Document ID: EPA-HQ-OPP-2006-0848-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-11-08T05:00Z

FILE NAME:   company.wpt   (1/1/2006) (xml)

Template Number P25	

ATTENTION: 

All commodity terms must comply with the Food and Feed Commodity
Vocabulary database (http://www.epa.gov/pesticides/foodfeed/).

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be removed prior to sending the document to the Federal Register Staff. 
Instructional text and prompts in green font should also be removed.

COMPANY FEDERAL REGISTER DOCUMENT SUBMISSION TEMPLATE

(Template Number P25; 1/1/2006)

EPA Registration Division contact: [Barbara Madden, (703) 305-6463]	

INSTRUCTIONS:  Please utilize this outline in preparing tolerance
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TEMPLATE:

[Interregional Research Project No. 4]

[Insert petition number]

 Summary of Petitions

	EPA has received pesticide petitions ([insert petition number]) from
[Interregional Research Project No. 4, 681 US Hwy. No. 1 South, North
Brunswick, NJ 08902-3390; and Bayer CropScience, 2 T.W. Alexander Drive,
Research Triangle Park, NC 27709] 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 [vegetable, brassica, head and
stem, subgroup 5A] at [4.0] parts per million (ppm), [vegetable,
brassica, leafy greens, subgroup 5B] at [35] ppm, [vegetable, fruiting,
group 8] at [2.0] ppm, [vegetable, leafy, except brassica, group 4] at
[35] ppm, [carrot] at [0.15 ppm], [cotton, undelinted seed] at [0.02]
ppm, [cotton, gin byproducts] at [0.02 ppm], and [sunflower] at [0.08]
ppm; and establishing tolerances for combined inadvertent residues of
[fenamidone, [4H-imidazol-4-one,
3,5-dihydro-5-methyl-2-(methylthio)-5-phenyl-3-(phenyl-amino)-, (S)-]
and [its metabolite RPA 717879 (2,4-imidazolidinedione,
5-methyl-5-phenyl)] in or on [strawberries] at [0.02] 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.

A. Residue Chemistry 

.  [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.]

.  [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.]

.  [Complete residue data to support the requested tolerances on head
and stem brassica vegetables, leafy brassica greens, fruiting
vegetables, leafy vegetables, carrots, cotton, sunflower and
strawberries have been submitted to the Agency.]

B. Toxicological Profile

.  [A complete battery of acute toxicity studies for fenamidone has been
conducted.  The acute oral toxicity study in rats resulted in a LD50 of
>5000 mg/kg (males) and  >2028 mg/kg (females).  The acute dermal
toxicity study in rats resulted in a LD50 of >2000 mg/kg for both males
and females.  The acute inhalation study in rats resulted in a LC50 of >
5 mg/L for males and females.  Fenamidone was not irritating in the
primary eye irritation or primary dermal irritation studies.  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 NOEL was 500 mg/kg for males and
125 mg/kg for females.]

.  [Mutagenicity studies conducted include: a Salmonella typhimurium
reverse mutation assay (negative at the limits of cytotoxicity and
solubility with and without activation), in vitro unscheduled DNA
synthesis test in rat liver (negative at the limits of cytotoxicity), in
vitro chromosome aberrations test in human lymphocytes (positive at the
limits of cytotoxicity and solubility), TK+/- mouse lymphoma assay
(positive with activation, negative without), in vivo mouse micronucleus
test (negative with toxicity at 2000 mg/kg), and an in vivo unscheduled
DNA synthesis assay in the rat (negative at up to 2000 mg/kg with
toxicity at the high dose level).  Based on the data cited above,
fenamidone is not considered to be mutagenic.]

.  [A teratology study was conducted with rats administered (orally)
fenamidone on gestation days 6-15 at dose levels of 0, 25, 150, or 1000
mg/kg/day.  High dose dams had significantly decreased body weight and
food consumption.  High dose fetal body weights were less than controls
and correlated with slightly delayed skeletal ossification secondary to
maternal toxicity.  The NOEL for maternal and developmental toxicity is
150 mg/kg/day.  The LOEL was 1000 mg/kg/day.  A teratology study was
conducted with rabbits administered (orally) fenamidone on gestation
days 6-19 at dose levels of 0, 10, 30, or 100 mg/kg/day.  The maternal
NOEL was 10 mg/kg/day.  The developmental NOEL was 100 mg/kg/day.  The
maternal LOEL was 30 mg/kg/day, based on increased maternal liver
weights at 30 and 100 mg/kg/day.  Fenamidone demonstrates no potential
to cause developmental toxicity in mammals.  A two-generation definitive
reproduction study was conducted with rats administered (orally) in the
diet fenamidone at dose levels of 0, 3.9, 63.8, 328.3 mg/kg/day (males)
and 0, 5.15, 84.4, 459.6 mg/kg/day (females).  The NOEL for maternal and
offspring toxicity was 5.15 mg/kg/day.  The maternal NOEL was based on
decreased body weight and food consumption.  The pup NOEL is based on F1
pup body weight decrease. The reproductive NOEL was >328.3 mg/kg/day
(males) and >459.6 mg/kg/day (females).  Fenamidone is not considered a
reproductive toxicant at non-maternally toxic dose levels and shows no
evidence of endocrine effects. A developmental neurotoxicity study was
conducted with rats administered fenamidone on gestation days 6-20 at
dose levels of 0, 5.5, 23.2, 92.3, or 429 mg/kg/day, respectively. No
maternal deaths or clinical signs of toxicity were observed during the
study. However, at 429 mg/kg/day mean body weight gain was significantly
decreased. Litter viability and clinical signs in offsprings were
unaffected by treatment, but post-weaning body weight was significantly
decreased at the high dose of 429 mg/kg/day. The maternal NOAEL was 429
mg/kg/day and the offspring NOAEL was 92.3 mg/kg/day.]

  [In a 13-week range-finding study, fenamidone was administered in the
diets of male and female rats at dose levels of 0, 4.05, 10.41, 68.27,
343.93 mg/kg/day to males and 0, 4.81, 12, 83.33, 380.68 mg/kg/day to
females. The NOEL is 68.27 mg/kg/day (males) and 83.33 mg/kg/day
(females) and the LOEL is 343.93 mg/kg/day for males and 380.63
mg/kg/day for females based on adaptive liver changes at 68.27 mg/kg/day
and increased liver and thyroid weights at the highest dose tested.  In
a 13 week subchronic feeding study, fenamidone was administered in the
diet to mice at dose levels of 0, 11.33, 44.5, 220.2, 1064.3 mg/kg/day
to males and 0, 13.7, 54.1, 273.9, 1375.2 mg/kg/day to females. The NOEL
is 44.5mg/kg/day (males) and 54.1 mg/kg/day (females) and the LOEL is
220.2 mg/kg/day (males) and 273.9 mg/kg/day (females) based on 14%
increase in liver weight at the high dose. In a 28 day subchronic dermal
study, fenamidone was applied to skin of male and female New Zealand
white rabbits at doses of 0 or 1000 mg/kg/day for 6 hours/day, 5
days/week.  Treatment produced a slight decrease in food consumption
(8-10%) and body weight (6%) in males only.  In a 13-week study,
fenamidone was administered in the diets of male and female dogs at 0,
10, 100, and 500 mg/kg/day.  Based on clinical symptoms at the high
dose, the NOEL is 100 mg/kg/day and the LOEL is 500 mg/kg/day.  In a
subchronic neurotoxicity study, there was no evidence of neurotoxicity
when fenamidone technical was administered to rats for 13 weeks at
dosage levels up to 5000 ppm (395.6 and 414.2 mg/kg/day), the MTD.  The
NOEL for the study was 1000 ppm (equivalent to 74.2 and 83.4
mg/kg/day).]

.  [A 1-year oral study was conducted with dogs administered fenamidone
at dose levels of 0, 10, 100, and 1000 mg/kg/day in capsules.  The NOEL
is 100 mg/kg/day for both sexes, based on significantly increased liver
weights and biliary hyperplasia in the high dose.  The LOEL is 1000
mg/kg/day.  A 2-year combined chronic toxicity/ carcinogenicity study
was conducted with fenamidone administered in the diet to rats at doses
of 0, 2.83,7.07, 47.68, 260.13 mg/kg/day (males) and 0, 3.63, 9.24,
60.93, 335.10 mg/kg/day (females).  The no-observed-effect-level (NOEL)
for systemic toxicity is 2.83 mg/kg/day (males) and 3.36 mg/kg/day
(females).  The lowest-effect-level (LOEL) is 7.07 mg/kg/day (males) and
9.24 mg/kg/day (females).  No statistically significant, linear dose
response was observed for any tumor incidence.  A 104-week combined
carcinogenicity study in mice was conducted with mice administered
fenamidone in the diet at dose levels of 0, 9.5, 47.5, 525.5, 1100.2
mg/kg/day (males) and 0, 12.6, 63.8, 690.5, 1393.2 mg/kg/day (females). 
The NOEL was 9.5 mg/kg/day (males) and 12.6 mg/kg/day (females).  The
LOEL for carcinogenicity was 47.5 mg/kg/day (males) and 63.8 mg/kg/day
(females).  The NOEL is based on non-neoplastic liver changes and
decreased body weight gain at the top two dose levels.  Fenamidone
demonstrates no potential for carcinogenic effects in mammals.]

.  [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 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.]

.  [The major dietary metabolites of fenamidone, RPA 412708, RPA 410193
and RPA 412636 were evaluated for mammalian toxicity in an acute oral
toxicity study, a 90-day repeated dose study and in genotoxicity tests. 
The metabolites are considered to be of comparable toxicity to the
parent fenamidone.]

.  [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

.  [Fenamidone is registered for use on head and leaf lettuce, tomatoes,
tuberous and corm vegetables (subgroup 1c), bulb vegetables (group 3),
cucurbit vegetables (group 9), including tolerances for rotational wheat
and imported wine grapes.  There are no residential uses proposed for
fenamidone.  New petitions have been submitted to the Agency for
fruiting vegetables (group 8),  brassica vegetables (group 5), leafy
vegetables (group 4), carrots, cotton, sunflowers (seed treatment), and
strawberries (rotational only).  Therefore the aggregate exposure would
consist of any potential exposures to fenamidone residues from carrots
plus the above food crops, drinking water, and imported wine.  The acute
reference dose (aRfD) of 0.92 mg/kg bw/day is based on a NOAEL of 92
mg/kg bw/day from the developmental 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.]

.  [Acute and chronic dietary analyses were conducted to estimate
exposure to potential fenamidone residues in/on the crops and crop
groups of tuberous and corm vegetables, leafy vegetables, bulb
vegetables, fruiting vegetables, cucurbit vegetables, brassica
vegetables, cotton, carrots, sunflower, and imported wine as well as
rotational strawberries.   Tier III analyses were conducted for both the
acute and chronic scenarios using the DEEM( (Exponent, Inc.) software. 
The acute dietary exposure estimates at the 99.9th percentile of
exposure for the US Population was 2.2% of the acute Reference Dose
(aRfD).  The population subgroup with the highest exposure was Infants
at 7.3% of the aRfD.  Chronic dietary exposure estimates from potential
residues of fenamidone for the US Population was 2.2% of the chronic RfD
(cRfD).  The sub-population with the highest exposure was Children 1-2
at 4.2% of the cRfD.].

.  [US EPA’s Standard Operating Procedure (SOP) for Drinking Water
Exposure and Risk Assessments was used to perform the drinking water
assessment.  This SOP uses a variety of tools to conduct drinking water
assessments, including water models such as SCI-GROW, FIRST,
PRZMS/EXAMS, and available monitoring data.  If monitoring data are not
available, then the models are used to predict potential residues in
surface and ground water and the highest levels are assumed to be the
drinking water residue.  In the case of fenamidone, monitoring data do
not exist, therefore SCI-GROW and FIRST were used to estimate a water
residue.  The calculated drinking water levels of comparison (DWLOC) for
acute and chronic exposure for all adults and children exceed the
modeled drinking water estimated environmental concentration (EEC).  The
acute DWLOC values are 31504 ppb for the general population, 8530 ppb
for infants and 8789 ppb for children, compared to  the worst-case acute
drinking water EEC of 10.47 ppb.  The chronic DWLOC values are 957 ppb
for the general population, 268 ppb for infants and 275 ppb for children
1-2, compared to a worst-case chronic drinking water EEC of 8.2 ppb. 
These drinking water levels of comparison are based on conservative
dietary (food) exposures and are typically expected to be much higher
under actual use scenarios.]

.  [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

.  [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 that will be used for exposure to
residues of fenamidone in food for infants and children (the most highly
exposed subgroups) is 7.3% (acute assessment for infants) and 4.2%
(chronic assessment for children 1-2), respectively. There are no
non-dietary concerns for infants and children.  As with adults, drinking
water levels of comparison are higher than the worst case drinking water
estimated concentrations and are expected to use well below 100% of the
reference dose, if they occur at all.  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.]

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