Document ID: EPA-HQ-OPP-2013-0161-0003
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2013-06-05T04:00Z

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and shallot, fresh leaves at 1.5 ppm, as they will be superseded by the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 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
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.]

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.  

otal 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 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.]

	

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(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]

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