Document ID: EPA-HQ-OPP-2006-0481-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-06-14T04:00Z

FILE
NAME:
company.
wpt
(
7/
1/
2005)
(
xml)
Template
Number
P25
ATTENTION:

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

All
text
in
blue
font
(
instructions
for
preparing
the
document),
should
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
(
1/
1/
2005)

EPA
Registration
Division
contact:
[
Janet
Whitehurst,
703­
305­
6129]

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:

Valent
U.
S.
A.
Company
5f7016
EPA
has
received
a
pesticide
petition
(
5f7016])
from
[
Valent
U.
S.
A.
Company],
[
1600
Riviera
Ave.,
Walnut
Creek,
CA
94596­
8025]
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
[
fluopicolide]
in
or
on
the
raw
agricultural
commodity
[
Grape
at
2
parts
per
million
(
ppm),
Raisin
at
6
ppm,
Vegetable,
leafy,
except
brassica,
group
4
at
20
ppm,
Vegetable,
fruiting,
group
8
at
2
0.8
ppm,
Vegetable,
cucurbit,
group
9
at
0.4
ppm,
Potato
at
0.02
ppm,
Sweet
potato,
roots
at
0.02
ppm,
Wheat
forage
at
0.2
ppm,
Wheat
grain
at
0.02
ppm,
Wheat
hay
at
0.5
ppm,
and
Wheat
straw
at
0.5ppm.
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
fate
of
fluopicolide
in
plants
is
clearly
understood.
Metabolism
studies
were
conducted
with
grapes,
potato,
and
lettuce.
The
metabolic
profile
of
fluopicolide
was
similar
in
all
three
crops
and
demonstrated
that
fluopicolide
is
degraded
by
oxidation
and
hydrolysis.
The
primary
residue
found
in
all
crops,
and
the
only
residue
of
concern,
is
the
parent
molecule
fluopicolide.
]

2.
Analytical
method.
[
A
practical
analytical
method
utilizing
liquid
chromatography
and
mass
spectrometry
detection
is
available
and
has
been
validated
for
detecting
and
measuring
levels
of
fluopicolide
in
and
on
crops.
The
validated
limit
of
quantitation
is
0.01
ppm.]

3.
Magnitude
of
residues.
[
Residue
data
for
the
use
of
fluopicolide
on
the
commodities
listed
within
this
notice
has
been
submitted.]

B.
Toxicological
Profile
1.
Acute
toxicity.
[
A
battery
of
acute
toxicity
studies
places
technical
fluopicolide
in
toxicity
category
IV.
No
evidence
of
sensitization
was
observed
in
guinea
pigs.
In
an
acute
neurotoxicity
study
in
rats,
only
statistically
lower
body
temperature
was
observed
6
hours
after
dosing
at
the
limit
dose
of
2000
mg/
kg.
No
other
treatment­
related
changes
were
noted
in
the
study,
and
the
NOAEL
was
considered
to
be
100
mg/
kg.
]

2.
Genotoxicty.
[
Fluopicolide
has
been
evaluated
for
genotoxicity
using
a
battery
of
tests,
including
bacterial
reverse
mutation
tests,
a
mammalian
cell
gene
mutation
(
HPRT)
assay,
an
in
vivo
mouse
micronucleus
assay,
an
in
vitro
chromosome
aberration
test,
and
an
in
vivo
unscheduled
3
DNA
synthesis
test.
The
weight
of
evidence
from
all
of
these
assays
shows
that
fluopicolide
is
not
genotoxic.]

3.
Reproductive
and
developmental
toxicity.
[
i.
In
a
developmental
toxicity
study
in
rats
gavage
dosed
from
gestation
days
7
to
20
at
levels
of
0,
5,
60
or
700
mg/
kg/
day,
evidence
of
maternal
and
fetal
toxicity
was
observed
at
700
mg/
kg/
day,
the
highest
dose
tested.
The
maternal
and
fetal
NOAEL
was
60
mg/
kg/
day
based
on
statistically
lower
body
weights
in
dams
and
fetuses,
and
skeletal
findings
in
fetuses
that
included
delayed
ossification
of
some
bones
and
slight
increases
in
the
incidence
of
various
rib
and
thoracic
vertebrae
anomalies.
ii.
In
a
developmental
toxicity
study
with
rabbits,
pregnant
animals
were
given
oral
doses
of
0,
5,
20
or
60
mg/
kg/
day
on
gestation
days
6
to
28.
At
the
high
dose,
15
animals
were
sacrificed
following
spontaneous
abortions
and
3
animals
were
found
dead.
The
few
surviving
animals
in
this
group
had
live
fetuses
at
cesarean
sectioning
but
other
than
lower
fetal
weight
and
crown/
rump
length,
no
treatment­
related
findings
were
observed
upon
external,
visceral
and
skeletal
examinations
of
these
fetuses.
The
NOAEL
for
maternal
and
fetal
toxicity
was
20
mg/
kg/
day.
iii.
In
a
2­
generation
reproductive
toxicity
study,
fluopicolide
was
administered
to
rats
at
dietary
levels
of
0,
100,
500,
or
2000
ppm.
The
NOAEL
was
500
ppm
(
equivalent
to
26
and
33
mg/
kg/
day
for
males
and
females,
respectively)
for
developing
offspring
and
for
parental/
systemic
toxicity.
The
LOAEL
was
2000
ppm
based
on
decreased
body
weight
and
organ
weight
changes
in
both
F0
and
F1
adults
and
F1
and
F2
pups.
The
reproductive
NOAEL
was
2000
ppm.
]

4.
Subchronic
toxicity.
[
Ninety­
day
feeding
studies
were
conducted
in
dogs,
mice
and
rats.
i.
No
evidence
of
toxicity
was
observed
in
dogs
up
to
the
limit
dose
of
1000
mg/
kg/
day.
The
NOAEL
in
dogs
is
1000
mg/
kg/
day.
ii.
In
90­
day
feeding
studies
in
both
CD­
1
and
C57BL/
6
mice,
liver
was
the
only
target
organ
identified
with
hepatocellular
hypertrophy
seen
at
dietary
levels
of
320
ppm
and
higher.
The
NOAEL
in
C57BL/
6
mice
was
200
ppm
(
equivalent
to
37.8
and
52.8
mg/
kg/
day
in
males
and
females,
respectively).
iii.
In
a
90­
day
rat
study
with
dietary
levels
of
100,
1400
and
20,000
ppm,
the
maximum
tolerated
dose
(
MTD)
was
exceeded
at
20,000
ppm
based
on
body
weight
gain
of
30
to
40%
below
control.
The
target
organs
identified
in
rats
were
the
liver
(
centrilobular
hypertrophy)
in
both
sexes
and
the
kidneys
in
males
(
accumulation
of
hyaline
droplets,
single
cell
death
at
the
proximal
tubule
epithelium,
slight
foci
of
basophilic
tubules
and
granular
casts)
at
1400
ppm
and
20000
ppm.
The
NOAEL
was
100
ppm,
equivalent
to
7.4
and
8.4
mg/
kg/
day,
in
males
and
females,
respectively.
iv.
In
a
subchronic
neurotoxicity
study,
rats
were
treated
with
0,
200,
1400
or
10000
ppm
in
the
diet
for
13
weeks.
The
NOAEL
for
systemic
toxicity
is
1400
ppm
(
107
mg/
kg/
day
in
males
and
125
mg/
kg/
day
in
females)
based
on
findings
in
the
liver
and
kidney.
There
were
4
no
neurotoxicity
findings.
The
NOAEL
for
neurotoxicity
is
10,000
ppm
(
781
mg/
kg/
day
in
males
and
866
mg/
kg/
day
in
females).
iii.
In
a
subchronic
dermal
toxicity
study,
male
and
female
rats
were
treated
with
fluopicolide
at
dose
levels
of
0,
100,
250,
500
and
1000
mg/
kg/
day.
There
were
no
effects
at
any
dose
level.
The
NOAEL
of
the
study
is
1000
mg/
kg/
day.]

5.
Chronic
toxicity.
[
i.
Lower
body
weight
gain
at
the
limit
dose
of
1000
mg/
kg/
day
was
the
only
treatmentrelated
effect
noted
in
a
52­
week
dog
study
performed
at
70,
300,
and
1000
mg/
kg/
day
by
gavage.
Thus,
the
NOAEL
in
dogs
was
established
at
300
mg/
kg/
day.
ii.
Chronic
toxicity/
carcinogenicity
was
assessed
in
rats
at
dietary
levels
of
50,
200,
750
and
2500
ppm.
The
NOAEL
was
200
ppm
(
8.4
mg/
kg/
day
in
males
and
10.8
mg/
kg/
day
in
females)
based
on
microscopic
changes
in
the
liver
and
kidneys
similar
to
those
observed
in
the
90­
day
rat
study.
No
evidence
of
carcinogencity
was
observed
in
rats
up
to
2500
ppm.
iii.
The
oncogenic
potential
of
fluopicolide
was
investigated
in
C57BL/
6
mice
at
dietary
levels
of
0,
50,
400,
or
3200
ppm.
Significantly
lower
body
weight
gain
was
seen
at
3200
ppm
in
conjunction
with
a
slight
decrease
in
food
consumption.
Increased
liver
weight
and
centrilobular
hepatocellular
hypertrophy
were
observed
at
400
and
3200
ppm
in
both
sexes.
In
addition
at
3200
ppm,
an
increased
incidence
of
hepatocellular
adenomas
was
noted
in
both
sexes,
but
the
incidence
of
hepatocellular
carcinomas
was
not
affected.
The
NOAEL
was
50
ppm
(
equivalent
to
7.9
and
11.5
mg/
kg/
day
in
males
and
females,
respectively).
Subsequent
mechanistic
work
demonstrated
a
marked
transient
hepatocellular
proliferation,
which
returned
to
control
levels
after
28
days
of
treatment.
This
was
accompanied
by
a
clear
induction
of
total
cytochrome
P­
450
and
related
enzymes.
These
results
parallel
findings
with
Phenobarbital,
which
has
a
well
understood
thresholdbased
mechanism
of
rodent
tumor
formation
commonly
known
to
be
of
no
relevance
to
humans.
]

6.
Animal
metabolism.
[
The
animal
metabolism
of
fluopicolide
is
well
understood.
Fluopicolide
is
rapidly
absorbed
and
excreted
when
administered
to
rats
and
the
resulting
tissue
residues
are
very
low.
The
metabolic
pathway
for
fluopicolide
is
similar
in
rodents,
goats
and
hens.
Metabolism
in
livestock
proceeded
primarily
via
hydroxylation
and
hydrolysis.]

7.
Metabolite
toxicology.
[
Four
metabolites
(
AE
C653711,
AE
C657188,
AE
C657378,
and
AE
1344122)
were
identified
as
low­
level
plant
and/
or
soil
metabolites
of
fluopicolide.
Several
of
the
metabolites
were
identified
at
low
levels
in
the
rat
following
fluopicolide
or
AE
C653711
administration
and
were
therefore
covered
by
the
tox
studies
conducted
with
the
parent
molecule.
All
compounds
were
tested
for
acute,
subchronic
(
28­
day)
and
genetic
toxicity
and
AE
C653711
and
AE
C657188
were
additionally
studied
in
in
vivo
ADME
studies.
All
were
found
to
be
5
equally
or
less
toxic
than
the
parent
molecule
itself.
These
metabolites
are
therefore
considered
not
toxicologically
relevant
to
the
overall
assessment
of
fluopicolide
human
health..
]

8.
Endocrine
disruption.
[
The
toxicology
database
for
fluopicolide
is
current
and
complete.
No
special
studies
to
evaluate
the
potential
endocrine
effects
of
fluopicolide
have
been
conducted.
However,
the
studies
in
this
database
include
evaluation
of
the
potential
effects
on
reproduction
and
development,
and
an
evaluation
of
the
pathology
of
the
endocrine
organs
following
shortor
long­
term
exposure.
These
studies
revealed
no
endocrine­
related
effects.]

C.
Aggregate
Exposure
1.
Dietary
exposure.
[
An
assessment
was
conducted
to
evaluate
potential
risks
due
to
chronic
and
acute
dietary
exposure
of
the
U.
S.
population
subgroups
to
residues
of
fluopicolide.
This
analysis
covers
all
pending
crop
uses.
]

i.
Food.
[
Acute:
No
appropriate
toxicological
endpoint
attributable
to
a
single
exposure
was
identified
in
the
available
toxicology
studies
conducted
with
fluopicolide.
Since
no
acute
toxicological
endpoints
could
be
established,
the
acute
aggregate
risk
is
considered
to
be
negligible.

Chronic:
Chronic
assessments
were
conducted
to
evaluate
potential
risks
due
to
chronic
dietary
exposure
to
the
U.
S.
population
and
selected
population
subgroups
to
residues
of
fluopicolide.
This
analysis
was
conducted
using
the
Cumulative
and
Aggregate
Risk
Evaluation
System
(
CARES)
using
actual
field
trial
residue
and
estimated
percent
crop
treated.
]

ii.
Drinking
water.
[
Acute:
Since
no
acute
toxicological
endpoints
could
be
established,
the
acute
aggregate
risk
is
considered
to
be
negligible.

Chronic:
A
tier
II
PRZM/
EXAMS
assessment
was
conducted
to
determine
the
EECs
in
the
standard
EPA
pond
and
the
EDWCs
in
the
Standard
Index
Reservoir
associated
with
fluopicolide
on
crops.
The
EXPRESS,
PRZM/
EXAMS
shell
was
used
to
conduct
the
modeling.
The
worst
case
scenario
was
used
in
the
drinking
water
exposure
assessment
and
a
refined
chronic
drinking
water
exposure
risk
analysis
was
conducted
using
the
CARES
Water
Wizard.
]
6
2.
Non­
dietary
exposure.
[
There
is
a
potential
residential
exposure
to
adults
applying
,
and
adults
and
children
entering
residential
turf
areas
treated
with
fluopicolide.
Based
on
the
application
of
fluopicolide
to
residential
turf,
conservative
estimates
of
exposure
were
calculated
for
both
children
and
adults.
All
estimates
resulted
in
calculated
margins
of
exposure
in
excess
of
100.]

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".
EPA
does
not
have,
at
this
time,
available
data
to
determine
whether
fluopicolide
has
a
common
mechanism
of
toxicity
with
other
substances
or
how
to
include
this
pesticide
in
a
cumulative
risk
assessment.
For
the
purposes
of
this
tolerance
action,
EPA
has
not
assumed
that
fluopicolide
has
a
common
mechanism
of
toxicity
with
other
substances.]

E.
Safety
Determination
1.
U.
S.
population.
[
Acute:
No
appropriate
toxicological
endpoint
attributable
to
a
single
exposure
was
identified
in
the
available
toxicology
studies
conducted
with
fluopicolide.
Since
no
acute
toxicological
endpoints
could
be
established,
the
acute
aggregate
risk
is
considered
to
be
negligible.

Chronic:
The
aggregate
risk
of
the
US
population
to
fluopicolide
was
determine
and
the
resultant
exposure
value
was
expressed
in
terms
of
margin
of
exposure
(
MOE),
which
was
calculated
by
dividing
the
no
observable
adverse
effect
level
(
NOAEL)
by
the
exposure
for
each
population
subgroup.
In
addition,
exposure
was
also
expressed
as
a
percent
of
the
chronic
reference
dose
(%
cRfD).
The
results
of
the
chronic
dietary
and
drinking
water
exposure
and
risk
analyses
presented
here,
demonstrate
that
there
is
a
reasonable
certainty
that
no
harm
will
result
to
the
U.
S.
population
or
sensitive
sub­
populations,
including
infants
and
children,
from
chronic
dietary
exposure
resulting
from
the
proposed
uses
of
fluopicolide.]

2.
Infants
and
children.
[
Acute:
No
appropriate
toxicological
endpoint
attributable
to
a
single
exposure
was
identified
in
the
available
toxicology
studies
conducted
with
fluopicolide.
Since
no
acute
toxicological
endpoints
could
be
established,
the
acute
aggregate
risk
is
considered
to
be
negligible.

Chronic:
The
results
of
the
chronic
dietary
and
drinking
water
exposure
and
risk
analysis
demonstrate
that
there
is
a
reasonable
certainty
that
no
harm
will
result
to
the
U.
S.
subpopulations
of
infants
and
children
from
chronic
dietary
exposure
resulting
from
the
proposed
uses
of
fluopicolide.
The
percentile
of
chronic
dietary
exposure
(
food)
was
highest
among
children
1
to
2
years
of
age.
The
percentile
of
chronic
drinking
water
exposure
was
highest
7
among
infants
"
0"
years
of
age.
The
percentile
aggregate
chronic
exposure
from
food
and
water
was
highest
among
infants
"
0"
years
of
age.
The
maximum
chronic
exposure
from
food
and
water
for
each
population
sub­
group
was
estimated
to
be
less
than
1
%
of
the
c­
PAD.]

F.
International
Tolerances
[
There
are
no
CODEX
tolerances
for
residues
of
fluopicolide]