EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS

PUBLISHED IN THE FEDERAL REGISTER  (11/11/2011)

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 # 2F8075) 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
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 1. by amending the tolerances 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 commodities: Cattle, meat 

byproducts; Goat, meat byproducts; Horse, meat byproducts; Milk; and Sheep, 

meat byproducts, by extending the expiration date for these temporary tolerances 

until December 31, 2016. 

2. to establish an exemption from the requirement of a tolerance for “NA‐Remove”

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. “NA-Remove”

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

and quantitation by gas chromatography with mass spectrometry is used to measure 

and evaluate the chemical residues. 

3. Magnitude of residues. “NA‐Remove”

      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 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 were detected in kidney tissues.  These results concur with those of an earlier ruminant
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metabolism study (MRID 45283005) at a dose of 10 ppm.  Although the results of this livestock

feeding study indicate that no finite residues are 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 from a diet comprised of 

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

soybean hulls, wheat grain, and wheat milled byproducts results in a total dietary 

burden that is significantly lower than the levels that would require tolerances in 

poultry and poultry byproducts. 

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”
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 EPA has evaluated the available toxicity data on pyraflufen-ethyl 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. Specific information on the nature of 

the adverse effects caused by pyraflufen-ethyl as well as the no-observed-adverseeffect-level (NOAEL) and the lowest-observed-adverse-effect-level (LOAEL) from 

the toxicity studies reviewed can be found at http://www.regulations.gov in the 

document “Pyraflufen-ethyl: Human Health Risk Assessment for a Section 3 

Registration of New Food Uses on Tree Nuts (Crop Group 14), Pistachios, Pome 

Fruit (Crop Group 11-10), and Stone Fruit (Crop Group 12), Hops, Grapes, Olives, 

and Pomegranates,” at page 17 in docket ID number EPA-HQ-OPP-2010-0426. 

 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 animal metabolism studies or plant metabolism studies on cotton, 

potatoes, and mandarin 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 

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. 
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C. Aggregate Exposure

 1. Dietary exposure. Quantitative acute dietary exposure and risk 

assessments are performed for a food-use pesticide if a toxicological study has 

indicated the possibility of an effect of concern occurring as a result of a 1-day or 

single exposure. No such effects attributable to a single exposure (dose) were 

observed in oral toxicity studies, including the developmental toxicity studies in rats 

and rabbits conducted with pyraflufen-ethyl; therefore, a quantitative acute dietary 

exposure assessment is not necessary. Chronic dietary risk analyses were conducted 

using Dietary Exposure Evaluation Model Software with the Food Commodity 

Intake Database (DEEM-FCID). These dietary exposure assessments used the 

following assumptions: 100 percent crop treated (PCT) and tolerance-level residues 

for pyraflufen-ethyl on all treated crops except corn, cottonseed, potato, soybean, 

wheat, pome fruit, stone fruit, pomegranate, olive, grape, tree nuts, pistachio, hops, 

and peanuts for which one half of the combined Levels of Quantification (LOQs) for 

the parent and the metabolite were used since all field trial residue levels were less 

than the LOQ. Exposure estimates to water were based on modeling with FIRST, 

PRZM/EXAMS, and SCI-GROW. 

 i. Food. Using the exposure assumptions listed above, chronic exposure 

to pyraflufen-ethyl from food including the proposed new uses on hops and peanuts 

will incrementally utilize <1% of the cPAD of 0.172 mg/kg/day for all population 

groups. 

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

determined to be pyraflufen-ethyl. Based on the First Index Reservoir Screening 

Tool (FIRST), Pesticide Root Zone Model/Exposure Analysis Modeling System 

(PRZM/EXAMS), and Screening Concentration in Ground Water (SCI-GROW) 

models, the estimated drinking water concentrations (EDWCs) of pyraflufen-ethyl 

for acute exposures are estimated to be 1,247 parts per trillion (ppt) for surface 

water and 1.8 ppt for ground water. For chronic exposures for non-cancer and 

cancer assessments, the EDWCs are estimated to be 281 ppt for surface water and 

1.8 ppt for ground water. 

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

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

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. 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. Current available data and 

information does not indicate or suggest that pyraflufen-ethyl has a common 

mechanism of toxicity with other substances. Therefore, for the purposes of this 

Food Quality Protection Act (FQPA) document, assessment of cumulative risk is not 

required. 

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. A worse case estimate, using proposed tolerance values, of chronic 

dietary exposure of pyraflufen-ethyl from hops and peanuts 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 
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risks to human health. The complete toxicity data set 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. There is essentially no incremental cancer risk associated with 

pyraflufen-ethyl treated hops and peanuts. Cancer risk was calculated by EPA as 

listed 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 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 hops and peanuts 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 EDWCs for 

surface and ground water, it is not expected the aggregate exposure to children will 

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 in the reproduction study with 

pyraflufen-ethyl. There are no residual uncertainties for pre- and/or post-natal 

exposure. 

F. International Tolerances
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There are no Codex maximum residue levels (MRLs) established for 

residues of pyraflufen-ethyl and the acid metabolite, E-1, expressed in terms of 

parent on any crop. Canada has not established MRLs for pyraflufen-ethyl.