EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR 

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER 

(1/1/2010)

EPA Registration Division contact: Kathryn Montague Product Manager 23 (703) 

305- 1243

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 and brackets, 

i.e., “[insert company name],” with the information specific to your action.

TEMPLATE:

[Nichino America, Inc.]

[Pesticide Petition No. xxxxxx]

EPA has received a pesticide petition (PP # xxxxxx) from Nichino America, Inc. 

4550 New Linden Hill Road Suite 501 Wilmington, DE 19808 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 180.585

1. by establishing a tolerance for residues of the herbicide,

pyraflufen-ethyl [ethyl 2-chloro-5-(4-chloro-5-difluoromethoxy-1-methyl-1Hpyrazol-3-yl)-4-fluorophenoxyacetate] and its acid metabolite, E-1 [2-chloro-5-(4-

chloro-5-difluoromethoxy-1-methyl-1H-pyrazol-3-yl)-4-fluorophenoxyacetic acid], 

expressed in terms of the parent, in or on the following raw agricultural 

commodities: almond hulls at 0.02 parts per million (ppm) and nuts, tree group 14 

at 0.01 parts per million (ppm), pistachio at 0.01 parts per million (ppm), fruit, 

pome fruit group 11 at 0.01 parts per million (ppm), fruit, stone fuit group 12 at 0.01

parts per million (ppm), pomegranates at 0.01 parts per million (ppm), olives at 0.01

parts per million (ppm), grapes at 0.01 parts per million (ppm), and hops at 0.05

parts per million (ppm).

2. to establish an exemption from the requirement of a tolerance for “NARemove”
2

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 qualitative nature of the residues of 

pyraflufen-ethyl (ET-751) in corn, soybeans, and wheat and pasture grass is 

adequately understood. The metabolism of pyraflufen-ethyl has been studied in 

cotton, wheat, and potato. Metabolism in the plant involves ester hydrolysis, demethylation on the pyrazole ring and further degradation of the phenoyxyacetate 

moiety to bound polar metabolites. The nature of the residue is adequately 

understood and the residues of concern are the parent, pyraflufen-ethyl, and the 

acid metabolite, E-1, only.

2. Analytical method. Aqueous organic solvent extraction, column clean up, 

and quantitation by gas chromatography is used to measure and evaluate the 

chemical residues.

3. Magnitude of residues. Several residue trials were conducted in almonds, 

pecans, apples, pears, grapes, and hops to satisfy the required EPA region locations. 

Based on these data, it is proposed that the Agency establish new tolerances in 

almond hulls at 0.02 ppm, nuts, tree group 14 at 0.01 ppm, pistachio at 0.01 ppm, 

fruit, pome fruit group 11 at 0.01 ppm, fruit, stone fuit group 12 at 0.01 ppm,

pomegranates at 0.01 ppm, olives at 0.01 ppm, grapes at 0.01 ppm, and hops at 0.05

ppm.

 4. Magnitude of the residue in animals.--i. Ruminants. The results of the meat 

and milk 28-day feeding study conclude that no finite residues of the parent, ET-751 

or the metabolites E-9, and E-15 can be detected in milk at a dose level of 10 ppm, 

and that no residues of either ET-751, E-5, or E-9, are detected in muscle, liver or 

fat tissues, and low level residues of 0.0534 ppm in kidney tissues. These results 

concur with those of an earlier ruminant metabolism study (MRID 45283005) at a 

dose of 10 ppm. Although the results of this livestock feeding study indicates that no 

finite residues could be detected in meat and milk commodities from the anticipated 

dietary burdens, we are using an anticipated residue value in milk calculated to be 

of 0.007 ppm.

 ii. Poultry. The maximum poultry dietary burden results from a diet 

comprised of cotton meal, corn grain, corn milled byproducts, soybean seed, 

soybean meal, soybean hulls, wheat grain, and wheat milled byproducts for a total 

dietary burden that is significantly lower than the levels that would require the 

proposal of tolerances in poultry. This conclusion is based on the exaggerated rate 

metabolism studies carried out on pyraflufen-ethyl and its acid metabolite. 

Therefore, an exemption from tolerances in poultry meat, meat byproducts, fat, and 
3

eggs under 40 CFR 180.6(a)(3) and (b) is proposed as it is not possible to establish 

with certainty whether finite residues will be incurred, but there is no reasonable 

expectation of finite residues.

B. Toxicological Profile

1. Acute toxicity. [Insert text.] “NA-Remove”

2. Genotoxicty. [Insert text.] “NA-Remove”

3. Reproductive and developmental toxicity. [Insert text.] “NA-Remove”

4. Subchronic toxicity. [Insert text.] “NA-Remove”

5. Chronic toxicity. [Insert text.] “NA-Remove”

EPA has evaluated the available toxicity data and considered its validity, 

completeness, and reliability as well as the relationship of the results of the studies 

to human risk. EPA has also considered available information concerning the 

variability of the sensitivities of major identifiable subgroups of consumers,

including infants and children. The nature of the toxic effects caused by pyraflufenethyl as well as the no observed adverse effect level (NOAEL) and the lowest 

observed adverse effect level (LOAEL) from the toxicity studies reviewed are 

discussed in the Federal Register of April 30, 2003 (68 FR 23046) (FRL-7300-9).

6. Animal metabolism. The qualitative nature of the residues of 

pyraflufen-ethyl and its acid metabolite, E-1, in animals is adequately understood. 

Pyraflufen-ethyl is rapidly absorbed, metabolized, and excreted to feces and urine, 

with greater than 90% of the administered dose excreted within 24 hours in rats. 

Based on metabolism studies with goats, hens, and rats, there is no reasonable 

expectation that measurable pyraflufen-ethyl-related residues will occur in meat, 

milk, poultry, or eggs from the proposed use.

7. Metabolite toxicology. No toxicologically significant metabolites 

were detected in plant or animal metabolism studies for cotton, potatoes, or 

mandarine oranges.

8. Endocrine disruption. Chronic, lifespan, and multigenerational 

bioassays in mammals and acute and subchronic studies on aquatic organisms and 

wildlife did not reveal any endocrine effects for pyraflufen-ethyl. Any endocrine 
4

related effects would have been detected in this comprehensive series of required 

tests. The probability of any such effect due to agricultural uses of pyraflufenethyl is negligible.

C. Aggregate Exposure

1. Dietary exposure. Acute dietary risk assessments are performed for 

a food-use pesticide, if toxicological study has indicated the possibility of an effect of 

concern occurring as a result of a one-day or single exposure. No adverse effect 

attributable to a single exposure (dose) was observed in oral toxicity studies, 

including the developmental toxicity studies in rats and rabbits. Therefore, EPA 

did not identify an acute dietary endpoint and an acute dietary assessment was not 

performed. Chronic dietary risk analyses was conducted to estimate potential 

pyraflufen-ethyl residues in/on the following crops: almond, beechnut, Brazil nut, 

butternut, cashew, chestnut, chinquapin, filbert, hickory nut, macadamia nut, 

pecans, walnuts, pistachio, apple, crabapple, loquat, mayhaw, pear, oriental pear, 

quince, apricot, sweet cherry, tart cherry, nectarine, plum, Chickasaw, Damson 

plum, Japanese plum, plumcot, fresh prune, pomegranates, olives, grapes and hops 

and anticipated residues in milk of 0.007 ppm, using Dietary Exposure Evaluation 

Model Software with the Food Commodity Intake Database (DEEM-FCID). These 

estimates assuming tolerance level residues in the established and proposed 

commodities except corn, cottonseed, potato, soybean seeds, and wheat grains had 

nondetectable residues. Exposure estimates to water were based on modeling with 

FIRST and SCI-GROW.

i. Food. The chronic population adjusted dose (cPAD) for the 

general population, based on residues at the tolerance levels and 1⁄2 of the combined 

LOQs for the parent and metabolites for corn, soybeans, potato, wheat, and cotton.

A default processing factor of 6.5 X for dry potato, 1.5x for corn syrup, an 

experimental processing factor of 0.6x for cotton seed oil and calculated milk value 

of 0.007 ppm. One hundred percent crop treated (%CT) was assumed for all crop 

commodities. The new crops will incrementally utilize <1% of the cPAD of 0.2

mg/kg/day for the U.S. population and <1% of cPAD for children (1-6 years). 

ii. Drinking water. The residue of concern in drinking water was 

determined to be pyraflufen-ethyl. Based on the FIRST and SCI-GROW models, 

the EECs of pyraflufen-ethyl for acute exposures are estimated to be 1247 parts per 

trillion (ppt) for surface water and 1.8 ppt for ground water. The EECs for chronic 

exposures are estimated to be 281 ppt for surface water and 1.8 ppt for ground 

water.

2. Non-dietary exposure. EPA calculated the non-dietary exposure 

scenarios in the Federal Register May 12, 2004 (69 FR 26305) (FRL-7358-2).

Pyraflufen-ethyl is registered in several non-food sites, including airports, 

commercial plants, nurseries and ornamental plantings; established ornamental 

turf; railroad, roadside, and utility rights-of-ways, and other similar non-crop areas. 
5

D. Cumulative Effects

Pyraflufen-ethyl belongs to the protox inhibitor class of compounds, and chemically 

is a 3-phenylpyrazole. The herbicidal activity of protox inhibitors is due to the 

inhibition of protoporphyrinogen IX oxidase. All relevant toxicological data has 

been provided to EPA. Chemicals with a similar mode of action, i.e., the protox 

inhibitors, have different chemical structures compared to pyraflufen-ethyl. 

Although other protox inhibitors have a similar herbicidal mode of action, there is 

no information available to suggest that these compounds exhibit a similar toxicity 

profile in the mammalian system. We are aware of no information to indicate or 

suggest that pyraflufen-ethyl has any toxic effects on mammals that would be 

cumulative with those of any other chemical. Since pyraflufen-ethyl is relatively 

non-toxic, cumulative effects of residues and other compounds are not anticipated. 

Therefore, for the purposes of this Food Quality Protection Act (FQPA) document, 

there should be no consideration of cumulative risk that would require assessment.

E. Safety Determination

1. U.S. population.

i. Acute risk. No adverse effect attributable to a single exposure (dose) of 

pyraflufen-ethyl was observed in the oral toxicity studies, including the 

developmental toxicity studies in rats and rabbits. Therefore, an acute reference 

dose was not established and no acute risk is expected.

ii. Chronic Risk. Based on the chronic toxicity data, the cPAD for pyraflufen-ethyl 

is considered to be 0.172 mg/kg/day. This value is based on the NOAEL of 17.2 

mg/kg/day observed in the chronic rat feeding study and a safety (uncertainty) 

factor of 100, the worse case estimate of chronic dietary exposure of pyraflufenethyl from cotton, potatoes, corn, soybean, and wheat, almond, beechnut, Brazil nut, 

butternut, cashew, chestnut, chinquapin, filbert, hickory nut, macadamia nut, 

pecans, walnuts, pistachio, apple, crabapple, loquat, mayhaw, pear, oriental pear, 

quince, apricot, sweet cherry, tart cherry, nectarine, plum, Chickasaw, Damson 

plum, Japanese plum, plumcot, fresh prune, pomegranates, olives, grapes and hops 

and calculated value of 0.007 ppm in milk will utilize less than 1% of the cPAD for 

the general U.S. population. EPA generally has no concern for exposures below 

100% of the RfD because the RfD represents the level at or below which daily 

aggregate dietary exposure over a lifetime will not pose appreciable risks to human 

health. The complete and reliable toxicity data and the conservative chronic 

exposure assumptions support the conclusion that there is a reasonable certainty of 

no harm from dietary (food) exposure to pyraflufen-ethyl and the acid metabolite 

residues. Moreover, as exposure to residues of pyraflufen-ethyl and the acid 

metabolite via water is negligible, there is a reasonable certainty of no harm from 

aggregate exposure to pyraflufen-ethyl and the acid metabolite residues.

iii. Cancer Risk. Cancer risk was calculated by the EPA in the Federal Register

May 12, 2004 (69 FR 26305) (FRL-7358-2) for both food and water. This assessment 

substantially overstates risk because it is based on the assumption that all 
6

commodities covered by pyraflufen-ethyl tolerances contain tolerance level residues. 

The cancer risk estimate was in the range of 1 in 1 million and does not exceed the 

Agency’s level of concern for exposure from either food or water sources. 

2. Infants and children. The chronic dietary exposure of pyraflufenethyl and the acid metabolite from corn, soybeans, and wheat and calculated value 

in milk will utilize < 1% of the cPAD for children (1-6 years). Exposure to potential 

residues in drinking water is expected to be negligible. In the Federal Register May

12, 2004 (69 FR 26305) (FRL-7358-2) after calculating DWLOCs and comparing 

them to the EECs for surface and ground water, EPA does not expect the aggregate 

exposure to children to exceed the Agency’s level of concern.

There is no evidence of increased susceptibility of rat or rabbit fetuses following in 

utero exposure in the developmental studies with pyraflufen-ethyl. There is no 

evidence of increased susceptibility of young rats n the reproduction study with 

Pyraflufen-ethyl. EPA concluded there are no residual uncertainties for pre- and/or 

post-natal exposure.

F. International Tolerances

There are no Codex maximum residue level established for residues of 

pyraflufen-ethyl and the acid metabolite, E-1, expressed in terms of parent on any 

crops.