EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE 

PETITIONS PUBLISHED IN THE FEDERAL REGISTER 

EPA Registration Division contact: (703) 305-7390

Interregional Research Project No. 4 (IR-4)

Petition Number (PP#) 3E8150

Summary of Petition

EPA has received a pesticide petition, PP# 3E8150, from Interregional Research Project 

Number 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 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 

ginseng at 0.80 parts per million (ppm); bean, succulent 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 tolerances 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will be superseded by the tolerances described above.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 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 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 significant metabolite was 

RPA410193 (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 

RPA406012 (4.5% of TRR in carrot tops). 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 validated enforcement methods are available for determining residues of 
3

fenamidone and relevant metabolites. 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 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 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 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 
4

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. 

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.]
5

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

based on NHANES consumptions data. The acute dietary exposure estimates at the 95th 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. Chronic 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 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. 

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 nonfood), thereby eliminating any potential for residential 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 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 produce a 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 3.3% of the aRfD and 50% 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 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 MRLs are not yet established for fenamidone. To be evaluated in 2014]