Document ID: EPA-HQ-OPP-2018-0514-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2019-05-14T04:00Z

EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER  

Branch Chief (Acting): Tawanda Maignan, maignan.tawanda@epa.gov, 
703-308-8050

TEMPLATE:

Interregional Research Project No. 4 (IR-4)

Petition #: 8E8684

	EPA has received a pesticide petition (PP#: 8E8684) from the INTERREGIONAL RESEARCH PROJECT No. 4 (IR-4), RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY, 500 COLLEGE ROAD EAST, SUITE 201W, PRINCETON, NJ  08540 requesting, 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, including its metabolites and degradates, in the commodities below. Compliance with the plant commodity tolerance levels is to be determined by measuring only the sum of the parent pyraflufen-ethyl, ethyl 2-[2-chloro-5-(4-chloro-5-difluoromethoxy)-1-methyl-1H-pyrazol-3-yl]-4-fluorophenoxy] acetate, and its acid metabolite, E-1, 2-chloro-5-(4-chloro-5-difluoromethoxy-1-methyl-1H-pyrazol-3-yl)-4-fluorophenoxyacetic acid, calculated as the stoichiometric equivalent of pyraflufen-ethyl in or on the raw agricultural commodities: Hop, dried cones at 0.02  parts per million (ppm); Fruit, stone, group 12-12 at 0.01 ppm; Nut, tree, group 14-12 at 0.01 ppm; Vegetable, tuberous and corm, subgroup 1C at 0.02 ppm; Fruit, small, vine climbing, except fuzzy kiwifruit, subgroup 13-07F at 0.01 ppm; Tropical and subtropical, small fruit, edible peel, subgroup 23A at 0.01 ppm; and Cottonseed subgroup 20C at 0.04 ppm.
   
   Upon approval of the aforementioned tolerances, it is proposed that 40 CFR 180.585 be amended to remove the established tolerances for the residues of the herbicide, pyraflufen-ethyl, including its metabolites and degradates, in the commodities below. Compliance with the plant commodity tolerance levels is to be determined by measuring only the sum of the parent pyraflufen-ethyl, ethyl 2-[2-chloro-5-(4-chloro-5-difluoromethoxy)-1-methyl-1H-pyrazol-3-yl]-4-fluorophenoxy] acetate, and its acid metabolite, E-1, 2-chloro-5-(4-chloro-5-difluoromethoxy-1-methyl-1H-pyrazol-3-yl)-4-fluorophenoxyacetic acid, calculated as the stoichiometric equivalent of pyraflufen-ethyl in or on the raw agricultural commodities: Fruit, stone, group 12 at 0.01 parts per million (ppm), Nut, tree, group 14 at 0.01 ppm, Potato at 0.02 ppm, Pistachio at 0.01 ppm, Grape at 0.01 ppm, Olive at 0.01 ppm and Cotton, undelinted seed at 0.04 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 qualitative nature of the residues of Pyraflufen-ethyl in Hop, dried cones is adequately understood.  The metabolism of Pyraflufen-ethyl has been studied in cotton, wheat, potato, and mandarin oranges.  Metabolism in the plant involves ester hydrolysis, de-methylation 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. Residues of Pyraflufen-ethyl and E-1 metabolite were extracted from crop matrices with acetonitrile:1N HCL.  Following extraction, an aliquot of the extract was partitioned against ethyl acetate:hexane and cleaned up by SCX solid phase extraction.  The resulting extract was derivatized with diazomethane to convert E-1 to E-15.  The derivatized extract was then purified by NH2 and graphitized carbon black solid phase extraction.  The purified extract is concentrated to dryness, reconstituted in toluene, and then submitted to GC-MS analysis.  Lowest level of method validation (LLMV) is 0.010 ppm and limit of detection (LOD) is 0.0045 ppm. 

	3. Magnitude of residues in Hop, dried cone. -- Residue trials were conducted in Hop, dried cone to satisfy the required EPA region locations.  There were no residues of Pyraflufen-ethyl and E-1 metabolite found in any Hop, dried cone sample greater than the LLMV of 0.01 ppm. Based on these data, it is proposed that the Agency establish new tolerances in Hop, dried cone at 0.02 ppm, which is the sum of Pyraflufen-ethyl and E-1 metabolite at their respective LLMV values of 0.01 ppm. 

Magnitude of the residue in animals. -- Ruminants. The results of the meat and milk 28-day feeding study conclude that no finite residues of the parent, Pyraflufen-ethyl 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 Pyraflufen-ethyl, 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 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, an anticipated residue value in milk calculated to be of 0.007 ppm is being used.  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.  See below. 

	2. Genotoxicty. See below. 

	3. Reproductive and developmental toxicity. See below. 

	4. Subchronic toxicity. See below. 
 
	5. Chronic toxicity. See below. 
 
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-adverse-effect-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 Hops and Peanuts," at page 18 in docket ID number EPA-HQ-OPP-2011-1002. 

	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 Pyraflufen-
ethyl is negligible. 

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, and pistachio 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.  Estimated drinking water concentrations (EDWC) were calculated using PRZM/EXAMS (surface water) and SCI-GROW (groundwater).

	i. Food. Using the exposure assumptions listed above, chronic exposure to Pyraflufen-ethyl from food including the proposed new uses utilize <1% of the chronic population adjusted dose (cPAD) of 0.2 mg/kg/day for all population groups and subgroups, including children 1-2 years old, the most highly exposed population subgroup.

	ii. Drinking water.  Tier 2 EDWCs of Pyraflufen-ethyl residues for surface water were calculated using the Pesticide Root Zone Model (PRZM-EXAMS).  The EDWC for ground water was calculated using SCI-GROW.  EDWCs were 0.295 ppb and 0.268 ppb for the chronic and cancer dietary exposure assessment, respectively.  

	2. Non-dietary exposure. EPA calculated non-dietary exposure scenarios as listed 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.

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 (RfD) 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 0.2 mg/kg/day.  This value is based on the NOAEL of 20 mg/kg/day observed in a chronic dietary rat study and a safety (uncertainty) factor of 100.  A worse case estimate, using proposed tolerance values, of chronic dietary exposure of Pyraflufen-ethyl 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 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 the conversion of crop groups.  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 Pyraflufen-ethyl and the acid metabolite 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

	There are no Canadian, Codex, or EU maximum residue levels (MRLs) established for residues of Pyraflufen-ethyl and the acid metabolite, E-1 for Hops.  However, when a U.S. tolerance is established, it will be requested that the established tolerance is harmonized with Canada, Codex, and the EU.