Document ID: EPA-HQ-OPP-2006-0504-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-07-05T04:00Z

COMPANY
FEDERAL
REGISTER
DOCUMENT
SUBMISSION
TEMPLATE
(
1/
1/
2006)

EPA
Registration
Division
contact:
[
Ms.
Joanne
Miller,
PM
23,
(
703)
305­
6224]

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

TEMPLATE:

Bayer
CropScience
[
5F6959]

EPA
has
received
a
pesticide
petition
(
5F6959)
from
Bayer
CropScience,
2
T.
W.
Alexander
Drive,
P.
O.
Box
12014,
Research
Triangle
Park,
NC
27709
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
180.600
by
increasing
established
tolerances
for
the
residues
of
propoxycarbazone,
methyl
2­[[[(
4,5­
dihydro­
4­
methyl­
5­
oxo­
3­
propoxy­
1H­
1,2,4­
triazol­
1­
yl)
carbonyl]
amino]
sulfonyl]
benzoate
and
its
metabolite,
methyl
2­[[[(
4,5­
dihydro­
3­(
2­
hydroxypropoxy)
­
4­
methyl­
5­
oxo­
1H­
1,2,4­
triazol­
1­
yl)
carbonyl]
amino]
sulfonyl]
benzoate
in
or
on
the
raw
agricultural
commodities
wheat
forage
from
1.5
parts
per
million
(
ppm)
to
11
ppm,
and
of
propoxycarbazone,
methyl
2­[[[(
4,5­
dihydro­
4­
methyl­
5­
oxo­
3­
propoxy­
1H­
1,2,4­
triazol­
1­
yl)
carbonyl]
amino]
sulfonyl]
benzoate,
in
or
on
the
raw
agricultural
commodities
cattle,
goat,
horse,
sheep,
meat
byproducts
from
0.05
ppm
to
0.3
ppm,
and
milk
from
0.004
ppm
to
0.03
ppm.
EPA
has
determined
that
the
petition
contains
data
or
information
regarding
the
elements
set
forth
in
section
408
(
d)(
2)
of
the
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
metabolism
of
propoxycarbazone
sodium
(
MKH 
6561)
in
wheat
was
rapid,
as
only
minor
amounts
of
propoxycarbazone
sodium
were
found
in
some
of
the
wheat
matrices.
The
primary
metabolic
pathway
in
wheat
appeared
to
be
hydroxylation
of
the
propoxy
side
chain
of
propoxycarbazone
sodium
to
give
Pr­
2­
OH
MKH 
6561,
methyl
2­[[[(
4,5­
dihydro­
3­(
2­
hydroxypropoxy)­
4­
methyl­
5­
oxo­
1H­
1,2,4­
triazol­
1­
yl)
carbonyl]
amino]
sulfonyl]
benzoate.
Hydrolysis
of
Pr­
2­
OH
MKH 
6561
then
gave
Pr­
2­
OH
NMT
and,
probably
the
sulfonamide
methyl
ester
which
was
not
observed
in
any
wheat
matrices.
Hydrolysis
of
the
sulfonamide
methyl
ester
gave
sulfonamide
acid,
which
was
in
equilibrium
with
saccharin.
A
minor
metabolic
pathway
was
demethylation
of
propoxycarbazone
sodium
to
yield
N­
desmethyl
MKH 
6561.

2.
Analytical
method.
i.
Plant.
The
proposed
tolerance
expression
is
MKH 
6561
and
Pr­
2­
OH
MKH 
6561.
An
analytical
method
was
developed
to
measure
these
two
analytes
in
plant
matrices.
The
method
was
validated
in
wheat
tissues.
MKH 
6561
and
Pr­
2­
OH
MKH 
6561
were
extracted
from
the
wheat
tissues
with
0.05
M
NH4OH
using
accelerated
solvent
extraction.
Trifluoroacetic
acid
(
0.5
mL)
and
an
isotopically
labeled
internal
standard
were
added
to
the
extract.
The
whole
extract
was
loaded
onto
a
C 
18
solid
phase
extraction
(
SPE)
cartridge.
The
C 
18
SPE
cartridge
was
washed
with
aqueous
trifluoroacetic
acid
(
0.1%)
and
aqueous
acetic
acid
(
0.1%).
A
three
to
one
mixture
of
acetonitrile
and
aqueous
acetic
acid
(
0.1%)
was
used
to
elute
the
analytes
from
the
C 
18
SPE
cartridge.
Water
and
acetic
acid
were
added
to
the
sample
which
was
analyzed
by
LC/
MS/
MS.
ii.
Animal.
The
proposed
tolerance
expression
is
MKH 
6561.
An
analytical
method
was
developed
to
measure
this
analyte
in
animal
tissues
and
milk.
The
method
was
validated
in
animal
tissues
and
milk.
MKH 
6561
was
extracted
from
the
tissues
with
0.05
M
NH4OH.
using
accelerated
solvent
extraction.
Trifluoroacetic
acid
(
0.5
mL)
and
an
isotopically
labeled
internal
standard
were
added
to
the
extract
which
was
then
centrifuged
at
2,000
rpm
for
10
minutes.
Approximately
half
of
the
sample
was
loaded
onto
a
C 
18
SPE
cartridge.
The
C 
18
SPE
cartridge
was
washed
with
aqueous
trifluoroacetic
acid
(
0.1%)
and
aqueous
acetic
acid
(
0.1%).
A
three
to
one
mixture
of
acetonitrile
and
aqueous
acetic
acid
(
0.1%)
was
used
to
elute
the
analytes
from
the
C 
18
SPE
cartridge.
Water
and
acetic
acid
were
added
to
the
sample
which
was
analyzed
by
LC/
MS/
MS.
Milk
samples
were
analyzed
by
amending
an
aliquot
of
milk
with
trifluororacetic
acid
(
0.5
mL)
and
isotopically
labeled
internal
standard.
The
sample
was
purified
by
C 
18
SPE
as
described
above.
The
resultant
sample
was
analyzed
by
LC/
MS/
MS.

3.
Magnitude
of
residues.
Twenty
(
18
'
harvest';
2
'
decline')
spring
or
winter
wheat
trials
were
conducted
to
measure
the
residues
on
wheat
forage
at
a
0­
day
Preharvest
Interval
(
PHI).
Following
one
foliar
spray
application
with
propoxycarbazone­
sodium
70%
WG(
70
g
ai/
100
g
product)
to
wheat
at
BBCH
12
 
30
growth
stage
and
a
total
seasonal
target
rate
of
0.040
lb
ai/
A
(
45
g
ai/
ha)
and
harvest
immediately
after
the
application,
the
highest
average
field
trial
(
HAFT)
total
propoxycarbazone
residue
as
well
as
the
maximum
total
propoxycarbazone
single
residue
was
11
ppm
for
wheat
forage.
B.
Toxicological
Profile
1.
Acute
toxicity.
i.
Propoxycarbazone
sodium
is
of
very
low
acute
toxicity
to
fasted
rats
following
a
single
oral
administration.
The
acute
oral
LD50
is
>
5,000
milligrams/
kilogram/
body
weight
(
mg/
kg/
bwt)
for
males
and
females.
ii.
Propoxycarbazone
sodium
is
not
toxic
to
rats
following
a
single
dermal
application.
The
acute
dermal
LD50
is
>
5,000
mg/
kg/
bwt
for
males
and
females.
iii.
An
acute
inhalation
study
with
rats
showed
low
toxicity
with
a
4 
hour
dust
aerosol
LC50
5,030
mg/
m3
air
for
males
and
females.
iv.
An
eye
irritation
study
in
rabbits
showed
minimal
irritation
completely
reversible
within
48
hours.
v.
A
dermal
irritation
study
in
rabbits
showed
slight
irritation
completely
reversible
within
48
hours.
vi.
Propoxycarbazone
sodium
has
no
skin
sensitizing
potential
under
the
conditions
of
the
maximization
test
in
guinea
pigs.

2.
Genotoxicty.
The
genotoxic
action
of
Propoxycarbazone
sodium
was
studied
in
bacteria
and
mammalian
cells
with
the
aid
of
various
in
vitro
test
systems
(
Salmonella
microsome
test,
hypoxanthine
guanine
phophoribosy
transferase
(
HGPRT)
test
with
chinese
hamster
V79
cells,
cytogenetic
study
with
chinese
hamster
V79
cells,
and
unscheduled
DNA
synthesis
(
UDS)
test)
and
in
one
in
vivo
test
(
micronucleus
test).
None
of
the
tests
revealed
any
evidence
of
a
mutagenic
or
genotoxic
potential
of
propoxycarbazone
sodium.
The
compound
did
not
induce
point
mutation,
DNA
damage
or
chromosome
aberration
(
CA).

3.
Reproductive
and
developmental
toxicity.
i.
In
a
2 
generation
reproduction
study,
Wistar
rats
were
administered
propoxycarbazone
sodium
at
levels
of
0,
1,000,
4,000,
or
16,000
ppm
in
the
diet.
The
no
observe
adverse
effect
level
(
NOAEL)
for
reproductive
parameters
was
established
at
16,000
ppm
(
1,231
mg/
kg
bwt/
day
in
males
and
1,605
mg/
kg
bwt/
day
in
females),
the
highest
dose
tested
(
HDT).
The
parental
NOAEL
was
1,000
ppm
(
80
mg/
kg
bwt/
day
in
F1
males
and
93
mg/
kg
bwt/
day
in
F0
females).
ii.
A
developmental
toxicity
study
was
conducted
with
Wistar
rats
via
oral
gavage
of
propoxycarbazone
sodium
at
levels
of
0,
100,
300,
and
1,000
mg/
kg
bwt/
day
on
days
6
through
19
of
gestation.
There
were
no
signs
of
maternal
toxicity,
embryotoxicity,
fetotoxicity,
or
teratogenicity
at
the
level
of
1,000
mg/
kg
bwt/
day.
Therefore,
the
maternal
and
developmental
NOAELs
for
rats
were
established
at
1,000
mg/
kg
bwt/
day,
the
limit
dose
for
this
study
type.
No
teratogenic
potential
of
propoxycarbazone
sodium
was
evident
in
rats.
iii.
Himalayan
rabbits
were
administered
propoxycarbazone
sodium
at
levels
of
0,
20,
100,
500,
or
1,000
mg/
kg
bwt/
day
by
oral
gavage
on
days
6
through
28
post
coitum
in
a
test
for
developmental
toxicity.
A
maternal
NOAEL
of
100
mg/
kg
bwt/
day
was
established
based
on
cold
ears,
alopecia,
swelling
of
vulva,
decreased
feed,
and
water
intake,
body
weight
loss,
gastrointestinal
tract
(
GI)
effects,
liver
effects,
and
thyroid
hormone
level
effects.
The
gestation
rate
NOAEL
of
100
mg/
kg
bwt/
day
was
based
on
one
abortion
(
assessed
as
secondary
due
to
maternal
toxicity)
at
500
mg/
kg
bwt/
day.
The
NOAEL
for
fetal
parameters
of
500
mg/
kg
bwt/
day
was
based
on
placental
effects,
increased
post­
implantation
loss,
decreased
number
of
fetuses,
decreased
fetal
weight,
retarded
fetal
skeletal
ossification,
and
possible
increase
in
lobulation
of
liver
in
fetuses
at
1,000
mg/
kg
bwt/
day.
No
teratogenic
potential
of
propoxycarbazone
sodium
was
evident
in
rabbits.

4.
Subchronic
toxicity.
i.
A
28 
day
dermal
toxicity
study
in
Wistar
rats
established
a
local
and
systemic
NOAEL
of
1,000
mg/
kg
bwt/
day
(
the
dermal
limit
dose)
for
males
and
females.
ii.
A
14 
week
feeding
study
was
conducted
with
Wistar
rats
at
dietary
dose
levels
of
0,
250,
1,000,
4,000,
or
20,000
ppm.
The
NOAEL
was
determined
to
be
4,000
ppm
(
286.4
mg/
kg
bwt/
day
in
males
and
350.6
mg/
kg
bwt/
day
in
females)
based
upon
increased
water
consumption
(
reversible
during
the
4 
week
recovery
period)
and
an
irritative
effect
of
the
forestomach
epithelium
(
reversible
during
the
4 
week
recovery
period)
in
males
and
females
dosed
at
20,000
ppm
as
well
as
reduced
glucose
and
triglyceride
levels
in
females
only
dosed
at
20,000
ppm.
iii.
A
91 
day
feeding
study
was
conducted
with
B6C3F1
mice
at
dietary
dose
levels
of
0,
625,
2,500,
or
10,000
ppm.
The
NOAELs
determined
for
males
and
females
were
625
ppm
(
205
mg/
kg
bwt/
day)
and
2,500
ppm
(
1,159
mg/
kg
bwt/
day),
respectively,
based
on
decreased
body
weights
in
2,500
ppm
males
and
10,000
ppm
females.
iv.
A
2 
month
range­
finding
feeding
study
in
Beagle
dogs,
at
levels
of
0,
1,000,
5,000,
10,000,
and
40,000
ppm
in
the
diet
established
a
NOAEL
of
10,000
ppm
(
322.2
mg/
kg
bwt/
day
in
males
and
285.6
mg/
kg
bwt/
day
in
females)
based
on
elevated
hepatic
biotransformation
enzymes
at
40,000
ppm.

5.
Chronic
toxicity.
i.
A
2 
year
chronic/
oncogenicity
study
was
conducted
with
male
and
female
Fischer
344
rats
at
dietary
levels
of
0,
50,
500,
or
1,000
mg/
kg
bwt/
day
for
approximately
the
first
seven
months
of
the
study
(
dose
adjustment).
From
approximately
seven
months
to
study
termination,
the
doses
were
0,
1,000,
10,000,
and
20,000
ppm
in
the
diet.
A
chronic
toxicity
NOAEL
of
1,000
ppm
(
43
mg/
kg
bwt/
day
in
males
and
49
mg/
kg
bwt/
day
in
females)
was
determined
based
on
increased
urine
pH
and
decreased
body
weight
gain
at
1 
year
(
but
not
2
years)
at
10,000
ppm
and
20,000
ppm.
No
carcinogenic
potential
was
indicated.
ii.
B6C3F1
mice
were
administered
propoxycarbazone
sodium
via
the
diet
at
levels
of
0,
280,
1,400,
and
7,000
ppm
in
a
2 
year
chronic
feeding/
carcinogenicity
study.
The
chronic
toxicity
NOAEL
was
established
at
1,400
ppm
(
369.0
mg/
kg/
day
in
males
and
626.9
mg/
kg
bwt/
day
in
females)
based
on
retarded
body
weight
development.
No
carcinogenic
potential
was
indicated.
iii.
A
1 
year
feeding
study
in
Beagle
dogs
was
conducted
at
0,
2,000,
10,000,
and
25,000
ppm
in
the
diet.
The
NOAEL
in
males
was
determined
to
be
10,000
ppm
(
258.0
mg/
kg
bwt/
day)
based
upon
increased
absolute
adrenal
gland
weight
without
an
increase
in
relative
adrenal
gland
weight
and
slight
enlargement
of
zona
fasciculata
microscopically,
without
a
correlation
to
adrenal
gland
weight
in
males
dosed
at
25,000
ppm.
The
NOAEL
in
females
was
determined
to
be
2,000
ppm
(
55.7
mg/
kg
bwt/
day)
based
upon
decreased
food
consumption
and
decreased
relative
heart
weight
in
females
dosed
at
10,000
and
25,000
ppm.
6.
Animal
metabolism.
i.
A
single
oral
dose
of
2
mg/
kg/
bwt
[
triazolinone­
3­
14C]
MKH 
6561
was
administered
to
rats.
Between
22%
and
24%
of
the
administered
dose
was
absorbed.
Maximum
plasma
radiation
levels
were
observed
0.33
hours
after
dosing.
Within
48
hours
of
dosing,
between
CA
88%
and
97%
of
the
radioactivity
was
excreted
via
urine
and
feces.
Approximately
80 
88%
of
the
excreted
radioactivity
was
unchanged
parent
compound.
The
highest
single
metabolite
concentration
was
CA
3%
of
the
administered
dose.
The
terminal
elimination
half­
live
for
total
radioactivity
was
CA
12 
13
hours,
so
no
bioaccumulation
of
MKH 
6561
or
its
metabolites
will
occur.
ii.
Single
oral
doses
of
2
mg/
kg/
bwt
and
200
mg/
kg/
bwt
[
phenyl­
UL­
14C]
MKH 
6561
were
administered
to
rats.
Between
CA
21 
31%
of
the
administered
dose
was
absorbed.
Maximum
plasma
radiation
levels
were
observed
after
0.33
hours
(
low
dose)
and
1 
hour
(
high
dose).
Within
48
hours
of
dosing,
CA
97 
104%
of
the
administered
dose
was
eliminated
via
urine
and
feces.
Approximately
75 
86%
of
the
administered
dose
was
eliminated
as
unchanged
parent
compound.
The
maximum
single
metabolite
concentration
was
8.8%
of
the
administered
dose.
At
the
end
of
the
study,
less
than
0.25%
of
the
administered
dose
was
found
in
organs
and
tissues.
In
a
separate
bile
fistulation
experiment,
the
predominantly
fecal
elimination
was
confirmed
to
be
due
to
incomplete
absorption
of
radioactivity
from
the
GI
tract.
The
terminal
elimination
half­
live
for
total
radioactivity
was
CA
9 
11
hours,
so
no
bioaccumulation
of
MKH 
6561
or
its
metabolites
will
occur.
iii.
Laying
hens
were
given
a
daily
dose
of
protonated
MKH 
6561
[
phenyl­
UL­
14C]
at
3.12
mg/
kg/
bwt
for
three
consecutive
days.
The
residue
levels
were
1.343
ppm
in
liver,
0.017
ppm
in
muscle,
0.014
ppm
in
fat,
0.006
ppm
in
the
day 
1
eggs,
0.009
ppm
in
the
day 
2
eggs,
and
0.012
ppm
in
the
day 
3
eggs.
The
residue
levels
based
on
a
theoretical
1x
application
rate,
as
determined
from
residue
levels
observed
in
the
propoxycarbazone
sodium
(
MKH 
6561)
wheat
field
trials
would
all
be
considerably
less
than
0.001
ppm.
The
major
residue
identified
in
tissues
and
eggs
were
MKH 
6561,
Pr­
2­
OH
MKH 
6561,
MKH 
6561
sulfonamide
methyl
ester,
and
saccharin.
The
major
metabolic
pathway
of
MKH 
6561
[
phenyl­
UL­
14C]
in
poultry
was
hydrolysis
of
the
parent
compound
producing
N­
methyl
propyl
triazolinone
and
sulfonamide
methyl
ester.
The
sulfonamide
methyl
ester
was
then
converted
to
saccharin.
A
minor
pathway
involved
hydroxylation
at
the
2 
position
of
the
triazolinone
propoxy
group.
In
the
liver,
the
major
metabolic
pathway
led
to
the
formation
of
protein
bound
MKH 
6561
residue
through
conjugation
with
the
amino
acid
serine.
iv.
Laying
hens
were
given
a
daily
dose
of
protonated
MKH 
6561
[
triazolinone­
3­
14C]
at
2.91
mg/
kg/
bwt
for
three
consecutive
days.
The
residue
levels
were
0.184
ppm
in
liver,
0.044
ppm
in
muscle,
0.015
ppm
in
the
fat,
0.011
ppm
in
the
day 
1
egg,
0.016
ppm
in
the
day 
2
egg,
and
0.022
ppm
in
the
day 
3
egg.
The
residue
levels
in
tissues
and
eggs
based
on
a
theoretical
1x
application,
as
determined
from
the
residue
levels
observed
in
the
MKH 
6561
wheat
field
trials,
would
all
be
considerably
less
that
0.001
ppm.
The
metabolism
of
MKH 
6561
[
triazolinone­
3­
14C]
appeared
to
involve
both
hydroxylation
at
the
2 
position
of
the
propoxy
group
and
hydrolysis
of
the
phenyl
sulfonamide
linkage.
v.
Goats
were
dosed
with
1.0
mg/
kg/
bwt
of
MKH 
6561
[
phenyl­
UL­
14C]
for
three
consecutive
days.
Residue
levels
were
3.643
ppm
in
liver,
0.486
ppm
in
kidney,
0.009
ppm
in
muscle,
0.004
ppm
in
fat,
0.015
ppm
in
day 
1
milk
and,
0.022
ppm
in
day 
2
milk.
The
metabolic
pathway
was
based
on
hydrolysis
of
the
sulfonamide
to
yield
MKH 
6561
sulfonamide
methyl
ester
and
saccharin.
The
saccharin
was
then
conjugated
to
proteins
which
were
found
mainly
in
the
liver
and
kidney.
vi.
Goats
were
dosed
with
MKH 
6561
[
triazolinone­
3­
14C]
at
a
dose
of
0.98
mg/
kg/
bwt
for
3
consecutive
days.
Residue
levels
were
0.171
ppm
in
liver,
0.425
ppm
in
kidney,
0.040
ppm
in
muscle,
0.007
ppm
in
fat,
0.046
ppm
in
day 
1
milk,
and
0.057
ppm
in
day 
2
milk.
The
metabolism
of
propoxycarbazone
sodium
involved
the
cleavage
of
the
phenyl
sulfonylurea
side
chain
and
the
hydroxylation
of
the
propyl
side
chain
on
the
triazolinone
ring
system
after
the
cleavage
of
the
phenyl
sulfonylurea
side
chain.

7.
Metabolite
toxicology.
i.
4­
OH­
saccharin
is
of
low
acute
toxicity
to
fasted
rats
following
a
single
oral
administration.
The
acute
oral
LD50
is
>
5,000
mg/
kg/
bwt
for
males
and
females.
4­
OH­
saccharin
is
considered
non­
mutagenic
with
and
without
S9
mix
in
the
plate
incorporation
as
well
as
in
the
preincubation
modification
of
the
Salmonella
microsome
test.
ii.
MKH 
8394
is
of
very
low
acute
toxicity
to
fasted
rats
following
a
single
oral
administration.
The
acute
oral
LD50
is>
5,000
mg/
kg/
bwt
for
males
and
females.
MKH 
8394
is
considered
non
mutagenic
with
and
without
S9
mix
in
the
plate
incorporation
as
well
as
in
the
preincubation
modification
of
the
Salmonella
microsome
test.
iii.
KTS 
9061
(
Pr­
2­
OH
MKH 
6561)
is
not
toxic
to
fasted
rats
following
a
single
oral
administration.
The
acute
oral
LD50
is>
5,000
mg/
kg/
bwt
for
males
and
females.
KTS 
9061
is
considered
non
mutagenic
with
and
without
S9
mix
in
the
plate
incorporation
as
well
as
in
the
preincubation
modification
of
the
Salmonella/
microsome
test.
KTS 
9061
is
considered
non­
clastogenic
with
and
without
S9
mix
CA
test
in
vitro
using
chinese
hamster
V79
cells.
Wistar
rats
were
administered
KTS 
9061
via
the
diet
at
levels
of
0,
800,
4,000,
and
10,000
ppm
for
approximately
four
weeks.
The
NOAEL
was
determined
to
be
10,000
ppm
(
905.3
mg/
kg
bwt/
day
in
males
and
880.0
mg/
kg
bwt/
day
in
females),
the
HDT.
iv.
KTS 
9304
has
low
to
moderate
acute
toxicity
to
fasted
rats
following
a
single
oral
administration.
The
acute
oral
LD50
was
263
mg/
kg/
bwt
in
males
and
1,756
mg/
kg/
bwt
in
females.
KTS 
9304
is
considered
non­
mutagenic
with
and
without
S9
mix
in
the
plate
incorporation
as
well
as
in
the
preincubation
modification
of
the
Salmonella/
microsome
test.

8.
Endocrine
disruption.
There
is
no
evidence
to
suggest
that
propoxycarbazone
sodium
has
an
effect
on
the
endocrine
system.
Studies
in
this
data
base
include
evaluation
of
the
potential
effects
on
reproduction
and
development,
and
an
evaluation
of
the
pathology
of
the
endocrine
organs
following
short­
term
and
long­
term
exposure.
These
studies
revealed
no
endocrine
effects
due
to
propoxycarbazone
sodium.

C.
Aggregate
Exposure
1.
Dietary
exposure.
Using
the
Dietary
Exposure
Evaluation
Model
software
with
the
Food
Commodity
Intake
Database
(
DEEM­
FCID),
ver.
2.0,
and
the
USDA
1994 
1996
and
1998
Nationwide
Continuing
Surveys
of
Food
Intake
by
Individuals
(
CSFII)
database,
the
dietary
exposure
and
risk
from
food
and
drinking
water
was
calculated.

i.
Food.
Estimates
of
chronic
dietary
exposure
to
residues
of
propoxycarbazone
sodium
utilized
the
current
and
new
proposed
tolerances
in
wheat
forage,
wheat
hay,
wheat
straw,
and
wheat
grain
of
11,
0.15,
0.05,
0.02,
respectively,
in
cattle,
sheep,
goats,
horses,
and
hogs
meat,
and
meat
byproducts
,
of
0.05
and
0.3
ppm,
respectively,
and
in
milk
of
0.03
ppm.
Other
assumptions
were
that
100%
of
the
target
crop
would
be
treated
with
propoxycarbazone
sodium
and
that
no
loss
of
residue
would
occur
due
to
processing
or
cooking.
For
chronic
exposures,
a
reference
dose
(
RfD)
of
0.748
mg/
kg/
day
was
assumed
based
on
and
NOAEL
of
74.8
mg/
kg
bwt/
day
from
the
2­
generation
reproduction
study
in
rats.
A
safety
factor
of
100
was
used
based
on
interspecies
extrapolation
(
10x)
and
intraspecies
variability
(
10x).
The
FQPA
safety
factor
was
reduced
to
1x
resulting
in
a
chronic
population
adjusted
dose
(
cPAD)
of
0.748
mg/
kg/
day.
Using
these
conservative
assumptions,
dietary
residues
of
propoxycarbazone
sodium
contribute
0.001316
mg/
kg/
day
(
0.2%
of
the
cPAD)
for
children
1
to
2
years
old,
the
most
sensitive
sub­
population.
For
the
U.
S.
population,
the
exposure
was
0.000305
mg/
kg/
day
(<
1%
of
the
cPAD).
EPA
concluded
in
the
Federal
Register
/
Vol.
69,
No.
129
/
Wednesday,
July
7,
2004:
"
An
effect
of
concern
attributable
to
a
single
exposure
(
dose)
was
not
identified
from
the
oral
toxicity
studies
including
the
developmental
toxicity
studies
in
rat
and
rabbits.
Abortions
seen
in
the
developmental
toxicity
study
in
rabbits
at
1,000
mg/
kg/
day
during
GD
19 
28,
were
not
considered
to
be
a
single
dose
effect.
Since
they
occur
late
in
gestation
after
repeated
exposures.
[
sic]"

ii.
Drinking
Water.
For
calculating
drinking
water
exposure,
the
Estimated
Environmental
Concentrations
(
EEC)
were
used
as
published
by
EPA
in
the
FR
Vol.
69,
129,
p.
40778,
04­
Jul­
04.
EPA
used
the
FQPA
Index
Reservoir
Screening
Tool
(
FIRST)
or
the
Pesticide
Root
Zone
Model/
Exposure
Analysis
Modeling
System
(
PRZM/
EXAMS),
to
produce
estimates
of
pesticide
concentrations
in
surface
water.
The
screening
concentration
in
ground
water
(
SCI­
GROW)
model
is
used
to
predict
pesticide
concentrations
in
shallow
ground
water.
Based
on
the
FIRST
and
SCI­
GROW
models,
the
EECs
of
propoxycarbazone
sodium
for
acute
exposures
are
estimated
to
be
2.3
parts
per
billion
(
ppb)
for
surface
water
and
0.4
ppb
for
ground
water.
The
EECs
for
chronic
exposures
are
estimated
to
be
0.9
ppb
for
surface
water
and
0.4
ppb
for
ground
water.

EECs
derived
from
these
models
are
incorporated
in
the
calculation
of
the
dietary
risk
and
included
in
the
above
expression
of
the
%
cPAD.

2.
Non­
dietary
exposure.
There
are
no
current
non­
food
uses
for
propoxycarbazone
sodium
registered
under
the
Federal
Insecticide,
Fungicide,
and
Rodenticide
Act,
as
amended.
No
non­
food
uses
are
proposed
for
this
active
ingredient
and
no
non­
dietary
exposures
are
expected
for
the
general
population.

D.
Cumulative
Effects
Propoxycarbazone
sodium
is
a
sulfonamide
herbicide.
There
is
no
information
to
suggest
that
any
chemical
in
this
class
of
herbicides
has
a
common
mechanism
of
mammalian
toxicity
or
that
chemicals
in
this
class
produce
similar
effects
so
it
is
not
appropriate
to
combine
exposures
of
propoxycarbazone
sodium
with
other
herbicides.

E.
Safety
Determination
1.
U.
S.
population.
As
presented
previously,
the
exposure
of
the
U.
S.
general
population
to
propoxycarbazone
sodium
is
low,
and
the
risks,
based
on
comparisons
to
the
RFD,
are
minimal.
The
margins
of
safety
from
the
use
of
propoxycarbazone
sodium
are
well
within
EPA's
acceptable
limits.
Bayer
Corporation
concludes
that
there
is
a
reasonable
certainty
that
no
harm
will
result
to
the
U.
S.
population
from
aggregate
exposure
to
propoxycarbazone
sodium
residues.

2.
Infants
and
children.
The
complete
toxicological
data
base
including
the
developmental
toxicity
and
2 
generation
reproduction
studies
were
considered
in
assessing
the
potential
for
additional
sensitivity
of
infants
and
children
to
residues
of
propoxycarbazone
sodium.
The
developmental
toxicity
studies
in
rats
and
rabbits
revealed
no
increased
sensitivity
of
rats
or
rabbits
to
in­
utero
exposure
to
propoxycarbazone
sodium.
The
2 
generation
reproduction
study
did
not
reveal
any
increased
sensitivity
of
rats
to
in­
utero
or
postnatal
exposure
to
propoxycarbazone
sodium.
Furthermore,
none
of
the
other
toxicology
studies
revealed
any
data
demonstrating
that
young
animals
were
more
sensitive
to
propoxycarbazone
sodium
than
adult
animals.
In
the
FR
Vol.
69,
129,
p.
40778,
04­
Jul­
04
EPA
concluded:
"
The
toxicology
database
is
complete
for
FQPA
purposes
and
there
are
no
residual
uncertainties
for
pre­/
post­
natal
toxicity.
Based
on
the
quality
of
the
exposure
data,
EPA
determined
that
the
10X
SF
to
protect
infants
and
children
should
be
removed."

F.
International
Tolerances
There
are
currently
no
Codex,
Canadian,
or
Mexican
tolerances
established
for
propoxycarbazone
sodium.
The
European
Community
has
established
cereal
(
incl.
wheat)
tolerances
of
0.02
ppm.