EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE 

PETITIONS PUBLISHED IN THE FEDERAL REGISTER 

EPA Registration Division contact: Tony Kish

Interregional Research Project No. 4

Petition #5E8434

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

(IR-4), 500 College 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 4–15A, Leafy greens subgroup at 60.0 ppm

including amaranth, Chinese; amaranth, leafy; aster, Indian; blackjack; cat’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, 

tanier; swiss chard; and violet, Chinese; crops in the proposed Crop Subgroup 4–15B, Brassica leafy 

greens subgroup at 55 ppm including Arugula; broccoli raab; broccoli, Chinese; cabbage, abyssinian; 

cabbage, seakale; Chinese cabbage, bok choy; collards; cress, 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 including 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. Cottonseed Subgroup

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-(methylthio)-5-phenyl-3-(phenylamino)-, (S)- in or on raw agricultural commodity 

Brassica, head and stem, subgroup 5A at 5.0 ppm, Brassica, leafy greens, subgroup 5B at 55 ppm, 

Cotton, undelinted seed at 0.02 ppm, Cilantro, leaves at 60 ppm, and Vegetable, leafy, except 

Brassica, group 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 

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.
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A. Residue Chemistry

1. Plant metabolism. The plant metabolism of fenamidone (RPA 407213) 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 significant metabolite was 

RPA 410193 (17% of the total radioactive residue (TRR) in grapes, 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 (TRR) 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. Independently validated 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 rotary 

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 detection (LC/MS/MS). The method limit of quantification 

(LOQ) is 0.02 ppm or lower for fenamidone in all raw agricultural commodities and processed 

fractions.

3. Magnitude of residues. Magnitude of residue trials were conducted for fenamidone on basil in 

field and greenhouse. Trials were conducted in the various required regions across the United States 

and in greenhouses 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 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 NOAEL was 500 mg/kg for 

males and 125 mg/kg for females.

2. Genotoxicity. Fenamidone is not considered 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 developmental 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 occurred 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 absolute 
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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 measured reproductive parameters.

4. Subchronic toxicity. In a 13-week subchronic feeding study in rats, the NOAEL was 10.41

mg/kg/day (males) and 12.00 mg/kg/day (females). The LOAEL was 68.27 mg/kg/day for males and 

83.33 mg/kg/day for females based on increased liver weights and histopathological changes in liver 

of males. In a 13-week subchronic feeding study in mice, the NOAEL was 44.49 mg/kg/day (males) 

and 54.13 mg/kg/day (females). The LOAEL was 220.17 mg/kg/day (males) and 273.86 mg/kg/day 

(females) based on increased liver weights and histopathological changes at the high dose. In a 28-

day dermal toxicity 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 NOAEL was 500 mg/kg/day, 

the highest dose tested. In a subchronic neurotoxicity study in rats, there was no evidence 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 NOAEL for the study was 1000 ppm (equivalent to 

73.5 and 83.4 mg/kg/day).

5. Chronic toxicity. The target organ in chronic studies 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 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 type 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 toxic than the parent. There was no 

evidence of treatment-related oncogenicity in long-term studies in rats and mice. Therefore, 

fenamidone 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) 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 consecutive days were fed to rats. Fenamidone was relatively well absorbed at a nominal dose 

of 3 mg/kg in both sexes and intensively 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 radioactivity 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. 
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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 dietary metabolites of fenamidone, RPA 412708, RPA 410193 

and RPA 412636 were evaluated for mammalian toxicity in acute oral toxicity, 90-day dietary, and 

genotoxicity studies. 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 aquatic organisms and wildlife did not reveal endocrine effects. Any 

endocrine-related effects would have been detected in this definitive 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 assessment was conducted for fenamidone that 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 acute reference dose (aRfD) of 

1.25 mg/kg bw/day is based on a NOAEL of 125 mg/kg bw/day from the acute neurotoxicity study in 

rat and the standard 100X uncertainty factor (10X interspecies 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 dietary exposure estimates at the 95th 

percentile of exposure for the US Population was 3.37% of the acute Reference Dose (aRfD). The 

population subgroup with the highest exposure 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) using 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 numerous crops. 
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The maximum Tier II EDWCs of total fenamidone 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 

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 residential 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 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 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 completeness 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 Population 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 children, 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 highly exposed subgroups) is 4.78% and 87.2% 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
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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 vegetables 

(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), brassica 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 have 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 bell 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), broccoli and 

cabbage (5 ppm), mustard greens (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).