EPA REGI STRATION DIVI SION COMPANY NOTI CE OF FILING FOR PESTICIDE

PETITIONS PUBLIS HED I N THE FEDERAL REGI STER EPA Registration Division contact: (703) 305 - 7390 Interregional Research Project No. 4 (IR- 4) Petition Number (PP#) 3E8150 Summary of Petition EPA ha s received a pesticide petition, PP# 3E8150, from Interregional Research Project Number 4, 500 C ollege 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

e stablishing a tolerance for residues of fenamidone, [4H - imidazol - 4 - one, 3,5 - dihy dro - 5 - methyl - 2 - (methylthio) - 5 -phenyl - 3 - (phenylamino) - , (S ) - ] , in or on the raw agricultural commodity ginseng at 0.80 parts per million (ppm) ; bean, s ucculent at 0.80 ppm ; onion, bulb, subgroup 03 - 07A at 0.20 ppm ; and onion, green, subgroup 03 - 07B at 1.5 ppm . Upon approval of the aforementioned tolerances, the petition additionally requests to remove the established toleranc es in or on garlic at 0.20; garlic, great headed at 0.20 ppm; leek at 1.5 ppm; onion, bulb at 0.20 ppm; onion, green at 1.5 ppm; onion, welsh at 1.5 ppm; shallot, bulb at 0.20 ppm; and shallot, fresh leaves at 1.5 ppm, as they will be superseded by

the tolerances described above. EPA has determined that the petition contains data or information regarding the elements set forth in section 408(d)(2) of the FFDCA; however, EPA has not fully

evaluated the sufficiency o f 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 plant metabolism of fenamidone (RPA407213) was evaluated in five distinct crops (lettuce, tomatoes , potatoes, carrots and grapes) and is adequately understood. In all cases, the primary

residue was the parent compound. The only s ignificant metabolite was RPA410193 (17% of the total radioactive residue (TRR) in grapes, 9% o f the total radioactive residue (TRR) in tomatoes, <1% of the total radioactive residue (TRR) in lettuce (mostly in the wrapper leaves), and <1% of the total radioactive residue (TRR) in potatoes (haulm or tubers)), and RPA406012 (4.5% of TRR in carrot top s). RPA412708 and RPA412636 were minor metabolites reported in the lettuce and potato studies and may account for part of the unidentified residue reported in the grape and tomato metabolism studies.] 2. Analytical method. [Although residue levels approaching the proposed tolerances are unlikely, independently

v alidated enforcement methods are available for determining residues of3

fenamidone and relevant metabolites. Residues are first extracted from the crop matrix by b lending or shaking with a mixture of acetonitrile and water. A fter filtration, an aliquot of the extract is rotary evaporated to near dry

ness, then diluted with water. C leanup is accomplished on a HR- P poly meric solid phase extraction (SPE) cartridge and an amino SPE cartridge. Residu es are quantified by HPL C with tandem mass spectrometric detection (LC/MS/MS). The method limits of quantification (LOQ) are 0.02 ppm or lower for fenamidone, and its metabolites, RPA 412636, RPA 412708, and RPA 410193 in test raw agricultural commodities and processed fractions.] 3. Magnitude of residues . [ Magnitude of residue trials were conducted for fenamidone on ginseng, lima beans and snapbeans. Trials were conducted in the various required regions across the United States in accordance with EPA guidance for crop field trials under OPPTS 860.1500.] B. Toxicological Profile 1. Acute toxicity . [ Fenamidone has low acute toxicity by the oral, dermal and inhalation routes of exposure (Toxicity Categories III and IV) . Fenamidone was moderately ir ritating to the eye (Toxicity

C ategory

III), but not irritating to the skin (Toxicity C ategory

IV) . The dermal sensitization study

in guinea pigs was negative. Inan acute neurotoxicity s tudy in rats, fenamidone was not neurotoxic at doses up to the limit dose of 2000 mg/kg. The NO AEL was 500 mg/kg for males and 125 mg/kg for females.] 2. Genotoxic i ty . [Fenamidone is not considered to be mutagenic based on a battery o f in vitro and in vivo mutagenicity

studies. 3. Reproductive and developmental toxicity . [ Fenamidone did not demonstrate any qualitative or quantitative increased susceptibility in the rat and rabbit developmental toxicity studies or the 2 - generation rat reproduction study . In rabbits, there were no developmental effects up to the hi ghest dose tested and in the presence of maternal toxicity . Inthe rat, developmental findings and maternal findings both occurred at the limit dose. In the reproduction study (Sprague Dawley

rat), decreased absolute brain weight and pup body w eight occurred at the same dose levels as decreased absolute brain weight and parental body weight, food consumption, and increased liver and spleen weight. Therefore, pup effects occurred only in the presence of maternal toxicity . There were no effects on fertility

or other me asured reproductive parameters. ] 4. Subchronic toxicity. [In a 13 - week subchronic feeding study in rats, the NO AEL was 10.41 mg/kg/day

(males) and 12.00 mg/kg/day ( females). The LO AEL was 68.27 mg/kg/day f or males and 83.33 mg/kg/day f or f emales based on increased liver weights and histopatho logical changes in liver of males . In a 13 - week subchronic feeding study in mice, the NO AEL was 44.49 mg/kg/day

(males) and 54.1 3 mg/kg/day ( females). The LO AEL was 220.17 mg/kg/day (males) and 273.86 mg/kg/day

(females) based on increased liver weight s and histopathological changes at the high dose. Ina

2 8 - day dermal toxicity

s tudy in rats, a slight decrease in food consumption and body weight was observed in males at 1000 mg/kg/day . In a 13 - week s tudy in dogs, the NO AEL was 500 mg/kg/day, the highest dose tested . In a subchronic neurotoxicity s tudy in rats, there was no4

evi dence of neurotoxicity at dietary l evels up to 5000 ppm (392.3 and 414.2 mg/kg/day in males and females, respectively

), the maximum tolerated dose . The NO AEL for the study was 1000 ppm (equivalent to 73.5 and 83.4 mg/kg/day ).] 5. Chronic toxicity . [ The target organ in chronic s tudies in the mouse and dog was the liver , and in rat , the target organs were the liver and thy roid. Inthe chronic toxicity rat study, the systemic NOAEL was based on diffuse C - cell hy perplasia of the thy

roid in both sexes as the most sensitive indicator of toxicity . At higher doses, follicular cells and the liver were affected. The similarity in the systemic NOAELs and the ty pe of toxicity

observed (primarily

liver) for the 90 - day

rat studies with the parent and plant metabolites (RPA 412636, RPA 412708, and RPA 410193) demonstrated that, on a subchronic basis, the plant metabolites were not more toxi c than the parent. There was no evidence of treatment - related oncogenicity in long - term studies in rats and mice. Therefore, f enamidone is not likely

to be a human carcinogen. ] 6. Animal metabolism . [ Metabolism studies conducted with goat and hen demo nstrate that fenamidone is rapidly

m etabolized and excreted. Residue levels in edible animal tissues (meat, milk and eggs) are negligible and do accumulate in those tissues. The metabolic pathway proceeds via cleavage of the amino -phenyl group and the thiomethyl group with further metabolism by hydroxylation. There is also evidence to indicate that glucuronide and sulfate conjugates are formed. A single low dose (3 mg/kg), a single high dose (300 mg/kg) and a low dose (3 mg/kg) administered for 15 conse cutive days were fed to rats. F enamidone was relatively well absorbed at a nominal dose of 3 mg/kg in both sexes and intensively m etabolized by

p hase I (oxidation, reduction and hydrolysis) and II (conjugation) reactions. The elimination of radiolabeled fenamidone was relatively rapid with the majority

of the administered dose being excreted via the biliary route (for the low dose experiments). The comparison of the levels of radioactivity recovered in bile kinetic and ADME studies suggested that a part of the radioactivity excreted via the bile could be reabsorbed and subsequently

re - excreted via the urine. H igh levels of radioactivity m easured in blood samples from the tissue kinetics also supported this hy pothesis. At the high dose level fenamidone w as not very w ell absorbed: S ome 50 - 60% of the radioactivity w as present as parent compound in the feces. Radioactivity

w as widely

distributed in the tissues with predominance in the thy roids, blood, liver, kidneys, fat and pancreas. F enamidone is theref ore expected to be rapidly and extensively metabolized and excreted in mammals.] 7. Metabolite toxicology . [ The major dietary m etabolites of fenamidone, RPA 412708, RPA 410193 and RPA 412636 were evaluated for mammalian toxicity in acute oral toxicity, 90 - day dietary, and genotoxicity s tudies . The metabolites are not considered to be more toxic than the parent compound .] 8. Endocrine disruption . [Chronic, lifespan, and multi - generational bioassays in mammals and acute and subchronic studies on aquati c organisms and wildlife did not reveal endocrine effects. Any endocrine - related effects would have been detected in this definitive array o f required tests. The probability

of any such effect due to agricultural uses of fenamidone is negligible.]5

C. A ggregate Exposure 1. Dietary exposure . [ A dietary e xposure assessment was conducted for fenamidone that included all current and proposed uses of fenamidone Therefore the aggregate exposure would consist of any

p otential exposures to fenamidone residues from food and water. The acute reference dose (aRfD) of 1.25 mg/kg bw/day i s based on a NOAEL of 125 mg/kg bw/day f rom the acute neurotoxicity

s tudy in rat and the standard 100X uncertainty f actor (10X inter species and 10X intraspecies). The chronic RfD (c RfD) of 0.03 mg/kg bw/day i s based on a NOAEL of 2.83 mg/kg bw/day from the two - ye ar rat chronic study and the UF of 100X.] i. Food. [Acute and chronic dietary analyses were conducted to estimate exposure to potential fenamidone residues in/on the crop s and crop groups mentioned above. Tier I analyses were conducted by

the Agency for both the acute and chronic scenarios using the DEEM - FCID software based on NHANES consumptions data . The acute dietar y e xposure estimates at the 95 th percentile of exposure for the US Population was 3 .31 % of the acute Reference Dose (aRfD). The population subgroup with the highest exposure was Children 3 - 5 at 4.59 % of the aRfD. C hronic dietary exposure estimates from potential residues of fenamidone for the US Population was 50.0 % of the chronic RfD (cRfD). The sub -population with the highest exposure was Children 1 - 2 at 84.8 % of the cRfD. ] ii. Drinking water . [ The drinking water residues used in the dietary risk assessment were EFED modeled values for ground and surf ace water. The modeled EDWCs (estimated drinking water concentrations) are reported for total fenamidone residues, which includes parent and its degradation products, RPA 412636, RPA 412108, RPA 411639, RPA 413255, RPA 409446, and RPA 410995. S urface wat er EDWCs were calculated using a Tier II model for surface water PRZM (Version 3.122) and EXAMS (Version 2.98.04) using the PE5 platform. The EDWC in ground water were estimated using SCI - GROW (Version 2.3). E DWCs in surface source water were corrected u sing the default percent crop area factor (0.87). The default PCA was applied because fenamidone can be used on numerous crops. The maximum Tier II EDWCs of total fenamidone residues in surface source water are not expected to exceed 47.88 μg/Lfor the 1 in 10 year daily peak concentration 12.86 μg/Lfor the 1 in 10 year annual average concentration, and 6.89 μg/L for the 30 ye ar annual average concentration. The maximum concentration of total fenamidone residues in shallow groundwater are not expected to exceed 176 μg/L . ] 2. Non - dietary exposure . [Fenamidone is not registered for residential uses (food or non food), thereby

eliminating any

potential for res idential exposure or non - occupational exposure.]6

D. Cumulative Effects [Section 408(b)(2)(D)(v) requires that, when considering whether to establish, modify, or revoke a tolerance, the Agency

c onsider “available information” concerning the cumulative e ffects of a particular pesticide’s residues and other substances that have a common mechanism of toxicity . There is no available data to determine whether fenamidone has a common mechanism of toxicity with other substances or how to include this pesticide in a cumulative risk assessment. Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, fenamidone does not appear to produce a toxic metabolite produced by o ther substances. For the purpos es of this tolerance petition, therefore, it has not been assumed that fenamidone has a common mechanism of toxicity with other substances.] E. Safety Determination 1. U.S. population . [Using the assumptions and data described above, based on the comp leteness and reliability o f the toxicity

data, it is concluded that the dietary e xposure (food and water) from the proposed uses of fenamidone will utilize at most 3 .3 % of the aRfD and 50 % of the cRfD for the US Population. EPA generally has no concern fo r exposures below 100% of the RfD because the RfD represents the level at or below which daily aggregate exposure over a lifetime will not pose appreciable risk to human health . Therefore, there is a reasonable certainty t hat no harm will occur to the US P opulation from aggregate exposure (food and drinking water) to residues of fenamidone.] 2. Infants and children . [In consideration of the toxicology database as discussed above, EPA has determined that there is no extra sensitivity o f infants and children, and therefore the default FQPA safety

f actor can be removed. U sing the assumptions and data described in the exposure section above, the percent of the aRfD and cRfD from exposure to residues of fenamidone in food and water for children 3 - 5 (the most highly exposed subgroups) is 4.6 % and 85 % of the acute and chronic RfD , respectively . There are no non - dietary concerns for infants and children. Therefore, there is a reasonable certainty that no harm will occur to infants and children from aggregate exposure to residues of fenamidone.] F. International Tolerances [Codex MRL s are not yet established for fenamidone. To be evaluated in 2014 ]