EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE

PETITIONS PUBLISHED IN THE FEDERAL REGISTER

EPA Registration Division contact: T ony Kish

Interregional Research Project No. 4 Petition #5E8434

EPA has re ceived a pesticide petition ( 5E8434 ) from Interregional Research Project No. 4 (IR

- 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 :

1) establishing a tolerance for residues of fenamidone, 4H

- imidazol

- 4

- one, 3,5

- dihydro

- 5

- methyl

- 2

- (methylthio)

- 5

- phenyl

- 3

- (phenylamino)

- , (S)

- in or on the raw agricultural commodity basil, fresh leaves at 30 parts per million (ppm )
, basil, dried leaves at 200 ppm

. Additionally tolerances are proposed for the crops in the proposed Crop Subgroup 4

– 15 A, Leafy greens subgroup at 60.0 ppm including amaranth, Chinese; amaranth, leafy; aster, Indian; blackjack; c at’s whiskers; chervil, fresh leaves; cham

- chwi; cham

- na

- mul; chipilin; chrysanthemum, garland; cilantro, fresh leaves; corn salad; cosmos; dandelion; dang

- gwi; dillweed; dock; dol

- nam

- mul; ebolo; endive; escarole; fameflower; feather cockscomb; good king henry; huauzontle; jute, leaves; lettuce, bitter; lettuce, head; lettuce, leaf; orach; parsley, fresh leaves; plantain, buckhorn; primrose, English; purslane, garden; purslane, winter; radicchio; spinach; spinach, malabar; spinach, New Zealand; spinach,
ta nier; swiss chard; and violet, Chinese; crops in the proposed Crop Subgroup 4

– 15 B, Brassica leafy greens subgroup at 55 ppm including Arugula; broccoli raab; broccoli, Chinese; cabbage, abyssinian; cabbage, seakale; Chinese cabbage, bok choy; collards; cre ss, garden; cress, upland; hanover salad; kale; maca; mizuna; mustard greens; radish, leaves; rape greens; rocket, wild; shepherd’s purse; turnip greens; and watercress; crops in the proposed Crop Subgroup 22B, Leaf petiole vegetable subgroup at 60 ppm inc luding Cardoon; celery; celery, Chinese; fuki; rhubarb; udo; zuiki and the
crops in the proposed Crop Group 5

– 15 : Brassica Head and Stem Vegetable at 5.0 ppm including broccoli; Brussels sprouts; cabbage; cabbage, Chinese, napa; and cauliflower

. C ottonsee d S ubgroup 20C at 0.02 ppm , Kohlrabi at 5. 0 ppm , Celtuce at 60 ppm , Fennel, Florence, fresh leaves and stalk at 60 ppm , and;

2) remove established tolerances for residues of fenamidone, 4H

- imidazol

- 4

- one, 3,5

- dihydro

- 5

- methyl

- 2

- (methylthi o)

- 5

- phenyl

- 3

- (phenylamino)

- , (S)

- in or on raw agricultural commodity B rassica, head and stem, s ubgroup 5A at 5.0 ppm , B rassica, leafy greens, s ubgroup 5B at 55 ppm , Cotton, undelinted seed at 0.02 ppm , Cilantro, leaves at 60 ppm , and Ve ge table, leafy, except Brassica, g roup 4 at 60 ppm

. 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 of the submit ted data at this time or whether the data supports granting of the petition. Additional data may be needed before EPA rules on the petition.3

A. Residue Chemistry

1. Plant metabolism

. The plant metabolism of fenamidone (RPA 407213) was evaluated in f ive distinct crops (lettuce, tomatoes , potatoes, carrots and grapes) and is adequately understood. In all cases, the primary residue was the parent compound. The only significant metabolite was RPA 410193 (17% of the total radioactive residue (TRR) in gr apes, 9% of 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 (TR R) in potatoes (haulm or tubers ), and RPA 406012 (4.5% of TRR in carrot tops). RPA 412708 and RPA 412636 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

. I ndependently va lidated enforcement methods are available for determining residues of fenamidone in crops . Residues are first extracted from the crop matrix by blending or shaking with a mixture of acetonitrile and water. After filtration, an aliquot of the extract is r otary evaporated to near dryness, then diluted with water. Cleanup is accomplished on a HR

- P polymeric solid phase extraction (SPE) cartridge and an amino SPE cartridge. Residues are quantified by HPLC with tandem mass spectrometric detectio n (LC/MS/MS). The method limit of quantification (LOQ) is 0 .02 ppm or lower for fenamidone in all raw agricultural commo dities and processed fractions.

3. Magnitude of residues

. Magnitude of residue trials were conducted for fenamidone on basil in field and greenh ouse . Trials were conducted in the various required regions across the United States and in greenhouses in accordance with EPA guidance for crop fi eld trials under OPPTS 860.1500

. B. Toxicological Profile

1. Acute toxicity. Fenamidone has low acu te toxicity by the oral, dermal and inhalation routes of
exposure (Toxicity Categories III and IV) . Fenamidone was mode rately irritating to the eye (Toxicity Category III), but not irritating to the skin (Toxicity Category IV) . The dermal sensitization study in guinea pigs was negative. In an acute neurotoxicity study in rats, fenamidone was not neurotoxic at doses up to the limit dose of 2000 mg/kg. The NO A EL was 500 mg/kg for

m ales and 125 mg/kg for females.

2. Genotoxic i ty

. Fenamidone is not c onsidered to be mutagenic based on a battery of 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 devel opmental toxicity studies or the 2

- generation rat reproduction study. In rabbits, there were no developmental effects up to the highest dose tested and in the presence of maternal toxicity. In the rat, developmental findings and maternal findings both oc curred at the limit dose. In the reproduction study (Sprague Dawley rat), decreased absolute brain weight and pup body weight occurred at the same dose levels as decreased absolute4

brain weight and parental body weight, food consumption, and increased liv er 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 for males and 83.33 mg/kg /day for females based on increased liver weights and histo patho logical changes in liver of males . In a 13

- week subchronic feeding stu dy 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. In a 28

- day dermal tox icity study in rats, a slight decrease in food consumption and body weight was observed in males at 1000 mg/kg/day. In a 13

- week study in dogs, the NO A EL was 500 mg/kg/day, the highest dose tested . In a subchronic neurotoxicity study in rats, there was n o evi dence of neurotoxicity at dietary levels up to 5000 ppm (392.3 and 414.2 mg/kg/day in males and females, respectively), the maximum tolerated dose . The NO A EL 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 thyroid. In the chronic toxicity rat study, the systemic NOAEL was based on diffuse C

- cell hyperplasia of the thyroid in both sexes a s the most sensitive indicator of toxicity. At higher doses, follicular cells and the liver were affected. The similarity in the systemic NOAELs and the type of toxicity observed (primarily liver) for the 90

- day rat studies with the parent and plant meta bolites (RPA 412636, RPA 412708, and RPA 410193) demonstrated that, on a subchronic basis, the plant metabolites were not more toxic 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 demonstrate that fenamidone is rapidly metabolized and excreted. Residue levels in edible animal tissues (meat, milk and eggs) a re 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 con jugates 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 consecutive days were fed to rats. Fenamidone was relatively well absorbed at a nominal dose of 3 mg/kg in both sexes and intensi vely metabolized by phase 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. High levels of ra dioactivity measured in blood samples from the tissue kinetics also supported this hypothesis. At the high dose level fenamidone was not very well absorbed: Some 50

- 60% of the radioactivity was present as parent compound in the feces.5

Radioactivity was widely distributed in the tissues with predominance in the thyroids, blood, liver, kidneys, fat and pancreas. Fenamidone is therefore expected to be rapidly and extensively metabolized and excreted in mammals.

7. Metabolite toxicology. The major diet ary metabolites of fenamidone, RPA 412708, RPA 410193 and RPA 412636 were evalua ted for mammalian toxicity in acute oral toxicity, 90

- day dietary, and genotoxicity studies . The metabolites are not consider ed 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 aquatic organisms and wildlife did not reveal endocrine effects. Any endocrine

- related effects would have been detected in this de finitive array of required tests. The probability of any such effect due to agricultural uses of fenamidone is negligible.

C. Aggregate Exposure

1. Dietary exposure

. A dietary exposure assessmen t was conducted for fenamidone t hat included all
current and proposed uses of fenamidone Therefore the aggregate exposure would consist of any potential exposures to fenamidone residues from food and water. The acu te reference dose (aRfD) of 1.25 mg/kg bw/day is based on a NOAEL of 125 mg/kg bw/day from the acu te neurotoxicity study in rat and the standard 100X uncertainty factor (10X inter species and 10X intraspecies). The chronic RfD (cRfD) of 0.03 mg/kg bw/day is based on a NOAEL of 2.83 mg/kg bw/day from the two

- year 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 crops 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 (Ver 4.02) based on NHANES consumptions data . The acute dietar y exposure estimates at the 95 th percentile of exposure for the US Population was 3 .37 % of the acute Reference Dose (aRfD). The population subgroup with the highest ex p osure was Children 1

- 2 at 4.78 % of the aRfD. Chronic dietary exposure estimates from potential residues of fenamidone for the US Population was 51.5 % of the chronic RfD (cRfD). The sub

- population with the highest exposure was Children 1

- 2 at 87.2 % of the cRfD.

ii. Drinking water

. The drinking water residues used in the dietary risk assessment were EFED modeled values for ground and surface 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. Surface water EDWCs were calculated using a Tier II model for surface water PRZM (Version 3.122) and EXAMS (Version 2.98.04) u sing the PE5 platform. The EDWC in ground water were estimated using SCI

- GROW (Version 2.3). EDWCs in surface source water were corrected using the default percent crop area factor (0.87). The default PCA was applied because fenamidone can be used on nu merous crops.6

The maximum Tier II EDWCs of total f enamidone residues in surface source water are not expected to exceed 47.88 μg/L for the 1 in 10 year daily peak concentration 12.86 μg/L for the 1 in 10 year annual average concentration, and 6.89 μg/L for the 30 year annual average concentration. The

ma ximum 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 residenti al exposure or non

- occupational exposure.

D. Cumulative Effects

Section 408(b)(2)(D)(v) requires that, when considering whether to establish, modify, or revoke a tolerance, the Agency consider “available information” concerning the cumulative effects 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 c umulative 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 have a common toxic metabolite produced by other substances. For the purposes 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 complete ness and reliability of the toxicity data, it is concluded that the dietary exposure (food and water) from the proposed uses of fenamidone will utilize at most 3

. 37 % of the aRfD and 51.5 % of the cRfD for the US 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 exposure over a lifetime will not pose appreciable risk to human health

. Therefore, there is a reasonable certainty that no harm will occur to the US Po pulation 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 of infants and childre n, and therefore the default FQPA safety factor can be removed. Using 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 1

- 2 (the most h ighly exposed subgroups) is 4.78 % and 87.2 % of the acute and chronic RfD , respectively. There are no non

- dietary conce rns for infants and children. Therefore, there is a reasonable certainty that no harm will occur to infants and children from aggregate e xposure to residues of fenamidone.

F. International Tolerances7

Codex MRLs are not yet established for fenamidone. Tolerances have been established in Canada for root vegetable, except radish and sugar beets (CSG 1B at 0.15 ppm), tuberous and corm vege tables (CSG 1C at 0.02 ppm), ginseng (0.80 ppm), onion, bulb (CSG 3

- 07A at 0.20 ppm), onion, green (CSG

- 07B at 1.5 ppm), leafy vegetables, except brassica (CG 5 at 60 ppm), turnip tops (55 ppm), brassica head and stem vegetables (CSG 5A at 5.0 ppm), brass ica leafy greens (CSG 5B at 55 ppm), fruiting vegetables, except nonbell peppers (CG 8 at 1.0 ppm), okra and nonbell pepper (3.5 ppm), cucurbit vegetables (CG 9 at 0.15 ppm)succulent beans except cowpeas (0.80 ppm) and cottonseed (0.02 ppm). Tolerances ha ve been established in Europe for carrots, garden beets and parsnips (0.15 ppm); potato (0.02 ppm), onion, bulb (0.20 ppm), onion, green (1.5 ppm), broccoli (5 ppm), cabbage (0.02 ppm), lettuce, head and leaf, celery and endive (40 ppm), spinach (60 ppm), succulent beans (0.02 ppm), tomatoes and be ll pepper (1.0 ppm), okra 0.02 ppm), cucurbit vegetables (0.20 ppm); cottonseed (0.05 ppm) and sunflower (0.05 ppm). Tolerances have been established in Japan for carrots (0.15 ppm), potato (0.02 ppm), bulb onions (0.20 ppm), green onions (1.5 ppm), brocc oli and cabbage (5 ppm), mustard gree ns (5 ppm); Chinese cabbage (55 ppm); head and leaf lettuce (20ppm); tomato and bell pepper (1.0 ppm ); melons (0.15 ppm); cotton seed (0.02 ppm) and sunflower seed (0.02 ppm).