Document ID: EPA-HQ-OPP-2006-0103-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-03-15T05:00Z

FILE
NAME:
company.
wpt
(
2/
1/
2003)

ATTENTION:

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

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

COMPANY
FEDERAL
REGISTER
DOCUMENT
SUBMISSION
TEMPLATE
(
2/
1/
2003)

EPA
Registration
Division
contact:
[
Hoyt
Jamerson,
(
703)
308­
9368]

INSTRUCTIONS:
Please
utilize
this
outline
in
preparing
tolerance
petition
documents.
In
cases
where
the
outline
element
does
not
apply
please
insert
"
NA­
Remove"
and
maintain
the
outline.
The
comment
notes
that
appear
on
the
left
margin
represent
hidden
typesetting
codes
designed
to
expedite
the
processing
of
the
Federal
Register
document.
Please
do
not
remove
or
alter
these
comment
notes
or
change
the
margins,
font,
or
format
in
your
document.
Simply
replace
the
instructions
that
appear
in
italics
and
brackets,
i.
e.,
"[
insert
company
name],"
with
the
information
specific
to
your
action.

TEMPLATE:

[
Crompton
Corporation]

[
3E6535]

EPA
has
received
a
pesticide
petition
([
3E6535])
from
[
Crompton
Corp.],
[
74
Amity,
Bethany,
CT
06525]
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.

Options
(
pick
one)

1.
by
establishing
a
tolerance
for
residues
of
triflumizole,

[[
1­[
1­((
4­
chloro­
2­(
trifluoromethyl)
phenyl)
imino)­
2­
propoxyethyl]­
1H­
imidazole]]
in
or
on
the
raw
agricultural
commodity
[
filberts]
at
[
0.05]
parts
per
million
(
ppm).
EPA
has
determined
that
the
petition
contains
data
or
information
regarding
the
elements
set
forth
in
section
408(
d)(
2)
of
the
2
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.
[
In
crops,
the
metabolism
of
[
14C]­
Phenyl]
triflumizole
was
investigated
in
cucumber,
pears,
grapes
and
apples.
The
major
metabolites
were:
N­(
4­
chloro­
2­
trifluoromethylphenyl)­
n­
propoxyacetamidine
(
FM­
6­
1),
N­(
4­
chloro­
2­
trifluoromethyphenyl)­
npropoxyacetanilide
(
FD­
1­
1)
and
the
free
or
conjugated
products
of
N­(
4­
chloro­
2­
trifluoromethylphenyl)­
hydroxyacetamidine
(
the
O­
dealkylation
product
of
FM­
6­
1),
N­(
4­
chloro­
2­
trifluoromethylphenyl)­
hydroxyacetanilide
(
FD­
2­
1)
and
the
triflumizole
aniline
(
FA­
1­
1)..]

2.
Analytical
method.
[
The
analytical
method
is
suitable
for
analyzing
crops
for
residues
of
triflumizole
and
its
aniline
containing
metabolites
at
the
proposed
tolerance
levels.
The
analytical
method
has
been
independently
validated.
Residue
levels
of
triflumizole
are
converted
to
FA­
1­
1
by
acidic
and
alkaline
reflux,
followed
by
distillation.
Residues
are
then
extracted
and
subjected
to
SPE
purification.
Detection
and
quantitation
are
conducted
by
a
gas
chromatography
equipped
with
nitrogen
phosphorus
detector,
electron
capture
detector
or
mass
spectrometry
detection.
The
limit
of
quantitation
of
the
method
has
been
determined
at
0.05
ppm
for
the
combined
residues
of
triflumizole
and
FA­
1­
1
in
filberts.
The
enforcement
methodology
has
been
submitted
to
the
Food
&
Drug
Administration
for
publication
in
the
Pesticide
Analytical
Manual,
Vol.
II
(
PAM
II).]

3.
Magnitude
of
residues.
[
Field
trials
were
conducted
at
3
locations
in
commercial
growing
areas
of
the
United
States,
to
evaluate
the
quantity
of
triflumizole
residues
in
filberts.
Treated
and
control
samples
of
filbert
nuts
were
collected
at
21
days
prior
to
harvest.
The
residue
in
all
treated
samples
was
<
0.05
ppb.]

B.
Toxicological
Profile
1.
Acute
toxicity.
[
The
data
base
includes
the
following
studies:
a
rat
acute
oral
study
with
a
LD50
of
1.42
g/
kg;
a
rabbit
acute
dermal
study
with
a
LD50
>
5
g/
kg;
a
rat
acute
inhalation
study
with
a
LC50
>
3.2
mg/
l;
a
rabbit
primary
ocular
irritation
study
which
showed
mild
irritation;
a
rabbit
primary
dermal
irritation
study
which
showed
no
irritation;
a
guinea
pig
dermal
sensitization
study
which
showed
slight
dermal
sensitization
potential.
]
3
2.
Genotoxicity.
[
Triflumizole
was
negative
in
all
genotoxicity
assays
including:
Ames
assay
in
S.
typhimurium,
gene
conversion
assay
in
yeast
strain
D4,
REC
assay
in
B.
subtilis,
unscheduled
DNA
synthesis
(
UDS)
assay
in
cultured
rat
hepatocytes,
chromosome
aberration
assay
in
cultured
Chinese
hampster
ovary
(
CHO);
cells
and
a
mouse
micronucleus
assay.
]

3.
Reproductive
and
developmental
toxicity.
[
In
a
developmental
toxicity
study,
triflumizole
was
administered
by
oral
gavage
to
pregnant,
female
Sprague
Dawley
rats
at
dosage
levels
of
0,
10,
35
or
120
mg/
kg/
day.
Maternal
toxicity,
as
evidenced
by
a
substantial
reduction
in
body
weight
gain,
was
seen
at
35
and
120
mg/
kg/
day.
At
these
dosage
levels
there
was
a
decrease
in
fetal
viability
in
the
form
of
late
resorptions.
There
were
no
teratogenic
effects.
The
no
observed
adverse
effect
level
(
NOAEL)
for
maternal
and
developmental
toxicity
was
10
mg/
kg/
day.
Triflumizole
was
also
administered
by
oral
gavage
to
pregnant,
female
New
Zealand
White
rabbits
at
dosage
levels
of
0,
5,
25,
or
50
mg/
kg/
day.
At
a
dose
level
of
50
mg/
kg/
day
there
was
a
reduction
in
body
weight
gain
in
kits.
There
were
no
developmental
or
teratogenic
effects.
The
NOAEL
for
maternal
toxicity
was
25
mg/
kg/
day
and
the
NOAEL
for
developmental
toxicity
was
greater
than
50
mg/
kg/
day.
The
reproductive
toxicity
of
triflumizole
was
evaluated
in
a
rat
reproduction
study,
conducted
on
three
generations,
at
dietary
concentrations
of
0,
30
70
and
170
ppm.
Fertility
was
not
affected
by
treatment.
There
was
an
increase
in
placental
weight
in
the
F1b,
F2b,
and
F3b
litters
and
an
increase
in
gestation
length
at
170
ppm
at
the
F1a
and
F3a
mating
intervals
and
at
70
ppm
at
the
F3a
mating
interval.
The
NOAEL
for
systemic
parental
toxicity
was
170
ppm
(
8.5
mg/
kg/
day).
The
NOAEL
for
offspring
was
70
ppm
(
3.5
mg/
kg/
day)
based
upon
effects
seen
in
high
dose
litters,
which
included
increased
incidences
of
hydroureter
and
space
between
the
body
wall
and
organs.
The
NOAEL
for
reproductive
effects
was
30
ppm
(
1.5
mg/
kg/
day)
based
upon
the
observed
increase
in
gestation
length.]

4.
Subchronic
toxicity.
[
To
assess
sub­
acute
dermal
toxicity,
triflumizole
was
applied
to
the
backs
of
male
and
female
Sprague
Dawley
rats
for
three
weeks.
High
dose
female
rats
exposed
to
1,000
mg/
kg/
day
exhibited
mild
fatty
vacuolation
in
the
liver,
which
was
within
the
range
of
normal
biological
variation.
Therefore,
the
NOAEL
for
sub­
acute
dermal
toxicity
in
rats
was
greater
than
1,000
mg/
kg/
day.]

5.
Chronic
toxicity.
[
Triflumizole
was
fed
to
male
and
female
Beagle
dogs
for
one
year
at
dietary
concentrations
of
0,
100,
300
and
1,000
ppm
to
assess
chronic
toxicity.
At
a
dosage
level
of
1,000
ppm
there
was
an
increase
in
serum
liver
enzymes
and
a
decrease
in
RBC
concentration.
The
NOAEL
for
chronic
toxicity
in
dogs
was
300
ppm
(
7.5
mg/
kg/
day).

Triflumizole
was
fed
to
male
and
female
Sprague
Dawley
rats
for
two
years
at
dietary
concentrations
of
0,
100,
400
and
1,600
ppm
to
assess
chronic
toxicity.
At
the
high
dose
level
there
was
a
substantial
reduction
in
body
weight
gain
in
males
and
females.
At
the
mid
and
high
dose
levels
there
was
an
increase
in
liver
weight.
Ovary
weight
was
increased
in
high
dose
female
rats,
and
kidney
weights
were
elevated
in
high
dose
animals.
Alanine
amino­
transferase
and
lactose
dehydrogenase
4
were
elevated
in
high
dose
males
and
females,
respectively.
High
dose
females
had
an
increased
incidence
of
ovarian
follicular
cysts,
while
high
dose
males
exhibited
pancreatic
acinar
cell
atrophy.
Fatty
vacuolization
of
the
liver
was
seen
at
all
dose
levels
and
hepatocytic
hypertrophy
was
seen
in
high
and
mid­
dose
males
and
females.
Female
rats
given
400
or
1,600
ppm
had
an
increased
incidence
of
basophilic
foci/
areas
of
hepatocytic
alteration.
Effects
at
100
ppm
were
confined
to
hepatocytic
fatty
vacuolation
and
hypertrophy
in
females.
These
changes
were
less
severe
than
those
seen
in
rats
given
400
or
1,600
ppm
and
were
considered
by
the
laboratory
to
be
indicative
of
adaptive
metabolic
change.
The
dietary
level
of
100
ppm
(
5
mg/
kg/
day)
is
considered
to
be
a
NOAEL.]

6.
Animal
metabolism
.
[
Triflumizole,
[
14
C­
Phenyl]
1­(
1­((
4­
chloro­
2­
trifluoromethylphenyl)
imino)­
2­
propoxyethyl)­
1H­
imidazole,
was
found
to
be
rapidly
absorbed
and
excreted
in
rats.
Two
days
after
oral
dosing,
78%
was
found
to
be
excreted
in
the
urine
and
20%
in
the
feces.
No
sex
difference
was
noted.
It
appears
that
the
loss
of
the
imidazole
ring
was
the
basic
step
in
the
metabolic
pathway
of
this
fungicide
in
mammals.
The
elimination
of
the
imidazole
ring
yielded
initially
N­(
4­
chloro­
2­
trifluoromethylphenyl)­
n­
propoxyacetamidine
(
FM­
6­
1),
and
N­(
4­
chloro­
2­
trifluoromethylphenyl)­
n­
propoxyacetanilide
(
FD­
1­
1).
Other
hydroxylated
metabolites
identified
(
free,
or
as
sulfate/
glucuronide
conjugates)
included,
among
others,
N­(
4­
chloro­
2­
trifluoromethylphenyl)­
hydroxyacetamidine
(
FM­
8­
1);
4­
chloro­
2­
trifluoromethylhydroxyacetanilide
(
FD­
2­
1);
and
4­
chloro­
2­
trifluoromethyl­
6­
hydroxyaniline
(
FA­
1­
5).]

7.
Metabolite
toxicology
.
[
Both
plant
and
animals
produce
the
same
metabolites
that
were
identified
in
the
metabolism
studies;
therefore,
the
toxicity
of
the
metabolites
has
essentially
been
evaluated
in
the
rat
toxicology
studies.]

8.
Endocrine
disruption.
[
In
the
rat
reproduction
study
there
was
an
increase
in
placental
weight
in
females
at
the
high
dose
level
of
170
ppm.
There
was
also
a
biologically
significant
increase
in
gestation
length
in
high
dose
F0
and
F2
females
(
F1a
and
F3a
intervals).
The
NOEL
for
endocrine
effects
is
70
ppm
(
3.5
mg/
kg/
day).]

C.
Aggregate
Exposure
1.
Dietary
exposure.

i.
Food.
[
Tolerances
have
been
established
for
the
combined
residues
of
triflumizole
and
its
metabolites
containing
the
4­
chloro­
2­
trifluoromethylaniline
moiety,
calculated
as
the
parent
compound,
in
or
on
apples,
pears,
grapes,
cucurbit
vegetables,
strawberries,
sweet
cherries,
and
tart
cherries.
Tolerances
have
also
been
established
for
the
combined
residues
of
triflumizole
and
the
metabolite
4­
chloro­
2­
hydroxy­
6­
trifluoromethylaniline
sulfate
and
other
metabolites
containing
the
4­
chloro­
2­
trifluoromethylaniline
moiety,
calculated
as
the
parent
compound,
in
or
on
eggs,
milk,
meat,
fat,
and
meat
by­
products
of
cattle,
goats,
hogs,
horses,
poultry
and
sheep.
5
The
Dietary
Exposure
Evaluation
Model
(
DEEMTM)
was
used
to
estimate
acute
and
chronic
dietary
exposure.
For
acute
exposure
estimates,
tolerance
level
residues,
modified
DEEM
processing
factors
for
apples
and
grapes,
and
an
assumption
of
100%
crop
treatment
was
used
for
all
registered
uses
and
including
the
filbert
use.
Chronic
exposure
estimates
utilized
anticipated
residues
for
the
apple,
grape,
pear,
cherry,
cucurbit
vegetable,
strawberry,
and
milk
commodities,
modified
DEEM
processing
factors
for
apples
and
grapes,
and
average
weighted
percent
crop
treated
information
for
apple,
grape,
and
pear
commodities.
Tolerance
level
residues,
DEEM
default
processing
factors,
and
100%
crop
treated
were
used
for
all
other
commodities.]

ii.
Drinking
water.
[
Drinking
water.
Tier
I
screen
models
FIRST
(
First
Index
Reservoir
Screening
Tool)
and
SCI­
GRO
(
Screening
Concentrations
in
Ground
Water)
were
used
to
predict
estimates
of
triflumizole
concentrations
in
surface
and
groundwater,
respectively.
The
predicted
acute
estimated
environmental
concentrations
(
EEC)
were
191
ppb
for
surface
water,
and
0.12
ppb
for
ground
water.
The
predicted
chronic
EECs
were
40
ppb
for
surface
water,
and
0.12
ppb
for
ground
water.]

2.
Non­
dietary
exposure
.
[
There
are
no
registered
or
proposed
uses
for
application
by
homeowners.
For
the
proposed
residential
uses,
only
professional
handlers
would
apply
triflumizole
to
woody
ornamentals
(
trees,
shrubs,
vines).
Triflumizole
is
not
used
or
proposed
for
use
on
lawns
or
turf.
Therefore,
residential
exposure
is
not
likely.]

D.
Cumulative
Effects
[
The
potential
for
cumulative
effects
of
triflumizole,
an
imidazole,
and
other
substances
that
have
a
common
mechanism
of
toxicity
was
considered.
The
mammalian
toxicity
of
triflumizole
is
well
defined.
No
reliable
information
exists
to
indicate
that
toxic
effects
produced
by
triflumizole
would
be
cumulative
with
those
of
any
other
chemical
compounds.
Therefore,
consideration
of
a
common
mechanism
of
toxicity
with
other
compounds
is
not
appropriate.
Thus
only
the
potential
risks
of
triflumizole
are
considered
in
the
aggregate
exposure
assessment.]

E.
Safety
Determination
[
1.
U.
S.
population
i.
Short­
Term
Risk.
The
acute
Population
Adjusted
Dose
(
aPAD)
of
0.03
mg/
kg
bw/
day,
applicable
only
to
the
population
subgroup
females
13­
50
years,
was
based
on
the
NOAEL
of
10
mg/
kg/
day
from
the
rat
developmental
study,
a
300x
uncertainty
factor,
and
a
1x
FQPA
safety
factor.
Acute
dietary
exposure
to
females
13­
50
years
was
0.006385
mg/
kg
bw/
day,
and
was
19%
of
the
aPAD.
The
acute
drinking
water
level
of
concern
(
DWLOC)
was
calculated
to
be
710
ppb,
and
the
model­
predicted
acute
EECs
of
191
ppb
for
surface
water
and
0.12
ppb
for
groundwater
are
less
than
this
DWLOC.
Therefore,
acute
aggregate
exposure
from
triflumizole
is
not
expected
to
exceed
the
aPAD.
6
ii.
Chronic
Risk.
The
chronic
Population
Adjusted
Dose
(
cPAD)
of
0.005
mg/
kg
bw/
day
was
based
on
the
NOAEL
of
1.5
mg/
kg/
day
from
the
rat
reproduction
study,
a
300x
uncertainty
factor,
and
a
1x
FQPA
safety
factor.
The
chronic
dietary
exposure
to
the
general
U.
S.
population
was
0.000400
mg/
kg
bw/
day
and
was
8%
of
the
cPAD.
The
chronic
DWLOC
was
calculated
to
be
160
ppb,
and
the
model­
predicted
chronic
EECs
of
40
ppb
for
surface
water
and
0.12
ppb
for
groundwater
are
less
than
this
DWLOC.
Therefore,
chronic
aggregate
exposure
from
triflumizole
is
not
expected
to
exceed
the
cPAD.]

2.
Infants
and
children.
[
i.
Short­
Term
Risk.
No
acute
dietary
endpoint
of
concern
was
determined
to
be
applicable
for
infants
and
children.

ii.
Chronic
Risk.
The
chronic
dietary
exposure
to
infants
was
0.000547
mg/
kg
bw/
day,
and
was
11%
of
the
cPAD.
Chronic
dietary
exposure
to
children
1­
6
years
old,
the
most
highly
exposed
population
subgroup,
was
0.000892
mg/
kg
bw/
day,
and
was
18%
of
the
cPAD.
The
chronic
DWLOC
was
calculated
to
be
45
ppb
for
infants
and
41
ppb
for
children
and
the
model­
predicted
chronic
EECs
of
40
ppb
for
surface
water
and
0.12
ppb
for
groundwater
are
less
than
the
DWLOCs.
Therefore,
chronic
aggregate
exposure
from
triflumizole
is
not
expected
to
exceed
the
cPAD.]

F.
International
Tolerances
[
There
are
no
Codex,
Canadian
or
Mexican
maximum
residue
limits
established
for
triflumizole
on
filberts.]