Document ID: EPA-HQ-OPP-2006-0204-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-08-02T04:00Z

1
COMPANY
FEDERAL
REGISTER
DOCUMENT
SUBMISSION
TEMPLATE
(
9/
1/
99)

EPA
Registration
Division
contact:
Jim
Tompkins
,
703­
305­
5697
[
INSTRUCTIONS:
Please
utilize
this
outline
in
preparing
tolerance
petition
documents.
In
cases
where
the
outline
element
does
not
apply
please
insert
?

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and
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i.
e.,
?[
insert
company
name],?
with
the
information
specific
to
your
action.

I.
Nissan
Chemical
Industries,
Ltd.

PP
0F6076
Summary
of
Petitions
EPA
has
received
a
pesticide
petition
(
PP
0F6076)
from
Nissan
Chemical
Industries,
Ltd
(
Nissan),
7­
1,
3­
Chome,
Kanda­
Nishiki­
Cho
Chiyoda­
Ku,
Tokyo
101­
0054
Japan,
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
quizalofop­
P­
ethyl
in
or
on
the
raw
agricultural
commodities
sunflower
seeds
at
2.0
parts
per
million
(
ppm)
flax
seed
at
0.05
ppm
,
wheat
at
0.05
ppm
and
barley
at
0.05
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.
Plant
metabolism
studies
have
been
conducted
for
soybeans,
cotton,
tomatoes,
potatoes,
and
sugar
beets.
These
studies
have
been
previously
reviewed
and
accepted
by
EPA
(
see
PP#
3F4268).
In
summary,
quizalofop­
P­
ethyl
ester
is
metabolized
by
cleavage
at
three
sites
as
follows.

1.
Hydrolysis
of
the
ethyl
ester
to
form
the
quizalofop­
p
acid
(
primary
pathway).

2.
Cleavage
of
the
enol
ether
linkage
in
the
acid,
between
the
phenyl
and
quinoxalinyl
rings,
to
form
2
phenols.

3.
Cleavage
of
the
ether
linkage
between
the
isopropanic
group
and
the
phenyl
ring
to
form
a
phenol.

The
plant
metabolism
data
show
that
the
quizalofop­
P­
ethyl
ester
itself
does
not
translocate,
but
is
rapidly
hydrolyzed
to
the
corresponding
acid.
The
phenols
conjugate
with
the
plant
sugars.
Metabolism
studies
in
soybeans
using
the
racemic
mixture
quizalofop
ethyl
ester
and
the
resolved
D+
isomer
show
nearly
identical
pathways.

The
nature
of
the
quizalofop­
P­
ethyl
ester
residue
in
cottonseed,
potatoes,
tomatoes,
soybeans,
and
sugar
beets
is
adequately
understood.
The
residues
of
concern
are
quizalofop­
p
ethyl
ester
and
its
acid
metabolite,
quizalofop­
p,
and
the
S
enantiomers
of
both
the
ester
and
the
acid,
all
expressed
as
quizalofop­
p
ethyl
ester.

2.
Analytical
method.
Data
Collection
Method.
The
analytical
method
(
MRID
44967703)
used
to
collect
sunflower
and
flax
field
and
processing
data
is
briefly
described
below.

The
method
involves
refluxing
samples
with
methanolic
potassium
hydroxide
to
convert
quizalofop­
P­
ethyl
and
quizalofop­
P
residues
to
2­
methoxy­
6­
chloroquinoxaline
(
MeCHQ).
The
solution
is
then
acidified
and
partitioned
with
hexane
to
extract
the
MeCHQ.
The
hexane
fraction
is
cleaned
up
by
gel
permeation
chromatography.
The
appropriate
fraction
is
collected,
concentrated
and
made
up
to
final
volume
with
hexane.
Residues
are
quantified
using
normal
phase
high­
pressure
liquid
chromatography
(
HPLC)
with
fluorescence
detection.
The
limit
of
quantitation
of
the
method
is
0.05
ppm.

The
analytical
method
used
to
collect
wheat
and
barley
field
and
processing
data
(
Report
No.
MLIR­
02­
01)
is
similar
to
the
method
used
for
flax
and
sunflower,
but
has
a
few
modifications.
The
modified
method
requires
a
silica
SPE
purification
for
wheat
and
barley
hay
and
straw
matrices
prior
to
GPC
cleanup.
The
determination
and
quantitation
of
the
MeCHQ
is
conducted
using
reverse­
phase
HPLC
with
the
fluorescence
detection.
The
limit
of
quantitation
of
the
method
is
still
0.05
ppm.

Independent
Method
Validation.
The
analytical
method
used
for
sunflower
and
flax
data
collection
(
MRID
44967703)
was
subjected
to
an
independent
laboratory
validation
(
MRID
44967704).
Untreated
control
sunflower
seeds
were
fortified
with
quizalofop­
P­
ethyl
and
quizalofop­
P
at
0.05
ppm
and
2.00
ppm.
The
method
was
successfully
validated
for
both
analytes.

The
analytical
method
used
for
wheat
and
barley
data
collection
(
Report
No.
MLIR­
02­
01)
was
subjected
to
an
independent
laboratory
validation
(
Study
No.
EN­
CAS
01­
0040).
Each
trial
consisted
of
two
subsets,
one
for
quizalofop­
P­
ethyl
and
the
other
for
quizalofop­
P.
Each
subset
included
two
unfortified
control
samples
and
two
fortifications
at
the
Limit
of
Quantitation
(
LOQ,
0.05
ppm),
at
2X
the
LOQ
(
0.10
ppm)
and
at
6.5
ppm,
the
highest
residue
level
found
in
a
3
related
residue
study.
The
method
was
successfully
validated
for
both
analytes
and
the
results
are
shown
in
the
following
table.

3.
Magnitude
of
residues.

Magnitude
of
the
Residue
 
Sunflower
Crop
Field
Trials
Eight
field
trials
were
conducted
in
1998
using
various
varieties
of
sunflowers
(
MRID
44967701).
Trial
sites
were
located
in
Kansas
(
1
site),
North
Dakota
(
4
sites),
South
Dakota
(
2
sites),
and
Texas
(
1
site).
Sunflower
seeds
were
harvested
60
to
61
days
following
two
postemergent
applications
(
6
to
7
day
spray
interval)
with
an
emulsifiable
concentrate
(
EC)
formulation
of
quizalofop­
P­
ethyl.
The
target
application
rates
were
0.0537
lb
ai/
A
for
the
first
application
and
0.0672
lb
ai/
A
for
the
second
application.

Samples
of
seeds
(
including
hulls)
were
analyzed
for
residues
of
quizalofop­
P­
ethyl
and
quizalofop­
P,
expressed
as
quizalofop­
P­
ethyl,
using
a
validated
analytical
method
(
Report
No.
SARS­
98­
06).
The
overall
recoveries
were
79%
for
quizalofop­
P­
ethyl
and
87%
for
quizalofop­
P.
The
limit
of
quantitation
was
0.05
ppm.
The
samples
were
stored
frozen
28
to
136
days
from
collection
to
extraction.

The
residues
of
quizalofop­
P­
ethyl
and
quizalofop­
P
(
expressed
as
quizalofop­
P­
ethyl)
ranged
from
0.145
ppm
to
1.32
ppm
in
sunflower
seeds.

Magnitude
of
the
Residue
 
Sunflower
Processing
Studies
A
processing
study
was
conducted
using
sunflowers
grown
in
North
Dakota
in
1998
(
MRID
44967702).
Sunflower
seeds
were
harvested
60
days
after
a
single
application
of
an
EC
formulation
of
quizalofop­
P­
ethyl
at
0.604
lb
ai/
A
(
5x
the
proposed
seasonal
application
rate).
The
seeds
were
processed
using
a
simulated
commercial
procedure
into
meal
and
oil
and
the
samples
were
analyzed
using
a
validated
method
(
MRID
44967703).
The
limit
of
quantitation
of
the
analytical
method
is
0.05
ppm.
Overall
recoveries
averaged
74%
for
quizalofop­
P­
ethyl
and
87%
for
quizalofop­
P
in
meal,
and
89%
for
quizalofop­
P­
ethyl
and
88%
for
quizalofop­
P
in
oil.
Samples
were
stored
frozen
21
to
172
days
before
extraction.

Average
residues
of
quizalofop­
P­
ethyl
and
quizalofop­
P
(
expressed
as
quizalofop­
Pethyl
were
2.45
ppm
in
seeds,
2.87
ppm
in
meal,
and
<
0.05
ppm
in
oil.
Therefore,
residues
of
quizalofop­
P­
ethyl
are
not
likely
to
concentrate
in
meal
or
in
oil.

Magnitude
of
the
Residue
 
Flax
Crop
Field
Trials
Five
trials
were
conducted
in
1999,
one
trial
each
in
Minnesota
and
South
Dakota
and
three
trials
in
North
Dakota
(
Report
No.
SARS­
99­
10).
Each
treated
plot
received
two
sequential
postemergent
applications
of
an
EC
formulation
of
quizalofop­
P­
ethyl
applied
at
proposed
label
rates
using
ground
broadcast
spray
equipment.
The
applications
were
made
with
a
6
to
8
day
4
spray
interval.
The
target
application
rates
were
12.0
fluid
ounces
of
product/
acre/
application
(
0.0806
lb
ai/
A)
for
the
first
application
and
12.0
fluid
ounces
of
product/
acre/
application
(
0.0806
lb
ai/
A)
for
the
second
application.

Samples
of
flaxseeds
from
four
of
the
sites
were
analyzed
for
residues
of
quizalofop­
Pethyl
and
quizalofop­
P
expressed
as
quizalofop­
P­
ethyl
using
a
validated
analytical
method
(
Report
No.
SARS­
98­
6).
The
overall
recoveries
for
the
method
validations
averaged
93%
+
2.5
for
quizalofop­
P­
ethyl
and
92%
+
4.6
for
quizalofop­
P.
The
limit
of
quantification
(
LOQ)
was
0.05
ppm.
The
results
of
the
analysis
of
the
treated
samples
from
the
field
sites
indicate
that
residues
were
less
than
the
LOQ
(
0.05
ppm).

Magnitude
of
the
Residue
­
Flax
Processing
Studies
A
processing
study
of
flax
processed
commodity
(
meal)
was
conducted
using
flax
grown
in
Minnesota
in
1999
(
Report
No.
SARS­
99­
11).
The
trial
consisted
of
a
control
plot
and
two
treated
plots.
Each
plot
received
either
a
single
application
of
0.322
lb
ai/
A
and
the
other
plot
received
a
treatment
of
0.806
lb
ai/
A,
respectively,
2X
and
5X
the
maximum
annual
use
rate
permitted
on
the
labeling.
The
flaxseeds
were
harvested
at
normal
crop
maturity,
74
days
after
application
and
processed
into
flax
meal.
An
untreated
control
and
5X
exaggerated
RAC
flaxseed
samples
were
analyzed
using
a
validated
method.
The
method
was
validated
on
flaxseed
as
part
of
the
"
Magnitude
of
Quizalofop­
P­
Ethyl
and
Quizalofop­
P
Residues
in
the
Raw
Agricultural
Commodity,
Flaxseeds
(
Report
No.
SARS­
98­
10)
for
both
analytes
at
the
levels
of
0.05
ppm
and
5.0
ppm.
The
overall
recoveries
for
the
method
validations
averaged
93%
+
2.5
for
quizalofop­
Pethyl
and
92%
+
4.6
for
quizalofop­
P
in
flaxseed.
The
LOQ
for
quizalofop­
P­
ethyl
and
quizalofop­
P
was
set
at
0.05
ppm
for
flaxseed.

Since
there
were
no
residues
above
the
LOQ
in
the
5X
treated
sample
and
1X
raw
agricultural
commodity
samples
in
the
magnitude
of
residue
study
(
Report
No.
SARS­
99­
10),
the
samples
were
not
processed
into
meal.

Magnitude
of
the
Residue
 
Wheat
Crop
Field
Trials
Thirty­
three
field
trials
using
spring
and
winter
wheat
varieties
were
initiated
in
2001
in
U.
S.
EPA
Regions
2,
4,
5,
6,
7,
8,
and
11
and
Canadian
PMRA
Zones
5,
7,
7A,
and
14.
Forage,
hay,
grain,
and
straw
samples
were
collected
at
normal
harvest
intervals
following
one
preplant
broadcast
application
made
one
day
prior
to
planting
(
except
at
three
sites
where
the
applications
were
made
on
the
same
day
as
the
planting)
with
an
emulsifiable
concentrate
(
EC)
formulation
of
quizalofop­
P­
ethyl.
The
formulation
was
applied
by
ground
equipment
at
the
maximum
label
use
rate
of
0.068
lb
ai/
A
(
76
g
ai/
ha).
The
residues
of
quizalofop­
P­
ethyl
and
quizalofop­
P
(
expressed
as
quizalofop­
P­
ethyl)
were
not
detectable
in
treated
samples.
The
exceptions
were
for
one
straw
and
grain
sample,
each
with
one
sample
with
residues
at
the
LOD,
and
18
additional
samples
with
residues
<
LOD.
Based
on
these
results,
it
can
be
concluded
that
the
uptake
of
quizalofop­
P­
ethyl
by
wheat
or
from
soil
treated
with
the
formulation
is
negligible.
5
Magnitude
of
the
Residue
 
Wheat
Processing
Studies
A
processing
study
was
conducted
using
wheat
grown
in
a
third
plot
established
in
Idaho
specifically
for
processing
fractions.
This
plot
received
one
preplant
broadcast
application
of
the
quizalofop­
P­
ethyl
formulation
at
an
exaggerated
5X
rate
of
0.34
lb
ai/
A
(
381
g
ai/
ha)
(
±
5%).
At
this
site,
grain
samples
weighing
approximately
200
lb
were
collected
from
the
untreated
and
5X
rate
treated
plots
for
processing
by
procedures
that
simulate
commercial
practices.
Samples
collected
at
the
processing
facility
were
whole
grain,
bran,
flour,
germ,
middlings,
and
shorts.
No
detectable
residues
were
found
in
the
5X
rate
whole
grain
and
processed
fractions;
therefore
the
concentration
factors
for
all
processed
fractions
were
<
1.
Therefore,
residues
of
quizalofop­
Pethyl
are
not
likely
to
concentrate
in
processed
wheat
products.

Magnitude
of
the
residue
 
Barley
Crop
Field
Trials
Twenty­
five
field
trials
using
spring
and
fall
varieties
of
barley
were
initiated
in
2001
in
U.
S.
EPA
Regions
1,
5,
7,
9,
10,
and
11
and
Canadian
PMRA
Zones
5B,
7,
and
14.
Hay,
grain,
and
straw
samples
were
collected
at
normal
harvest
intervals
following
one
preplant
broadcast
application
made
one
day
prior
to
planting
(
except
at
two
sites
where
the
applications
were
made
on
the
same
day
as
the
planting)
with
an
emulsifiable
concentrate
(
EC)
formulation
of
quizalofop­
P­
ethyl.
The
formulation
was
applied
by
ground
equipment
at
the
maximum
label
use
rate
of
0.068
lb
ai/
A
(
76
g
ai/
ha).
Residues
were
below
the
detection
limits
(
ND)
for
all
samples
except
for
five
untreated
control
samples
and
six
treated
samples.
With
one
exception,
the
residues
in
samples
with
detectable
residues
were
less
than
the
LOQ
of
0.05
ppm.
The
one
positive
untreated
control
result
(
0.095
ppm)
was
likely
a
result
of
laboratory
contamination
at
the
time
of
sample
processing/
grinding.

Magnitude
of
the
Residue
in
Plants.

The
studies
submitted
include
field
trials
in
three
regions
for
succulent
beans,
six
additional
sites
for
dry
beans
in
four
regions
and
five
additional
sites
in
three
regions
for
sugar
beets.

In
conjunction
with
previously
submitted
data,
an
adequate
amount
of
geographically
representative
crop
field
trial
residue
data
were
presented
which
show
that
the
proposed
tolerances
should
not
be
exceeded
when
quizalofop
ethyl
is
formulated
into
Assure<
Register>
and
used
as
directed.

Magnitude
of
the
Residue
in
Animals.

A
ruminant
feeding
study
has
been
submitted
and
reviewed
by
EPA.
In
summary,
three
groups
of
three
lactating
dairy
cows
(
plus
a
control
group)
were
fed
0.1,
0.5,
and
5.0
ppm
quizalofop
ethyl
ester
(
encapsulated)
for
28
consecutive
days.
Milk
was
collected
daily
and
a
subsample
was
divided
into
skim
milk
and
cream.
Two
cows
were
sacrificed
after
28
days
with
samples
of
fat,
skeletal
muscle,
liver,
and
kidney
being
collected
and
analyzed.
The
remaining
cow
6
in
each
test
group
was
fed
a
regular
diet
without
encapsulated
quizalofop
ethyl
ester
for
7
additional
days
before
sacrifice.
Whole
milk,
skim
milk,
and
cream
from
the
control,
and
the
0.1
and
0.5
ppm
dose
groups
showed
no
quizalofop
to
<
0.02
ppm
(
0.05
ppm
in
cream).
From
the
5
ppm
dose,
quizalofop
residues
ranged
from
0.01
to
0.02
ppm
in
whole,
and
when
these
samples
were
separated
into
cream
and
skim
milk,
the
quizalofop
partitioned
into
the
cream
with
residues
plateauing
at
0.26
to
0.31
ppm.
No
quizalofop
to
<
0.02
ppm
was
detected
in
skeletal
muscle,
and
to
<
0.05
ppm
was
detected
in
any
liver
or
fat
sample
from
any
of
the
three
doses.
Quizalofop
was
detected
in
one
kidney
sample
as
0.05
ppm
from
the
5
ppm
dose.

From
the
feed
items
in
this
petition,
all
of
the
feed
items
in
cattle
diets
can
be
treated
with
quizalofop
ethyl
ester.
A
theoretical
beef
cattle
diet
consisting
of
canola
meal,
bean
and
pea
forage,
pea
hay,
and
sugar
beet
tops
which
none­
the­
less
maximizes
the
potential
quizalofop
exposure
of
2.1
ppm.
A
theoretical
dairy
cattle
diet
consisting
of
pea
and
bean
forage
would
none­
the­
less
maximize
the
potential
quizalofop
exposure
at
2.4
ppm.
Substitutions
of
other
feed
items
and
varying
their
percentages
in
the
diets
would
give
a
lower
dietary
quizalofop
burden.

The
results
of
the
quizalofop
ethyl
ester
bovine
feeding
study
show
that
finite
residues
will
actually
occur
in
milk
and
tissues
from
the
feeding
of
quizalofop
ethyl
ester
treated
RACS
or
their
processed
feed
items
when
Assure<
Register>
II
is
used
as
directed.
The
established
quizalofop
and
quizalofop
ethyl
ester
tolerance
in
milk,
and
in
fat,
meat,
and
meat
by­
products
of
cattle,
goats,
hogs,
horse,
and
sheep
are
adequate
and
need
not
be
increased
from
these
additional
uses.

A
poultry
feeding
study
has
been
submitted
and
reviewed.
In
summary,
3
groups
of
20
hens
(
plus
1
control
group)
were
dosed
with
encapsulated
quizalofop
ethyl
ester
at
0.1,
0.5,
and
5
ppm
daily
for
28
consecutive
days.
Eggs
were
collected
daily,
and
after
28
days
3/
4
of
the
hens
in
each
test
group
were
sacrificed,
and
samples
of
fat,
liver,
kidney,
breast
and
thigh
muscles
were
collected
and
analyzed.
Tissues
from
each
test
group
were
pooled
prior
to
analysis.
The
remaining
five
hens
were
fed
a
regular
poultry
diet
without
quizalofop
ethyl
ester
for
an
additional
7
days
before
sacrifice.
No
quizalofop
residues
were
detected
in
the
liver
to
<
0.05
ppm,
and
in
breast
and
thigh
muscles
to
<
0.02
ppm
for
any
dose
administered.
From
the
5
ppm
dose,
one
kidney
sample
showed
0.09
ppm
quizalofop,
two
fat
samples
were
0.05
and
0.06
ppm
quizalofop,
and
one
egg
sample
was
0.02
ppm
quizalofop.

The
results
of
the
quizalofop
ethyl
ester
poultry
feeding
study
show
that
while
it
is
not
possible
to
establish
with
certainty
whether
finite
residues
will
actually
occur
in
eggs
and
tissues
from
the
feeding
of
quizalofop
ethyl
ester
treated
RACS
or
their
processed
feed
items
when
Assure<
Register>
II
is
used
as
directed,
there
is
a
reasonable
expectation
for
such
residues
to
occur.
The
established
tolerance
of
quizalofop
and
quizalofop
ethyl
ester
in
eggs,
and
in
fat,
meat,
and
meat
by­
products
of
poultry
are
adequate
and
need
not
be
changed
from
these
additional
uses.

B.
Toxicological
Profile
7
1.
Acute
toxicity.
Several
acute
toxicology
studies
were
conducted,
and
the
overall
results
placed
technical
grade
quizalofop
ethyl
in
toxicity
Category
III.
These
include
the
following
studies
in
Category
III:
acute
oral
toxicity
(
LD50s
1480
and
1670
for
female
and
male
rats,
respectively)
and
eye
irritation
(
mild
effects;
reversible
within
4
days).
Dermal
toxicity
(
LD50
>
5,000
mg/
kg;
rabbit),
inhalation
toxicity
(
LC50
>
5.8
mg/
L;
rat)
and
dermal
irritation
were
classified
within
Category
IV.
Technical
quizalofop
ethyl
was
not
a
dermal
sensitizer.

2.
Genotoxicty.
Technical
quizalofop
ethyl
was
negative
in
the
following
genotoxicity
tests:
bacterial
gene
mutation
assays
with
E.
coli
and
S.
typhimurium;
gene
mutation
assays
in
Chinese
hamster
ovary(
CHO)
cells
;
in
vitro
DNA
damage
assays
with
B.
subtillis
and
in
rat
hepatocytes;
and
an
in
vitro
chromosomal
aberration
test
in
CHO
cells.

3.
Reproductive
and
developmental
toxicity.
A
developmental
toxicity
study
in
rats
administered
dosage
levels
of
0,
30,
100,
and
300
mg/
kg/
day.
The
maternal
toxicity
no­
observed
effect
level
(
NOEL)
was
30
mg/
kg/
day
and
a
developmental
toxicity
NOEL
was
greater
than
the
highest
dose
tested
(
HDT)
of
300
mg/
kg/
day.
The
maternal
NOEL
was
based
on
reduced
food
consumption
and
increased
liver
weights.

A
developmental
toxicity
study
in
rabbits
administered
dosage
levels
of
0,
7,
20,
and
60
mg/
kg/
day
with
no
developmental
effects
noted
at
60
mg/
kg/
day
(
HDT).
The
maternal
toxicity
NOEL
was
20
mg/
kg/
day
based
on
decreases
in
food
consumption
and
body
weight
gain
at
60/
mg/
kg/
day
(
HDT).

A
two­
generation
reproduction
study
in
rats
fed
diets
containing
0,
25,
100
or
400
ppm
(
or
approximately
0,
1.25,
5,
and
20
mg/
kg/
day,
respectively)
with
a
developmental
(
systemic
effects)
NOEL
of
1.25
mg/
kg/
day
for
F2B
weanlings
based
on
increased
liver
weights
and
increased
incidence
of
eosinophilic
changes
in
the
livers
at
5.0
mg/
kg/
day.
These
liver
changes
were
considered
to
be
physiological
or
adaptive
changes
to
compound
exposure
among
weanlings.
When
access
to
the
mother's
feed
is
available,
it
is
a
common
observation
that
young
rats
will
begin
consuming
chow
prior
to
complete
weaning
at
21
days
of
age.
Consumption
could
not
be
quantified;
therefore,
the
maternal
consumption
was
assumed
as
the
NOEL.
If
normalized
on
a
body
weight
basis,
exposures
to
the
weanling
rats
were
likely
higher.
The
parental
NOEL
of
5.0
mg/
kg/
day
was
based
on
decreased
body
weight
and
premating
weight
gain
in
males
at
20
mg/
kg/
day
(
HDT).

4.
Subchronic
toxicity.
A
90­
day
study
was
conducted
in
rats
fed
diets
containing
0,
40,
128,
and
1,280
ppm
(
or
approximately
0,
2,
6.4,
and
64
mg/
kg/
day,
respectively).
The
NOEL
was
2
mg/
kg/
day,
based
on
increased
liver
weights
at
6.4
mg/
kg.

A
90­
day
feeding
study
in
mice
was
conducted
with
diets
that
contained
0,
100,
316
or
1,000
ppm
(
or
approximately
0,
15,
47.4,
and
150
mg/
kg/
day,
respectively).
The
NOEL
was
<
15
mg/
kg/
day,
the
lowest
dose
tested
(
LDT),
based
on
increased
liver
weights
and
reversible
8
histopathological
effects
in
the
liver
at
the
LDT.

A
6­
month
feeding
study
in
dogs
was
conducted
with
diets
that
contained
0,
25,
100,
or
400
ppm
(
or
approximately
0,
0.625,
2.5,
and
10
mg/
kg/
day,
respectively).
The
NOEL
was
2.5
mg/
kg/
day
based
on
increased
blood
urea
nitrogen
at
10
mg/
kg/
day.

A
21­
day
dermal
study
was
conducted
in
rabbits
at
doses
of
0,
125,
500,
or
2,000
mg/
kg/
day.
The
NOEL
was
2,000
mg/
kg/
day
(
HDT).

5.
Chronic
toxicity.
An
18­
month
carcinogenicity
study
was
conducted
in
CD­
1
mice
fed
diets
containing
0,
2,
10,
80,
or
320
ppm
(
or
approximately
0,
0.3,
1.5,
12,
or
48
mg/
kg/
day,
respectively).
No
carcinogenic
effects
were
observed
under
the
conditions
of
the
study
at
levels
up
to
and
including
12
mg/
kg/
day.
A
marginal
increase
in
the
incidence
of
hepatocellular
tumors
was
observed
at
48
mg/
kg/
day,
the
HDT,
which
exceeded
the
maximum
tolerated
dose
(
MTD).
(
See
the
discussion
by
the
EPA
Carcinogenicity
Peer
Review
Committee.
Toxicology
Branch
Peer
Review
Committee:
Draft
Document
on
Assure
based
on
November
5,
1986
CPRC
Meeting
Dated
December
9,
1986).

A
two­
year
chronic
toxicity/
carcinogenicity
study
was
conducted
in
rats
fed
diets
containing
0,
25,
100,
or
400
ppm
(
0,
0.9,
3.7,
or
15.5
mg/
kg/
day
for
males
and
0,
1.1,
4.6,
or
18.6
mg/
kg/
day
for
females,
respectively).
No
carcinogenic
effects
were
observed
under
the
conditions
of
the
study
at
levels
up
to
and
including
18.6
g/
kg/
day
(
HDT).
The
systemic
NOEL
was
0.9
mg/
kg/
day
based
on
altered
red
cell
parameters
and
slight/
minimal
centrilobuler
enlargement
of
the
liver
at
3.7
mg/
kg/
day.

A
one­
year
feeding
study
was
conducted
in
dogs
fed
diets
containing
0,
25,
100,
or
400
ppm
(
or
approximately
0,
0.625,
2.5,
or
10
mg/
kg/
day,
respectively).
The
NOEL
was
10
mg/
kg/
day
(
HDT).

The
Carcinogenicity
Peer
Review
Committee
(
CPRC)
of
HED
has
evaluated
the
rat
and
mouse
cancer
studies
on
quizalofop
along
with
other
relevant
short­
term
toxicity
studies,
mutagenicity
studies,
and
structure
activity
relationships.
The
CPRC
concluded,
after
three
meetings
and
an
evaluation
by
the
EPA
Science
Advisory
Panel
(
SAP),
that
the
classification
should
be
a
Category
D
(
not
classifiable
as
to
human
cancer
potential).
No
new
cancer
studies
were
required.
(
CPRC
Report:
Peer
Review
of
Assure,
February
6,
1987;
JA
Quest
to
RJ
Taylor.
SAP
Findings
(
Assure)
Document
signed
by
Steve
Johnson,
December
23,
1987).

The
first
CPRC
review
tentatively
concluded
that
quizalofop
should
be
classified
as
a
Category
B2
(
probable
human
carcinogen).
That
classification
was
based
on
liver
tumors
in
female
rats,
ovarian
tumors
in
female
mice,
and
liver
tumors
in
male
mice.
This
classification
was
downgraded
to
a
Category
C
(
possible
human
carcinogen)
at
a
second
CPRC
review.
The
change
in
classification
resulted
from
a
reexamination
of
the
liver
tumors
in
female
rats
and
ovarian
tumors
in
female
mice.
The
first
peer
review
had
found
a
statistically
significant
positive
trend
for
liver
carcinomas
in
female
rats.
Subsequent
to
this
conclusion,
a
tumor
data
reevaluation
showed
a
reduced
number
of
carcinomas.
Although
there
remained
a
statistically
significant
positive
trend
for
carcinomas
in
the
study,
the
CPRC
concluded
that
the
carcinomas
were
not
biologically
significant
given
the
few
9
carcinomas
identified
(
one
at
the
mid­
dose
and
two
at
the
high
dose).
Noting
that
this
level
of
carcinomas
was
within
historical
levels,
the
CPRC
concluded
that
administration
of
quizalofop
did
not
appear
to
be
associated
with
the
liver
carcinomas.

The
CPRC
had
first
attached
importance
to
the
fact
that
the
ovarian
tumors
in
female
mice,
were
statistically
significant
at
the
high
dose
compared
to
historical
control
values,
and
statistically
significant
when
compared
to
concurrent
controls.
However,
review
of
further
historical
control
data
showed
that
the
level
of
ovarian
tumors
in
the
quizalofop
study
was
similar
to
the
background
rate
in
several
other
studies.
Given
this
information
and
the
fact
that
the
quizalofop
study
showed
no
hyperplasia
of
the
ovary,
no
signs
of
endocrine
activity
related
to
ovarian
function,
and
no
dose
response
relationship,
the
CPRC
concluded
that
the
ovarian
tumors
were
probably
not
compoundrelated

The
findings
of
the
second
CPRC
review
were
presented
to
the
SAP.
The
SAP
concurred
with
the
CPRC
conclusion
that
the
liver
tumors
in
female
rats
and
the
ovary
tumors
in
female
mice
showed
no
evidence
of
carcinogenicity.
However,
the
SAP
disagreed
with
CPRC's
classification
of
quizalofop
as
a
Category
C
based
on
the
liver
tumors
in
male
mice.
The
SAP
concluded
that
the
mouse
liver
tumors
did
not
support
such
a
classification
because
the
tumors
occurred
at
a
dose
above
the
MTD
and
because
they
were
not
statistically
significant
if
they
had
a
"
p"
value
of
less
than
0.05.
The
SAP
believed
that
such
greater
statistical
rigor
was
appropriate
for
variable
tumor
endpoints
such
as
male
mouse
liver
tumors.

Following
the
SAP
review,
the
CPRC
changed
the
classification
for
quizalofop
to
Category
D.
The
Category
D
classification
is
based
on
an
approximate
doubling
in
the
incidence
of
male
mice
liver
tumors
between
controls
and
the
high
dose.
This
finding
was
not
considered
strong
enough
to
warrant
the
finding
of
a
Category
C
(
possible
human
carcinogen),
since
the
increase
was
of
marginal
statistical
significance,
occurred
at
a
high
dose
that
exceeded
the
predicted
MTD,
and
occurred
in
a
study
in
which
the
concurrent
control
for
liver
tumors
was
somewhat
low
compared
to
the
historical
controls;
while
the
high
dose
group
was
at
the
upper
end
of
previous
historical
control
groups.

EPA
has
found
the
evidence
on
the
carcinogenicity
of
quizalofop­
p
ethyl
ester
in
animals
to
be
equivocal
and,
therefore,
concludes
that
quizalofop­
p
ethyl
ester
does
not
induce
cancer
in
animals.

Important
to
this
conclusion
was
the
following
evidence:

(
1)
The
only
statistically
significant
tumor
response
that
appears
compound­
related
was
seen
at
a
single
dose
in
a
single
sex
in
a
single
species;

(
2)
the
response
was
only
marginally
statistically
significant;

(
3)
the
response
was
only
significant
when
benign
and
malignant
tumors
were
combined;

(
4)
the
tumors
were
in
the
male
mouse
liver;

(
5)
the
tumors
were
within
historical
controls;
and
10
(
6)
the
mutagenicity
studies
were
negative.

In
some
circumstances,
a
finding
of
animal
carcinogenicity
would
be
made
despite
any
one,
or
even
several,
of
the
six
factors
noted.
However,
the
combination
of
all
of
these
factors
casts
sufficient
doubt
on
the
reproducibility
of
the
response
in
the
high
dose
male
mouse
and
therefore,
EPA
concluded
that
the
evidence
on
carcinogenicity
is
equivocal.

6.
Animal
metabolism.
Animal
metabolism
studies
have
been
conducted
with
laying
hens
and
lactating
goats
using
14C­
phenyl
and
14C­
quinoxaline
quizalofop
ethyl
ester.
These
studies
were
reviewed
and
accepted
by
EPA.
EPA
concluded
that
the
metabolism
of
quizalofop­
P­
ethyl
is
adequately
understood.

The
primary
metabolic
pathway
in
ruminants
is
via
hydrolysis
of
the
ethyl
ester
to
form
the
quizalofop­
P
methyl
ester.
In
poultry,
the
primary
metabolic
pathway
is
also
the
hydrolysis
of
the
ethyl
ester
to
form
the
quizalofop­
P
acid,
followed
by
the
methyl
esterification
to
form
the
quizalofop
methyl
ester
as
a
minor
pathway
of
metabolism.
The
residues
of
concern
are
quizalofop
ethyl,
quizalofop
methyl,
and
quizalofop,
all
expressed
as
quizalofop
ethyl.
There
is
no
evidence
that
the
metabolites
of
quizalofop
ethyl,
as
identified
in
animal
metabolism
studies,
have
any
toxicological
significance.

7.
Metabolite
toxicology.
There
is
no
evidence
that
the
metabolites
of
quizalofop
ethyl
as
identified
as
either
the
plant
or
animal
metabolism
studies
are
of
any
toxicological
significance.

8.
Endocrine
disruption.
No
special
studies
investigating
potential
estrogenic
or
other
endocrine
effects
of
quizalofop­
P­
ethyl
have
been
conducted.
However,
the
standard
battery
of
required
toxicology
studies
has
been
completed.
These
include
an
evaluation
of
the
potential
effects
on
reproduction
and
development,
and
an
evaluation
of
the
pathology
of
the
endocrine
organs
following
repeated
or
long­
term
exposure
to
doses
that
far
exceed
likely
human
exposures.
Based
on
these
studies
there
is
no
evidence
to
suggest
that
quizalofop­
P­
ethyl
has
an
adverse
effect
on
the
endocrine
system.

C.
Aggregate
Exposure
11
(
i)
1.
Dietary
exposure.
Dietary
Exposure.
Acute
and
chronic
dietary
risk
assessments
were
conducted
for
quizalofop­
P­
ethyl
using
the
Dietary
Exposure
Evaluation
Model
(
DEEM)
and
the
USDA
Continuing
Survey
of
Food
Intake
by
Individuals
(
CSFII,
for
1994
to
1996,
as
contained
in
DEEM).
For
these
assessments
it
was
assumed
that
100%
of
the
crop
was
treated
with
quizalofop­
P­
ethyl.
Established
or
proposed
tolerances
were
used
to
estimate
dietary
exposure
from
the
consumption
of
cereal
grains,
dairy
products,
dried
and
succulent
shelled
peas
and
beans,
edible
pod
legume
vegetables,
leaves
of
root
and
tuber
vegetables,
legume
vegetables,
meat,
poultry,
canola,
carob,
cottonseed,
peppermint,
pineapples,
spearmint,
sugarcane/
molasses,
sunflowers,
flax,
wheat
and
barley.
Given
flax's
tolerance
level
of
0.05
ppm
and
its
scarcity
in
the
human
diet,
quizalofop­
P­
ethyl
on
flax
does
not
contribute
to
the
acute
dietary
and
chronic
exposure.

A.
Acute
Dietary
Exposure.
The
predicted
acute
exposure
at
the
95
th
percentile
in
the
U.
S.
population
for
all
commodities
was
0.001160
mg/
kg
bw/
d.
The
population
subgroup
with
the
highest
predicted
level
of
acute
exposure
was
the
non­
nursing
infants
(<
1
year)
subgroup
(
0.003315
mg/
kg
bw/
d).
Based
on
an
acute
NOEL
of
20
mg/
kg
bw/
d
and
a
100­
fold
safety
factor,
the
acute
reference
dose
(
aRfD)
is
0.2
mg/
kg
bw/
d.
No
additional
uncertainty
factors
were
assigned
for
susceptible
populations.
For
the
U.
S.
population,
the
predicted
exposure
is
equivalent
to
0.58
%
of
the
aRfD.
Because
the
predicted
exposures,
expressed
as
percentages
of
the
aRfD,
are
well
below
100%,
there
is
reasonable
certainty
that
no
acute
effects
would
result
from
dietary
exposure
to
quizalofop­
P­
ethyl.

B.
Chronic
Dietary
Exposure.
The
predicted
chronic
exposure
in
the
U.
S.
population
for
all
commodities
was
0.000424
mg/
kg
bw/
d.
The
population
with
the
highest
predicted
level
of
chronic
exposure
(
0.001184
mg/
kg
bw/
d)
was
the
non­
nursing
infants
(<
1
year)
subgroup.
Based
on
a
chronic
NOEL
of
0.9
mg/
kg
bw/
d
and
a
100­
fold
safety
factor,
the
chronic
reference
dose
(
cRfD)
would
be
0.009
mg/
kg
bw/
d.
No
additional
uncertainty
factors
were
assigned
for
susceptible
populations.
For
the
population
subgroup
with
the
highest
level
of
exposure
(
non­
nursing
infants
(<
1
year),
the
exposure
would
be
equivalent
to
13.2%
of
the
cRfD.
Because
the
predicted
exposures,
expressed
as
percentages
of
the
cRfD,
are
well
below
100%,
there
is
reasonable
certainty
that
no
chronic
effects
would
result
from
dietary
exposure
to
quizalofop­
P­
ethyl.

i.
Food.
Not
applicable.

ii.
Drinking
water.
There
is
no
established
maximum
concentration
level
for
quizalofop­
Pethyl
in
water.
Tier
1
drinking
water
assessments
were
conducted
for
ground
and
surface
water
to
determine
the
risk
of
exposure
to
quizalofop­
P­
ethyl.
The
method
used
was
a
comparison
of
the
calculated
Drinking
Water
Level
of
Comparison
(
DWLOC)
value
to
the
Drinking
Water
Estimated
Concentration
(
DWEC)
value.
The
results
show
that
all
of
the
12
DWEC
values
are
lower
than
the
DWLOC
values.
Therefore,
exposure
to
quizalofop­
Pethyl
in
drinking
water
is
not
a
concern..

2.
Non­
dietary
exposure.
Quizalofop­
P­
ethyl
is
not
registered
for
any
use
that
could
result
in
non­
occupational,
non­
dietary
exposure
to
the
general
population.

D.
Cumulative
Effects
(
b)
There
is
no
evidence
to
indicate
or
suggest
that
quizalofop­
P­
ethyl
has
any
toxic
effects
on
mammals
that
would
be
cumulative
with
those
of
any
other
chemicals.

E.
Safety
Determination
A
dietary
exposure
assessment
for
the
herbicide
quizalofop
p­
ethyl
was
conducted
using
Novigen's
Dietary
Exposure
Evaluation
Model
(
DEEMTM
)
Version
7.76.
Dietary
exposure
to
quizalofop
p­
ethyl
was
based
upon
the
following
crop
group
uses:
dairy
products,
dried
shelled
pea
and
bean
(
including
soybeans),
edible
pod
legume
vegetables,
leaves
of
root
and
tuber
vegetables,
legume
vegetables,
meat,
poultry,
succulent
shelled
peas
and
beans;
and
the
following
crop
uses:
canola,
cottonseed,
peppermint,
pineapples,
spearmint,
sugarcane/
molasses,
sunflowers,
flax,
wheat
and
barley.

1.
U.
S.
population.
For
the
overall
U.
S.
population,
the
predicted
acute
exposure
would
be
0.001160
mg/
kg
bw/
day,
or
at
the
95th
percentile.
Based
on
an
acute
NOEL
of
20
mg/
kg
bw/
d
and
a
100­
fold
uncertainty
factor,
the
acute
reference
dose
(
aRfD)
would
be
0.2
mg/
kg
bw/
d.
For
the
U.
S.
population
the
predicted
acute
exposure
is
equivalent
to
0.58%
or
less
of
the
estimated
aRfD.
The
predicted
chronic
exposure
for
the
overall
U.
S.
population
subgroup
was
0.000424
mg/
kg
bw/
day.
Based
on
a
chronic
NOEL
of
0.9
mg/
kg
bw/
d
and
a
100­
fold
safety
factor,
the
chronic
reference
dose
(
cRfD)
would
be
0.009
mg/
kg
bw/
d.
For
the
U.
S.
population,
the
predicted
exposure
is
equivalent
to
4.7%
of
the
cRfD.
Because
the
predicted
exposures,
expressed
as
percentages
of
the
cRfD,
are
well
below
100%,
there
is
reasonable
certainty
that
no
acute
or
chronic
effects
would
result
from
dietary
exposure
to
quizalofop
p­
ethyl.

2.
Infants
and
children.
The
population
subgroup
with
the
highest
predicted
level
of
acute
exposure
was
the
non­
nursing
infants
(<
1
year)
subgroup
with
an
exposure
of
0.003315
mg/
kg
bw/
day
(
95th
percentile).
Based
on
an
acute
NOEL
of
20
mg/
kg
bw/
d
and
a
100­
fold
safety
factor,
the
acute
reference
dose
(
aRfD)
would
be
0.2
mg/
kg
bw/
d.
The
acute
exposure
for
nonnursing
infants
(<
1
year)
would
be
equivalent
to
1.66%
of
the
aRfD.
The
population
subgroup
with
the
highest
predicted
level
of
chronic
exposure
was
the
non­
nursing
infants
(<
1
year)
subgroup
with
an
exposure
of
0.001184
mg/
kg
bw/
day.
Based
on
a
chronic
NOEL
of
0.9
mg/
kg
bw/
d
and
a
100­
fold
safety
factor,
the
chronic
reference
dose
(
cRfD)
would
be
0.009
mg/
kg
bw/
d.
The
chronic
exposure
for
non­
nursing
infants
(<
1
year)
would
be
equivalent
to
13.2%
of
the
cRfD.
Because
the
predicted
exposures,
expressed
as
percentages
of
the
cRfD,
are
well
below
100%,
there
is
reasonable
certainty
that
no
acute
or
chronic
effects
would
result
from
dietary
exposure
to
quizalofop
p­
ethyl.
13
F.
International
Tolerances
Harmonization
of
Tolerances:
There
are
no
Mexican,
Canadian
or
Codex
MRL's/
tolerances;
therefore,
compatibility
is
not
an
issue.