 

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

<EPA Registration Division contact: Laura Nollen, (703) 305-7390>

 

<Interregional Research Project Number 4 (IR-4)>

<Petition Number 9E7612>

<	EPA has received a pesticide petition (PP# 9E7612) from Interregional
Research Project Number 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 180.484 by establishing a tolerance for residues of
flutolanil, N-(3-(1-methylethoxy)phenyl)-2-(trifluoromethyl)benzamide
and its metabolites converted to 2-(trifluoromethyl) benzoic acid and
calculated as flutolanil in or on the raw agricultural commodities
ginseng at 3.5 parts per million (ppm); vegetable, Brassica, leafy,
group 5 at 0.11 ppm; and turnip, greens at 0.11 ppm.  EPA has determined
that the petition contains data or information regarding the elements
set forth in section 408 (d)(2) of  FDDCA; 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 metabolic profile of flutolanil is well
understood and has been elucidated in three dissimilar crops: peanuts,
rice and cucumber. The metabolic profile is similar in all crops. The
major route of degradation is 4'-0-dealkylation to
desisopropylflutolanil (M-4), followed by conjugation. Other metabolites
may occur at very low levels due to hydroxylation and oxidation of the
side chain, hydroxylation of the aniline ring, and methylation of the
hydroxyl groups.  These minor metabolites were also subject to
conjugation. The residues of concern are the parent (flutolanil) and M-4
(desisopropyl flutolanil).>

<	2. Analytical method. Residues of flutolanil and M-4 are extracted
from macerated samples with acetone or a mixture of methanol and water. 
For cabbage and ginseng, an aliquot of the extract is diluted with water
and analyzed using HPLC-MS/MS.  For broccoli and mustard greens, the
acetone extract is diluted with water and the residues are partitioned
into a mixture of ethyl acetate and dichloromethane.  This solvent is
dispelled and the residue is reconstituted in acetone for purification
through Florisil.  The purified eluent is taken to dryness and the
residues are reconstituted in a mixture of acetonitrile and water. 
Residues of flutolanil and M-4 are chromatographed and quantified using
an HPLC–MS/MS.  The Limit of Quantitation is 0.05 ppm for each
flutolanil and M-4.>

<	3. Magnitude of residues. Maximum residues of flutolanil and M-4 in
ginseng (dry) and mustard greens were 2.17 ppm and 0.06 ppm flutolanil,
respectively, with no M-4 residues detected in any sample.  No
detectable residues of either flutolanil or M-4 (Limit of Quantitation
was 0.05 ppm for each molecule) were detected in either broccoli or
cabbage.  Permanent tolerances of 3.5 ppm and 0.11 ppm are proposed for
ginseng, Brassica leafy vegetables (Crop Group 5) and turnip greens,
respectively.>

<B. Toxicological Profile>

<	1. Acute toxicity.  Acute toxicity data show that technical grade
flutolanil has relatively low acute toxicity (Category III and IV).
Flutolanil is not a dermal sensitizer, primary eye irritant, or primary
skin irritant.>

<	2. Genotoxicty. The toxicological database for flutolanil is complete.
 The database contains no evidence of genotoxicity attributable to
flutolanil. >

<	3. Reproductive and developmental toxicity. The Agency has set the
FQPA Safety Factor for flutolanil at 1X because there was no increased
sensitivity to fetuses as compared to maternal animals in the
developmental rat and rabbit studies and no increased sensitivity to
pups as compared to adults in a multi-generation reproduction study in
rats.>

<	4. Subchronic toxicity Subchronic and chronic toxicity studies showed
that the primary effects of flutolanil are increases in liver weight
combined with decreases in body weight. The available data for
flutolanil do not show neurotoxic, carcinogenic, or mutagenic effects.
Flutolanil is not a developmental or reproductive toxicant. There is no
evidence of increased susceptibility of rat or rabbit fetuses to
in-utero exposure or rat pups to post-natal exposure to flutolanil. No
toxic effects were observed in studies in which flutolanil was
administered by the dermal routes of exposure.>

<	5. Chronic toxicity. Only a chronic dietary endpoint was identified
for flutolanil.  The Agency has selected a chronic RfD/PAD of 0.50
mg/kg/day (NOAEL = 50 mg/kg/day; Uncertainty Factor = 100). This chronic
RfD/PAD is based on the chronic oral toxicity study in dogs in which
increased incidences of clinical signs (emesis, salivation, and soft
stool) occurred at LOAEL = 250 mg/kg/day following 65 weeks of
exposure.>

<	6. Animal metabolism. The metabolism of flutolanil has been
extensively studied in various species of mammals.  Studies in rats,
ruminants, and poultry suggest that flutolanil is not well absorbed
following oral administration. Once absorbed, however, it is rapidly
metabolized, primarily to desisopropylflutolanil and it conjugates, and
rapidly excreted via urine and feces.>

<	7. Metabolite toxicology. Flutolanil does not metabolize to a
significantly toxic metabolite nor does it share a toxic metabolite with
any other pesticide registered in the U.S.>

<	8. Endocrine disruption. No evidence of endocrine effects has been
observed in the subchronic, chronic or reproductive studies. The
potential for flutolanil to cause endocrine effects is not considered
relevant.>

<C. Aggregate Exposure>

<	1. Dietary exposure. Sufficient residue data for flutolanil are
available to assess tolerances and conduct a dietary risk assessment. 
No acute dietary risk assessment is necessary as no toxic effects from a
single oral dose have been observed in toxicology studies.  A Tier I
chronic riskassessment was conducted based on the Agency’s cPAD of 0.5
mg/kg bw/day using DEEM-FCID v. 2.16.  The maximum dietary risk for any
dietary subpopulation was a maximum of 2% of the cPAD (non-Hispanic,
non-white, non-black).>

<	i. Food. A Tier I risk analysis (assumed tolerance-level residues with
100% crop treated) was run including all proposed tolerances.  The
addition of ginseng (dry) and Brassica leafy vegetables at presumed
tolerance levels had a negligible effect on chronic dietary risk.>

<	ii. Drinking water. Worst-case drinking water values were included in
the chronic dietary risk assessment described above.  The drinking water
residues used in the dietary risk assessment were provided by the Ageny
in a memorandum (S. Abel: “Flutolanil Tier II Estimated Environmental
Concentration for Use in the Human Health Drinking WaterRisk Assessment,
D260066, 12/13/99)  The maximum drinking water residue of 0.00375 ppm
was incorporated in the DEEM-FCID into the food categories“water,
direct, all sources” and “water, indirect, all sources.”>

<	2. Non-dietary exposure. Flutolanil is currently registered for use on
the following residential non-dietary sites: Turf grass. The risk
assessment was conducted using the following residential exposure
assumptions: There are non-occupational uses associated with flutolanil.
Non-occupational handlers may mix, load, and apply flutolanil products
on turf grass. These exposures were assessed for inhalation risk.
Post-application inhalation exposure following turfgrass treatment is
considered negligible and was not assessed. Because certain flutolanil
products are registered for use on residential lawns, postapplication
exposure to infants may result in their hand-to-mouth activities on
treated turf. The MOE’s for these scenarios ranged from 6.7 x 102 to
1.4 x 103. These modeled exposures do not trigger the Agency’s Level
of Concern.>

<D. Cumulative Effects>

<Flutolanil has demonstrated only minimal toxicity in animal studies and
the mechanism of this toxicity is not known.  Flutolanil does not share
a mechanism of toxicity with another registered pesticide nor does it
share a common toxic metabolite with any other registered pesticide. 
There are no available data to indicate that flutolanil has a common
mechanism of toxicity with other substances.>

<E. Safety Determination>

<	1. U.S. population. An acute dietary endpoint has not been set for
flutolanil by the Agency due to a lack of observable toxic effects from
a single dose at any level tested.  A chronic dietary risk assessment
has been conducted using the Agency’s cPAD of 0.5 mg/kg bw/day.  The
calculated chronic daily exposure for the general US population is 0.
0.002672 mg/kg/bw/day which represents 0.5% of the cPAD.>

<	2. Infants and children. The Agency has set the FQPA factor for
flutolanil at 1X based on lack of neurotoxic and teratogenic effects in
chronic tests on rabbits and rats.  The highest chronic risk calculated
for any pre-teen dietary subgroup was 1.4% of the cPAD (non-nursing
infants).>

<F. International Tolerances>

<	There are no national or transnational MRLs for flutolanil on Brassica
(Cole) leafy vegetables or ginseng.>

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