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

Template Number P25	

	

COMPANY FEDERAL REGISTER DOCUMENT SUBMISSION TEMPLATE

(1/1/2006)

EPA Registration Division contact: Shaja R. Brothers, (703) 308-3194	

Interregional Research Project Number 4 (IR-4) 

	EPA has received pesticide petitions ([6E7137, 6E7139) from [IR-4], 
[500 College Road East, Suite 201W, Princeton, New Jersey, 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 180.574 by
establishing tolerances for residues of fluazinam in or on the following
raw agricultural commodities: 

PP# 6E7137

Vegetable, legume, edible podded, subgroup 6A, except pea at 0.15 part
per million (ppm); Brassica, leafy greens, subgroup 5B 0.02 ppm;
Brassica, head and stem, subgroup 5A at 0.01 ppm; and Turnip, tops at
0.02.

IR-4 has also requested to establish residues of fluazinam and its
metabolite AMGT in or on Bushberry subgroup 13B; Berry, aronia;
blueberry, Lowbush; currant, buffalo; guava, Chilean; Barberry,
European; cranberry, highbush; honeysuckle; jostaberry; Juneberry;
lingonberry; currant, native; salal; and buckthorn, sea at 4.5 ppm

PP# 6E7139

Ginseng at 3 ppm; Bean, dry at 0.01 ppm; and Pea and bean, succulent
shelled, subgroup 6B, except pea at 0.02 ppm

 

                                      

.     The residue of concern is best defined as the parent, fluazinam in
most crops and as the parent, fluazinam and its metabolite, AMGT, in
fruit crops (grape and blueberry).  

the peanut or potatoes metabolism studies.  It is analogous to the
cysteine conjugate of AMPA found in rats.  Identifiable residues in
plant metabolism studies either closely resemble fluazinam in structure
or are the result of re_incorporation of the fluazinam carbon pool into
natural products. 

    Ruminant and poultry metabolism studies demonstrated that the
transmittal of residues from the feed of goats and hens through to meat,
milk, and eggs was low.  Total 14C residues were below 1 ppm in all
tissues, milk and eggs.  Identifiable residues were less than 2% of the
administered dose in all matrices, except for chicken fat and liver.

.     i.  Ginseng. Data from 4 field trials on ginseng (4 applications
at 0.8 lb a.i./A) showed that residues of fluazinam from duplicate
samples at each location ranged from 0.28 to 1.4 ppm in the RAC ginseng
root harvested 30 days after the last application.

    ii.  Brassica.  A total of 8 field trials were conducted on
broccoli, 10 field trials on cabbage and 11 field trials on mustard
greens with application of fluazinam in transplant water at 0.055 lbs
a.i./1000 plants.  Crops were harvested 60 to 113 days after application
for cabbage and broccoli and 25 to 78 days after application for mustard
greens.  No residues of fluazinam were found in any sample of broccoli
or cabbage harvested from all location (all were below the LOQ of 0.01
ppm).  The maximum residue found in mustard greens was 0.01 ppm, which
is the LOQ for this matrix.

    iii.  Beans.  A total of 11 field trials were conducted on snap
beans, 7 field trials on lima beans and 13 field trials on dry beans. 
Two applications at 0.45 lbs a.i./A were made to snap, lima and dry
beans with the first application at early bloom, however the interval
between applications ranged from 2 to 6 days for snap beans, 3 to 6 days
for lima beans and about 14 days for dry beans. Harvest intervals were
10-21 days, 28-71 days and 31-57 days for snap, lima and dry beans,
respectively.  In snap beans, residues of fluazinam ranged from <0.02
ppm to 0.109 ppm with mean residues of 0.08 ppm.   Residues in lima
beans and dry beans were all below the LOQ’s of 0.02 and 0.01 ppm,
respectively.

    iv.  Blueberry.  A total of 13 field trials were conducted with
fluazinam on blueberry (6 applications at 0.65 lb a.i./A).  For fruit
harvested 23-32 days after the last application, residues of fluazinam
in/on blueberry ranged from 0.042 to 3.0 ppm with a mean residue of 0.91
ppm.  Residues of the metabolite AMGT in/on blueberry ranged from 0.025
to 0.28 ppm with a mean residue of 0.094 ppm.  Maximum total residues of
fluazinam plus AMGT in/on blueberry were 3.28 ppm.

.  

    A battery of acute toxicity studies was conducted which placed
technical fluazinam in Toxicity Category III for oral LD50, dermal LD50,
dermal irritation, Category II for inhalation LC50 and Category I for
eye irritation.  Technical fluazinam showed potential for dermal
sensitization.

.  

   In a two_generation reproductive toxicity study, the NOEL for
reproductive effects was 100 ppm (10.1 mg/kg bw/day).  The NOEL for
parental toxicity was 20 ppm (2.1 mg/kg bw/day).

    In a rat developmental study, there were no developmental effects
observed at non_maternally toxic doses.  The developmental NOEL was 50
mg/kg bw/day and the LOEL was 250 mg/kg bw/day, based upon statistically
significant decreased mean fetal body weight and other evidence
suggestive of delayed fetal development related to maternal toxicity.
The maternal NOEL was shown to be 50 mg/kg bw/day. 

    The NOEL for the 13-week feeding study in rats was 50 ppm (4.1 mg/kg
bw/day).  The LOEL was 500 ppm (41 mg/kg bw/day), based on periacinar
hepatocellular hypertrophy and sinusoidal chronic inflammation in males,
increased liver weights in males and increased lung weights in females.

    In a 13-week dog study, the NOEL was 10 mg/kg bw/day.  The LOEL was
100 mg/kg bw/day, based on ocular change observed ophthalmoscopically
and liver effects consisting of increased relative liver to body weight,
bile duct hyperplasia with or without cholangiofibrosis and increased
plasma phosphatase levels.

    In a 21-day dermal study, the NOEL for systemic effects was 10 mg/kg
bw/day.  The LOEL was 100 mg/kg bw/day, based on hepatocelluar
hypertrophy and increases in AST and cholesterol levels. 

    In a subchronic neurotoxicity study, no effects considered to be
indicative of neurotoxicity were observed at the highest dose tested,
3000 ppm (233 mg/kg bw/day).  The NOEL for systemic toxicity (body
weight differences) was 1000 ppm (74 mg/kg bw/day). 

. 

    Fluazinam was not carcinogenic in rats.  A NOEL of 10 ppm (0.43
mg/kg bw/day) of fluazinam was established based on the following
effects at 1000 and/or 100 ppm: lower food consumption and efficiency of
food utilization, slight anemia, elevated cholesterol, increased liver
weights, an increased number of macroscopic liver and testes lesions and
an increased incidence of microscopically observed lung, liver,
pancreas, lymph node and testes lesions.

    An additional study was conducted to further define the NOEL for
long_term effects in the rat.  In the second study, a NOEL of 50 ppm
(2.2 mg/kg bw/day) was established based on liver and testes effects.

    Two long_term feeding studies were conducted in mice.  In the first,
the NOEL for all effects was 10 ppm (1.14 mg/kg bw/day) and the LOEL was
100 ppm (11.2 mg/kg bw/day) based on the treatment_related effects
observed in the liver.

    A second oncogenicity study in mice was conducted at 1000, 3000 and
7000 ppm to ensure that an MTD dose was studied.  Findings included
increased female mortality, reduced body weight gains, increased brain
weights and/or liver weights.  An impurity in the test material used in
this study resulted in vacuolation of the white matter of the brain and
cervical spinal cord in treated animals. A statistically significant
higher incidence of hepatocellular adenomas was observed in the 3000 ppm
dose males.  Hepatocellular adenomas are common tumors in male mice. 
There was no dose relationship in the induction of the adenoma and no
increase in hepatocellular carcinomas.  It is concluded that fluazinam
is not carcinogenic in the mouse. 

. 

   The same metabolic processes occur in plants and animals but
metabolism in plants is more extensive than in animals. All of the major
identified metabolites in both plants and animals retain the
phenylpyridinylamine structure.  Many of the metabolites resulting from
fluazinam are similar in plants and animals and, therefore, have already
been evaluated toxicologically.  

.  

    Acute Risk Tier 1 acute dietary exposure analyses were conducted for
fluazinam in/on ginseng, beans (Subgroups 6A, 6B and 6C), head and stem
Brassica, leafy Brassica greens, blueberry, peanuts, potatoes and
imported wine grapes to determine the exposure contribution of these
commodities to the diet and to ascertain the acute risk potential. The
estimates were based on proposed tolerance level residues for all the
crops, peanut and potato processing studies, market share assumptions of
100% crop treated (except wine grapes where it was assumed that 100% of
the imported wine grapes would be treated and 23% of wine consumed in
the US is imported), and consumption data from USDA’s CSFII (1994
through 1996 and 1998) continuing survey of food intake.

    Even using all of the worst-case exposure scenarios listed above,
the Tier 1 95th percentile acute dietary exposure (per capita) for the
U.S. population was estimated to be 0.001085 mg/kg bw/day or 0.22% of
the aPAD. The highest acute exposure estimate (95th percentile) was
observed in all infants (<1 year) subpopulation: 0.004921 mg/kg bw/day. 
This corresponds to only 0.98% of the aPAD.

    Chronic Risk Tier 1 dietary exposure analyses were conducted for
fluazinam in/on ginseng, beans (Subgroups 6A, 6B and 6C), head and stem
Brassica, leafy Brassica greens, blueberry, peanuts, potatoes and
imported wine grapes to determine the exposure contribution of these
commodities to the diet and to ascertain the chronic risk potential. The
estimates were based on proposed tolerance level residues for all the
crops, peanut and potato processing studies, market share assumptions of
100% crop treated (except wine grapes where it was assumed that 100% of
the imported wine grapes would be treated and 23% of wine consumed in
the US is imported), and consumption data from USDA’s CSFII (1994
through 1996 and 1998) continuing survey of food intake.

    Even using all of the worst-case exposure scenarios listed above,
the Tier 1 chronic dietary exposure estimates resulted in an estimated
exposure for the U.S. population of 0.000215 mg/kg bw/day.  This
exposure corresponds to 2.2% of the cPAD of 0.01mg/kg bw/day.  The
highest exposure estimate was calculated for the children 1-2 years of
age population subgroup.  This exposure was determined to be 0.000373
mg/kg bw/day (3.7% of the cPAD).

. 

    Data from developmental toxicity studies in the rat and rabbit, a
2_generation reproduction study and a developmental neurotoxicity study
were considered.  These studies, which were described earlier,
demonstrated no increased sensitivity of rats or rabbits to in utero or
gavage exposure of pups to fluazinam.  In addition, the multigeneration
reproductive toxicity study did not identify any increased sensitivity
of rats to in utero or postnatal exposure.  For all four studies,
parental NOELs were lower than or equivalent to the developmental or
offspring NOELs.  It is concluded that the standard margin of safety
will protect the safety of infants and children and that an additional
FQPA safety factor is not warranted. 

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