Document ID: EPA-HQ-OPP-2006-0848-0009
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2008-12-03T05:00Z

EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE
PETITIONS PUBLISHED IN THE FEDERAL REGISTER  

EPA Registration Division contact: [Tony Kish; 703-308-9443]

 

INSTRUCTIONS:  Please utilize this outline in preparing the pesticide
petition.  In cases where the outline element does not apply, please
insert “NA-Remove” and maintain the outline. Please do not change
the margins, font, or format in your pesticide petition. Simply replace
the instructions that appear in green, i.e., “[insert company
name],” with the information specific to your action.

TEMPLATE:

[Bayer CropScience]

[Insert petition number]

 Summary of Petitions

EPA has received pesticide petitions ([insert petition number]) from
[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
[180.579] by establishing a tolerance for [indirect or inadvertent]
residues of [fenamidone (4H-imidazol-4- one,
3,5-dihydro-5-methyl-2-(methylthio)-5-phenyl-3-(phenylamino)-, (S)-) and
its metabolite RPA 717879 (2,4-imidazolidinedione, 5-methyl-5-phenyl)]
in or on the raw agricultural commodities [Corn, field, forage] at
[0.50] parts per million (ppm), [Corn, field, grain] at [0.02] ppm,
[Corn, stover] at [0.35] ppm, [Corn, sweet, forage] at [0.15] ppm,
[Corn, sweet, kernel plus cob with husks removed] at [0.20] ppm,
[Soybean, forage] at [0.20] ppm, [Soybean, hay] at [0.20] ppm, and
[Soybean, seed] 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 

	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.  [Field residue trials were conducted to
determine the magnitude of fenamidone residue in corn and soybeans
planted as rotational crops following treatment of fenamidone to soil. 
The number of trials is equal to or greater than that described in EPA's
review of Bayer CropScience’s field rotational crop study protocol
(EPA-OPP document D337553).] 

B. Toxicological Profile

1. Acute toxicity.  [A complete battery of acute toxicity studies for
fenamidone has been conducted.  Fenamidone has very low acute toxicity
by the oral, dermal and inhalation routes of exposure.  Fenamidone was
moderately irritating to the eye and non-irritating to the skin.  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.]

	2. Genotoxicty.  [Fenamidone is not considered to be mutagenic based on
a battery of in vitro and in vivo mutagenicity studies.] 

	3. Reproductive and developmental toxicity.  [A teratology study was
conducted using rats, with a resulting NOEL for maternal and
developmental toxicity of 150 mg/kg/day.  The LOEL was 1000 mg/kg/day,
based on significantly decreased body weight and food consumption in
dams, and decreased fetal body weights with slightly delayed skeletal
ossification secondary to maternal toxicity.  A rabbit teratology study
resulted in a maternal NOEL of 10 mg/kg/day and a developmental NOEL of
100 mg/kg/day (HDT).  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 reproduction study was conducted with rats with a
resulting NOEL for maternal and offspring toxicity of 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.
The maternal NOAEL was 429 mg/kg/day and the offspring NOAEL was 92.3
mg/kg/day, based on decreased body weights during post-weaning.]

4. Subchronic toxicity.  [In a 13-week subchronic feeding study in rats,
the NOEL was 68.27 mg/kg/day (males) and 83.33 mg/kg/day (females).  The
LOEL was 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 in mice, the NOEL was 44.5mg/kg/day (males) and 54.1
mg/kg/day (females).  The LOEL was 220.2 mg/kg/day (males) and 273.9
mg/kg/day (females) based on increased liver weight at the high dose. In
a 28 day subchronic dermal study in rabbits, treatment produced a slight
decrease in food consumption and body weight in males at 1000 mg/kg/day.
 In a 13-week study in dogs, the NOEL was 100 mg/kg/day and the LOEL was
500 mg/kg/day.  In a subchronic neurotoxicity study in rats, there was
no evidence of neurotoxicity 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).]

5. Chronic toxicity.  [A 1-year oral study with dogs resulted in a NOEL
of 100 mg/kg/day for both sexes, based on significantly increased liver
weights and biliary hyperplasia in the high dose.  The LOEL was 1000
mg/kg/day.  A 2-year combined chronic toxicity/ carcinogenicity study in
rats resulted in a NOEL for systemic toxicity of 2.83 mg/kg/day (males)
and 3.36 mg/kg/day (females).  The LOEL was 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 resulted in a NOEL of 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.]

	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 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.]

	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 what included all current and proposed uses of fenamidone.
Therefore the aggregate exposure would consist of any potential
exposures to fenamidone residues from inadvertent residues in corn and
soybean in addition to the previously registered crops. The acute
reference dose (aRfD) of 1.25 mg/kg bw/day is based on a NOAEL of
125mg/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 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 3.5% of the acute Reference Dose
(aRfD).  The population subgroup with the highest exposure was Infants
at 14% of the aRfD.  Chronic dietary exposure estimates from potential
residues of fenamidone for the US Population was 3% of the chronic RfD
(cRfD).  The sub-population with the highest exposure was Children 1-2
at 9% of the cRfD.]

	ii. Drinking water.  [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 42210 ppb for the general population,
10747 ppb for infants and 11360 ppb for children 1-2, compared to  the
worst-case acute drinking water EEC of  178 ppb from the June 21, 2007
EPA HED risk assessment.  The chronic DWLOC values are 947 ppb for the
general population, 265 ppb for infants and 255 ppb for children 1-2,
compared to a worst-case chronic drinking water EEC of 178 ppb from the
above EPA reference.  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.]

	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 from the proposed uses of fenamidone
will utilize at most 3.5% of the aRfD and 3% 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.  Drinking water levels of comparison based on the dietary
and aggregate exposures are greater than highly conservative estimated
levels, and would be expected to be well below the 100% level of the
RfD, if they occur at all.  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 that
will be used for exposure to residues of fenamidone in food for infants
and children (the most highly exposed subgroups) is 14% (acute
assessment for infants) and 9% (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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