kg bw/day 

based on a NOAEL of 4 mg/kg bw/day in the rat chronic/oncogenicity study in rats 

with an uncertainty factor of 100.]

 i. Food. [Tier 1 acute and chronic dietary risk assessments were conducted to 

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

penflufen residues. This assessment includes all proposed primary crops and 

inadvertent or rotational crop residues. Penflufen residues in tissues and milk were 

not included in the assessment because of negligible residues in the animal feed 

items. The assessment assumed 100% of the crops were treated. The Tier 1 acute 

and chronic assessments were conducted using DEEM-FCIDTM, Version 4.02 

software. Consumption data used in this program were taken from NHANES 2-day 

food consumption data for 2005-2010. With these conservative assumptions, acute 

exposure (95th percentile) for food only utilizes 0.19% of the aPAD for the US 

Population and 0.69% for all infants, the most highly exposed subpopulation. 

Chronic exposure for food only utilizes 0.10% of the cPAD for the US Population 

and 0.36% of the cPAD for all infants, the most highly exposed subpopulation.]

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

from ground water and surface water sources were used as reported in the “Tier I 

Drinking Water Exposure Assessment for the New Chemical Registration of 

Penflufen (DP # 386698)” for the residues of penflufen and the major environmental 

metabolites BYF 14182-3-hydroxybutyl and BYF 14182-pyrazolyl-AAP, resulting 

from penflufen use on potatoes, wheat, corn, beans, soybeans, canola, sunflowers, 
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cotton, alfalfa, and rice. The screening model FIRST (FQPA Index Reservoir 

Screening Tool, version 1.1, 01/01/07) was used to calculate the surface water 

EDWCs. Estimated groundwater EDWCs were calculated using the screening 

model SCI-GROW (Screening Concentrations in Ground Water, version 

2.3,07/29/03). The highest EDWC (16.6 ppb) resulted from the application of 

penflufen to potatoes and was used in both the acute and chronic dietary 

assessments.] 

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

penflufen is not anticipated.

D. Cumulative Effects

 [Section 408(b)(2)(D)(v) requires that, when considering whether to establish, 

modify, or revoke a tolerance, the Agency consider “available information” 

concerning the cumulative effects of a particular pesticide’s residues and “other 

substances that have a common mechanism of toxicity.” Penflufen is a novel 

succinate-dehydrogenase inhibitor (SDHI). EPA has not made a common 

mechanism of toxicity finding as to penflufen and any other substances and 

penflufen does not appear to produce a toxic metabolite produced by other 

substances.]

E. Safety Determination

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

and reliable toxicity data package and highly conservative assumptions. Chronic 

aggregate dietary exposure (food and water) utilizes 0.10% of the cPAD for the US 

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

population utilizes 0.19% of the aPAD. Non-dietary exposure of the U.S. population 

to penflufen 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 penflufen.]

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

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, chronic aggregate 

dietary exposure (food and water) utilizes 0.36% of the cPAD for all infants, the 

most highly exposed subpopulation. Acute aggregate dietary exposure (food and 

water) utilizes 0.64% of the aPAD for all infants, the most highly exposed 

subpopulation. Non-dietary exposure of children to penflufen 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 

penflufen.]
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F. International Tolerances

 [Tolerances in alfalfa forage and hay, tuberous and corm vegetables (CSG 

1C), grain, legume vegetables (CG 6), foliage of legume vegetables (CG7), cereal 

grain (CG 15), cereal grain, forage, fodder and straw (CG 16), oilseeds(CG 20) and 

cotton gin by-products have been established in the US and Canada at 0.01 ppm for 

all commodities. Australia has established maximum residue limits in cereal grains, 

cotton seed, potatoes, rape seed, milk, eggs and edible offal and meat of poultry and 

mammals at 0.01 ppm for all commodities. In the EU, tolerances have been 

approved in potatoes at 0.01 ppm. Tolerances in sugar beets are being proposed to 

minimize trade barriers between the participating regions.]