EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR 

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER 

EPA Registration Division contact: Laura Nollen, (703) 305-7390

Interregional Research Project Number 4 (IR-4)

Petition Number 9E7612

EPA has received a pesticide petition (PP# 9E7612) from Interregional 

Research Project Number 4 (IR-4), 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 180.484 by

establishing a tolerance for residues of flutolanil, N-(3-(1-methylethoxy)phenyl)-2-

(trifluoromethyl)benzamide and its metabolites converted to 2-(trifluoromethyl) 

benzoic acid and calculated as flutolanil in or on the raw agricultural commodities

ginseng at 3.5 parts per million (ppm); vegetable, Brassica, leafy, group 5 at 0.11 ppm; 

and turnip, greens at 0.11 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. The metabolic profile of flutolanil is well understood and 

has been elucidated in three dissimilar crops: peanuts, rice and cucumber. The 

metabolic profile is similar in all crops. The major route of degradation is 4'-0-

dealkylation to desisopropylflutolanil (M-4), followed by conjugation. Other 

metabolites may occur at very low levels due to hydroxylation and oxidation of the 

side chain, hydroxylation of the aniline ring, and methylation of the hydroxyl 

groups. These minor metabolites were also subject to conjugation. The residues of 

concern are the parent (flutolanil) and M-4 (desisopropyl flutolanil).

2. Analytical method. Residues of flutolanil and M-4 are extracted from 

macerated samples with acetone or a mixture of methanol and water. For cabbage 

and ginseng, an aliquot of the extract is diluted with water and analyzed using 

HPLC-MS/MS. For broccoli and mustard greens, the acetone extract is diluted with 

water and the residues are partitioned into a mixture of ethyl acetate and 

dichloromethane. This solvent is dispelled and the residue is reconstituted in 
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acetone for purification through Florisil. The purified eluent is taken to dryness 

and the residues are reconstituted in a mixture of acetonitrile and water. Residues 

of flutolanil and M-4 are chromatographed and quantified using an HPLC–MS/MS. 

The Limit of Quantitation is 0.05 ppm for each flutolanil and M-4.

3. Magnitude of residues. Maximum residues of flutolanil and M-4 in ginseng 

(dry) and mustard greens were 2.17 ppm and 0.06 ppm flutolanil, respectively, with 

no M-4 residues detected in any sample. No detectable residues of either flutolanil 

or M-4 (Limit of Quantitation was 0.05 ppm for each molecule) were detected in 

either broccoli or cabbage. Permanent tolerances of 3.5 ppm and 0.11 ppm are 

proposed for ginseng, Brassica leafy vegetables (Crop Group 5) and turnip greens, 

respectively.

B. Toxicological Profile

1. Acute toxicity. Acute toxicity data show that technical grade flutolanil has 

relatively low acute toxicity (Category III and IV). Flutolanil is not a dermal 

sensitizer, primary eye irritant, or primary skin irritant.

2. Genotoxicty. The toxicological database for flutolanil is complete. The 

database contains no evidence of genotoxicity attributable to flutolanil.

3. Reproductive and developmental toxicity. The Agency has set the FQPA 

Safety Factor for flutolanil at 1X because there was no increased sensitivity to 

fetuses as compared to maternal animals in the developmental rat and rabbit studies 

and no increased sensitivity to pups as compared to adults in a multi-generation 

reproduction study in rats.

4. Subchronic toxicity Subchronic and chronic toxicity studies showed that the 

primary effects of flutolanil are increases in liver weight combined with decreases in 

body weight. The available data for flutolanil do not show neurotoxic, carcinogenic, 

or mutagenic effects. Flutolanil is not a developmental or reproductive toxicant. 

There is no evidence of increased susceptibility of rat or rabbit fetuses to in-utero 

exposure or rat pups to post-natal exposure to flutolanil. No toxic effects were 

observed in studies in which flutolanil was administered by the dermal routes of

exposure.

5. Chronic toxicity. Only a chronic dietary endpoint was identified for 

flutolanil. The Agency has selected a chronic RfD/PAD of 0.50 mg/kg/day (NOAEL 

= 50 mg/kg/day; Uncertainty Factor = 100). This chronic RfD/PAD is based on the 

chronic oral toxicity study in dogs in which increased incidences of clinical signs 

(emesis, salivation, and soft stool) occurred at LOAEL = 250 mg/kg/day following 65 

weeks of exposure.

6. Animal metabolism. The metabolism of flutolanil has been extensively 

studied in various species of mammals. Studies in rats, ruminants, and poultry 

suggest that flutolanil is not well absorbed following oral administration. Once 
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absorbed, however, it is rapidly metabolized, primarily to desisopropylflutolanil and 

it conjugates, and rapidly excreted via urine and feces.

7. Metabolite toxicology. Flutolanil does not metabolize to a significantly toxic 

metabolite nor does it share a toxic metabolite with any other pesticide registered in 

the U.S.

8. Endocrine disruption. No evidence of endocrine effects has been observed in 

the subchronic, chronic or reproductive studies. The potential for flutolanil to cause 

endocrine effects is not considered relevant.

C. Aggregate Exposure

1. Dietary exposure. Sufficient residue data for flutolanil are available to 

assess tolerances and conduct a dietary risk assessment. No acute dietary risk 

assessment is necessary as no toxic effects from a single oral dose have been 

observed in toxicology studies. A Tier I chronic riskassessment was conducted 

based on the Agency’s cPAD of 0.5 mg/kg bw/day using DEEM-FCID v. 2.16. The 

maximum dietary risk for any dietary subpopulation was a maximum of 2% of the 

cPAD (non-Hispanic, non-white, non-black).

i. Food. A Tier I risk analysis (assumed tolerance-level residues with 100% 

crop treated) was run including all proposed tolerances. The addition of ginseng 

(dry) and Brassica leafy vegetables at presumed tolerance levels had a negligible 

effect on chronic dietary risk.

ii. Drinking water. Worst-case drinking water values were included in the 

chronic dietary risk assessment described above. The drinking water residues used 

in the dietary risk assessment were provided by the Ageny in a memorandum (S. 

Abel: “Flutolanil Tier II Estimated Environmental Concentration for Use in the 

Human Health Drinking WaterRisk Assessment, D260066, 12/13/99) The maximum 

drinking water residue of 0.00375 ppm was incorporated in the DEEM-FCID into 

the food categories“water, direct, all sources” and “water, indirect, all sources.”

2. Non-dietary exposure. Flutolanil is currently registered for use on the 

following residential non-dietary sites: Turf grass. The risk assessment was 

conducted using the following residential exposure assumptions: There are nonoccupational uses associated with flutolanil. Non-occupational handlers may mix, 

load, and apply flutolanil products on turf grass. These exposures were assessed for 

inhalation risk. Post-application inhalation exposure following turfgrass treatment 

is considered negligible and was not assessed. Because certain flutolanil products 

are registered for use on residential lawns, postapplication exposure to infants may 

result in their hand-to-mouth activities on treated turf. The MOE’s for these 

scenarios ranged from 6.7 x 102to 1.4 x 103. These modeled exposures do not trigger

the Agency’s Level of Concern.

D. Cumulative Effects
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Flutolanil has demonstrated only minimal toxicity in animal studies and the 

mechanism of this toxicity is not known. Flutolanil does not share a mechanism of 

toxicity with another registered pesticide nor does it share a common toxic 

metabolite with any other registered pesticide. There are no available data to 

indicate that flutolanil has a common mechanism of toxicity with other substances.

E. Safety Determination

1. U.S. population. An acute dietary endpoint has not been set for flutolanil by 

the Agency due to a lack of observable toxic effects from a single dose at any level 

tested. A chronic dietary risk assessment has been conducted using the Agency’s 

cPAD of 0.5 mg/kg bw/day. The calculated chronic daily exposure for the general 

US population is 0. 0.002672 mg/kg/bw/day which represents 0.5% of the cPAD.

2. Infants and children. The Agency has set the FQPA factor for flutolanil at 

1X based on lack of neurotoxic and teratogenic effects in chronic tests on rabbits 

and rats. The highest chronic risk calculated for any pre-teen dietary subgroup was 

1.4% of the cPAD (non-nursing infants).

F. International Tolerances

There are no national or transnational MRLs for flutolanil on Brassica

(Cole) leafy vegetables or ginseng.