1

EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE

PETITIONS PUBLISHED IN THE FEDERAL REGISTER

I nterregional R esearch Project N umber 4 (IR

- 4)

P P# 5E8382

EPA has received a pesticide petition ( P P# 5E8382 ) from I nterregional R esearch Project

N umber 4 (IR

- 4)

, IR

- 4 Headquarters, Rutgers, The State University of New Jersey, 500

College Road East, Suite 201 W, Princeton NJ 08540 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, (1 H

- Pyrazole

- 4

- carboxamide, N

- [2

- (1,3

- dimethylbutyl)phenyl]

- 5

- fluoro

- 1,3

- dimethyl

- ) in or on the raw agricultural

commodities O nion, bulb, subgroup 3

- 07A at 0.01 parts per million (ppm) ; and O nion , green,

subgroup 3

- 07B at 0.015 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

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. The magnitude of the residue trials in dry bulb and green

onions were conducted in the various required regions across the United States and Canada

in accordance with guidance for crop field trials under OCSPP 860.1500 and Regulative

Directives Dir98

- 02 Dir2010

- 05 to support the requested tolerances.2

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 LD 50 in rats is greater than 2000 mg/kg. The dermal LD 50 value in rats is greater

than 2000 mg/kg. The inhalation LC 50 for a four

- hour exposure (nose only) is greater than

2022.5 g/m 3

. 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

.

4. Reproductive and developmental toxicity. In the rat two

- generatio n 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, decrease d body weight gain,

alterations in food consumption, increased liver weight wit h associated hepatocellular

hypertrophy, and decreased thymus weight in bot h 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) base d on a slight decrease in litter size in both the P and F 1

- generations. For males th e NOAEL was greater than 4000 ppm in males (>338.6 mg /kg

bw/day) based on n o reproductive findings observed at the highest dose tested. The offspring

NOAE L 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 food3

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 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. The4

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 N

- demethylation 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.

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 crop5

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, 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

- occupational 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 is6

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.

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,

MRLs have been approved in potatoes at 0.01 ppm. Tolerances in bulb vegetables, onion, dry

(CSG 3

- 07A) and bulb vegetables, onion, green (CSG 3

- 07B) are being proposed.