OFFICE
OF
PREVENTION,
PESTICIDES,
AND
TOXIC
SUBSTANCES
UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
MEMORANDUM
DATE:
22­
JUN­
2005
SUBJECT:
Revised
as
per
30­
day
Error
Only
Registrant
Comments.
Sethoxydim:
HED
Chapter
of
the
Reregistration
Eligibility
Decision
(
RED)
Document.
PC
Code
121001,
DP
Barcode
D318165.

Regulatory
Action:
Phase
2
Reregistration
Action
Risk
Assessment
Type:
Single
Chemical,
Aggregate
FROM:
William
H.
Donovan,
Ph.
D.,
Chemist
and
Risk
Assessor
Kimyata
Morgan,
Ph.
D.,
Toxicologist
Wade
Britton,
Industrial
Hygenist
Reregistration
Branch
3
(
RRB3)/
Health
Effects
Division
(
HED)
(
7509C)

THRU:
Danette
Drew,
Branch
Senior
Scientist
RRB3/
HED
(
7509C)

TO:
James
Parker,
Chemical
Review
Manager
Reregistration
Branch
1
Special
Review
and
Registration
Division
(
SRRD)
(
7508C)

Attached
is
HED's
preliminary
human
health
risk
assessment
conducted
for
the
purposes
of
issuing
a
Reregistration
Eligibility
Decision
(
RED)
for
sethoxydim.
The
residue
chemistry
and
risk
assessment
was
provided
by
William
Donovan
(
RRB3),
the
occupational/
residential
exposure
assessment
by
Wade
Britton
(
RRB3),
the
hazard
characterization
by
Kimyata
Morgan
(
RRB3),
the
dietary
analyses
by
David
Soderberg
and
Nancy
Dodd,
and
the
drinking
water
assessment
by
William
Eckel
of
the
Environmental
Fate
and
Effects
Division
(
EFED).
Page
2
of
71
Table
of
Contents
1.0
EXECUTIVE
SUMMARY
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4
2.0
PHYSICAL/
CHEMICAL
PROPERTIES
CHARACTERIZATION
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9
2.1
Chemical
Identity
and
Structure
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9
2.2
Physical
and
Chemical
Properties
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9
2.3
Physical/
Chemical
Properties
Characterization
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10
3.0
HAZARD
CHARACTERIZATION
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10
3.1
Hazard
Profile
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10
3.2
FQPA
Considerations
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16
3.3
Recommendation
of
a
Developmental
Neurotoxicity
Study
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21
3.4
Hazard
Identification
and
Toxicity
Endpoint
Selection
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21
3.5
Special
FQPA
Safety
Factor
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29
3.6
Endocrine
Disruption
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30
4.0
EXPOSURE
ASSESSMENT
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30
4.1
Summary
of
Proposed/
Registered
Uses
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30
4.2
Dietary
Exposure/
Risk
Pathway
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34
4.2.1
Residue
Profile
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34
4.2.2
Dietary
Exposure
Analyses
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39
4.2.2.1Acute
Dietary
Exposure
Analysis
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39
4.2.2.2Chronic
Dietary
Exposure
Analysis
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41
4.3
Water
Exposure/
Risk
Pathway
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41
4.4
Residential
Exposure/
Risk
Pathway
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42
4.4.1
Non­
Occupational
(
Residential)
Handler
Exposure
and
Risk
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43
4.4.2
Non­
Occupational
(
Residential)
Postapplication
Exposure
and
Risk
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44
4.4.2.1
Non­
Occupational
Risk
Characterization
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45
4.4.3
Non­
Occupational
Off­
Target
Exposure
and
Risk
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46
4.4.3.1Recreational
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46
4.4.3.2
Spray
Drift
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46
4.4.3.3
Exposure
from
Use
of
Tobacco
­
Health
Risk
Assessment
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47
5.0
AGGREGATE
RISK
ASSESSMENTS
AND
RISK
CHARACTERIZATION
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48
5.1
Acute
Aggregate
Risk
Assessment
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48
5.2
Short­
Term
Aggregate
Risk
Assessment
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49
5.3
Chronic
Aggregate
Risk
Assessment
(
Food
and
Drinking
Water)
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50
6.0
CUMULATIVE
RISK
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52
Page
3
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71
7.0
OCCUPATIONAL
EXPOSURE/
RISK
PATHWAY
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52
7.1
Occupational
Handler
Exposure
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53
7.2
Occupational
Postapplication
Exposure
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55
7.3
Incidents
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55
8.0
DATA
NEEDS/
LABEL
REQUIREMENTS
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56
8.1
Chemistry
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56
8.2
Toxicology
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56
9.0
TOLERANCE
REASSESSMENT
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57
10.0
APPENDIX
­
Names
and
Structures
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61
10.1
Names
and
Structures
of
Sethoxydim
and
Some
Metabolites/
Analytes
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61
10.2
Toxicology
Data
Requirements
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64
10.3
Non­
critical
Toxicology
Studies
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65
Page
4
of
71
1.0
EXECUTIVE
SUMMARY
Sethoxydim
is
a
selective,
systemic,
postemergence
herbicide
used
for
the
control
of
annual
and
perennial
grass
weeds
in
broadleaf
crops.
Sethoxydim
is
a
member
of
the
cyclohexenone
class
of
pesticides
(
Fundamentals
of
Pesticides,
4th
Edition,
G.
Ware,
1994).
The
other
members
of
this
class
include
cycloxydim,
clethodim,
and
tralkoxydim.

Tolerances
are
currently
established
(
40
CFR
§
180.412)
for
residues
of
sethoxydim
and
its
metabolites
on
a
variety
of
agricultural
commodities
at
levels
ranging
from
0.2
ppm
to
75.0
ppm.
Permanent
tolerances
are
also
established
in/
on
the
meat
and
fat
of
cattle,
goats,
hogs,
horses,
poultry,
and
sheep
at
0.2
ppm;
meat
byproducts
of
cattle,
goats,
hogs,
horses,
and
sheep
at
1.0
ppm
(
2.0
ppm
in
meat
byproducts
of
poultry);
eggs
at
2.0
ppm,
and
milk
at
0.5
ppm.
The
tolerance
expression
for
plant
and
livestock
commodities
includes
the
combined
residues
of
sethoxydim
and
its
metabolites
containing
the
2­
cyclohexen­
1­
one
moiety
(
calculated
as
the
herbicide)
as
specified
in
40
CFR
§
180.412.

Sethoxydim
is
currently
registered
on
agricultural
crops
such
as
various
fruits,
tree
nuts,
vegetables
and
herbs,
as
well
as
non­
agricultural
sites,
including
ornamentals
and
flowering
plants,
recreational
areas,
rights­
of­
way,
along
fences
and
hedgerows,
and
public
and
commercial
buildings/
structures
(
non­
agricultural­
outdoors).

Hazard
Assessment
The
toxicity
database
for
sethoxydim
is
complete
and
there
are
no
datagaps.
The
acute
toxicity
data
indicate
that
sethoxydim
is
minimally
toxic
(
Category
III)
via
oral,
dermal,
and
inhalation
routes
of
exposure.
It
is
neither
irritating
to
the
eye
nor
the
skin
(
Category
IV).

The
database
on
sethoxydim
indicates
that
the
liver
is
a
major
target
for
this
chemical.
In
the
chronic
toxicity
study
(
dogs),
there
were
significantly
increased
absolute
and
relative
liver
weights
accompanied
by
supportive
clinical
chemistry
and
histopathology.
Dose­
related
clinical
chemistry
abnormalities
were
observed
in
both
sexes
and
included
increased
alkaline
phosphatase
and
ALT
and
decreased
albumin
and
cholesterol
synthesis.
Dose­
related
histopathologic
lesions
were
found
in
the
liver,
spleen,
and
bone
marrow.
A
mild
hepatocellular
cytoplasmic
alteration
was
found
in
low­
(
1/
6),
mid­
(
3/
6),
and
high­
(
6/
6)
doses
in
males,
and
in
the
mid­
(
1/
6)
and
high­(
6/
6)
doses
in
females.
In
addition,
adverse
liver
effects
were
also
observed
via
the
oral
route
in
another
species
(
mice)
and
via
another
route
of
exposure
(
inhalation)
in
rats.

Dose
Response
Assessment
and
Food
Quality
Protection
Act
(
FQPA)
Decision
On
December
2,
2004,
the
HED
Risk
Assessment
Review
Committee
(
RARC)
revisited
the
need
for
a
developmental
neurotoxicity
study
for
sethoxydim.
During
that
meeting,
the
RARC
concurred
with
the
risk
assessment
team
that
the
evidence
does
not
support
the
need
for
a
Page
5
of
71
developmental
neurotoxicity
study;
noting
that
the
clinical
signs
observed
at
the
high
dose
are
likely
to
be
a
high
dose
phenomena.
Additionally,
the
RARC
recommended
that
the
"
tail
abnormalities"
be
classified
as
adverse
developmental
malformations
in
the
prenatal
developmental
study
in
rats
and
2­
generation
reproductive
study
in
rats
(
see
Hazard
Characterization
section
3.1
for
full
discussion).
Given
these
findings,
the
RARC
recommended
to
waive
the
requirement
for
a
developmental
neurotoxicity
study.
The
FQPA
factor
is
reduced
to
1X.

The
HIARC
concluded
that
the
degree
of
concern
was
low
for
pre­
and/
or
postnatal
toxicity
resulting
from
exposure
to
sethoxydim
and
determined
that
the
special
FQPA
SF
can
be
reduced
(
1X)
since
there
are
no
residual
uncertainties
for
pre­
and/
or
postnatal
toxicity.

A
rat
developmental
study
was
used
to
select
the
dose
and
endpoint
for
establishing
the
acute
RfD
(
aRfD)
of
1.8
mg/
kg/
day.
The
acute
RfD
(
aRfD)
was
calculated
by
dividing
the
No­
Observed­
Adverse­
Effect­
Level
(
NOAEL)
of
180
mg/
kg/
day
from
this
study
by
an
uncertainty
factor
(
UF)
of
100
[
10X
for
interspecies
extrapolation
and
10X
for
intraspecies
variation].
The
Lowest­
Observed­
Adverse­
Effect­
Level
(
LOAEL)
for
this
study
(
650
mg/
kg/
day)
was
based
on
filamentous
tail
and
lack
of
tail
due
to
the
absence
of
sacral
and/
or
caudal
vertebrae,
and
delayed
ossification
in
the
hyoids,
vertebral
centrum
and/
or
transverse
processes,
sternebrae
and/
or
metatarsals,
and
pubes
in
pups.
This
RfD
is
applicable
to
the
general
U.
S.
population,
including
infants
and
children.
As
the
acute
Population­
Adjusted­
Dose
(
aPAD)
is
equal
to
the
aRfD
divided
by
the
FQPA
SF
(
1X),
then
the
aPAD
is
equal
to
the
aRfD
(
1.8
mg/
kg/
day).

The
mouse
combined
chronic
toxicity/
carcinogenicity
study
was
used
to
select
the
dose
and
endpoint
for
establishing
the
cRfD
of
0.14
mg/
kg/
day
and
because
the
FQPA
SF
is
1X,
the
cPAD
is
also
0.14
mg/
kg/
day.
The
NOAEL
of
14
mg/
kg/
day
and
the
LOAEL
of
41.2
mg/
kg
was
based
on
early
onset
of
liver
effects
including
hepatocellular
hypertrophy
and
fatty
degeneration.
A
100­
fold
uncertainty
factor
(
10X
interspecies
and
10X
intraspecies)
was
applied.

Sethoxydim
is
not
a
likely
human
carcinogen
based
on
lack
of
evidence
of
carcinogenicity
in
rats
and
mice;
therefore,
a
dietary
cancer
exposure
analysis
was
not
conducted.

HIARC
did
not
identify
dermal
toxicity
endpoints
because
no
dermal
or
systemic
toxicity
was
seen
following
repeated
dermal
applications
of
sethoxydim
at
the
limit­
dose
to
rabbits,
in
addition
there
is
no
concern
for
pre­
natal
toxicity
in
rabbits
and
a
low
level
of
concern
for
pre­
natal
toxicity
in
rats.
A
dermal
absorption
factor
is
not
required
since
quantification
of
non­
cancer
risks
is
not
required.

A
rat
developmental
study
was
used
to
select
the
dose
and
endpoint
for
short­
term
incidental
oral
exposure.
The
basis
for
the
endpoint
was
the
maternal
NOAEL
of
180
mg/
kg/
day
and
maternal
LOAEL
of
650
mg/
kg/
day
based
on
irregular
gait
observed
in
dams
on
the
first
day
of
dosing.
Intermediate­
term
incidental
oral
exposure
not
anticipated;
therefore,
no
endpoint
was
selected.
Page
6
of
71
A
rat
28­
day
inhalation
study
was
used
for
dose
and
endpoint
selection
of
0.3
mg/
L
(
81
mg/
kg/
day).
The
LOAEL
of
2.4
mg/
L
(
651
mg/
kg/
day)
was
based
on
liver
weight,
clinical
chemistry
(
bilirubin)
and
histology.
The
dose/
endpoint
is
derived
from
a
study
conducted
via
the
appropriate
route
of
concern
and
used
for
all
inhalation
exposure
durations.

Residential
Exposure
Estimates
Homeowners
who
apply
sethoxydim
to
ornamental
gardens
and
turf
may
be
exposed
for
shortterm
(
up
to
30
days)
durations
via
the
dermal
and
inhalation
routes.
Short­
term
postapplication
exposures
to
children
may
result
from
incidental
oral
contact
via
hand­
to­
mouth
activities
with
treated
turf.
The
HED
HIARC
did
not
identify
dermal
toxicity
endpoints
for
sethoxydim,
therefore,
only
exposure
from
inhalation
(
adult
handlers)
and
incidental
ingestion
(
children)
were
assessed.
Inhalation
risk
was
estimated
using
the
NOAEL
of
81
mg/
kg/
day
from
a
28­
day
rat
inhalation
study.
The
NOAEL
was
based
upon
increased
liver
weight,
clinical
chemistry
(
increased
total
serum
bilirubin),
and
liver
histopathology.
The
risk
for
postapplication
toddler
short­
term
incidental
ingestion
(
hand­
to­
mouth,
turf­
to­
mouth,
soil­
to­
mouth)
was
estimated
using
the
NOAEL
of
180
mg/
kg/
day
from
a
rat
developmental
toxicity
study.

HED's
level
of
concern,
in
this
instance,
is
an
margin
of
exposure
(
MOE)
=
100
(
10x
inter­
species
extrapolation,
and
10x
intra­
species
variation)
for
all
residential
population
groups.
MOEs
estimated
for
residential
handlers
range
from
1.4E+
6
to
1.6E+
6.
MOEs
estimated
for
short­
term
postapplication
incidental
ingestion
range
from
26,000
for
hand­
to­
mouth
incidental
exposures
to
7.6E+
6
for
soil
ingestion
incidental
exposures.
The
resulting
MOEs
are
above
the
target
MOE
of
100
and,
therefore,
are
not
of
concern
to
HED.

Dietary
Exposure
Estimates
Sethoxydim
acute
and
chronic
dietary
exposure
assessments
were
conducted
using
the
Dietary
Exposure
Evaluation
Model
software
with
the
Food
Commodity
Intake
Database
(
DEEMFCID
 
,
Version
1.33),
which
incorporates
consumption
data
from
USDA's
Continuing
Surveys
of
Food
Intakes
by
Individuals
(
CSFII),
1994­
1996
and
1998.
The
acute
and
chronic
analyses
are
limited
refined
dietary
risk
assessments.
The
acute
assessment
used
tolerance
level
residues
for
most
crops
but
limited
refinement
was
obtained
through
the
incorporation
of
field
trial
data
and
experimental
processing
factors
for
some
of
the
crops
expected
to
be
more
highly
associated
with
dietary
exposure
to
sethoxydim.
For
the
chronic
analysis,
tolerance
level
residues
were
used
for
crops
and
anticipated
residue
estimates
were
used
for
meat
and
milk.
The
acute
analyses
used
the
maximum
percent
crop­
treated
provided
by
BEAD
and
the
chronic
analyses
used
the
average
percent
crop­
treated.
The
acute
and
chronic
dietary
analyses
for
sethoxydim
show
that
the
estimated
risks
from
acute
and
chronic
dietary
exposure
to
sethoxydim
are
below
the
Agency's
level
of
concern
(<
100%)
for
the
US
population
and
all
population
subgroups.
From
the
chronic
analysis,
the
cPAD
was
2.7%
for
the
general
US
population
and
7.5%
for
all
infants
(<
1
year
old).
From
the
acute
analysis,
the
exposure
at
the
99.9th
percentile
(
99.9th
percentile
used
because
the
assessment
incorporated
estimates
of
percent
crop­
treated,
field
trial
data
and
some
experimental
Page
7
of
71
processing
data)
was
5.3%
of
the
aPAD
for
the
general
US
population
and
9.2%
of
the
aPAD
for
children
1­
2
years
old
and
also
children
3­
5
years
old
(
the
two
most
highly
exposed
population
subgroups).

Drinking
Water
Exposure
Estimates
EFED
provided
the
Estimated
Drinking
Water
Concentrations
(
EDWCs)
for
sethoxydim
and
all
its
degradates
based
on
modeling
results
assuming
the
maximum
use
rate
for
any
crop
registered
for
sethoxydim
use.
The
maximum
single
use
rate
is
0.47
lb
active
ingredient
per
acre
(
lb
ai/
A).
The
maximum
seasonal
use
rate
is
1.875
lb
ai/
A,
consisting
of
four
applications
at
0.47
lb
ai/
A,
with
a
retreatment
interval
(
RTI)
of
14
days.
The
surface
water
estimates
were
calculated
using
the
linked
FIRST
simulation
models.
For
surface
water,
the
acute
(
peak)
value
for
total
sethoxydim
residues
was
130
ppb,
and
the
chronic
(
annual
average)
value
for
total
sethoxydim
residues
was
16
ppb.
The
acute
and
chronic
groundwater
EDWCs
of
1.5
ppb
for
total
residues
was
estimated
using
the
SCIGROW
model.
Both
surface
and
groundwater
values
represent
upper­
bound
conservative
estimates
for
concentrations
that
might
be
found
in
surface
water
and
groundwater
due
to
the
use
of
sethoxydim.

Aggregate
Exposure
Scenarios
and
Risk
Conclusions
Human
health
aggregate
risk
assessments
have
been
conducted
for
the
following
exposure
scenarios:
acute
and
chronic
aggregate
exposure
(
food
+
drinking
water),
and
short­
term
aggregate
exposure
(
food
+
drinking
water
+
residential).
A
cancer
aggregate
risk
assessment
was
not
performed
because
sethoxydim
shows
no
evidence
of
carcinogenicity.
For
short­
and
intermediate­
term
aggregate
exposure/
risk
assessments,
the
inhalation
exposures
estimated
for
adult
handlers
cannot
be
combined
with
dietary
exposure
due
to
lack
of
common
toxicity
via
the
oral
(
neurotoxicity)
and
inhalation
(
hepatotoxicity)
routes
of
exposure.
Intermediate­
and
longterm
residential
exposure
was
neither
expected
nor
assessed.
No
quantification
of
dermal
exposure
is
required
for
any
time
period.

Acute
Aggregate
The
partially
refined
acute
dietary
exposure
(
food
only)
estimates
are
below
HED's
level
of
concern
(<
100%
aPAD)
at
the
99.9th
exposure
percentile
for
the
general
U.
S.
population
(
5.2%
of
the
aPAD)
and
all
other
population
subgroups.
The
most
highly
exposed
population
subgroups
were
Children
1­
2
years
old
and
Children
3­
5
years
old,
both
at
9.2
%
of
the
aPAD.
The
EDWCs
generated
by
EFED
are
less
than
HED's
calculated
DWLOCs
for
acute
exposure
to
sethoxydim
in
drinking
water.
Therefore,
the
acute
aggregate
risk
associated
with
the
registered
uses
of
sethoxydim
does
not
exceed
HED's
level
of
concern
for
the
general
U.
S.
population
or
any
population
subgroups.

Chronic
Aggregate
Page
8
of
71
The
partially
refined
chronic
dietary
exposure
(
food
only)
estimates
are
below
HED's
level
of
concern
(<
100%
cPAD)
for
the
general
U.
S.
population
(
2.7%
of
the
cPAD)
and
all
other
population
subgroups.
The
most
highly
exposed
population
subgroup
is
All
Infants
(<
1
year
old),
at
7.5%
of
the
cPAD.
The
EDWCs
generated
by
EFED
are
less
than
HED's
calculated
DWLOCs
for
acute
exposure
to
sethoxydim
in
drinking
water.
Therefore,
the
chronic
aggregate
risk
associated
with
the
registered
uses
of
sethoxydim
does
not
exceed
HED's
level
of
concern
for
the
general
U.
S.
population
or
any
population
subgroups.

Short­
Term
Aggregate
The
short­
term
exposures
to
Children
(
1­
2
years
old)
result
in
MOE's
that
are
greater
than
100
and
are
not
of
concern.
Likewise,
chronic
dietary
exposures
are
less
than
HED's
level
of
concern.
An
aggregate
risk
analysis
was
conducted
by
combining
chronic
dietary
exposure
with
residential
incidental
oral
exposures
[
hand­
to­
mouth,
object­
to­
mouth,
and
soil
ingestion]
for
children
1­
2
years
old.
Based
on
the
aggregate
food
and
residential
exposures,
short­
term
DWLOCs
were
calculated
for
comparison
the
surface
and
ground
water
EDWC
values.
The
EDWCs
generated
by
EFED
are
less
than
HED's
calculated
DWLOCs
for
short­
term
exposure
to
sethoxydim
in
drinking
water.
Therefore,
the
short­
term
aggregate
risks
associated
with
the
registered
uses
of
sethoxydim
do
not
exceed
HED's
level
of
concern
for
Children
1­
2
years
old.

Occupational
Exposure
Estimates
Sethoxydim
is
currently
registered
for
use
on
agricultural
crops
such
as
various
fruits,
tree
nuts,
vegetables
and
herbs,
as
well
as
non­
agricultural
sites,
including
ornamentals
and
flowering
plants,
recreational
areas,
rights­
of­
way,
along
fences
and
hedgerows,
and
public
and
commercial
buildings/
structures
(
non­
agricultural
outdoors).
The
potential
for
occupational
exposure
to
sethoxydim
exists
in
a
variety
of
exposure
scenarios.
Which
include
the
handling
of
sethoxydim
during
mixing,
loading,
and
applying
processes
(
i.
e.
mixer/
loaders,
applicators,
flaggers,
and
mixer/
loader/
applicators)
and
a
potential
for
postapplication
worker
exposure
from
entering
into
areas
previously
treated
with
sethoxydim.
Short­
term
and
intermediate­
term
exposures
(
1
to
6
months)
may
occur,
however,
long­
term
exposures
(
greater
than
6
months)
are
not
expected.
The
HED
HIARC
did
not
identify
dermal
toxicity
endpoints
for
sethoxydim,
therefore,
only
inhalation
exposures
were
estimated.
The
risk
for
inhalation
exposures
was
estimated
using
the
NOAEL
of
81
mg/
kg/
day
from
a
28­
day
rat
inhalation
study.
Estimated
MOEs
range
from
2,400
to
3.2E+
7.
The
resulting
MOEs
are
above
the
target
MOE
of
100
(
10x
inter­
species
extrapolation,
10x
intraspecies
variation)
and,
therefore,
are
not
of
concern
to
HED.

2.0
PHYSICAL/
CHEMICAL
PROPERTIES
CHARACTERIZATION
2.1
Chemical
Identity
and
Structure
Page
9
of
71
S
H
3
C
CH3
OH
CH
3
O
N
O
CH
3
IUPAC
Name:
(
±
)
­(
EZ)­
2­(
1­
ethoxyiminobutyl)­
5­[
2­(
ethylthio)
propyl]­
3­
hydroxycyclohex­
2­
enone
CAS
Name:
(
±
)
­
2­[
1­(
ethoxyimino)
butyl]­
5­[
2­(
ethylthio)
propyl]­
3­
hydroxy­
2­
cyclohexen­
1­
one
CAS
Registry
No.:
74051­
80­
2
Chemical
Class:
cyclohexenone
herbicide
Empirical
Formula:
C
17
H
29
NO
3
S
Molecular
Structure:

Sethoxydim
2.2
Physical
and
Chemical
Properties
of
Sethoxydim
Table
2.2.1.
Physical
and
Chemical
Properties
of
Sethoxydim
Property
Description
Color
brown
Physical
state
viscous
liquid
Odor
garlic­
like
Boiling
Point
>
130

C
at
6
x
10­
1
mm
Hg
Density,
bulk
density,
or
specific
gravity
1.058
specific
gravity
at
20

C
Solubility
Water
at
25

C:
2.57
x
10
2
at
pH
5,
4.39
x
10
3
at
pH
7;
organic
solvents
(
methanol,
n­
octanol,
ethyl
acetate,
n­
hexane,
toluene,
xylene,
and
olive
oil)
at
20

C:
freely
soluble
(>
10
3
g/
100
mL).

Vapor
pressure
1.6
x
10
­
7
mm
Hg
at
25

C
Dissociation
constant
pKa
is
4.6
at
pH
4.5
and
25

C
Octanol/
water
partition
coefficient
Kow
is
3.26
x
10
3
at
pH
5;
45.1
at
pH
7
pH
3.95
at
20

C
Table
2.2.1.
Physical
and
Chemical
Properties
of
Sethoxydim
Property
Description
Page
10
of
71
Stability
stable
at
normal
temperatures
(
24

C)
and
in
the
presence
of
metals
(
zinc
or
iron
powder);
unstable
at
elevated
temperatures
(
54

C)
and
in
the
presence
of
sunlight.

Sethoxydim
is
a
racemate
[
designated
(
±
)
]
of
geometrical
isomers
[
designated
(
E)
and
(
Z)].

2.3
Physical/
Chemical
Properties
Characterization
Technical
sethoxydim
is
a
liquid.
It
is
soluble
in
water
and
most
organic
solvents.

3.0
HAZARD
CHARACTERIZATION
3.1
Hazard
Profile
The
database
for
sethoxydim
is
complete
and
there
are
no
data
gaps.
The
scientific
quality
of
the
database
for
sethoxydim
is
relatively
high
and
the
toxicity
profile
can
be
characterized
for
all
effects.

The
acute
toxicity
data
indicate
that
sethoxydim
is
minimally
toxic
(
Category
III)
via
oral,
dermal,
and
inhalation
routes
of
exposure.
It
is
neither
irritating
to
the
eye
nor
the
skin(
Category
IV).

The
database
on
sethoxydim
indicates
that
the
liver
is
a
major
target
for
this
chemical.
In
the
chronic
toxicity
study
(
dogs),
there
were
significantly
increased
absolute
and
relative
liver
weights
accompanied
by
supportive
clinical
chemistry
and
histopathology.
Dose­
related
clinical
chemistry
abnormalities
were
observed
in
both
sexes
and
included
increased
alkaline
phosphatase
and
ALT
and
decreased
albumin
and
cholesterol
synthesis.
Dose­
related
histopathologic
lesions
were
found
in
the
liver,
spleen,
and
bone
marrow.
A
mild
hepatocellular
cytoplasmic
alteration
was
found
in
low­
(
1/
6),
mid­
(
3/
6),
and
high­
(
6/
6)
doses
in
males,
and
in
the
mid­
(
1/
6)
and
high­(
6/
6)
doses
in
females.
In
addition,
adverse
liver
effects
were
also
observed
via
the
oral
route
in
another
species
(
mice)
and
via
another
route
of
exposure
(
inhalation)
in
rats.

HIARC
concluded
that
there
was
low
concern
for
pre­
and/
or
postnatal
toxicity
resulting
from
exposure
to
sethoxydim.
There
was
evidence
of
qualitative
susceptibility
in
the
developmental
rat
study
with
the
occurrence
of
more
severe
effects
in
the
fetuses
(
delayed
ossification
and
tail
abnormalities)
than
in
the
maternal
animals
(
irregular
gait
and
decreased
activity).
However,
these
effects
were
only
observed
at
a
high
dose.
A
single
tail
anomaly
was
seen
in
the
F1b
offspring
of
the
two­
generation
reproduction
rat
study
(
1/
344
pups).
The
developmental
toxicity
study
in
rabbits
did
not
exhibit
either
quantitative
or
qualitative
susceptibility.
The
special
FQPA
safety
factor
is
reduced
to
1X.
Page
11
of
71
There
is
no
evidence
of
neurotoxicity.
The
clinical
signs
following
sethoxydim
exposure
in
the
prenatal
developmental
toxicity
study
in
the
rat
were
irregular
gait,
decreased
activity,
excessive
salivation,
and
anogenital
staining.
These
effects
were
only
observed
in
animals
receiving
very
high
doses
of
sethoxydim
(
650
mg/
kg/
day
and
1000
mg/
kg/
day).
Irregular
gait
was
observed
in
12/
24
dams
at
650
mg/
kg/
day
and
10/
10
dams
at
1000
mg/
kg/
day
on
the
first
day
of
dosing,
after
3
doses
the
signs
began
to
dissipate.
Decreased
activity
was
noted
in
1/
34
dams
at
650
mg/
kg/
day
and
in
4/
10
dams
at
1000
mg/
kg/
day
and
reversed
after
several
days.
Excessive
salivation
was
noted
in
23/
34
dams
at
650
mg/
kg/
day
and
10/
10
dams
at
1000
mg/
kg/
day.
Anogenital
staining
was
documented
in
13/
34
dams
at
650
mg/
kg/
day
and
7/
10
dams
at
1000
mg/
kg/
day.
All
clinical
signs
reported
were
transient,
with
the
exception
of
the
anogenital
staining
which
did
not
reverse.
Because
the
clinical
signs
occurred
shortly
after
dosing,
only
occurred
at
very
high
treatment
doses
(
over
one
half
the
limit
dose)
and
were
transitory,
it
is
unlikely
that
the
signs
observed
are
the
result
of
a
primary
systemic
effect
on
the
nervous
system
but,
rather,
are
reflective
of
the
general
toxicity
at
the
high
dose.
It
should
be
noted
that
clinical
signs
indicative
of
nervous
system
effects
were
not
observed
in
any
other
standard
toxicity
study
for
sethoxydim.
Although
none
of
these
other
studies
dosed
up
to
650
and
1000
mg/
kg/
day,
a
MTD
was
reached
because
of
evidence
of
other
toxicities
(
e.
g.,
liver
effects
or
body
weight
reductions).

There
were
no
developmental
effects
seen
in
the
rat
and
rabbit
prenatal
studies
indicative
of
an
effect
on
the
nervous
system.
The
main
effect
seen
in
the
rat
and
rabbit
prenatal
studies
was
an
increased
incidence
of
fetal
skeletal
variations
due
to
delayed
ossification.
In
the
rat
prenatal
study,
tail
abnormalities
(
filamentous
tail
or
lack
of
a
tail)
were
noted.
These
abnormalities
were
observed
at
a
very
low
incidence
(
10
fetuses
in
7
litters,
650
mg/
kg
bw
day)
and
at
high
treatment
doses
(
650
and
1000
mg/
kg/
day).
In
the
2­
generation
reproduction
study
in
rat,
a
tail
anomaly
(
short,
thread­
like
tail,
no
anal
opening,
hindlimbs
curved
toward
central
midline)
was
found
in
one
pup
in
the
F2b
generation
(
1/
344
total
pups;
in
1/
4
litters).
Tail
abnormalities
are
sometimes
thought
to
relate
to
CNS
malformations;
however,
in
this
case,
these
tail
abnormalities
are
not
likely
to
be
the
result
of
a
primary
neurotube
effect.
In
the
rat
prenatal
study,
there
is
no
description
of
any
effect
on
neural
tube
derived
structures.
Furthermore,
the
class
of
compounds,
cyclohexones,
do
not
demonstrate
neurotoxicity
or
developmental
malformations
of
the
nervous
system.
In
addition
the
acute
risk
assessment
is
based
on
the
results
of
the
rat
developmental
toxicity
study
and
is
protective
of
these
effects.

Therefore,
after
a
weight­
of­
evidence
examination
of
all
the
toxicological
studies
available
in
the
database,
the
requirement
for
a
developmental
neurotoxicity
study
is
waived.
The
FQPA
safety
factor
is
reduced
to
1X.

Neither
local
nor
systemic
toxic
effects
were
observed
in
the
21­
day
dermal
toxicity
study
in
rabbits
indicating
that
there
is
a
low
level
of
concern
for
toxicity
via
the
dermal
route
of
exposure.
The
acute
inhalation
toxicity
study
demonstrated
that
sethoxydim
induced
hepatotoxicity
similar
to
that
observed
by
oral
routes
of
exposure.
In
a
4­
week
inhalation
toxicity
study
with
sethoxydim,
toxicity
based
on
increased
liver
weight
accompanied
by
alterations
in
clinical
chemistry
(
increased
bilirubin)
and
liver
histopathology
at
the
highest
dose
tested
(
651
mg/
kg/
day)
Page
12
of
71
was
observed.

Sethoxydim
is
classified
as
"
not
a
likely
human
carcinogen".
No
increase
in
any
tumors
were
found
in
carcinogenicity
studies
in
rats
or
mice.
No
specific
signs
of
immunotoxicity
were
indicated
by
any
of
the
guideline
studies.

There
was
no
evidence
that
sethoxydim
induces
any
endocrine
disruption.
Furthermore,
all
mutagenicity
studies
are
negative
and
there
is
no
mutagenicity
concern.
Sethoxydim
is
rapidly
excreted
and
tissue
accumulation
is
negligible.
No
significant
differences
in
pharmacokinetic
parameters
were
seen
among
dosing
groups
or
between
sexes.

Acute
Toxicity:
The
acute
toxicity
database
for
sethoxydim
is
considered
complete
for
acute
oral,
acute
dermal,
acute
inhalation,
dermal
and
eye
irritation,
and
dermal
sensitization.
Sethoxydim
has
a
low
order
of
toxicity
via
the
oral,
dermal,
and
inhalation
routes
of
exposure
(
Category
III).
It
is
neither
irritating
to
the
eye
nor
the
skin
(
Category
IV).
It
is
not
an
eye
or
skin
irritant.
Based
on
the
lack
of
sensitization
of
guinea
pigs
treated
with
the
formulation
(
Poast),
the
requirement
for
a
dermal
sensitization
study
in
guinea
pigs
was
waived.
The
acute
toxicity
data
for
sethoxydim
are
summarized
below
in
Table
3.1.1.

Table
3.1.1
Acute
Toxicity
Profile
for
Sethoxydim
Guideline
No.
Study
Type
MRIDs
#
Results
Toxicity
Category
870.1100
Acute
Oral­
Rats
00045847
LD50
=
M:
3125
mg/
kg
F:
2676
mg/
kg
III
870.1200
Acute
Dermal­
Rats
00045848
LD50
=
>
5000
mg/
kg
III
870.1300
Acute
Inhalation­
Rats
00045849
LC50
=
M:
6.03
m/
L
F:
6.28
m/
L
Aerosol
composed
of
NP­
55
(
25%),
DMSO
(
75%).
III
870.2400
P
r
i
m
a
r
y
E
y
e
Irritation­
Rabbits
00045850
No
Irritation
IV
870.2500
P
r
i
m
a
r
y
S
k
i
n
Irritation­
Rabbits
00045851
No
Irritation
IV
870.2600
Dermal
Sensitization­
Guinea
pigs
00045852
Study
waived
based
on
lack
of
sensitization
in
guinea
pigs
treated
with
the
formulation
(
Poast).

Table
3.1.2
Subchronic,
Chronic,
and
Other
Toxicity
Profile
Page
13
of
71
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
870.3100a
90­
Day
oral
toxicity
rodents
(
rats)
00045859
(
1978)/
Acceptable/
Doses:
0,
33,
100,
300,
900,
2700
ppm
(
M:
0,
2,
7,
20,
60,
196
mg/
kg/
day;
F:
0,
2,
7,
21,
66,
201
mg/
kg/
day)
Males:
NOAEL
=
60,
LOAEL
=
196
mg/
kg/
day
Females:
NOAEL
=
66,
LOAEL
=
201
mg/
kg/
day,
based
on
decreases
in
body
weight,
body
weight
gain,
and
food
efficiency.

870.3100b
90­
Day
oral
toxicity
rodents
(
mice)
00045858
(
1978)/
Acceptable/
Doses:
0,
100,
300,
900,
2700
ppm
(
M:
0,
15,
46,
137,
374
mg/
kg/
day
F:
0,
17,
53,
164,
486
mg/
kg/
day)
Males:
NOAEL
=
46,
LOAEL
=
137
mg/
kg/
day
Females:
NOAEL
=
53,
LOAEL
=
164
mg/
kg/
day,
based
on
increased
liver
weight
and
histopathological
evidence
of
hepatocellular
hypertrophy.

870.3150
90­
Day
oral
toxicity
(
nonrodents­
dogs)
00045860
(
1980)/
Unacceptable/
Doses:
0,
120,
600,
3000
ppm
(
M:
0,
4,
19,
89
mg/
kg/
day;
F:
0,
3,
17,
86
mg/
kg/
day)
Males
&
Females:
NOAEL
not
identified,
LOAEL
=
3.4
mg/
kg/
day,
based
on
possible
treatmentrelated
clinical
findings
of
cystitis
of
urinary
bladder.

870.3200
21­
Day
dermal
toxicity
(
rabbits)
41987203
(
1991)/
Acceptable/
Doses:
0,
40,
200,
1000
mg/
kg/
day.
Males
&
Females:
NOAEL
=
1000
mg/
kg/
day
(
HDT),
LOAEL
not
established.
No
localized
or
systemic
effects.

870.3250
90­
Day
dermal
toxicity
NA
NA
870.3465
4­
Week
inhalation
toxicity
(
rat)
44021202
(
1993)/
Acceptable/
Doses:
0,
0.04,
0.3,
and
2.4
mg/
L
Males
&
Females:
NOAEL
=
0.3
mg/
L
(
81mg/
kg/
day),
LOAEL
of
2.4
mg/
L
(
651
mg/
kg/
day),
based
on
increased
liver
weight,
clinical
chemistry
(
increased
total
serum
bilirubin),
and
liver
histopathology.

870.3700a
Prenatal
developmental
toxicity
(
rats)
43092902
(
1993)/
Acceptable/
Doses:
0,
50,
180,
650,
1000
mg/
kg/
day
Maternal:
NOAEL
=
180
mg/
kg/
day,
LOAEL
=
650
mg/
kg/
day,
based
on
irregular
gait,
decreased
activity,
excessive
salivation,
and
anogenital
staining.

Developmental:
NOAEL
=
180mg/
kg/
day,
LOAEL
=
650
mg/
kg/
day,
based
on
21­
22%
decrease
in
fetal
weights,
filamentous
tail
and
lack
of
tail
due
to
the
absence
of
sacral
and/
or
caudal
vertebrae,
and
delayed
ossification
in
the
hyoids,
vertebral
centrum
and/
or
transverse
processes,
sternebrae
and/
or
metatarsals,
and
pubes.
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
Page
14
of
71
870.3700b
Prenatal
developmental
toxicity
(
rabbits)
43092901
(
1993)/
Acceptable/
Doses:
0,
80,
160,
320,
400
mg/
kg/
day
Maternal:
NOAEL
=
320
mg/
kg/
day,
LOAEL
=
400
mg/
kg/
day,
based
on
37%
reduction
in
body
weight
gain
without
significant
differences
in
group
mean
body
weights,
and
decreased
food
consumption
during
dosing
Developmental:
NOAEL
320
mg/
kg/
day,
LOAEL
=
400
mg/
kg/
day
(
HDT),
based
on
an
increase
in
the
incidence
of
incompletely
ossified
6th
sternebrae.

870.3800
Reproduction
and
fertility
effects
(
rats)
41510606,
43366401
(
1983)/
Acceptable/
Doses:
0,
150,
600,
3000
ppm
(
0,
7.5,
30,
150
mg/
kg/
day)
Systemic:
NOAEL
>
150
mg/
kg/
day,
LOAEL
not
established
Reproductive:
NOAEL
>
150
mg/
kg/
day,
LOAEL
>
150
mg/
kg/
day
Offspring:
NOAEL
=
30
mg/
kg/
day,
LOAEL
=
150
mg/
kg/
day,
based
on
decreased
pup
weight
in
F2b
during
lactation.

870.4100a
Chronic
toxicity
(
rodents)
NA;
see
870.4300
NA
870.4100b
Chronic
toxicity
(
dogs)
00152669
(
1984)/
Acceptable/
Doses:
0,
300,
600,
or
3600
ppm.
(
Overall
time­
weighted
average
doses
were
0,
9,
18,
and
110
mg/
kg/
day,
respectively,
for
males
and
0,
9,
20,
and
129
mg/
kg/
day,
respectively,
for
females.)
Males:
NOAEL
=
17.5
mg/
kg/
day,
LOAEL
=
110
mg/
kg/
day
Females:
NOAEL
=
20
mg/
kg/
day,
LOAEL
=
129
mg/
kg/
day,
based
on
increase
hemosiderosis
in
the
spleen
and
depressed
myeloid
erythropoiesis
in
the
sternal
bone
marrow,
increased
absolute
and
relative
liver
weights,
increased
alkaline
phosphatase
and
ALT
levels.

870.4200a
Carcinogenicity
(
rats)
N/
A;
see
870.4300
N/
A
870.4200b
Carcinogenicity
(
mice)
00100527
(
1981)/
Acceptable/
Doses:
0,
40,
120,
360,
or
1080
ppm
(
equivalent
to
0,
5,
14,
41,
or
134
mg/
kg
/
day
for
males
and
0,
5,
15,
44,
or
143
mg/
kg
/
day
for
females)
Males:
NOAEL
=
14
mg/
kg/
day,
LOAEL
=
41
mg/
kg/
day,
based
on
early
onset
of
liver
effects
including
hepatocellular
hypertrophy
and
fatty
degeneration
in
male
mice.

No
evidence
of
carcinogenicity.
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
Page
15
of
71
870.4300
Combined
Chronic/
carcinogenicity
(
rats)
MRID
#
43939101
(
1995)/
Acceptable/
Doses:
0,
264,
1000,
or
3000
ppm
(
0,
12,
48,
and
143
mg/
kg/
day
for
males
and
0,
17,
66,
204
mg/
kg/
day
for
females)
Male:
NOAEL
=
12
mg/
kg/
day,
LOAEL
=
48
mg/
kg/
day,
based
on
liver
toxicity
(
centrilobular
hepatocellular
hypertrophy).

Females:
NOAEL
=
66
mg/
kg/
day,
LOAEL
=
204
mg/
kg/
day,
based
on
decreased
body
weight,
body
weight
gain,
liver
toxicity
(
centrilobular
hepatocellular
hypertrophy),
and
lung
lesions
(
heart
failure
cells
and
interstitial
fibrosis).

No
evidence
of
carcinogenicity.

870.5100
Bacterial
reverse
mutation
00153604/
Acceptable/
Negative.

870.5100
Bacterial
reverse
mutation
41885904/
Acceptable/
Concentrations
313
to
5000
ug/
plate
Negative.

870.5100
Bacterial
reverse
mutation
41915901/
Acceptable/
Concentrations
312
to
5000
ug/
mL
Negative.

870.5300
In
vitro
mammalian
cell
gene
mutation
00155130/
Unacceptable/
highest
dose
tested
5000
ug/
mL
Negative.

870.5300
In
vitro
mammalian
cell
gene
mutation
41421301/
Acceptable/
Concentrations
500
to
5000
ug/
mL
Negative.

870.5300
In
vitro
mammalian
cell
gene
mutation
00130710/
Acceptable/
highest
dose
tested
10,000
mg/
kg
Negative.

870.5300
In
vitro
mammalian
cell
gene
mutation
00138950/
Acceptable/
Negative.

870.5550
Unscheduled
DNA
synthesis
(
rat
hepatocyte
cells)
41885905/
Acceptable/
Concentrations
10
to
507
ug/
mL
Negative.
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
Page
16
of
71
870.5915
In
vivo
sister
chromatid
exchange
(
chinese
hamster
bone
marrow)
41475206/
Acceptable/
Dose:
0,
0.5,
1.67,
5
g/
kg
Negative.

870.6200a
Acute
neurotoxicity
screening
battery
(
rats)
N/
A
N/
A
870.6200b
Subchronic
neurotoxicity
screening
battery
(
rats)
N/
A
N/
A
870.6300
Developmental
neurotoxicity
(
rats)
N/
A
N/
A
870.7485
Metabolism
and
pharmacokinetics
(
rats)
00045868
(
1980)/
Acceptable/
Excretion
is
extremely
rapid
and
tissue
accumulation
is
negligible,
assuming
DMSO
vehicle
does
not
affect
excretion
or
storage
of
NP­
55,
78.%
excreted
into
urine
and
20.1%
in
feces.

870.7485
Metabolism
and
pharmacokinetics
(
rats)
00153605
(
1985)/
Acceptable/
Administration
of
radioactively
labeled
NP­
55
yielded
0.8%
radioactivity
in
urine
identified
as
hydroxymetabolites
represented
by
6­
OH
M2SO2
&
2
other
metabolites
found
by
mass
spectrometry
were
MSO
and
M1SO.

870.7600
Dermal
penetration
N/
A
N/
A
3.2
FQPA
Hazard
Considerations
3.2.1
Adequacy
of
the
Toxicity
Data
Base
The
toxicology
database
for
sethoxydim
is
complete
and
there
are
no
datagaps.
Acceptable
developmental
toxicity
studies
have
been
performed
in
rats
and
rabbits.
In
addition,
an
acceptable
2­
generation
reproduction
study
has
also
been
performed
in
rats.
A
subchronic
neurotoxicity
study
is
being
submitted
and
will
be
evaluated
upon
submission.
Acute
and
developmental
Page
17
of
71
neurotoxicity
studies
were
not
required.

3.2.2
Evidence
of
Neurotoxicity
There
is
no
evidence
of
neurotoxicity
in
the
database.
Historically,
the
HIARC
met
on
March
19,
2003
and
concluded
that
"
there
is
a
concern
for
developmental
neurotoxicity
resulting
from
exposure
to
Sethoxydim"
and
recommended
that
this
study
be
conducted
based
on
"
irregular
gait
and
delayed
ossification
in
the
developmental
rat
study
and
developmental
(
tail)
abnormalities
that
were
observed
in
the
rat
developmental
toxicity
study
and
in
F1a
and
F1b
offsprings
in
the
2­
generation
reproduction
studies."
In
accordance
with
the
2002
OPP
Guidance
Document
on
Determination
of
the
Appropriate
FQPA
Safety
Factor(
s)
in
Tolerance
Assessment,
the
HIARC
concluded
that
a
Database
Uncertainty
Factor
of
10X
is
required
for
lack
of
a
subchronic
and
developmental
neurotoxicity
studies
(
TXR
0051694).

On
December
2,
2004,
the
HED
RARC
revisited
the
need
for
a
developmental
neurotoxicity
study
for
sethoxydim.
During
that
meeting,
the
RARC
concurred
with
the
risk
assessment
team
that
the
evidence
does
not
support
the
need
for
a
developmental
neurotoxicity
study;
noting
that
the
clinical
signs
observed
at
the
high
dose
are
likely
to
be
a
high
dose
phenomena.
Additionally,
the
RARC
recommended
that
the
"
tail
abnormalities"
be
classified
as
adverse
developmental
malformations
in
the
prenatal
developmental
study
in
rats
and
2­
generation
reproductive
study
in
rats
(
see
Hazard
Characterization
section
3.1for
full
discussion).
Given
these
findings,
the
RARC
recommended
to
waive
the
requirement
for
a
developmental
neurotoxicity
study
and
reduced
the
database
uncertainty
factor
to
1X.

3.2.3
Developmental
Toxicity
Study
The
rat
developmental
toxicity
study
(
1993,
MRID
43092902)
demonstrated
a
maternal
NOAEL
and
LOAEL
of
180
and
650
mg/
kg/
day,
respectively,
based
on
irregular
gait,
decreased
activity,
excessive
salivation
and
anogenital
staining.
The
developmental
NOAEL
and
LOAEL
were
180
and
650
mg/
kg/
day,
respectively,
based
on
21­
22%
decrease
in
fetal
weights,
filamentous
tail
and
lack
of
tail
due
to
the
absence
of
sacral
and/
or
caudal
vertebrae,
and
delayed
ossification
in
the
hyoids,
vertebral
centrum
and/
or
transverse
processes,
sternebrae
and/
or
metatarsals,
and
pubes.
The
rabbit
developmental
toxicity
study
(
1993,
MRID
43092901)
demonstrated
a
maternal
NOAEL
and
LOAEL
of
320
and
400
mg/
kg/
day,
respectively,
based
on
a
37%
reduction
in
body
weight
gain
and
decreased
food
consumption
during
dosing.
The
rabbit
developmental
NOAEL
and
LOAEL
were
320
and
400
mg/
kg/
day,
respectively,
based
on
an
increase
in
the
incidence
of
incompletely
ossified
6th
sternebrae.

Developmental
Rat
Study
Executive
Summary:
Pregnant
CD
®
rats
received
doses
of
0
(
vehicle
control),
50,
180,
650,
and
1000
mg/
kg/
day
by
gavage
between
gestation
days
6
and
15.
Satellite
dams
were
included
in
all
but
the
180
mg/
kg/
day
dose,
and
the
1000
mg/
kg/
day
group
consisted
entirely
of
satellites.
Page
18
of
71
Fetuses
carried
by
satellite
dams
were
not
examined.
The
dams
were
sacrificed
on
gestation
day
20,
and
their
uteri
and
ovaries
were
examined.
The
fetuses
were
examined
for
external,
visceral,
and
skeletal
anomalies.

There
were
no
deaths
in
any
group.
Clinical
signs,
seen
mostly
in
the
650
and
1000
mg/
kg/
day
dams,
included
irregular
gait
and
decreased
activity
which
reversed
after
several
days;
and
excessive
salivation
and
anogenital
staining
which
did
not
reverse.
Biologically
significant
decreases
in
maternal
body
weights
(
12­
15%,
compared
to
controls)
were
seen
only
in
the
1000
mg/
kg/
day
satellite
group.
No
compound­
related
gross
lesions
were
found.
The
LOAEL
for
maternal
toxicity
is
650
mg/
kg/
day
based
on
irregular
gait,
decreased
activity,
excessive
salivation,
and
anogenital
staining.
The
NOAEL
for
maternal
toxicity
is
180
mg/
kg/
day.

There
were
no
resorptions,
abortions,
premature
births,
or
dead
fetuses.
The
number
of
corpora
lutea,
implantation
sites,
resorptions,
and
viable
fetuses,
as
well
as
mean
litter
sizes
and
sex
ratios
were
similar
for
all
groups.
External
and
skeletal
anomalies,
including
filamentous
tail
and
lack
of
tail
due
to
the
absence
of
sacral
and/
or
caudal
vertebrae,
were
dose­
related,
but
visceral
anomalies
were
not.
The
LOAEL
for
developmental
toxicity
is
650
mg/
kg/
day
based
on
21­
22%
decrease
in
fetal
weights,
filamentous
tail
and
lack
of
tail
due
to
the
absence
of
sacral
and/
or
caudal
vertebrae,
and
delayed
ossification
in
the
hyoids,
vertebral
centrum
and/
or
transverse
processes,
sternebrae
and/
or
metatarsals,
and
pubes.
The
NOAEL
for
developmental
toxicity
is
180
mg/
kg/
day.

This
study
is
Acceptable­
Guideline,
and
satisfies
the
requirement
83­
3a
for
a
Developmental
Toxicity
study
in
rats.
Satellite
dams
were
added
at
the
650
and
1000
mg/
kg/
day
level
"...
to
clarify
maternal
effects
seen
in
pilot
studies."
There
was
no
mention
of
what
these
effects
were,
or
what
was
learned
from
the
satellite
animals.

Developmental
Rabbit
Study
Executive
Summary:
Sethoxydim
(
96.8%
a.
i.,
Lot
#
NS­
9203)
was
administered
in
1%
aqueous
carbosymethylcellulose
to
groups
of
15
pregnant
New
Zealand
White
rabbits
by
gavage
at
dose
levels
of
0,
80,
160,
320
or
400
mg/
kg/
day
from
gestation
day
6
through
18
(
gestation
day
0
was
the
day
of
mating).
Animals
were
sacrificed
on
gestation
day
30
and
uteri
were
examined
for
live
fetuses
and
intra­
uterine
deaths.
Fetuses
were
weighed
and
examined
for
external,
visceral
and
skeletal
alterations.

Body
weight
gains
were
reduced
during
the
dosing
period
in
comparison
to
control
values
by
37%
for
the
400
mg/
kg/
day
dose
group
without
significant
differences
in
group
mean
body
weights.
Food
consumption
values
were
similarly
decrease
in
the
highest
dose
group
(
by
10­
25%)
during
dosing.
The
LOAEL
for
maternal
toxicity
is
400
mg/
kg/
day
based
on
based
on
decreases
in
body
weight
gain
and
food
consumption.
The
NOAEL
for
maternal
toxicity
is
320
mg/
kg/
day.
Page
19
of
71
There
was
an
apparently
dose­
related
increase
in
the
incidence
of
incompletely
ossified
6th
sternebrae
(
1/
13,
4/
12,
3/
15,
6/
13
and
9/
13
litters
in
the
0,
80,
160,
320
and
400
mg/
kg/
day
groups,
respectively),
and
the
incidence
of
this
variation
at
the
highest
dose
level
was
outside
the
reported
historical
range
(
average
incidence
is
35.1%
of
litters
ranging
from
0­
57.1%).
However,
the
incidence
of
all
other
skeletal
ossifications
variations
was
not
increased
in
a
dose
related
manner.
The
LOAEL
for
developmental
toxicity
is
400
mg/
kg/
day
based
on
an
increase
in
the
incidence
of
incompletely
ossified
6th
sternebrae.
The
NOAEL
for
developmental
toxicity
is
320
mg/
kg/
day.

This
study
is
Acceptable­
Guideline
and
satisfies
the
requirement
for
a
guideline
series
§
83­
3b
developmental
toxicity
study
in
rabbits.

Two­
Generation
Reproduction
Study­
Rat
Executive
Summary:
In
a
2­
generation
reproduction
study
(
MRID
41510606),
NP­
55
(
sethoxydim
technical,
96.86
%
a.
i.,
Lot
#
KK­
1240)
was
administered
to
13
male
and
26
female/
group/
dose
F
0
Charles
River
CD
rats
at
dose
levels
of
0,
7.5,
30
or
150
mg/
kg/
day.
The
F
0
animals
produced
2
litters
(
F
1a
and
F
1b).
The
F
1b
animals
produced
2
litters
(
F
2a
and
F
2b).
Clinical
signs,
body
weights,
reproductive
parameters,
necropsy
and
histopathology
data
were
obtained
from
parental
animals
and/
or
offspring.

There
were
no
indications
of
systemic
toxicity
in
the
F
0
parental
animals.
In
the
F
1
dams
in
the
150
mg/
kg/
day
group,
maternal
body
weights
were
slightly
decreased
during
the
F
2a
and
F
2b
gestation
and
lactation
periods
(
8­
10%),
with
no
concomitant
effect
on
food
consumption.
The
150
mg/
kg/
day
F
2b
pups
had
a
decrease
in
body
weight
of
up
to
­
13%
by
lactation
day
21.
Malformations
were
only
observed
in
one
F
1b
(
1/
244
total
pups
in
litter)
and
two
F
2b
pups
(
2/
344
total
pups
in
litter).
In
the
F
1b
litter,
cleft
palate
was
observed
in
one
high
dose
pup.
In
the
F
2b
litter,
one
high­
dose
pup
had
a
thread­
like
tail,
no
anal
opening,
malformed
hindlimb,
malpositioned
kidneys
and
another
high­
dose
pup
had
cleft
lip,
cleft
palate
and
microphthalmia.
There
were
no
dose­
related
gross
or
microscopic
lesions,
or
developmental
variations
(
cannibalism
complicated
the
evaluation).

Parental
Systemic
Toxicity
NOAEL
>
150
mg/
kg/
day
Parental
Systemic
Toxicity
LOAEL
>
150
mg/
kg/
day
Offspring/
Developmental
Toxicity
NOAEL
=
30
mg/
kg/
day
Offspring/
Developmental
Toxicity
LOAEL
=
150
mg/
kg/
day
based
on
decreased
pup
body
weight
in
F1a,
F1b,
and
F2b
during
lactation.

Reproductive
Toxicity
NOAEL
>
150
mg/
kg/
day
Reproductive
Toxicity
LOAEL
>
150
mg/
kg/
day
Page
20
of
71
The
study
is
Acceptable­
Guideline
and
satisfies
the
requirement
for
a
guideline
series
83­
4
Reproduction
study
in
rats.

The
HIARC
determined
that
the
Parental
Systemic
Toxicity
NOAEL
is
>
150
mg/
kg/
day
(
HDT)
and
that
the
LOAEL
could
not
be
established,
based
on
the
endpoints
of
8­
10%
decreased
in
body
weight
seen
at
150
mg/
kg/
day
is
not
considered
adverse
(
LOEL
but
not
LOAEL
is
established).
The
Reproductive
Toxicity
NOAEL/
LOAEL
>
150
mg/
kg/
day
(
HDT).
The
Offspring
Toxicity
NOAEL
is
30
mg/
kg/
day,
the
LOAEL
is
150
mg/
kg/
day,
based
on
decreased
pup
body
weight
of
11­
13%
in
F1a,
F1b,
and
F2b
during
lactation.

3.2.5
Additional
Information
from
Literature
Search
A
literature
search
did
not
reveal
studies
with
sethoxydim
that
would
impact
risk
assessment.

3.2.6
Pre­
and/
or
Postnatal
Toxicity
3.2.6.1
Determination
of
Susceptibility
HIARC
concluded
that
there
was
evidence
of
qualitative
susceptibility
in
the
developmental
rat
study
with
the
occurrence
of
more
severe
effects
in
the
fetuses
(
delayed
ossification
and
tail
abnormalities)
than
the
maternal
animals
(
irregular
gait).
The
developmental
toxicity
study
in
the
rabbits
did
not
exhibit
either
quantitative
of
qualitative
susceptibility.
In
the
two­
generation
study,
there
is
evidence
of
qualitative
susceptibility
indicated
by
tail
anomaly
in
F
2b
offspring
(
based
on
evidence
of
qualitative
susceptibility,
see
degree
of
concern
analysis
and
residual
uncertainties
for
pre
and/
or
post­
natal
susceptibility
below).

3.2.6.2
Degree
of
Concern
Analysis
and
Residual
Uncertainties
for
Pre
and/
or
Post­
natal
Susceptibility
Since
there
is
evidence
of
increased
susceptibility
of
the
young
following
exposure
to
sethoxydim
in
the
rat
developmental
study,
the
HIARC
performed
a
Degree
of
Concern
Analysis
to:
1)
determine
the
level
of
concern
for
the
effects
observed
when
considered
in
the
context
of
all
available
toxicity
data;
and
2)
identify
any
residual
uncertainties
after
establishing
toxicity
endpoints
and
traditional
uncertainty
factors
to
be
used
in
the
risk
assessment
of
this
chemical.
If
residual
uncertainties
are
identified,
HIARC
examines
whether
these
residual
uncertainties
can
be
addressed
by
a
special
FQPA
safety
factor
and,
if
so,
the
size
of
the
factor
needed.
The
results
of
the
HIARC
Degree
of
Concern
analysis
for
sethoxydim
are
presented
as
follows:

The
degree
of
concern
is
low
for
the
fetal
effects
in
the
developmental
rat
study
since
the
fetal
anomalies
were
seen
only
at
the
high
dose
(
650
mg/
kg/
day)
which
is
closer
to
the
Limit
Dose
(
1000
mg/
kg/
day),
they
were
seen
in
the
presence
of
maternal
toxicity
(
irregular
gait)
and
clear
NOAELs/
LOAELs
were
established
for
maternal
and
developmental
toxicities.
Additionally,
the
Page
21
of
71
HIARC
concluded
at
that
time
that
the
level
of
concern
was
low
for
the
effects
observed
in
the
2­
generation
reproductive
study
because
the
LOAEL
for
offspring
toxicity
was
based
on
a
conservative
determination
of
a
minimal
response
(
1/
344
pups
in
F
2b
generation).

The
HIARC
concluded
that
the
degree
of
concern
was
low
for
pre­
and/
or
postnatal
toxicity
resulting
from
exposure
to
sethoxydim
and
determined
that
the
special
FQPA
SF
can
be
removed
(
1X)
since
there
are
no
residual
uncertainties
for
pre­
and/
or
postnatal
toxicity.

3.3
Recommendation
of
a
Developmental
Neurotoxicity
Study
3.3.1
Evidence
that
supports
requiring
a
Developmental
Neurotoxicity
Study
None.

3.3.2
Evidence
that
supports
not
requiring
a
Developmental
Neurotoxicity
Study
Based
on
the
results
seen
in
the
prenatal
developmental
toxicity
study
in
rats
and
2­
generation
reproduction
study
in
rats,
there
was
no
evidence
of
neurotoxicity.
All
clinical
signs
reported
in
the
rat
prenatal
developmental
toxicity
study
occurred
shortly
after
dosing,
only
occurred
at
very
high
treatment
doses
(
over
one
half
the
limit
dose)
and
were
transitory.
It
is
unlikely
that
the
clinical
signs
observed
are
the
result
of
a
primary
systemic
effect
on
the
nervous
system
but,
rather,
are
reflective
of
the
general
toxicity
at
the
high
doses.
There
were
no
developmental
effects
seen
in
the
rat
and
rabbit
prenatal
studies
indicative
of
an
effect
on
the
nervous
system.
There
is
no
description
of
any
effect
on
neural
tube
derived
structures
(
see
full
description
in
Hazard
Characterization
section
3.1).

3.3.2.1
Rationale
for
the
UFDB
(
when
a
DNT
is
recommended)

Given
the
findings
above
(
section
3.3.2),
a
database
uncertainty
factor
is
not
needed.

3.4
Hazard
Identification
and
Toxicity
Endpoint
Selection
3.4.1
Acute
Reference
Dose
(
aRfD)­
Females
age
13­
49
and
general
population
Study
selected:
The
prenatal
developmental
study
in
rats
was
used
to
select
the
dose
and
endpoint
for
establishing
the
aRfD
of
1.8
mg/
kg/
day
for
the
general
population
including
infants
and
children.
The
FQPA
SF
is
1X,
the
aPAD
is
also
1.8
mg/
kg/
day.
For
this
population,
the
endpoint
used
the
maternal
NOAEL
of
180
mg/
kg/
day
and
maternal
LOAEL
of
650
mg/
kg/
day
based
on
irregular
gait,
decreased
activity,
excessive
salivation,
and
anogenital
staining
observed
in
dams
on
the
first
day
of
dosing.
A
100­
fold
uncertainty
factor
(
10X
interspecies
and
10X
intraspecies)
was
Page
22
of
71
applied.

A
rat
developmental
study
was
used
to
select
the
dose
and
endpoint
for
establishing
the
aRfD
of
1.8
mg/
kg/
day
for
subpopulation
group
females
13­
50,
and
because
the
FQPA
SF
is
1X,
the
aPAD
is
also
1.8
mg/
kg/
day.
The
LOAEL
of
650
mg/
kg/
day
was
based
on
filamentous
tail
and
lack
of
tail
due
to
the
absence
of
sacral
and/
or
caudal
vertebrae,
and
delayed
ossification
in
the
hyoids,
vertebral
centrum
and/
or
transverse
processes,
sternebrae
and/
or
metatarsals,
and
pubes
in
pups.
The
fetal
anomalies
are
presumed
to
occur
following
a
single
dose
in
utero
and,
thus,
this
endpoint
would
be
applicable
to
females
13­
50
years
of
age.
A
100­
fold
uncertainty
factor
(
10X
interspecies
and
10X
intraspecies)
was
applied.

Acute
Reference
Dose
(
aRfD)
­
GENERAL
POPULATION
Executive
Summary:
See
summary­
section
3.2.3
Dose
and
Endpoint
for
Establishing
aRfD:
Maternal
NOAEL
=
180
mg/
kg/
day
based
on
based
on
irregular
gait
at
650
mg/
kg/
day
(
LOAEL).

Uncertainty
Factor
(
UF):
100
(
10X
for
interspecies
extrapolation
and
10X
for
intraspecies
variations)
was
applied.

Comments
about
Study/
Endpoint/
Uncertainty
Factor:
Irregular
gait
was
observed
in
12/
34
dams
on
the
first
day
of
dosing
and
thus
is
appropriate
for
this
risk
assessment.

Acute
Reference
Dose
(
aRfD)
­
FEMALES
13­
49
Executive
Summary:
See
summary­
section
3.2.3
Dose
and
Endpoint
for
Establishing
aRfD:
Developmental
NOAEL
=
180
mg/
kg/
day
based
on
filamentous
tail
and
lack
of
tail
due
to
the
absence
of
sacral
and/
or
caudal
vertebrae,
and
delayed
ossification
in
the
hyoids,
vertebral
centrum
and/
or
transverse
processes,
sternebrae
and/
or
metatarsals,
and
pubes
at
a
LOAEL
=
650
mg/
kg/
day.

Uncertainty
Factor
(
UF):
100
(
10X
for
interspecies
extrapolation
and
10X
for
intraspecies
variations)
was
applied.

Comments
about
Study/
Endpoint/
Uncertainty
Factor:
The
fetal
anomalies
are
presumed
to
occur
Acute
RfD
(
GENERAL
POPULATION)
=
180
mg/
kg
(
NOAEL)
=
1.8
mg/
kg
100
(
UF)
Page
23
of
71
after
a
single
dose
in
In
Utero
and
are
thus
appropriate
for
this
population
of
concern.

3.4.3
Chronic
Reference
Dose
(
cRfD)

Study
Selected:
The
mouse
combined
chronic
toxicity/
carcinogenicity
study
was
used
to
select
the
dose
and
endpoint
for
establishing
the
cRfD
of
0.14
mg/
kg/
day
and
because
the
FQPA
SF
is
1X,
the
cPAD
is
also
0.14
mg/
kg/
day.
The
NOAEL
of
14
mg/
kg/
day
and
the
LOAEL
of
41.2
mg/
kg/
day
was
based
on
early
onset
of
liver
effects
including
hepatocellular
hypertrophy
and
fatty
degeneration.
A
100­
fold
uncertainty
factor
(
10X
interspecies
and
10X
intraspecies)
was
applied.

MRID
No.:
43939101
(
1995)

Executive
Summary:
In
a
combined
chronic
toxicity/
carcinogenicity
study
(
MRID
00100527)
NP­
55
(
sethoxydim
technical,
95.4%
a.
i.,
lot
#
PN­
1­
2)
was
administered
to
60
BDF1
mice/
sex/
dose
in
the
diet
at
concentrations
of
40,
120,
360,
or
1080
ppm
(
equivalent
to
4.48,
13.77,
41.16,
or
134.46
mg/
kg
bw/
day
for
males
and
4.85,
14.86,
44.33,
or
142.85
mg/
kg
bw/
day
for
females)
for
24
months.
A
group
of
90
males
and
90
females
administered
the
vehicle­
(
acetone)
treated
food
served
as
the
control.
Additional
groups
of
10/
mice/
sex/
dose
were
sacrificed
at
12
months.

There
were
no
compound­
related
effects
on
clinical
signs
or
mortality.
The
final
body
weight
and
body
weight
gain
of
male
mice
in
the
1080­
ppm
group
were
reduced
by
10%
and
21%,
respectively,
compared
with
the
control
group.
Mean
body
weights
and
body
weight
gains
of
females
were
unaffected
by
treatment.
Both
absolute
and
relative
liver
weights
were
significantly
increased
(
by
115­
138%)
at
the
24
month
sacrifice
in
males
and
females
in
the
1080
ppm
group.
Increases
were
also
observed
in
males
and
females
(
relative
weight
only)
in
this
group
at
the
12­
month
interim
sacrifice.
At
the
24­
month
terminal
sacrifice,
increases
in
liver
weight
correlated
with
clinical
chemistry
parameters
of
elevated
alanine
aminotransferase
and
aspartate
aminotransferase
activities
and
the
microscopically­
observed
lesions
including
hepatocellular
hypertrophy
in
males
in
the
1080
ppm
group
(
all
p<
0.01).
Focal
granulomatous
inflammation,
fatty
degeneration,
and
hemosiderin
deposition
were
also
observed
in
the
livers
of
males
in
the
1080
ppm
group
(
all
p<
0.01).
Fatty
degeneration
of
the
liver
was
present
in
87%
of
males
in
the
1080
ppm
group
and
1%
of
males
in
the
control
group.
The
incidences
of
fatty
degeneration
(
p<
0.05)
and
hemosiderin
deposition
(
non­
significant)
in
the
liver
were
also
elevated
in
males
in
the
360
ppm
group,
although
the
increased
incidences
(
7­
8%)
were
small
compared
with
incidences
(
0­
1%)
in
the
control
group.
Only
the
incidence
of
fatty
degeneration
of
the
liver
was
Acute
RfD
(
FEMALES
13­
49)
=
180
mg/
kg
(
NOAEL)
=
1.8
mg/
kg
100
(
UF)
Page
24
of
71
significantly
elevated
in
female
mice
in
the
1080
ppm
group
at
24
months
(
control,
7%;
1080,
20%;
p<
0.01).

The
LOAEL
for
NP­
55
for
systemic
toxicity
is
360
ppm
in
the
diet
(
41.2
mg/
kg/
day)
based
on
early
onset
of
liver
effects
including
hepatocellular
hypertrophy
and
fatty
degeneration
in
male
mice.
The
NOAEL
is
120
ppm
in
the
diet
(
13.8
mg/
kg/
day).

This
chronic/
carcinogenicity
study
in
the
mouse
is
Acceptable/
Guideline
and
satisfies
the
guideline
requirement
for
a
chronic/
carcinogenicity
study
OPPTS
870.4300);
OECD
453]
in
mice.
Although
data
on
the
homogeneity,
concentration,
and
stability
of
the
test
material
in
the
diet
were
not
included
with
the
present
report,
acceptable
data
are
available
from
related
studies.

Dose
and
Endpoint
for
Establishing
cRfD:
NOAEL
of
14.0
mg/
kg/
day
for
male
mice
based
on
early
onset
of
liver
effects
including
hepatocellular
hypertrophy
and
fatty
degeneration
at
a
LOAEL
of
41.2
mg/
kg/
day.

Uncertainty
Factor(
s):
100
(
10X
for
interspecies
extrapolation
and
10X
for
intraspecies
variations)
was
applied.

Comments
about
Study/
Endpoint/
Uncertainty
Factor:
Appropriate
route
and
duration
for
the
chronic
RfD.
The
liver
toxicity
is
the
primary
effect
of
concern.
The
endpoint
selection
is
supported
by
the
chronic/
carcinogenicity
study
in
rat
where
liver
toxicity
(
centrilobular
hepatocellular
hypertrophy)
was
seen
at
a
comparable
LOAEL
(
48
mg/
kg/
day
in
male
rats.

3.4.4
Incidental
Oral
Exposure
(
Short­
Term)

Short­
Term
(
1­
30
days)

Study
Selected:
A
rat
developmental
study
was
used
to
select
the
dose
and
endpoint
for
shortterm
incidental
oral
exposure.
The
basis
for
the
endpoint
was
the
maternal
NOAEL
of
180
mg/
kg/
day
and
maternal
LOAEL
of
650
mg/
kg/
day
based
on
irregular
gait
observed
in
dams
on
the
first
day
of
dosing.

MRID
No:
43092902
(
1993)

Executive
Summary:
See
summary­
section
3.2.3
Chronic
RfD
=
14mg/
kg/
day
(
NOAEL)
=
0.14
mg/
kg/
day
100
(
UF)
Page
25
of
71
Dose
and
Endpoint
for
Risk
Assessment:
Maternal
NOAEL
=
180
mg/
kg/
day
based
on
based
on
irregular
gait
and
excessive
salivation
at
650
mg/
kg/
day
(
LOAEL).

Comments
about
Study/
Endpoint:
The
maternal
effects
are
appropriate
for
the
population
(
infants
and
children)
of
concerns
since
irregular
gait
was
observed
in
12/
34
dams
on
the
first
day
of
dosing,
peaking
on
gestation
day
8
(
i.
e.,
after
3
doses).
This
is
appropriate
for
this
exposure
period
of
concern.

Intermediate­
Term
(
1­
6
Months)

Study
Selected:
No
study
selected.
Intermediate­
term
exposure
not
anticipated.

3.4.5
Dermal
Absorption
Dermal
Absorption
Factor:
The
HIARC
concluded
that
calculation
of
a
dermal
absorption
factor
is
not
required
because
a
dermal
assessment
is
not
required
for
sethoxydim
(
see
below;
section
3.4.6).

3.4.6
Dermal
Exposure
(
Short­,
Intermediate­,
and
Long­
Term)

The
HIARC
concluded
that
for
all
durations
of
dermal
exposure,
quantification
of
non­
cancer
risk
is
not
required
based
on
the
following
factors:

°
No
dermal
or
systemic
toxicity
was
seen
following
repeated
dermal
applications
at
the
limit
dose
(
1000
mg/
kg/
day)
in
rabbits.

°
There
is
no
concern
for
pre­
natal
toxicity
in
rabbits.
Although
there
is
a
concern
for
developmental
effects
in
rats,
they
occurred
in
the
presence
of
maternal
toxicity
at
a
high
dose
(
650
mg/
kg/
day),
which
is
close
to
the
limit
Dose
(
1000
mg/
kg/
day).

3.4.7
Inhalation
Exposure
(
Short­
and
Intermediate­
Term)

Study
Selected:
A
rat
28­
day
study
was
used
for
dose
and
endpoint
selection
with
a
NOAEL
of
0.3
mg/
L
(
81
m/
kg/
day)
and
a
LOAEL
of
2.4
mg/
L
(
651
mg/
kg/
day)
which
was
based
on
liver
weight,
clinical
chemistry
(
bilirubin)
and
histology.
The
dose/
endpoint
is
derived
from
a
study
conducted
via
the
appropriate
route
of
concern
and
used
for
all
inhalation
exposure
durations.

MRID
No:
44021202
(
1993)

Executive
Summary:
In
a
28­
day
toxicity
study
(
MRID
44021202),
sethoxydim
(
96.8%;
batch
Page
26
of
71
no.
NS­
9212)
was
administered
by
inhalation
(
nose
only)
to
5
Wistar
rats/
sex/
dose
at
aerosol
analytical
concentrations
of
0.04,
0.3,
and
2.4
mg/
L.
The
control
group
received
filtered
air
only
and
the
sethoxydim
was
administered
as
received
from
the
sponsor.
Exposures
were
6
hours/
day,
5
days/
week,
for
a
total
of
21
exposures.
The
mass
median
aerodynamic
diameter
(
±
geometric
standard
deviation)
for
Groups
1,
2,
and
3
were
0.8
±
3.7
µ
m,
1.4
±
1.8
µ
m,
and
1.5
±
2.4
µ
m,
respectively.

No
animals
died
prior
to
terminal
sacrifice.
Clinical
signs
included
nasal
irritation
(
bloody
crust
formation
on
the
nose)
in
all
mid
and
high­
dose
rats,
salivation
during
and
after
exposure
in
highdose
rats,
and
fur
stained
with
the
test
substance
at
the
high
dose
throughout
most
or
all
of
the
study.
Body
weights
and
body
weight
gains
were
similar
to
controls
(
food
consumption
was
not
reported).
Clinical
chemistry
analysis
revealed
a
significant
increase
in
total
serum
bilirubin
high
dose
males
(
164%
of
controls;
p

0.05)
and
females
(
239%
of
controls;
p

0.02),
although
these
levels
are
not
considered
to
be
toxicologically
significant.
There
were
no
treatment­
related
findings
at
necropsy,
but
microscopic
examination
showed
an
increased
incidence
of
slight
(
grade
2)
centrilobular
hepatocyte
swelling
in
high­
dose
males
(
5/
5
vs.
1/
5
for
controls;
p<
0.05).
The
absolute
and
relative
(
to
terminal
body
weight)
liver
weights
were
increased
14­
16%
for
both
sexes
(
p

0.05
or
0.01
for
females
and
for
relative
weight
in
males).
The
liver
weight
increases
in
both
sexes
and
the
microscopic
changes
in
males
are
general
adaptive
responses
of
the
liver
to
a
xenobiotic
and
are
not
considered
adverse
effects.
A
slight
increase
was
also
seen
in
kidney
weights
of
high­
dose
males
(
6­
8%,
NS)
and
females
(
12­
13%,
p<
0.05
for
absolute
weight),
but
it
was
unclear
if
this
effect
was
treatment­
related
due
to
a
lack
of
histopathological
correlates.

Under
the
conditions
of
this
one­
month
study,
the
LOAEL
was
2.4
(
651
mg/
kg/
day)
based
on
increased
liver
weight,
clinical
chemistry
(
increased
total
serum
bilirubin),
and
liver
histopathology.
The
NOAEL
was
0.3
mg/
L
(
81
mg/
kg/
day),
for
both
male
and
female
rats.

This
28­
day
study
was
conducted
appropriately
and
is
Acceptable/
Non­
Guideline.

Dose/
Endpoint
for
Risk
Assessment:
NOAEL
is
0.3
mg/
L
(
81
mg/
kg/
day)
based
on
liver
weight,
clinical
chemistry
(
bilirubin)
and
histology
(
LOAEL
is
2.4
mg/
L
=
651
mg/
kg/
day).

Comments
about
Study/
Endpoint:
The
dose/
endpoint
is
derived
from
a
study
conducted
via
the
appropriate
route
of
concern.
The
HIARC
determined
that
this
study
could
be
used
for
all
durations,
however,
an
additional
Uncertainty
Factor
of
3X
is
required
when
assessing
risk
due
to
long­
term
exposure
(>
6
months)
since
there
is
evidence
of
progression
of
liver
toxicity
over­
time
(
14­
16%)
demonstrated
in
studies
conducted
via
the
oral
route.

3.4.8
Margins
of
Exposure
The
target
MOE
for
occupational
short­,
intermediate­,
and
long­
term
dermal
exposure/
risk
assessment
was
not
quantified.
No
endpoint
selected.
No
systemic
effect
at
limit
dose
(
1000
Page
27
of
71
mg/
kg/
day).

The
target
MOE
of
100
for
occupational
short­,
intermediate­
term
inhalation
exposure/
risk
assessments
includes
100X
(
10X
for
interspecies
extrapolation
and
10X
for
intraspecies
variations).

No
long­
term
exposure
anticipated;
however,
for
reference,
the
target
MOE
of
300
for
occupational
long­
term
inhalation
exposure/
risk
assessments
includes
the
conventional
100X
(
10X
for
interspecies
extrapolation
and
10X
for
intraspecies
variations)
and
an
additional
3X
based
on
concern
for
the
progression
of
hepatic
toxicity
following
long­
term
exposures
as
demonstrated
in
oral
studies.

The
target
MOE
of
100
for
residential
short­
term
incidental
oral
and
inhalation
exposure/
risk
assessments
includes
the
conventional
100X
(
10X
for
interspecies
extrapolation
and
10X
for
intraspecies
variations).

No
long­
term
exposure
anticipated;
however,
for
reference,
the
target
MOE
of
300
for
residential
long­
term
inhalation
exposure
risk
assessments
includes
the
conventional
100X
(
10X
for
interspecies
extrapolation
and
10X
for
intraspecies
variations),
and
a
3X
because
of
the
concern
for
progression
of
hepatic
toxicity
following
long­
term
exposure
as
demonstrated
in
oral
studies.

Table
3.4.8
Margins
of
Exposure
Route/
Duration
Short­
Term
(
1
­
30
days)
Intermediate­
Term
(
1
­
6
months)
Long­
Term
(>
6
months)

Occupational
(
Worker)
Exposure
Dermal
N/
A
N/
A
N/
A
Inhalation
100
100
N/
A
Residential
(
Non­
Dietary
Exposure)

Oral
100
N/
A
N/
A
Dermal
N/
A
N/
A
N/
A
Inhalation
100
N/
A
N/
A
N/
A
=
Not
applicable
3.4.9
Recommendation
for
Aggregate
Exposure
Risk
Assessments
As
per
1996
FQPA,
when
there
are
potential
residential
exposures
to
the
pesticide,
aggregate
risk
assessment
must
consider
exposures
from
three
major
sources:
oral,
dermal
and
inhalation
Page
28
of
71
exposures.
For
short­
term
aggregate
risk
assessments,
oral
and
inhalation
exposures
can
not
be
aggregated
because
of
a
lack
of
a
common
toxic
endpoint
across
the
exposure
routes.
Long­
term
aggregate
exposures
are
not
anticipated.
No
quantification
of
dermal
risk
assessments
are
required
for
any
time
period.
A
cancer
aggregate
risk
assessment
was
not
performed
because
sethoxydim
shows
no
evidence
of
carcinogenicity.

3.4.10
Classification
of
Carcinogenic
Potential
Sethoxydim
is
characterized
as
"
not
likely"
to
be
a
human
carcinogen
based
on
the
lack
of
increased
tumor
incidence
in
the
rat
and
mouse
carcinogenicity
studies.

Table
3.4.10
Summary
of
Toxicological
Doses
and
Endpoints
for
Sethoxydim
Exposure
Scenario
Dose
Used
in
Risk
Assessment,
UF
Special
FQPA
SF*
and
Level
of
Concern
for
Risk
Assessment
Study
and
Toxicological
Effects
Acute
Dietary
(
Females
13­
50
years
of
age
and
including
infants
and
children)
NOAEL
=
180
mg/
kg/
day
UF
=
100
Acute
RfD
=
1.8
mg/
kg/
day
FQPA
SF
=
1X
aPAD
=
acute
RfD
FQPA
SF
=
1.8
mg/
kg/
day
Rat
Developmental
Toxicity
Developmental
LOAEL
=
650
mg/
kg/
day
based
on
decreased
fetal
body
weight,
tail
abnormalities,
delayed
ossification.

Acute
Dietary
(
General
population
)
NOAEL
=
180
mg/
kg/
day
UF
=
100
Acute
RfD
=
1.8
mg/
kg/
day
FQPA
SF
=
1X
aPAD
=
acute
RfD
FQPA
SF
=
1.8
mg/
kg/
day
Rat
Developmental
Toxicity
Maternal
LOAEL
=
650
mg/
kg/
day
based
on
irregular
gait
that
was
observed
in
12/
34
dams
on
the
first
day
of
dosing.

Chronic
Dietary
(
All
populations)
NOAEL=
14
mg/
kg/
day
UF
=
100
Chronic
RfD
=
0.14
mg/
kg/
day
FQPA
SF
=
1X
cPAD
=
chronic
RfD
FQPA
SF
=
0.14
mg/
kg/
day
Mouse
Carcinogenicity
Study
LOAEL
=
41
mg/
kg/
day
based
on
liver
hypertrophy
and
fatty
degeneration.

Short­
Term
Incidental
Oral
(
1­
30
days)
NOAEL=
180
mg/
kg/
day
Residential
LOC
for
MOE
=
100
Occupational
=
NA
Rat
Developmental
Toxicity
Maternal
LOAEL
=
650
mg/
kg/
day
based
on
irregular
gait
that
was
observed
in
12/
34
dams
on
the
first
day
of
dosing.

Short­,
Intermediate­,
and
Long­
Term
Dermal
Dermal
(
or
oral)
study
NOAEL=
NA
Residential
LOC
for
MOE
=
NA
Occupational
LOC
for
MOE
NA
Quantification
of
dermal
exposure
risk
assessment
is
not
required
because
of
lack
of
dermal
&
pre­
natal
toxicity
in
rabbits,
and
the
low
dermal
absorption
physical
&
chemical
properties
of
sethoxydim.
Exposure
Scenario
Dose
Used
in
Risk
Assessment,
UF
Special
FQPA
SF*
and
Level
of
Concern
for
Risk
Assessment
Study
and
Toxicological
Effects
Page
29
of
71
Short­
Term
Inhalation
(
1
to
30
days)
Inhalation
study
NOAEL=
81
mg/
kg/
day
Residential
LOC
for
MOE
=
100
Occupational
LOC
for
MOE
=
100
28­
day
rat
inhalation
LOAEL
=
651
mg/
kg/
day
based
on
increased
liver
weight,
clinical
chemistry
(
increased
total
serum
bilirubin),
and
liver
histopathology.

Intermediate­
Term
Inhalation
(
1
to
6
months)
Inhalation
study
NOAEL=
81
mg/
kg/
day
Residential
LOC
for
MOE
=
100
Occupational
LOC
for
MOE
=
100
28­
day
rat
inhalation
LOAEL
=
651
mg/
kg/
day
based
on
increased
liver
weight,
clinical
chemistry
(
increased
total
serum
bilirubin),
and
liver
histopathology.

Long­
Term
Inhalation
(>
6
months)
Inhalation
study
NOAEL=
81
mg/
kg/
day
Residential
LOC
for
MOE
=
300
Occupational
LOC
for
MOE
=
300
28­
day
rat
inhalation
LOAEL
=
651
mg/
kg/
day
based
on
increased
liver
weight,
clinical
chemistry
(
increased
total
serum
bilirubin),
and
liver
histopathology.

Cancer
(
oral,
dermal,
inhalation)
"
Not
likely
human
carcinogen"
based
on
the
lack
of
evidence
of
carcinogenicity
in
rats
and
mice.

3.5
Special
FQPA
Safety
Factor
On
July
16,
2002
and
December
17,
2002,
the
HIARC
evaluated
the
potential
for
increased
susceptibility
of
infants
and
children
from
exposure
to
Sethoxydim
as
required
by
the
Food
Quality
Protection
Act
(
FQPA)
of
1996
according
to
the
2002
OPP
10x
Guidance
Document.
The
HIARC
concluded
that
the
degree
of
concern
was
low
for
pre­
and/
or
postnatal
toxicity
resulting
from
exposure
to
sethoxydim
and
determined
that
the
special
FQPA
SF
can
be
removed
(
1X)
since
there
are
no
residual
uncertainties
for
pre­
and/
or
postnatal
toxicity
based
on
the
following
evidence:

°
In
the
developmental
rat
study,
the
fetal
anomalies
were
seen
only
at
the
high
dose
(
650
mg/
kg/
day)
which
is
close
to
the
limit
dose
(
1000
mg/
kg/
day),
and
they
were
observed
in
the
presence
of
maternal
toxicity
(
irregular
gait).

°
Clear
NOAELs/
LOAELs
were
established
for
maternal
and
developmental
toxicities
in
the
rat
developmental
study.

°
In
the
2­
generation
reproductive
study,
the
LOAEL
for
offspring
toxicity
was
based
on
a
conservative
determination
of
a
minimal
response.
Page
30
of
71
3.6
Endocrine
Disruption
EPA
is
required
under
the
FFDCA,
as
amended
by
FQPA,
to
develop
a
screening
program
to
determine
whether
certain
substances
(
including
all
pesticide
active
and
other
ingredients)
"
may
have
an
effect
in
humans
that
is
similar
to
an
effect
produced
by
a
naturally
occurring
estrogen,
or
other
such
endocrine
effects
as
the
Administrator
may
designate."
Following
recommendations
of
its
Endocrine
Disruptor
and
Testing
Advisory
Committee
(
EDSTAC),
EPA
determined
that
there
was
a
scientific
basis
for
including,
as
part
of
the
program,
the
androgen
and
thyroid
hormone
systems,
in
addition
to
the
estrogen
hormone
system.
EPA
also
adopted
EDSTAC's
recommendation
that
the
Program
include
evaluations
of
potential
effects
in
wildlife.
For
pesticide
chemicals,
EPA
will
use
FIFRA
and,
to
the
extent
that
effects
in
wildlife
may
help
determine
whether
a
substance
may
have
an
effect
in
humans,
FFDCA
authority
to
require
the
wildlife
evaluations.
As
the
science
develops
and
resources
allow,
screening
of
additional
hormone
systems
may
be
added
to
the
Endocrine
Disruptor
Screening
Program
(
EDSP).
In
the
available
toxicity
studies
on
sethoxydim,
there
was
no
estrogen,
androgen,
and/
or
thyroid
mediated
toxicity.

When
additional
appropriate
screening
and/
or
testing
protocols
being
considered
under
the
Agency's
EDSP
have
been
developed,
sethoxydim
may
be
subjected
to
further
screening
and/
or
testing
to
better
characterize
effects
related
to
endocrine
disruption.

4.0
EXPOSURE
ASSESSMENT
4.1
Summary
of
Proposed/
Registered
Uses
Sethoxydim,
(+)­
2­[
1­(
ethoxyimino)
butyl]­
5­[
2­(
ethylthio)
propyl]­
3­
hydroxy­
2­
cyclohexen­
1­
one,
is
a
member
of
the
cyclohexenone
class
of
herbicides.
Sethoxydim
is
a
systemic,
postemergence
herbicide
which
controls
annual
and
perennial
grass
weeds
in
broadleaf
crops.
Sethoxydim
is
an
acetyl
CoA
carboxylase
(
fatty
acid
synthesis)
inhibitor.
Sethoxydim
inhibits
mitosis.

Poast
®
Herbicide
(
EPA
Reg.
No.
7969­
58)
is
an
emulsifiable
concentrate
which
contains
18%
sethoxydim
and
82%
inerts.
The
formulation
contains
1.5
lbs
active
ingredient/
gal.

Tolerances
are
currently
established
(
40
CFR
§
180.412)
for
combined
residues
of
sethoxydim
and
its
metabolites
on
a
variety
of
agricultural
commodities
at
levels
ranging
from
0.2
ppm
to
75.0
ppm.
Tolerances
are
also
currently
established
for
secondary
residues
in
meat,
fat,
and
meat
byproducts
of
cattle,
goats,
hogs,
horses,
poultry,
and
sheep
at
0.2
ppm
(
except
2.0
ppm
in
poultry,
mbyp);
eggs
at
2.0
ppm,
and
milk
at
0.05
ppm.
The
tolerance
expression
for
plant
and
livestock
commodities
includes
the
combined
residues
of
sethoxydim
and
its
metabolites
containing
the
2­
cyclohexen­
1­
one
moiety
(
calculated
as
the
herbicide)
as
specified
in
40
CFR
Page
31
of
71
§
180.412.
Page
32
of
71
Table
4.1
Summary
of
Sethoxydim
Use
Directions
Crop
Minimum
Time
From
Application
to
Harvest
(
PHI)
(#
of
days)
Maximum
Rate
Per
Acre
Per
Application
(
lb
ai/
acre)
Maximum
Rate
Per
Acre
Per
Season
(
lb
ai/
acre)

Alfalfa,
birdsfoot
trefoil,
and
sanfoin
(
dried)
14
0.47
1.2
Alfalfa,
birdsfoot
trefoil,
and
sanfoin
(
undried)
7
0.47
1.2
Apricot
25
0.47
0.94
Artichoke,
Globe
7
0.47
0.94
Asparagus
1
0.47
0.94
Avacado
(
nonbearing)
365
0.47
1.4
Beans
;
Dry,
Succulent
30
15
0.47
0.75
Beet
(
Garden)
60
0.47
0.94
Blueberry
30
0.47
0.94
Brassica
(
Crop
Group
5*)
30
0.28
0.56
Bulb
Vegetables
(
Crop
Group
3*)
30
0.28
0.84
Caneberries
(
Crop
Subgroup
13A*)
45
0.47
0.94
Canola/
Crambe/
Rapeseed
60
0.47
0.94
Carrot
30
0.47
0.94
Cherries
(
sweet
and
sour)
25
0.47
0.94
Christmas
tree
farms
n/
a
0.47
0.56
Citrus
(
Crop
Group
10*)
15
0.47
1.9
Clover
7
(
before
grazing,
feeding,
or
cutting
for
undried
forage)
0.47
1.2
Clover
hay
20
(
before
grazing,
feeding,
or
cutting
for
dry
hay)
0.47
1.2
Corn
(
Poast
®
protected
field
corn)
60
(
grain
or
fodder)
45
(
forage
and
silage)
0.28
0.56
Table
4.1
Summary
of
Sethoxydim
Use
Directions
Crop
Minimum
Time
From
Application
to
Harvest
(
PHI)
(#
of
days)
Maximum
Rate
Per
Acre
Per
Application
(
lb
ai/
acre)
Maximum
Rate
Per
Acre
Per
Season
(
lb
ai/
acre)

Page
33
of
71
Corn
(
Poast
®
protected
sweet
corn)
45
(
grain
or
fodder)
30
(
fresh
sweet
corn
or
forage
and
silage)
0.28
0.56
Cotton
40
0.47
1.4
Cranberry
60
0.47
0.94
Curcubits
(
Crop
Group
9*)
14
0.28
0.56
Date
(
nonbearing)
365
0.47
1.4
Deciduous
trees,
Nonfood
Crop
Areas,
Fallow
Land
n/
a
0.47
n/
a
Fescue
(
tall)
n/
a
0.47
n/
a
Fig
(
nonbearing)
365
0.47
1.4
Flax
75
0.28
0.75
Fruiting
Vegetables
(
Crop
Group
8*)
20
0.28
0.84
Grape
50
0.47
0.94
Head
and
Petiole
Type
Vegetables
(
Crop
Subgroup
4B*)
30
0.28
0.56
Horseradish
60
0.47
0.94
Leafy
Vegetables
(
Crop
Group
4*)
15
0.28
0.56
Lentil
50
0.47
0.75
Lingonberry,
Salal,
Juneberry
45
0.47
0.94
Mint
20
0.47
0.94
Nectarine
25
0.47
0.94
Non­
bearing
food
crops
n/
a
0.47
0.56
Nursery
plantings
n/
a
0.47
0.56
Table
4.1
Summary
of
Sethoxydim
Use
Directions
Crop
Minimum
Time
From
Application
to
Harvest
(
PHI)
(#
of
days)
Maximum
Rate
Per
Acre
Per
Application
(
lb
ai/
acre)
Maximum
Rate
Per
Acre
Per
Season
(
lb
ai/
acre)

Page
34
of
71
Olives
(
nonbearing)
365
0.47
1.4
Orchard
floor
middles
n/
a
0.09
0.09
Ornamentals
n/
a
0.47
0.56
Peach
25
0.47
0.94
Peanut
40
0.28
0.47
Peas,
Dry
Succulent
30
15
0.47
0.47
0.75
Pistachio
15
0.47
1.9
Plum
(
nonbearing)
365
0.47
1.4
Pome
fruits
(
Crop
Group
11*)
14
0.47
1.4
Pomegranate
(
nonbearing)
365
0.47
1.4
Potatoes,
Field
Sweet
(
East
US)
Sweet
(
West
US)
30
30
60
0.47
0.47
0.28
0.94
0.94
0.94
Prune
(
nonbearing)
365
0.47
1.4
Rights­
of­
way
n/
a
0.47
0.56
Roadsides
n/
a
0.47
0.56
Safflower
30
0.47
0.94
Set
Aside
Conservation
Land
n/
a
0.47
1.4
Soybean
75
0.47
0.94
Strawberry
7
0.47
0.47
Sugar
beet
60
0.47
0.94
Sunflower
70
0.47
0.47
Tobacco
42
0.28
0.75
Table
4.1
Summary
of
Sethoxydim
Use
Directions
Crop
Minimum
Time
From
Application
to
Harvest
(
PHI)
(#
of
days)
Maximum
Rate
Per
Acre
Per
Application
(
lb
ai/
acre)
Maximum
Rate
Per
Acre
Per
Season
(
lb
ai/
acre)

Page
35
of
71
Tree
Nuts
(
Crop
Group
14)
15
0.47
1.9
Tuberous
and
Corm
Vegetables
(
Crop
Subgroup
1C*)
30
0.47
0.94
Turf/
lawns
n/
a
0.47
0.56
Wildflowers
n/
a
0.47
0.56
*
Crop
groups
referenced
from
Code
of
Federal
Regulations
(
CFR)
40
Part
180.41.

4.2
Dietary
Exposure/
Risk
Pathway
Reference:
Sethoxydim.
Reregistration
Eligibility
Decision
(
RED).
Summary
of
Analytical
Chemistry
and
Residue
Data,
DP
Barcode
D318169,
William
Donovan,
22­
JUN­
2005.

4.2.1
Residue
Profile
Nature
of
the
Residue
­
Plants
and
Livestock
The
metabolism
of
sethoxydim
in
plants
is
adequately
understood,
based
on
adequate
metabolism
studies
which
are
available
on
soybeans,
tomatoes,
and
sugar
beets.
Sethoxydim
is
rapidly
metabolized
in
plants
to
a
multitude
of
cyclohexenone
derivatives
including
the
corresponding
sethoxydim
sulfoxide
(
MSO),
sethoxydim
sulfone
(
MSO2),
their
hydroxylated
and
desethoxylated
analogs,
and
oxazole
compounds.
Very
little
(

0.5%)
sethoxydim
(
MS)
is
left
unmetabolized.

The
metabolism
of
sethoxydim
in
ruminants
is
adequately
understood.
In
a
lactating
goat
fed
14Cring
labeled
sethoxydim
sulfoxide
(
14C­
MSO),
sethoxydim
sulfoxide
(
MSO)
was
oxidized
to
the
corresponding
sulfone
(
MSO2).
Desethylation
with
subsequent
methylation
at
the
sulfur
atom
also
occurred.
The
major
residues
in
milk
and
kidney
were
MSO
and
MSO2.
The
major
residues
in
liver
were
MSO2
and
MS.

The
metabolism
of
sethoxydim
in
poultry
is
adequately
understood.
In
one
study,
laying
hens
were
dosed
with
14C­
ring­
labeled­
sethoxydim
sulfoxide;
the
major
residues
in
eggs,
muscle,
fat,
skin,
and
liver
were
MSO
and
MSO2.
In
a
second
poultry
metabolism
study,
10
laying
hens
were
dosed
with
14C­
ring­
labeled­
sethoxydim;
the
major
residues
were
MSO
and
MSO2
in
muscle
and
liver,
and
MSO
and
MS
in
fat.
Page
36
of
71
The
residues
to
be
included
in
the
tolerance
expression
and
in
the
risk
assessment
for
plant
and
livestock
commodities
are
the
combined
residues
of
sethoxydim
and
its
metabolites
(
see
Appendix
for
stuctures)
containing
the
2­
cyclohexen­
1­
one
moiety
(
calculated
as
the
herbicide)
as
specified
in
40
CFR
§
180.412.

Residue
Analytical
Methods­
Plants
and
Livestock
Commodities
Adequate
enforcement
methodology
(
gas­
liquid
chromatography
with
flame
photometric
detection
[
GLC/
FPD]
in
the
sulfur
mode)
is
available
[
BASF
Wyandotte
Corporation's
(
BWC's)
Method
No.
30,
3/
15/
82;
MRID
44864501;
Method
I,
PAM
II]
to
enforce
the
tolerance
expression
in
plant
and
livestock
commodities.

Multiresidue
Methods
Multiresidue
data
for
sethoxydim,
sethoxydim
sulfoxide
(
MSO),
and
5­
hydroxy
sethoxydim
sulfone
(
5­
OH­
MSO2)
have
been
submitted.
Protocols
A
and
B
are
not
applicable;
protocols
C,
D,
and
E
were
tested.
Sethoxydim
and
its
metabolites
are
not
recovered
or
are
not
likely
to
be
recovered
by
FDA
multiresidue
methods.

Storage
Stability
Adequate
storage
stability
data
are
available
to
support
all
registered
uses
except
safflower
oil.
Storage
stability
data
for
sethoxydim,
MSO,
and
5­
OH­
MSO2
in
safflower
oil
(
or
another
oil)
stored
frozen
for
one
year
are
needed
since
storage
stability
data
for
sethoxydim
residues
in
oil
have
not
previously
been
submitted.

Crop
Field
Trial
Data
No
monitoring
data
were
used.
Field
trial
data
have
been
used.

Currently,
the
residues
included
in
the
tolerance
expression
for
plant
and
livestock
commodities
are
the
combined
residues
of
sethoxydim
and
its
metabolites
(
see
Appendix
for
stuctures)
containing
the
2­
cyclohexen­
1­
one
moiety
(
calculated
as
the
herbicide)
as
specified
in
40
CFR
§
180.412.
Because
sethoxydim
metabolism
is
similar
in
plant
and
animal
tissues,
resulting
in
formation
of
many
cyclohexenone
derivatives,
and
there
is
no
data
allowing
differentiation
of
the
toxicity
of
these
species
(
R.
Loranger,
D246356,
27­
MAY­
1998),
the
sethoxydim
risk
assessment
team
determined
that
the
existing
tolerance
expression
is
appropriate.
Moreover,
a
common
moiety
analytical
method
which
quantitates
all
compounds
containing
the
2­
cyclohexen­
1­
one
moiety
was
used
to
collect
residue
data.
This
method
was
successfully
validated
by
EPA
labs.
Accordingly,
the
sethoxydim
risk
assessment
team
also
determined
that
the
appropriate
residues
of
concern
for
risk
assessment
purposes
are
the
combined
residues
of
sethoxydim
and
its
metabolites
containing
the
2­
cyclohexen­
1­
one
moiety,
calculated
as
the
herbicide.
Page
37
of
71
Residue
Analytical
Methods­
Plants
and
Livestock
Commodities
Adequate
enforcement
methodology
(
gas­
liquid
chromatography
with
flame
photometric
detection
[
GLC/
FPD]
in
the
sulfur
mode)
is
available
[
BASF
Method
No.
30;
Method
I,
PAM
II]
to
enforce
the
tolerance
expression
in
plant
and
livestock
commodities.
Method
30
is
a
common
moiety
method,
where
residues
are
determined
as
3­[
2­(
ethylsulfonyl)­
propyl]
pentanedioic
acid
dimethyl
ester
(
DME)
and
its
3­
hydroxy
derivative,
3­[
2­(
ethoxysulfonyl)
propyl]­
3­
hydroxypentanedioic
acid
dimethyl
ester
(
DME­
OH),
respectively.
Sethoxydim
and
its
metabolites
are
oxidized
and
then
derivatized
to
DME
and
DME­
OH,
respectively.
The
limit
of
quantitation
for
each
analyte
is
0.05
ppm
sethoxydim
equivalents.

Processed
Food/
Feed
The
reregistration
requirements
for
magnitude
of
the
residue
in
the
processed
food/
feed
commodities
have
been
fulfilled.

Confined
Accumulation
in
Rotational
Crops
HED
(
D189273,
G.
Kramer,
8/
3/
93)
reviewed
a
confined
rotational
crop
study
(
Accession
#
42825)
and
a
limited
field
accumulation
study
(
MRID
41510612).
The
limited
field
study
used
soybeans
treated
with
14C­
ring­
labeled
sethoxydim
at
0.9
or
1.0
lb
ai/
A
and
cotton
treated
at
0.5
lb
ai/
A
as
primary
crops.
(
The
proposed
rate
on
herbs
is
0.56
lb
ai/
A/
season.)
The
rotational
crops
included
root
crops,
leafy
vegetables,
and
small
grains.
Total
radioactive
residues
(
TRRs)
were
<
0.005­
0.01
ppm
with
some
exceptions:
0.05
ppm
in
sorghum
forage
at
a
plantback
interval
of
30
days
(
0.5
lb
ai/
A
application
rate);
0.02
ppm
in
winter
wheat
forage
and
0.05
ppm
in
winter
wheat
straw
at
a
plantback
interval
of
134
days
(
1
lb
ai/
A
application
rate);
and
0.024
ppm
in
spring
wheat
grain
and
0.06
ppm
in
spring
wheat
straw
at
a
plantback
interval
of
283
days
(
0.5
lb
ai/
A
application
rate).
Approximately
60%
of
the
TRR
is
expected
to
be
in
the
form
of
sethoxydim
metabolites
(
based
on
soybean
and
alfalfa
studies).
Residues
in
all
the
limited
field
accumulation
trials
were
below
the
limit
of
quantitation
of
the
enforcement
method
(
0.1­
0.2
ppm)
for
all
RACs
at
all
plantback
intervals.
Since
residues
in
rotational
crops
were
expected
to
be
below
the
limit
of
quantitation
of
the
method,
HED
concluded
that
tolerances
were
not
required
at
that
time
for
rotational
crops
planted
greater
than
30
days
after
the
primary
crop
is
treated
with
sethoxydim.

The
limited
field
accumulation
study
indicated
that
residues
were
below
the
limit
of
quantitation
(
0.1
or
0.2
ppm
LOQ)
of
the
enforcement
method
in
all
rotational
crop
RACs
at
all
plantback
intervals.
Since
residues
in
rotational
crops
are
expected
to
be
below
the
limit
of
quantitation
of
the
method,
tolerances
are
not
required
for
rotational
crops
planted
greater
than
30
days
after
the
primary
crop
is
treated
with
sethoxydim.

A
plantback
restriction
of
at
least
30
days
should
be
added
to
the
label.
Page
38
of
71
Meat,
Milk,
Poultry,
and
Eggs
Dairy
cattle
and
poultry
feeding
studies
are
available.
Based
on
the
feeding
study
results
and
the
dietary
burden
calculations,
secondary
residues
in
livestock
commodities
may
be
expected
as
a
result
of
livestock
ingesting
feedstuffs
derived
from
crops
which
may
be
treated
with
sethoxydim.
Permanent
tolerances
are
established
(
40
CFR
§
180.412)
for
residues
of
the
herbicide
sethoxydim
and
its
metabolites
containing
the
2­
cyclohexen­
1­
one
moiety
in
meat
and
fat
of
cattle,
goats,
hogs,
horses,
poultry,
and
sheep
at
0.2
ppm;
meat
byproducts
of
cattle,
goats,
hogs,
horses,
and
sheep
at
1.0
ppm
(
2.0
ppm
in
meat
byproducts
of
poultry);
eggs
at
2.0
ppm,
and
milk
at
0.5
ppm.
The
existing
sethoxydim
permanent
tolerances
on
livestock
commodities
are
adequate.

International
Harmonization
A
comparison
of
Canadian
and
Mexican
MRLs
with
recommended
US
tolerances
for
sethoxydim
is
provided
in
Table
4.2.1.
The
Canadian
tolerances
on
various
legume
vegetables
are
significantly
less
than
those
needed
to
cover
residues
in
the
U.
S.
The
Mexican
MRLs
are
based
on
the
U.
S.
tolerance
levels.

Table
4.2.1.
Comparison
of
Canadian
and
Mexican
MRLs
with
Recommended
US
Tolerances.

Crop
US
Tolerance
(
ppm)
Canada
MRL
(
ppm)
Mexico
MRL
(
ppm)

Alfalfa
(
hay
&
forage)
40
­­­
40
Pea,
dry
40
­­­
40
Lentils
30
30
30
Peanut
25
­­­
25
Tomato
paste
4
15
4
Soybean
16
5
16
Pea,
succulent
10
10
10
Bean,
dry
20
10
­­­

Strawberry
10
10
10
Sunflower
7
7
­­­

Brassica
vegetables
5
­­­
5
Cotton,
seed
5
­­­
5
Raspberry
5
5
­­­

Bean,
succulent
15
5
­­­

Curcurbit
vegetables
4
­­­
4
Crop
US
Tolerance
(
ppm)
Canada
MRL
(
ppm)
Mexico
MRL
(
ppm)

Page
39
of
71
Fruiting
vegetables
4
­­­
4
Leafy
vegetables
4
­­­
4
Blueberry
4
4
­­­

Potato
4
4
4
Tomato
4
4
4
Artichoke
5
2
­­­

Cabbage
4
2
4
Cantaloupe
4
2
4
Cranberrry
2.5
2
­­­

Eggplant
4
2
4
Mustard
4
2
4
Mustard
greens
4
2
4
Spinach
4
2
4
Celery
4
1
4
Cucumber
4
1
4
Lettuce
4
1
4
Pumpkin
4
1
4
Squash
4
1
4
Bulb
vegetables
1
 
1
Grape
1
 
1
Citrus
fruit
0.5
 
0.5
Asparagus
4
0.5
­­­

Broccoli
4
0.5
4
Corn
0.5
0.5
­­­

Pepper
4
0.5
4
Flax
5
0.2
­­­

Onion
1
0.2
1
Turnip
 
0.2
1
Crop
US
Tolerance
(
ppm)
Canada
MRL
(
ppm)
Mexico
MRL
(
ppm)

Page
40
of
71
Apple
0.2
 
0.2
Carrot
1
0.1
 
4.2.2
Dietary
Exposure
Analyses
The
sethoxydim
dietary
exposure
assessment
was
conducted
using
the
Dietary
Exposure
Evaluation
Model
software
with
the
Food
Commodity
Intake
Database
(
DEEM­
FCID
 
,
Version
1.3),
which
incorporates
consumption
data
from
USDA's
Continuing
Surveys
of
Food
Intakes
by
Individuals
(
CSFII),
1994­
1996
and
1998.
The
1994­
1996,
and
1998
data
are
based
on
the
reported
consumption
of
more
than
20,000
individuals
over
two
non­
consecutive
survey
days.
Foods
"
as
consumed"
(
e.
g.,
apple
pie)
are
linked
to
EPA­
defined
food
commodities
(
e.
g.
apples,
peeled
fruit
­
cooked;
fresh
or
N/
S;
baked;
or
wheat
flour
­
cooked;
fresh
or
N/
S,
baked)
using
publicly
available
recipe
translation
files
developed
jointly
by
USDA/
ARS
and
EPA.
Consumption
data
are
averaged
for
the
entire
U.
S.
population
and
within
population
subgroups
for
chronic
exposure
assessment,
but
are
retained
as
individual
consumption
events
for
acute
exposure
assessment.

For
chronic
exposure
and
risk
assessment,
an
estimate
of
the
residue
level
in
each
food
or
foodform
(
e.
g.,
orange
or
orange
juice)
on
the
food
commodity
residue
list
is
multiplied
by
the
average
daily
consumption
estimate
for
that
food/
food
form.
The
resulting
residue
consumption
estimate
for
each
food/
food
form
is
summed
with
the
residue
consumption
estimates
for
all
other
food/
food
forms
on
the
commodity
residue
list
to
arrive
at
the
total
average
estimated
exposure.
Exposure
is
expressed
in
mg/
kg
body
weight/
day
and
as
a
percent
of
the
cPAD.
This
procedure
is
performed
for
each
population
subgroup.

For
acute
exposure
assessments,
individual
one­
day
food
consumption
data
are
used
on
an
individual­
by­
individual
basis.
The
reported
consumption
amounts
of
each
food
item
can
be
multiplied
by
a
residue
point
estimate
and
summed
to
obtain
a
total
daily
pesticide
exposure
for
a
deterministic
(
Tier
1
or
Tier
2)
exposure
assessment,
or
"
matched"
in
multiple
random
pairings
with
residue
values
and
then
summed
in
a
probabilistic
(
Tier
3/
4)
assessment.
The
resulting
distribution
of
exposures
is
expressed
as
a
percentage
of
the
aPAD
on
both
a
user
(
i.
e.,
those
who
reported
eating
relevant
commodities/
food
forms)
and
a
per­
capita
(
i.
e.,
those
who
reported
eating
the
relevant
commodities
as
well
as
those
who
did
not)
basis.
As
stated
above,
for
acute
and
chronic
assessments,
HED
is
concerned
when
dietary
risk
exceeds
100%
of
the
PAD.
The
DEEM­
FCID
 
analyses
estimate
the
dietary
exposure
of
the
U.
S.
population
and
32
population
subgroups.

4.2.2.1
Acute
Dietary
Exposure
Analysis
Reference:
Sethoxydim.
Acute
Dietary
Exposure
Assessment
for
Section
3
Registration
Actions,
DP
Barcode
D292905,
David
Soderberg,
11­
AUG­
2003.
Page
41
of
71
This
acute
assessment
used
tolerance
level
residues
for
most
of
the
crops
but
limited
refinement
was
obtained
through
the
incorporation
of
field
trial
data
and
experimental
processing
factors
for
some
of
the
crops
expected
to
be
more
highly
associated
with
dietary
exposure
to
sethoxydim.
Specifically,
field
trial
data
were
incorporated
for
apples,
pears
and
other
pome
fruits,
grapes,
oranges,
potatoes,
strawberries,
peaches,
succulent
green
peas,
succulent
green
beans,
and
succulent
lima
beans.
Empirical
processing
data
for
apples,
grapes,
tomatoes,
potatoes
and
oranges
were
also
used.
The
processing
data
for
orange
juice
was
also
translated
to
other
citrus
juices.
Percent
crop
treated
information
was
available
for
most
crops
and
was
used
wherever
possible
to
refine
the
assessment.
Tolerance
level
residues
were
used
for
meat,
poultry,
milk
and
eggs.

With
the
refinements
incorporated
in
this
assessment,
the
acute
dietary
analyses
for
sethoxydim
show
that
the
estimated
risks
from
acute
dietary
exposure
to
sethoxydim
are
below
the
Agency's
level
of
concern
(<
100%
aPAD)
for
the
US
population
and
all
population
subgroups
listed
in
Table
4.2.2.1.
Exposure
at
the
99.9th
percentile
was
5.3%
of
the
aPAD
for
the
general
US
population,
and
9.2%
of
the
aPAD
for
children
aged
1­
2
years,
and
also
children
aged
3­
5
years,
the
two
most
highly
exposed
population
subgroup.

Table
4.2.2.1.
Results
of
Acute
Dietary
Exposure
Analysis
Population
Subgroup
aPAD
(
mg/
kg/
day)
95th
Percentile
99th
Percentile
99.9th
Percentile
Exposure
(
mg/
kg/
day)
%
aPAD
Exposure
(
mg/
kg/
day)
%
aPAD
Exposure
(
mg/
kg/
day)
%
aPAD
General
U.
S.
Population
1.8
0.028
1.6
0.052
2.9
0.096
5.3
All
Infants
(<
1
year
old)
1.8
0.058
3.2
0.089
5.0
0.133
7.4
Children
1­
2
years
old
1.8
0.068
3.8
0.098
5.4
0.165
9.2
Children
3­
5
years
old
1.8
0.051
2.8
0.077
4.3
0.165
9.2
Children
6­
12
years
old
1.8
0.033
1.8
0.052
2.9
0.118
6.6
Youth
13­
19
years
old
1.8
0.021
1.2
0.036
2.0
0.078
4.3
Adults
20­
49
years
old
1.8
0.016
0.91
0.029
1.6
0.072
4.0
Females
13­
49
years
old
1.8
0.016
0.90
0.028
1.5
0.074
4.1
Table
4.2.2.1.
Results
of
Acute
Dietary
Exposure
Analysis
Population
Subgroup
aPAD
(
mg/
kg/
day)
95th
Percentile
99th
Percentile
99.9th
Percentile
Exposure
(
mg/
kg/
day)
%
aPAD
Exposure
(
mg/
kg/
day)
%
aPAD
Exposure
(
mg/
kg/
day)
%
aPAD
Page
42
of
71
Adults
50+
years
old
1.8
0.016
0.87
0.028
1.6
0.063
3.5
4.2.2.2
Chronic
Dietary
Exposure
Analysis
Reference:
Sethoxydim.
Acute
and
Chronic
Dietary
Exposure
Assessments
for
Section
3
Registration
Actions,
DP
Barcode
D289880,
Nancy
Dodd,
06­
MAY­
2003.

Sethoxydim
chronic
dietary
exposure
assessments
were
conducted
using
the
Dietary
Exposure
Evaluation
Model
software
with
the
Food
Commodity
Intake
Database
(
DEEM­
FCID
 
,
Version
1.3),
which
incorporates
consumption
data
from
USDA's
Continuing
Surveys
of
Food
Intake
by
Individuals
(
CSFII),
1994­
1996
and
1998.
The
chronic
DEEM­
FCID
 
analysis
used
mean
consumption
(
3
day
average)
data
and
gave
the
results
listed
in
Table
6.
The
chronic
analysis
(
limited
refined
dietary
risk
assessment)
used
tolerance
level
residues
for
all
crops,
percent
crop
treated
for
many
crops,
and
anticipated
residues
for
meat
and
milk.
The
most
highly
exposed
population
subgroup
is
infants,
at
7.5
%
of
the
cPAD.
The
results
of
this
analysis
indicate
that
the
chronic
dietary
risk
(
food
only)
associated
with
existing
uses
of
sethoxydim
is
below
the
Agency's
level
of
concern
(<
100%
cPAD)
for
the
general
U.
S.
population
and
all
population
subgroups
listed
in
Table
4.2.2.2.

Table
4.2.2.2.
Results
of
Chronic
Dietary
Exposure
Analysis
for
Sethoxydim.

Population
Subgroup
cPAD
(
mg/
kg/
day)
Exposure
(
mg/
kg/
day)
%
cPAD
General
U.
S.
Population
0.14
0.004
2.7
All
Infants
(<
1
year
old)
0.14
0.010
7.5
Children
1­
2
years
old
0.14
0.009
6.8
Children
3­
5
years
old
0.14
0.008
5.5
Children
6­
12
years
old
0.14
0.005
3.5
Youth
13­
19
years
old
0.14
0.003
2.4
Adults
20­
49
years
old
0.14
0.003
2.1
Females
13­
49
years
old
0.14
0.003
2.1
Table
4.2.2.2.
Results
of
Chronic
Dietary
Exposure
Analysis
for
Sethoxydim.

Population
Subgroup
cPAD
(
mg/
kg/
day)
Exposure
(
mg/
kg/
day)
%
cPAD
Page
43
of
71
Adults
50+
years
old
0.14
0.003
2.2
4.3
Water
Exposure/
Risk
Pathway
Reference:
Sethoxydim
Drinking
Water
Assessment
(
Tier
1)
for
Reregistration
Eligibility
Decision,
DP
Barcode:
D312559,
William
Eckel,
07­
FEB­
2005
The
Metabolism
Assessment
Review
Committee
(
MARC)
discussed
residues
of
the
herbicide
sethoxydim
in
water
on
May
14,
1998
(
R.
Loranger,
D246356,
27­
MAY­
1998).
The
predominant
degradates
in
soil
are
the
sulfoxide
and
sulfone
derivatives
of
the
parent
(
MSO
and
MSO2)
(
see
Appendix
for
structures).
These
degradates
are
expected
to
be
found
in
water
along
with
M1S
and
M2S.
Toxicology
data
for
the
four
degradates
expected
in
water
are
not
available.
In
the
absence
of
such
data,
the
MARC
concluded
that
these
degradates
should
be
considered
as
having
comparable
toxicity
as
the
parent.
Therefore,
for
risk
assessment
purposes
the
"
total
sethoxydim
residues"
in
water
should
be
used
instead
of
the
levels
for
only
parent
sethoxydim.

Little
if
any
monitoring
data
are
available
for
sethoxydim
to
determine
its
concentration
in
drinking
water
sources.
The
USGS
Pesticide
National
Synthesis
Project
(
http://
ca.
water.
usgs.
gov/
pnsp/
)
did
not
include
sethoxydim
(
nor
any
of
its
degradates)
in
its
list
of
pesticides
for
laboratory
analysis
of
ground
water
and
surface
water
samples.
Therefore,
modeling
estimates
were
used
to
quantify
possible
drinking
water
exposure.

Surface
water
­
Surface
water
assessment
used
a
Tier
1
model
called
FIRST,
or
FQPA
Index
Reservoir
Screening
Tool,
a
simulation
model
based
on
a
high
runoff
scenario
(
Mississippi
cotton)
with
a
storm
two
days
after
application.
The
modeling
was
performed
using
the
maximum
number
of
applications
(
four)
and
maximum
application
rate
of
0.47
pounds
(
2.5
pints)
active
ingredient
per
acre,
assuming
a
14­
day
RTI.
A
default
percent
cropped
area
factor
(
PCA)
of
87%
was
used
for
the
surface
water
assessment.
This
means
that
it
was
assumed
that
sethoxydimtreated
crops
were
grown
on
87%
of
the
acres
of
land
in
the
modeled
watershed.
This
is
the
highest
PCA
for
any
watershed
in
the
continental
U.
S.,
and
is
used
as
a
default
value
for
minor
crops.
Lower
PCA
values
could
have
been
applied
for
the
major
crops
on
which
sethoxydim
is
used
(
soybeans,
cotton,
and
corn).
However,
because
there
is
such
a
great
variety
of
uses,
it
is
likely
that
there
is
usage
on
major
and
minor
crops
in
the
same
watershed,
so
the
crop­
specific
PCA
may
not
be
applicable.
EDWCs
are
proportional
to
the
PCA
used.
The
FIRST
model
results
for
total
sethoxydim
residues
are
in
Table
4.3.

Ground
water
­
The
EDWC
for
ground
water
was
estimated
by
the
SCI­
GROW
model,
version
2.3.
The
results
of
the
model
for
acute
and
chronic
scenarios
(
Table
4.3)
are
1.5
ppb
for
parent
Page
44
of
71
sethoxydim
plus
degradates
when
assuming
a
maximum
use
rate
of
1.875
lb
ai/
A
per
year.

Table
4.3.
Estimated
Concentrations
of
Total
Sethoxydim
Residues
in
Drinking
Water.

Chemical
Surface
Water
(
ppb)
Groundwater
(
ppb)

Acute
Chronic
Acute
and
Chronic
Sethoxydim
130
16
1.5
4.4
Residential
(
Non­
Occupational)
Exposure/
Risk
Pathway
The
following
non­
occupational
assessment
was
extracted
from
the
HED
ORE
chapter
for
sethoxydim
(
W.
Britton.
DP318167,
6/
22/
05).

Sethoxydim
is
registered
for
residential
(
consumer)
use
on
ornamentals
and
flowering
plants,
recreational
areas,
and
buildings/
structures
(
outdoor).
Homeowners
who
apply
sethoxydim
to
ornamental
gardens
and
turf
may
be
exposed
for
short­
term
durations
via
the
dermal
and
inhalation
routes.
In
addition,
short­
term
postapplication
exposures
may
result
from
incidental
oral
exposures
(
children
only)
due
to
contact
with
sethoxydim­
treated
turf
in
public
(
recreational)
and
residential
settings.

Use
instructions
on
product
labeling
for
residential
applications
suggest
only
spot­
treatment,
which
is
not
considered
by
HED
to
result
in
consequential
exposures.
However,
because
no
recommendation
against
broadcast
lawn
use
appears
on
product
labeling,
it
is
assumed
that
such
a
use
could
occur
and,
therefore,
an
assessment
of
residential
postapplication
turf
exposure
was
performed.
No
endpoint
was
selected
for
intermediate­
term
incidental
ingestion
exposures
which
are
considered
unlikely.
This
decision
is
based
upon
the
frequency
(
no
more
than
twice
per
year)
and
method
of
application
(
spot­
treatment)
specified
by
product
labeling.
The
HED
HIARC
did
not
identify
a
dermal
endpoint
of
concern
for
sethoxydim.
Therefore,
only
exposure
from
inhalation
(
adult
handlers)
and
incidental
ingestion
(
children,
postapplication)
were
assessed.

Inhalation
risk
was
estimated
using
the
NOAEL
of
81
mg/
kg/
day
from
a
28­
day
rat
inhalation
study.
The
NOAEL
was
based
upon
increased
liver
weight,
clinical
chemistry
(
increased
total
serum
bilirubin),
and
liver
histopathology.
The
risk
for
short­
term
postapplication
toddler
incidental
ingestion
(
hand­
to­
mouth,
turf­
to­
mouth,
soil­
to­
mouth)
was
estimated
using
the
NOAEL
of
180
mg/
kg/
day
from
a
rat
developmental
toxicity
study.
This
NOAEL
was
based
upon
was
based
on
irregular
gait
observed
in
the
dams
on
the
first
day
of
dosing
HED's
level
of
concern,
in
this
instance,
is
an
MOE
=
100
(
10x
inter­
species
extrapolation,
and
10x
intra­
species
variation)
for
all
residential
population
groups.
MOEs
estimated
for
handlers
range
from
1.4E+
6
to
1.6E+
6.
MOEs
estimated
for
short­
term
postapplication
incidental
ingestion
range
from
26,000
for
hand­
to­
mouth
incidental
exposures
to
7.6E+
6
for
soil
ingestion
Page
45
of
71
incidental
exposures.
The
resulting
MOEs
are
above
the
target
MOE
of
100
and,
therefore,
are
not
of
concern
to
HED.

4.4.1
Non­
Occupational
(
Residential)
Handler
Exposure
and
Risks
As
previously
mentioned,
sethoxydim
exposure
to
residential
handlers
may
occur.
Residential
handler
scenarios
assessed
for
sethoxydim
are
as
follows:

°
Inhalation
exposure
from
mixing/
loading/
applying
liquids
for
low
pressure
handwand
application
°
Inhalation
exposure
from
mixing/
loading/
applying
liquids
for
backpack
sprayers
°
Inhalation
exposure
from
mixing/
loading/
applying
liquids
for
garden
hose­
end
sprayers
(
spot
treatment)

Residential
(
non­
occupational)
handler
risks
range
from
1.4E+
6
to
1.6E+
6
and,
therefore,
do
not
exceed
HED's
level
of
concern.
Results
from
exposure
and
risk
calculations
are
presented
in
Table
4.4.1.

A
series
of
assumptions
and
exposure
factors
served
as
the
basis
for
completing
the
residential
handler
risk
assessments.
Each
assumption
and
factor
is
detailed
in
the
HED
ORE
chapter.
In
addition
to
these
factors,
unit
exposure
values
were
used
to
calculate
handler
risk
estimates.
These
unit
exposure
values
were
taken
from
the
Pesticide
Handlers
Exposure
Database
(
PHED)
and
Outdoor
Residential
Exposure
Task
Force
(
ORETF)
studies.
The
handler
assessment
was
conducted
for
application
on
turf
and
ornamental
gardens
at
the
maximum
application
rate
of
0.47
lb
ai/
A.

Table
4.4.1:
Short­
term
Exposures
and
Risks
for
Residential
(
Non­
occupational)
Handlers
Exposure
Scenario
(
Scenario
#)
Inhalation
Unit
Exposure
(
Ug/
lb
ai)
1
Crop2
Application
Rate3
Daily
Area
Treated4
Inhalation
Dose
(
mg/
kg/
day)
5
Inhalation
MOE6
Mixer/
Loader/
App
Mixing/
Loading/
Applyi
ng
Liquids
for
Low
Pressure
Handwand
application
(
1)
30
Ornamentals,
Flowering
Plants,
Turf/
Lawn
0.02
lb
ai
per
gallon
5
Gallons
per
day
0.000049
1600000
Mixing/
Loading/
Applyi
ng
Liquids
for
Backpack
sprayer
application
(
2)
30
Ornamentals,
Flowering
Plants,
Turf/
Lawn
0.02
lb
ai
per
gallon
5
Gallons
per
day
0.000049
1600000
Mixing/
Loading/
Applyi
ng
Liquids
for
Garden
hose­
end
sprayer(
ORETF
­
conventional)
application
(
2)
17
Ornamentals,
Flowering
Plants,
Turf/
Lawn
0.47
lb
ai
per
acre
0.5
Acres
per
day
0.000057
1400000
1Baseline
inhalation
unit
exposures
represent
no
respirator.
Values
are
reported
in
the
PHED
Surrogate
Exposure
Guide
dated
August
1998
or
are
Page
46
of
71
from
data
submitted
by
the
Outdoor
Residential
Exposure
Task
Force
dated
May
2000.
2Crops
and
use
patterns
are
from
various
sources
including
LUIS
and
labels.
3Application
rates
are
based
on
maximum
values
found
in
various
sources
including
LUIS
and
various
labels.
In
most
scenarios,
a
range
of
maximum
application
rates
is
used
to
represent
the
range
of
rates
for
different
crops/
sites/
uses.
Most
application
rates
upon
which
the
analysis
is
based
are
presented
as
lb
ai/
A.
In
some
cases,
the
application
rate
is
based
on
applying
a
solution
at
concentrations
specified
by
the
label
(
i.
e.,
presented
as
lb
ai/
gallon).
4Amount
treated
is
based
on
the
area
or
gallons
that
can
be
reasonably
applied
in
a
single
day
for
each
exposure
scenario
of
concern
based
on
the
application
method
and
formulation/
packaging
type.
(
Standard
EPA/
OPP/
HED
values).
5Inhalation
dose
(
mg/
kg/
day)
=
[
unit
exposure
(
ug/
lb
ai)
*
0.001
mg/
g
unit
conversion
*
Inhalation
absorption
(
100%)
*
Application
rate
(
lb
ai/
acre
or
lb
ai/
gallon)
*
Daily
area
treated
(
acres
or
gallons)]
/
Body
weight
(
70
kg).
6Inhalation
MOE
=
NOAEL
(
81
mg/
kg/
day)
/
Daily
Inhalation
Dose.
Target
Inhalation
MOE
is
100.

4.4.2
Non­
Occupational
(
Residential)
Postapplication
Exposure
and
Risks
HED
uses
the
term
postapplication
to
describe
exposures
to
individuals
that
occur
as
a
result
of
being
in
an
environment
that
has
been
previously
treated
with
a
pesticide.
Sethoxydim
can
be
used
in
areas
that
can
be
frequented
by
the
general
population
including
residential
areas
(
i.
e.
home
lawns).
As
previously
mentioned,
there
is
potential
for
dermal
(
adults
and
children)
and
incidental
oral
exposure
(
children)
following
the
application
of
sethoxydim.

The
HED
Standard
Operating
Procedures
for
Residential
Exposure
Assessments
(
Draft,
December
18,
1997)
were
used
as
a
guideline
for
performing
the
residential
postapplication
assessment,
along
with
interim
changes
to
these
SOPs
which
were
adopted
by
the
HED
Exposure
Science
Advisory
Council
regarding
standard
values,
including,
for
turf
transferrable
residues,
turf
transfer
coefficients
and
hand­
to­
mouth
activities
(
Policy
11,
February
22,
2001).
While
toddler
short­
term
incidental
oral
exposures
are
estimated,
it
should
be
recognized
that
these
estimates
are
conservative
in
nature
due
to
the
application
method
specified
by
product
labeling
(
spottreatment
While
only
spot­
treatment
is
specified,
no
recommendation
against
broadcast
lawn
use
appears
on
product
labeling
and,
therefore,
it
is
assumed
that
this
could
occur.
The
HED
SOPs
for
Residential
Exposure
Assessments
that
pertain
to
turf
uses
were
adopted
based
upon
the
results
and
determinations
made
from
studies
involving
broadcast
lawn
applications.
The
spottreatment
method
of
application
specified
for
sethoxydim
is
intermittent
in
nature
and
should
reduce
the
likelihood
of
exposure.

Again,
HIARC
did
not
identify
a
dermal
endpoint
of
concern
for
sethoxydim
and,
because
inhalation
is
considered
negligible
for
postapplication
exposure,
only
toddler
incidental
oral
exposures
were
assessed.
Postapplication
risk
scenarios
assessed
for
sethoxydim
are
as
follows:

Toddler
­

°
Hand­
to­
Mouth
Activity
on
Turf
°
Object­
to­
Mouth
Activity
on
Turf
°
Incidental
Soil
Ingestion
MOEs
for
all
toddler
postapplication
risk
scenarios
(
short­
term)
are
not
a
risk
of
concern
(
i.
e.
MOE
less
than
100).
Results
are
presented
in
Tables
4.4.2.1,
4.4.2.2,
and
4.4.2.3.

4.4.2.1
Non­
Occupational
(
Residential)
Postapplication
Risk
Page
47
of
71
Characterization.

The
exposure
estimates
generated
are
based
on
some
upper­
percentile
(
i.
e.,
maximum
application
rate,
day­
zero
residues,
surface
area
and
hand­
to­
mouth
activity)
assumptions
and
are,
therefore,
considered
to
be
representative
of
central
to
high­
end
exposures.
The
uncertainties
associated
with
this
assessment
stem
from
the
use
of
an
assumed
amount
of
pesticide
available
from
turf,
and
assumptions
regarding
transfer
of
chemical
residues,
and
hand­
to­
mouth
activity,
as
well
as,
the
exposures
expected
from
a
spot­
treatment
application
as
specified
by
product
labeling.
This
is
considered
to
represent
Tier
1
assessment.
If
a
Tier
1
assessment
indicates
a
potential
concern,
a
more
detailed
exposure
assessment
is
warranted,
possibly
including
chemical­
specific
or
sitespecific
data.
exposure
assessment
is
warranted,
possibly
including
chemical­
specific
or
sitespecific
data.

Table
4.4.2.1:
Short­
term
Oral
Hand­
to­
Mouth
Exposure
and
Risk
for
Children
from
Treated
Lawns
Exposure
Scenario
For
mula
tion
Applicat
ion
Rate
(
lbai/
A)
Percent
ai
dislodgea
ble
TTR1
(

g/
cm2
)
Surface
Area
(
cm2)
Hand
to
Mouth
(
events/
hr)
Extracti
on
by
Saliva
Exposur
e
Time
(
hrs/
day)
Body
Weight
(
kg)
Daily
Dose2
(
mg/
kg
/
day)
MOE3
Hand­
to­
Mouth
(
using
5%
defalt)
Spr
ay
0.47
5
%
0.26
20
20
50%
2
15
0.007
26000
1
Turf
Transferrable
Residue
(
ug/
cm2)
=
Application
rate
(
lb
ai/
A)
x
Fraction
of
ai
Available
x
4.54E+
8
ug/
lb
x
2.47E­
8
A/
cm2
2
Daily
Dose
=
(
Turf
Transferrable
Residue
(
ug/
cm2)
x
Extraction
by
Saliva
x
Hand
Surface
Area
(
cm2/
event)
x
Frequency
(
events/
hr)
x
1E­
3
mg/
ug
x
ET
(
hrs/
day)]
/
[
Body
Weight
(
kg)]
3
MOE
=
Short­
Term
Oral
NOAEL
(
180
mg/
kg/
day)
/
Daily
Dose.

Table
4.4.2.2:
Short­
term
Oral
Object­
to­
Mouth
(
Turfgrass)
Exposure
and
Risk
for
Children
from
Treated
Lawns
Exposure
Scenario
Formulation
Application
Rate
(
lbai/
A)
Percent
ai
dislodgeable
TTR1
(

g/
cm2)
Surface
Area
Mouthed
(
cm2/
day)
Body
Weight
(
kg)
Daily
Dose2
(
mg/
kg/
day)
MOE3
Object­
to­
Mouth
(
turf)
Spray
0.47
20
%
1.05
25
15
0.0018
100000
1Grass
residue
(
ug/
cm2)
=
[
Application
Rate
(
lbs
ai/
A)
x
Fraction
of
ai
Available
x
4.54E+
8
ug/
lb
x
2.47E­
8
A/
cm2]
2
Daily
Dose
=
[
Grass
reside
(
ug/
cm2)
x
Surface
Area
Mouthed
(
cm2/
day)
x
1E­
3
mg/
ug]
/
[
Body
Weight
(
kg)]
3
MOE
=
Short­
Term
Oral
NOAEL
(
180
mg/
kg/
day)
/
Daily
Dose.

Table
4.4.2.3:
Short­
term
Exposure
and
Risk
for
Children
from
Ingestion
of
Soil
Exposure
Scenario
Formulation
Application
Rate
(
lbai/
A)
Fraction
of
ai
available
Soil
Residue1
(

g/
g)
Ingestion
Rate
(
mg/
day)
Body
Weight
(
kg)
Daily
Dose2
(
mg/
kg/
day)
MOE3
Soil
Ingestion
Spray
0.47
100%
3.5
100
15
2.4E­
05
7600000
1
Soil
residue
(
ug/
g)
=
[
Application
Rate
(
lbs
ai/
A)
x
Fraction
of
ai
Available
x
4.54E+
8
ug/
lb
x
2.47E­
8
A/
cm2
x
0.67
cm3/
g
soil]
2
Daily
Dose
=
[
Soil
reside
(
ug/
g)
x
Ingestion
rate
(
mg/
day)
x
1E­
6
g/
ug]
3
MOE
=
Short­
Term
Oral
NOAEL
(
180
mg/
kg/
day)
/
Daily
Dose.

4.4.3
Non­
Occupational
Off­
Target
Exposure
and
Risk
Page
48
of
71
4.4.3.1
Recreational
Uses
Sethoxydim
may
be
used
on
turf
at
recreational
use
sites
and,
therefore,
may
result
in
postapplication
exposure
to
adults
and
children
involved
in
recreational
activities.
Exposures
to
adults
and
children
from
the
use
of
sethoxydim
at
recreational
use
sites
are
assumed
to
be
the
same
as
those
assessed
for
residential
use
sites.
In
lieu
of
this,
a
separate
exposure
assessment
was
not
included.

4.4.3.2
Other
(
Spray
Drift,
etc.)

Spray
drift
is
always
a
potential
source
of
exposure
to
residents
nearby
to
spraying
operations.
This
is
particularly
the
case
with
aerial
application,
but,
to
a
lesser
extent,
could
also
be
a
potential
source
of
exposure
from
the
ground
application
method
employed
for
sethoxydim.
The
Agency
has
been
working
with
the
Spray
Drift
Task
Force,
EPA
Regional
Offices
and
State
Lead
Agencies
for
pesticide
regulation
and
other
parties
to
develop
the
best
spray
drift
management
practices.
On
a
chemical
by
chemical
basis,
the
Agency
is
now
requiring
interim
mitigation
measures
for
aerial
applications
that
must
be
placed
on
product
labels/
labeling.
The
Agency
has
completed
its
evaluation
of
the
new
data
base
submitted
by
the
Spray
Drift
Task
Force,
a
membership
of
U.
S.
pesticide
registrants,
and
is
developing
a
policy
on
how
to
appropriately
apply
the
data
and
the
AgDRIFT
computer
model
to
its
risk
assessments
for
pesticides
applied
by
air,
orchard
airblast
and
ground
hydraulic
methods.
After
the
policy
is
in
place,
the
Agency
may
impose
further
refinements
in
spray
drift
management
practices
to
reduce
off­
target
drift
with
specific
products
with
significant
risks
associated
with
drift.

4.4.4.3
Exposure
from
Use
of
Tobacco
­
Health
Risk
Assessment
In
assessing
exposure
through
use
of
tobacco,
HED
has
assumed
that
the
greatest
exposure
to
sethoxydim
would
come
from
cigarettes.
Further,
HED
has
assumed
that
the
average
U.
S.
smoker
smokes
15
cigarettes
per
day.
(
Pierce,
J.
P.,
et
al.
1989.
Tobacco
Use
in
1986
­
Methods
and
Basic
Tabulations
from
Adult
Use
of
Tobacco
Survey.
U.
S.
Dept.
of
Health
and
Human
Services
Publication
Number
OM90­
2004.
Office
on
Smoking
and
Health,
Rockville,
Maryland.)
Based
on
the
field
trial
data
provided
on
tobacco,
combined
residues
of
sethoxydim
and
metabolites
ranged
from
0.26
­
22.62
ppm
in/
on
six
samples
of
cured
tobacco
leaves.
An
average
residue
of
1.49
ppm
of
sethoxydim
and
its
metabolites
were
used
to
make
cigarettes.
The
results
of
the
tobacco
pyrolysis
study
for
total
radioactive
residues
(
TRR)
recovered
was
19%
and
30%
for
main
stream
and
side
stream
smoke,
respectively,
thus
approximately
total
for
sethoxydim
and
its
metabolites
is
0.73
ppm
(
1.49
ppm
x
49%).
Since
this
is
a
composited
sample
of
main­
stream
and
side­
stream
smoke,
it
greatly
exaggerates
the
actual
exposure
to
the
smoker,
whose
primary
route
of
exposure
is
via
main­
stream
smoke.
HED
has
further
assumed
that
100%
of
the
pesticide
residue
on
the
tobacco
is
inhaled
and
100%
inhaled
is
absorbed
(
i.
e.,
that
none
of
the
residue
is
exhaled
along
with
the
smoke).
These
assumptions
result
in
an
extreme
overestimate
of
actual
likely
exposure.
With
the
assumptions
regarding
residue
levels
and
smoking
frequency,
and
assuming
an
average
body
weight
of
70
kg,
HED
estimates
that
exposure
to
sethoxydim
will
not
exceed
0.00016
mg/
kg/
day
for
males
[
0.73
µ
g/
g
cigarette
×
1
g/
cigarette
×
15
cigarettes/
day
×
1
Page
49
of
71
mg/
1000
µ
g
÷
70
kg
body
weight
=
0.00016
mg/
kg/
day]
and
0.00018
mg/
kg/
day
for
females
(
60
kg
body
weight).

The
inhalation
NOAEL
is
81
mg/
kg/
day
(
all
durations)
and
is
based
on
a
28­
day
inhalation
study
in
the
rat.
HED
has
not
examined
intermediate­
or
long­
term
exposure
to
sethoxydim
via
tobacco
due
to
the
severity
and
quantity
of
health
effects
associated
with
the
use
of
tobacco
products.
Based
on
the
inhalation
NOAEL,
the
short­
term
MOE
for
sethoxydim
exposure
from
the
use
of
tobacco
is
estimated
to
be
greater
than
100
(
males:
81mg/
kg/
day
÷
0.00016
mg/
kg/
day
=
500,000;
females:
81
mg/
kg/
day
÷
0.00018
mg/
kg/
day
=
440,000).
This
is
a
highly
conservative
value
for
the
reasons
stated
above.
This
risk
is
below
HED's
level
of
concern
for
all
population
subgroups.

5.0
AGGREGATE
RISK
ASSESSMENTS
AND
RISK
CHARACTERIZATION
Aggregate
exposure
/
risk
assessments
were
performed
for
the
following
scenarios:
acute
and
chronic
aggregate
exposure
(
food
+
drinking
water)
and
short­
term
aggregate
exposure
(
residential
+
food
+
drinking
water).
A
cancer
aggregate
risk
assessment
was
not
performed
because
sethoxydim
is
not
carcinogenic.

Since
HED
does
not
have
reliable
ground
and
surface
water
monitoring
data,
water
modeling
data
were
used
to
compare
with
Drinking
Water
Levels
of
Comparsion
(
DWLOCs).
A
DWLOC
is
a
theoretical
upper
limit
on
a
pesticide's
concentration
in
drinking
water
in
light
of
total
aggregate
exposure
to
a
pesticide
in
food,
drinking
water,
and
through
residential
uses,
when
applicable.
A
DWLOC
will
vary
depending
on
the
toxicity
endpoint,
drinking
water
consumption,
body
weights,
and
pesticide
uses.
Different
population
subgroups
will
have
different
DWLOCs.
HED
uses
DWLOCs
in
the
risk
assessment
process
to
assess
potential
concern
for
exposure
associated
with
pesticides
in
drinking
water.
DWLOC
values
are
not
regulatory
standards
for
drinking
water.

To
calculate
DWLOCs,
the
dietary
food
estimates
(
from
DEEM­
FCID
 
)
were
subtracted
from
the
PAD
value
to
obtain
the
maximum
water
exposure
level.
DWLOCs
were
then
calculated
using
the
standard
body
weights
and
drinking
water
consumption
figures:
70kg/
2L
(
US
Population;
Adults
20­
49;
Adults
50+),
60
kg/
2L
(
Youth
13­
19;
Females
13­
49),
and
10kg/
1L
(
all
Infants
and
Children).

5.1
Acute
Aggregate
Risk
Assessment
(
Food
and
Drinking
Water)

The
acute
aggregate
risk
assessment
takes
into
account
exposure
estimates
from
dietary
consumption
of
sethoxydim
(
food
and
drinking
water).

The
limited
refined
acute
dietary
exposure
(
food
only)
estimates
are
below
HED's
level
of
concern
(<
100%
aPAD)
at
the
99.9th
exposure
percentile
for
the
general
U.
S.
population
(
5.2
%
Page
50
of
71
of
the
aPAD)
and
all
other
population
subgroups.
The
most
highly
exposed
subpopulations
were
children
aged
1­
2
and
children
aged
3­
5
years,
both
at
9.2%
of
the
aPAD.
The
EDWCs
generated
by
EFED
are
less
than
HED's
calculated
DWLOCs
for
acute
exposure
to
sethoxydim.
Table
5.1
summarizes
the
acute
aggregate
exposure
estimates
to
sethoxydim
residues.

Table
5.1.
Acute
DWLOC
Calculations
for
Sethoxydim.

Population
Subgroup
Acute
Scenario
aPAD
mg/
kg/
day
Acute
Food
Exp
mg/
kg/
day
Max
Acute
Water
Exp
mg/
kg/
day1
Ground
Water
EDWC
(
ppb)
2
Surface
Water
EDWC
(
ppb)
2
Acute
DWLOC
(

g/
L)
3
General
U.
S.
Population
1.8
0.096
1.704
1.5
130
5.96e+
04
All
Infants
(<
1year)
1.8
0.133
1.667
1.5
130
1.67e+
04
Children
1­
2
years
1.8
0.165
1.635
1.5
130
1.64e+
04
Children
3­
5
years
1.8
0.165
1.635
1.5
130
1.64e+
04
Children
6­
12
years
1.8
0.118
1.682
1.5
130
1.68e+
04
Youth
13­
19
years
1.8
0.078
1.722
1.5
130
5.17e+
04
Adults
20­
49
years
1.8
0.072
1.728
1.5
130
6.05e+
04
Females
13­
49
years
1.8
0.074
1.726
1.5
130
5.18e+
04
Adults
50+
years
1.8
0.063
1.737
1.5
130
6.08e+
04
1
Maximum
acute
water
exposure
(
mg/
kg/
day)
=
[(
acute
PAD
(
mg/
kg/
day)
­
acute
food
exposure
(
mg/
kg/
day)].
2
The
crop
producing
the
highest
level
was
used.
3
Acute
DWLOC(

g/
L)
=
[
maximum
acute
water
exposure
(
mg/
kg/
day)
x
body
weight
(
kg)]
[
water
consumption
(
L)
x
10­
3
mg/

g]

5.2
Short­
Term
Aggregate
Risk
Assessment
The
short­
term
aggregate
risk
assessment
estimates
risks
likely
to
result
from
1­
30
day
exposures
to
sethoxydim
residues
from
food,
drinking
water,
and
residential
pesticide
uses.
High­
end
estimates
of
the
residential
exposure
are
used
in
the
short­
term
assessment,
and
average
values
are
used
for
food
and
drinking
water
exposures.
Page
51
of
71
Short­
term
aggregate
risk
assessments
were
not
calculated
for
adult
handlers
because
oral
and
inhalation
endpoints
lack
a
common
toxicity
endpoint.
Further,
no
dermal
exposure
risk
assessment
is
required
because
there
is
no
dermal
or
systemic
toxicity
following
repeated
dermal
exposure,
susceptibility
in
rabbits
is
not
a
concern,
and
low
dermal
absorption
physical
and
chemical
properties.
Short­
term
aggregate
risk
assessments
are
required
for
children/
toddlers
because
there
is
a
potential
for
oral
postapplication
exposure
resulting
from
the
residential
uses
of
sethoxydim.
The
short­
term
residential
exposure
potential
for
sethoxydim
for
children/
toddlers
can
be
found
in
Table
5.2.
The
children/
toddlers
1­
2
years
of
age
scenario
was
chosen
because
it
was
the
highest
estimated
food
exposure
and
thus,
also
protective
of
children
3­
5
years
of
age.
As
the
MOEs
are
greater
than
100,
the
short­
term
aggregate
risks
are
below
HED's
level
of
concern.
For
surface
and
ground
water,
the
estimated
average
concentrations
of
sethoxydim
are
less
than
HED's
calculated
DWLOCs
for
sethoxydim
in
drinking
water
as
a
contribution
to
shortterm
aggregate
exposures.
Therefore,
HED
concludes
with
reasonable
certainty
that
residues
of
sethoxydim
in
drinking
water
do
not
contribute
significantly
to
the
short­
term
aggregate
human
health
risks
at
the
present
time.

Table
5.2.
Short­
Term
Aggregate
DWLOCs
for
Sethoxydim
Population
Subgroup
NOAEL
(
mg/
kg/
day)
Target
MOE
1
Target
Maximum
Exposure
2
(
mg/
kg/
day)
Estimated
Food
Exposure
(
mg/
kg/
day)
Estimated
Residential
Exposure
(
mg/
kg/
day)
Allowable
Water
Exposure
3
(
mg/
kg/
day)
Groundw
ater
EDWC
(

g/
L)
4
Surface
water
EDWC
(

g/
L)
4
DWLOC
5
(
µ
g/
L)

Short­
term:
Children
(
1­
2
years
old)
180
100
1.8
0.0095
0.0088
1.7817
1.5
16
1.78e+
04
1
The
short­
term
target
MOE
for
sethoxydim
includes
the
standard
intra­
and
inter­
species
uncertainty
factors
as
well
as
the
FQPA
uncertainty
safety
factor
of
10X.
2
Target
Max
Exposure
=
NOAEL
/
Target
MOE
3
Maximum
Water
Exposure
(
mg/
kg/
day)
=
Target
Maximum
Exposure
(
mg/
kg/
day)
­
Aggregate
Food
and
Residential
Exposure
(
mg/
kg/
day).
4
Estimate
for
the
highest
use
rate
was
chosen.
5
DWLOC
(
µ
g/
L)
=
Max.
water
exposure
(
mg/
kg/
day)
x
body
wt
(
kg)
÷
[(
10­
3
mg/
µ
g)
*
water
consumed
daily
(
L/
day)].
HED
standard
body
weight:
All
Infants/
Children,
10
kg.
HED
standard
daily
drinking
rate:
1
L/
day
for
children.

5.3
Chronic
Aggregate
Risk
Assessment
(
Food
and
Drinking
Water)

The
chronic
aggregate
risk
assessment
takes
into
account
average
exposure
estimates
from
dietary
consumption
of
sethoxydim
(
food
and
drinking
water).

The
partially
refined
chronic
dietary
exposure
estimates
are
below
HED's
level
of
concern
(<
100%
cPAD)
for
the
general
U.
S.
population
(
2.7%
of
the
cPAD)
and
all
population
subgroups.
The
most
highly
exposed
population
subgroup
is
Infants
(<
1
year
old),
at
7.5
%
of
the
cPAD.
The
EDWCs
generated
by
EFED
are
less
than
HED's
calculated
chronic
DWLOCs
for
chronic
exposure
to
sethoxydim
in
drinking
water.
Therefore,
the
chronic
aggregate
risk
associated
with
the
proposed
use
of
sethoxydim
does
not
exceed
HED's
level
of
concern
for
the
general
U.
S.
population
or
any
population
subgroups.
Table
5.3
summarizes
the
chronic
aggregate
exposure
estimates
to
sethoxydim
residues.
Page
52
of
71
Table
5.3.
Chronic
DWLOC
Calculations
for
Chronic
Exposure
to
Sethoxydim.

Population
Subgroup
Chronic
Scenario
cPAD
mg/
kg/
day
Chronic
Food
Exp
mg/
kg/
day
Max
Chronic
Water
Exp
mg/
kg/
day1
Ground
Water
EDWC
(
ppb)
2
Surface
Water
EDWC
(
ppb)
2
Chronic
DWLOC
(

g/
L)
3
U.
S.
Population
0.14
0.0038
0.1362
1.5
16
4.77e+
03
All
Infants
(<
1year)
0.14
0.0105
0.1295
1.5
16
1.30e+
03
Children
1­
2
years
0.14
0.0095
0.1305
1.5
16
1.31e+
03
Children
3­
5
years
0.14
0.0077
0.1323
1.5
16
1.32e+
03
Children
6­
12
years
0.14
0.0049
0.1351
1.5
16
1.35e+
03
Youth
13­
19
years
0.14
0.0033
0.1367
1.5
16
4.10e+
03
Adults
20­
49
years
0.14
0.0030
0.1370
1.5
16
4.80e+
03
Females
13­
49
years
0.14
0.0030
0.1370
1.5
16
4.11e+
03
Adults
50+
years
0.14
0.0031
0.1369
1.5
16
4.79e+
03
1Maximum
Chronic
Water
Exposure
(
mg/
kg/
day)
=
[
Chronic
PAD
(
mg/
kg/
day)
­
Chronic
Dietary
Exposure
(
mg/
kg/
day)]
2The
crop
producing
the
highest
level
was
used.
3
Chronic
DWLOC(

g/
L)
=
[
maximum
chronic
water
exposure
(
mg/
kg/
day)
x
body
weight
(
kg)]
[
water
consumption
(
L)
x
10­
3
mg/

g]
Page
53
of
71
6.0
CUMULATIVE
RISK
Unlike
other
pesticides
for
which
EPA
has
followed
a
cumulative
risk
approach
based
on
a
common
mechanism
of
toxicity,
EPA
has
not
made
a
common
mechanism
of
toxicity
finding
as
to
sethoxydim
and
any
other
substances
and
sethoxydim
does
not
appear
to
produce
a
toxic
metabolite
produced
by
other
substances.
For
the
purposes
of
this
tolerance
action,
therefore,
EPA
has
not
assumed
that
sethoxydim
has
a
common
mechanism
of
toxicity
with
other
substances.
For
information
regarding
EPA's
efforts
to
determine
which
chemicals
have
a
common
mechanism
of
toxicity
and
to
evaluate
the
cumulative
effects
of
such
chemicals,
see
the
policy
statements
released
by
EPA's
Office
of
Pesticide
Programs
concerning
common
mechanism
determinations
and
procedures
for
cumulating
effects
from
substances
found
to
have
a
common
mechanism
on
EPA's
website
at
http://
www.
epa.
gov/
pesticides/
cumulative/.

7.0
OCCUPATIONAL
EXPOSURE/
RISK
PATHWAY
The
following
occupational
assessment
was
extracted
from
the
HED
ORE
chapter
for
sethoxydim
(
W.
Britton.
DP312565,
3/
30/
05).

Sethoxydim
is
a
selective,
systemic,
post­
emergent
herbicide
used
for
the
control
of
annual
and
perennial
grass
weeds
in
broadleaf
crops.
Registered
use
sites
for
sethoxydim
include
agricultural
crops
such
as
various
fruits,
tree
nuts,
vegetables
and
herbs,
as
well
as
non­
agricultural
sites,
including
ornamental
and
flowering
plants,
recreational
areas,
rights­
of­
way,
along
fences
and
hedgerows,
and
public
and
commercial
buildings/
structures
(
outdoor).
Sethoxydim
is
formulated
for
occupational
use
as
a
liquid
product.

The
potential
for
occupational
exposure
to
sethoxydim
exists
in
a
variety
of
exposure
scenarios.
Such
scenarios
include
the
handling
of
sethoxydim
during
mixing,
loading,
and
applying
processes
(
i.
e.
mixer/
loaders,
applicators,
flaggers,
and
mixer/
loader/
applicators)
and
a
potential
for
postapplication
worker
exposure
from
entering
into
areas
previously
treated
with
sethoxydim.
Short­
term
(
1
to
30
days)
and
intermediate­
term
exposures
(
1
to
6
months)
may
occur,
however,
long­
term
exposures
(
greater
than
6
months)
are
not
expected.

The
HED
HIARC
did
not
identify
dermal
toxicity
endpoints
for
sethoxydim,
therefore,
occupational
handlers
were
assessed
for
both
short­
and
intermediate­
term
inhalation
exposures
only.
Inhalation
risk
was
estimated
using
the
inhalation
endpoint
NOAEL
from
a
28­
day
rat
study
(
NOAEL
=
81
mg/
kg/
day),
based
upon
increased
liver
weight,
clinical
chemistry
(
increased
total
serum
bilirubin),
and
liver
histopathology.
HED's
level
of
concern
for
occupational
inhalation
exposure
is
an
MOE
of
100
(
10x
for
inter­
species
extrapolation,
10x
for
intra­
species
variation).
In
accordance
with
HED's
Exposure
Science
Advisory
Council
(
SAC)
policy,
exposure
data
from
the
Pesticide
Handlers
Exposure
Database
(
PHED)
Version
1.1
as
presented
in
PHED
Surrogate
Exposure
Guide
(
8/
98)
were
used
with
other
HED
default
values
for
acres
treated
per
day,
body
Page
54
of
71
weight,
and
the
level
of
personal
protective
equipment
to
assess
the
handler
exposures.

7.1
Occupational
Handler
Handler
inhalation
exposure
and
risk
were
assessed
for
the
following
scenarios:

Mixer/
Loaders:

(
1)
Liquids
for
Aerial
Applications
(
2)
Liquids
for
Groundboom
Applications
(
3)
Rights­
of­
Way
Sprayer
Applications
Applicators:

(
4)
Aerial
Spray
Applications
(
5)
Groundboom
Spray
Applications
(
6)
Rights­
of­
Way
Sprayer
Applications
Flaggers:

(
7)
Flagging
for
Aerial
Spray
Applications
Mixer/
Loader/
Applicators:

(
8)
Liquids
for
Low
Pressure
Handwand
Sprayer
(
9)
Liquids
for
Backpack
Sprayer
(
10)
Liquids
for
High
Pressure
Handwand
Sprayer
(
11)
Liquids
for
Handgun
(
lawn)
Sprayer
(
ORETF)

The
MOEs
range
from
2,400
for
Mixing/
Loading/
Applying
Liquids
for
High
Pressure
Handwand
Application
to
3.2E+
7
for
Mixing/
Loading/
Applying
with
a
Handgun
Sprayer.
The
resulting
MOEs
are
above
the
target
MOE
of
100
and,
therefore,
are
not
a
risk
concern.
A
summary
of
the
MOEs
estimated
for
handlers
are
presented
in
Table
7.1.1.

Table
7.1.1:
Short­
and
Intermediate­
term
Baseline
Exposures
and
Risks
for
Occupational
Handlers
Exposure
Scenario
(
Scenario
#)
Inhalation
Unit
Exposure
(
Ug/
lb
ai)
1
Crop2
Application
Rate3
Daily
Area
Treated4
Inhalation
Dose
(
mg/
kg/
day)
5
Inhalation
MOE6
Mixer/
Loader
Exposure
Scenario
(
Scenario
#)
Inhalation
Unit
Exposure
(
Ug/
lb
ai)
1
Crop2
Application
Rate3
Daily
Area
Treated4
Inhalation
Dose
(
mg/
kg/
day)
5
Inhalation
MOE6
Page
55
of
71
Mixing/
Loading
Liquids
for
Aerial
application
(
1)
1.2
Berry,
Field
Crops,
Tree
(
fruit,
nut),
Vegetable,
Vine
0.47
lb
ai
per
acre
350
Acres
per
day
0.0028
29000
Mixing/
Loading
Liquids
for
Aerial
application
(
1)
1.2
High
Acreage
Field
Crops10
0.47
lb
ai
per
acre
1200
Acres
per
day
0.0097
8400
Mixing/
Loading
Liquids
for
Groundboom
application
(
2)
1.2
Berry,
Field
Crops,
Tree
(
fruit,
nut),
Vegetable,
Vine
0.47
lb
ai
per
acre
80
Acres
per
day
0.00064
130000
Mixing/
Loading
Liquids
for
Groundboom
application
(
2)
1.2
High
Acreage
Field
Crops8
0.47
lb
ai
per
acre
200
Acres
per
day
0.0016
50000
Mixing/
Loading
Liquids
for
Rights­
of­
Way
Sprayer
application
(
3)
1.2
Rights­
of­
Way
0.47
lb
ai
per
gallon
1000
Gallons
per
day
0.0081
10000
Applicator
Sprays
for
Aerial
application
(
2)
0.068
Berry,
Field
Crops,
Tree
(
fruit,
nut),
Vegetable,
Vine
0.47
lb
ai
per
acre
350
Acres
per
day
0.00016
510000
Sprays
for
Aerial
application
(
2)
0.068
High
Acreage
Field
Crops8
0.47
lb
ai
per
acre
1200
Acres
per
day
0.00055
150000
Sprays
for
Groundboom
application
(
3)
0.74
Berry,
Field
Crops,
Tree
(
fruit,
nut),
Vegetable,
Vine
0.47
lb
ai
per
acre
80
Acres
per
day
0.00040
200000
Sprays
for
Groundboom
application
(
3)
0.74
High
Acreage
Field
Crops18
0.47
lb
ai
per
acre
200
Acres
per
day
0.00099
82000
Sprays
for
Rights­
of­
Way
Sprayer
application
(
4)
3.9
Rights­
of­
Way
0.47
lb
ai
per
gallon
1000
Gallons
per
day
0.026
3100
Flagger
Flagging
for
Sprays
application
(
5)
0.35
Berry,
Field
Crops,
Tree
(
fruit,
nut),
Vegetable,
Vine
0.47
lb
ai
per
acre
350
Acres
per
day
0.00082
98000
Mixer/
Loader/
App
Mixing/
Loading/
Applyi
ng
Liquids
for
Low
Pressure
Handwand
application
(
6)
30
Misc
Crops
0.02
lb
ai
per
gallon
5
Gallons
per
day
0.000043
1900000
Mixing/
Loading/
Applyi
ng
Liquids
for
Backpack
sprayer
application
(
7)
30
Misc
Crops
0.02
lb
ai
per
gallon
5
Gallons
per
day
0.000043
1900000
Exposure
Scenario
(
Scenario
#)
Inhalation
Unit
Exposure
(
Ug/
lb
ai)
1
Crop2
Application
Rate3
Daily
Area
Treated4
Inhalation
Dose
(
mg/
kg/
day)
5
Inhalation
MOE6
Page
56
of
71
Mixing/
Loading/
Applyi
ng
Liquids
for
High­
Pressure
HandWand
application
(
8)
120
Rights­
of­
way
0.02
lb
ai
per
gallon
1000
Gallons
per
day
0.034
2400
Mixing/
Loading/
Applyi
ng
Liquids
for
Handgun
(
lawn)
Sprayer
(
ORETF)
application
(
9)
1.8
Turf/
Lawn
0.02
lb
ai
per
acre
5
Acres
per
day
0.0000026
32000000
1Baseline
inhalation
unit
exposures
represent
no
respirator.
Values
are
reported
in
the
PHED
Surrogate
Exposure
Guide
dated
August
1998
or
are
from
data
submitted
by
the
Outdoor
Residential
Exposure
Task
Force
dated
May
2000.
2Crops
and
use
patterns
are
from
the
labels.
3Application
rates
are
based
on
maximum
values
found
in
various
sources
including
LUIS
and
various
labels.
In
most
scenarios,
a
range
of
maximum
application
rates
is
used
to
represent
the
range
of
rates
for
different
crops/
sites/
uses.
Most
application
rates
upon
which
the
analysis
is
based
are
presented
as
lb
ai/
A.
In
some
cases,
the
application
rate
is
based
on
applying
a
solution
at
concentrations
specified
by
the
label
(
i.
e.,
presented
as
lb
ai/
gallon).
4Amount
treated
is
based
on
the
area
or
gallons
that
can
be
reasonably
applied
in
a
single
day
for
each
exposure
scenario
of
concern
based
on
the
application
method
and
formulation/
packaging
type.
(
Standard
EPA/
OPP/
HED
values).
5Inhalation
dose
(
mg/
kg/
day)
=
[
unit
exposure
(
ug/
lb
ai)
*
0.001
mg/
g
unit
conversion
*
Inhalation
absorption
(
100%)
*
Application
rate
(
lb
ai/
acre
or
lb
ai/
gallon)
*
Daily
area
treated
(
acres
or
gallons)]
/
Body
weight
(
70
kg).
6Inhalation
MOE
=
(
81
mg/
kg/
day)
/
Daily
Inhalation
Dose.
Target
Inhalation
MOE
is
100.
*
High
Acreage
Crops
include:
Alfalfa,
Corn,
Cotton,
and
Soybean
7.2
Short­/
Intermediate­/
Long­
Term
Postapplication
Risk
There
is
a
potential
for
dermal
exposure
to
scouts,
harvesters,
and
other
field
workers.
However,
because
a
dermal
endpoint
of
concern
was
not
identified,
and
postapplication
inhalation
exposure
is
expected
to
be
negligible,
an
occupational
postapplication
risk
assessment
was
not
conducted.
Based
upon
the
acute
toxicity
of
sethoxydim,
the
current
label
for
Poast
®
has
a
12­
hour
restricted
entry
interval
per
the
Worker
Protection
Standard
(
WPS).

7.3
Incidents
Sethoxydim
exposure
could
potentially
lead
to
symptoms
in
unprotected
applicators
and
other
handlers.
Of
the
databases
consulted
for
incident
reports
relating
to
sethoxydim
exposure,
the
data
collected
by
the
California
Department
of
Pesticide
Regulation
and
Poison
Control
Centers
were
the
only
that
offered
enough
documentation
to
warrant
any
conclusions
about
the
health
effects
of
sethoxydim.
The
most
common
symptoms
reported
included
rash,
eye
and
throat
irritation,
gastrointestinal
symptoms,
headache,
and
dizziness.
Two
of
the
more
serious
cases
reported
eye
problems
including
visual
defect
and
nonreactive
pupils.
However,
these
incident
reports
only
state
that
sethoxydim
was
present
and
the
exposure
was
likely
in
the
presence
of
pesticides
mixtures
(
unknown
origins).

8.0
DATA
NEEDS/
LABEL
REQUIREMENTS
8.1
Chemistry
Page
57
of
71
°
Two
safflower
field
trials
from
Region
10
°
Changes
to
the
Poast
label:

S
Specify
the
minimum
retreatment
interval
(
RTI)
for
all
crops.

S
Add
a
rotational
crop
restriction
that
specifies
a
30­
day
plant
back
interval
(
PBI)
for
all
non­
registered
crops.

8.2
Toxicology
None
8.3
Occupational/
Residential
None
Page
58
of
71
9.0
TOLERANCE
RESASSESSMENT
Tolerances
for
residues
of
sethoxydim
in/
on
plant
and
animal
commodities
are
expressed
in
terms
of
the
combined
residues
of
sethoxydim
[
2­[
1­(
ethoxyimino)
butyl]­
5­[
2­(
ethylthio)
propyl]­
3­
hydroxy­
2­
cyclohexen­
1­
one]
and
its
metabolites
containing
the
2­
cyclohexen­
1­
one
moiety,
calculated
as
sethoxydim.

A
summary
of
the
sethoxydim
tolerance
reassessments
is
presented
in
Table
9.0.

Tolerances
Listed
Under
40
CFR
§
180.412:

Adequate
residue
data
have
been
submitted
to
reassess
the
established
tolerances
for
sethoxydim
in/
on
the
listed
commodities.

TABLE
9.0.
Tolerance
Summary
for
Sethoxydim
Commodity
Established
Tolerance
(
ppm)
Recommended
Tolerance
(
ppm)
Comments
(
correct
commodity
definition)

Alfalfa,
Forage
40.0
40
Alfalfa,
Hay
40.0
40
Almond,
Hulls
2.0
2.0
Apple,
Dry
Pomace
0.8
0.80
Apple,
dried
pomace
Apple,
Wet
Pomace
0.8
­­­
Revoke:
not
a
significant
feedstuff
Apricot
0.2
0.20
Artichoke,
globe
5.0
5.0
Tolerance
with
Regional
Registration
Asparagus
4.0
4.0
Bean,
Dry,
Seed
20.0
20
Bean,
Forage
15.0
15
Cowpea,
forage
Bean,
Hay
50.0
50
Cowpea,
hay
Bean,
Succulent
15.0
15
Beet,
Garden
1.0
1.0
Beet,
garden,
roots
Beet,
Sugar,
Molasses
10.0
10
Beet,
Sugar,
Roots
1.0
1.0
Beet,
Sugar,
Tops
3.0
3.0
Blueberry
4.0
4.0
Caneberry
Subgroup
13a
5.0
5.0
Caneberry
subgroup
13A
Canola/
rapeseed
35.0
35
Rapeseed,
seed
Canola/
rapeseed,
meal
40.0
40
Rapeseed,
meal
Commodity
Established
Tolerance
(
ppm)
Recommended
Tolerance
(
ppm)
Comments
(
correct
commodity
definition)

Page
59
of
71
Carrot,
Roots
1.0
1.0
Carrot
Cattle,
Fat
0.2
0.20
Cattle,
Meat
0.2
0.20
Cattle,
Meat
Byproducts
1.0
1.0
Cherry,
Sweet
0.2
0.20
Cherry,
Tart
0.2
0.20
Citrus,
Dried
Pulp
1.5
1.5
Citrus,
Molasses
1.5
­­­
Revoke:
not
a
significant
feedstuff
Clover,
Forage
35.0
35
Clover,
Hay
50.0
55
The
maximum
residue
observed
was
50.7
ppm.

Coriander
4.0
4.0
Coriander,
leaves
Corn,
Field,
Grain
0.5
0.5
Corn,
Forage
2.0
2.0
Corn,
field,
forage
Corn,
Fodder
2.5
2.5
Corn,
field,
stover
Corn,
Sweet,
Forage
3.0
3.0
Corn,
Sweet,
Kernel
plus
Cob
with
Husks
Removed
0.4
0.40
Corn,
Sweet,
Stover
3.5
3.5
Cotton,
Seed,
Soapstock
15
­­­
Revoke:
not
a
significant
feedstuff
Cotton,
Undelinted
Seed
5.0
5.0
Cranberry
2.0
2.5
The
maximum
residue
observed
was
2.2
ppm.

Egg
2.0
2.0
Flax,
Meal
7
7.0
Flax,
Seed
5.0
5.0
Flax,
Straw
2.0
­­­
Revoke:
not
a
significant
feedstuff
Fruit,
citrus
0.5
0.50
Fruit,
citrus,
group
10
Fruit,
Pome
0.2
0.20
Fruit,
pome,
group
11
Goat,
Fat
0.2
0.20
Goat,
Meat
0.2
0.20
Goat,
Meat
Byproducts
1.0
1.0
Grape
1.0
1.0
Grape,
Raisin
2.0
2.0
Commodity
Established
Tolerance
(
ppm)
Recommended
Tolerance
(
ppm)
Comments
(
correct
commodity
definition)

Page
60
of
71
Hog,
Fat
0.2
0.20
Hog,
Meat
0.2
0.20
Hog,
Meat
Byproducts
1.0
1.0
Horse,
Fat
0.2
0.20
Horse,
Meat
0.2
0.20
Horse,
Meat
Byproducts
1.0
1.0
Horseradish
4.0
4.0
Juneberry
5.0
5.0
Lentil,
seed
30.0
30
Lingonberry
5.0
5.0
Milk
0.5
0.50
Nectarine
0.2
0.20
Peach
0.2
0.20
Peanut
25.0
25
Peanut,
Soapstock
75.0
­­­
Revoke:
not
a
significant
feedstuff
Pea,
Dry,
Seed
40.0
40
Pea,
Field,
Hay
40.0
40
Pea,
Field,
Vines
20.0
20
Pea,
Succulent
10.0
10
Peppermint,
tops
(
stems
and
leaves
30.0
30
Peppermint,
tops
Pistachio
0.2
0.20
Potato,
Flakes
8.0
8.0
Combine
these
two
tolerances
into
the
following:
Potato,
granules/
flakes
Potato,
Granules
8.0
8.0
Potato
waste,
processed
(
wet
and
dry)
8.0
8.0
Potato,
processed
potato
waste
Poultry,
Fat
0.2
0.20
Poultry,
Meat
0.2
0.20
Poultry,
Meat
Byproducts
2.0
2.0
Rhubarb
0.3
0.30
Tolerance
with
Regional
Registration
Safflower
15.0
15
Safflower,
seed
Two
additional
safflower
field
trials
Commodity
Established
Tolerance
(
ppm)
Recommended
Tolerance
(
ppm)
Comments
(
correct
commodity
definition)

Page
61
of
71
are
needed
from
Region
10.

Salal
5.0
5.0
Sheep,
Fat
0.2
0.20
Sheep,
Meat
0.2
0.20
Sheep,
Meat
Byproducts
1.0
1.0
Soybean
16.0
16
Soybean,
seed
Soybean,
Hay
10.0
10
Spearmint,
tops
(
stems
and
leaves)
30.0
30
Spearmint,
tops
Strawberry
10.0
10
Sunflower,
Meal
20.0
20
Sunflower,
Seed
7.0
7.0
Tomato,
Concentrated
Products
24
24
Tomato,
paste
Tomato,
Dry
Pomace
12.0
­­­
Revoke:
not
a
significant
feedstuff
Tree
Nut
0.2
0.20
Nut,
tree,
group
14
Vegetable,
Brassica,
Leafy,
Group
5
5.0
5.0
Additional
field
trials
in
CA
and
FL
are
still
required
for
mustard
greens.

Vegetable,
Bulb,
Group
3
1.0
1.0
Vegetable,
bulb,
group
3
Vegetable,
Cucurbit,
Group
9
4.0
4.0
Vegetable,
cucurbit,
group
9
Vegetable,
Fruiting,
Group
8
4.0
4.0
Vegetable,
fruiting,
group
8
Vegetable,
Leafy,
Except
Brassica,
Group
4
4.0
4.0
Vegetable,
leafy,
except
Brassica,
group
4
Tuberous
and
Corm
vegetable
crop
subgroup
4.0
4.0
Vegetable,
tuberous
and
corm,
subgroup
1C
Page
62
of
71
Sethoxydim
(
MS)
MSO
10.0
APPENDIX
10.1
Names
and
Structures
of
Sethoxydim
and
Some
Metabolites/
Analytes
Sethoxydim
=
MS;
2­[
1­(
ethoxyimino)
butyl]­
5­[
2­(
ethylthio)
propyl]­
3­
hydroxy­
2­
cyclohexen­
1­
one
DME
=
3­[
2­(
ethylsulfonyl)
propyl]­
pentanedioic
acid
dimethyl
ester
DME­
OH
=
3­[
2­(
ethylsulfonyl)
propyl]­
3­
hydroxypentanedioic
acid
dimethyl
ester
MSO
=
sethoxydim
sulfoxide;
2­[
1­(
ethoxyimino)
butyl]­
5­[
2­(
ethylsulfinyl)
propyl]­
3­
hydroxy­
2­
cyclohexen­
1­
one
MSO2
=
sethoxydim
sulfone;
2­[
1­(
ethoxyimino)
butyl]­
5­[
2­(
ethylsulfonyl)
propyl]­
3­
hydroxy­
2­
cyclohexen­
1­
one
M1SO
=
2­[
1­(
imino)
butyl]­
5­[
2­(
ethylsulfinyl)
propyl]­
3­
hydroxy­
2­
cyclohexen­
1­
one
M2SO
=
6­[
2­(
ethylsulfinyl)
propyl]­
6,7­
dihydro­
2­
propyl­
4(
5H)­
benzoxazolone
M2SO2
=
6­[
2­(
ethylsulfonyl)
propyl]­
6,7­
dihydro­
2­
propyl­
4(
5H)­
benzoxazolone
5­
OH­
MSO2
=
5­
hydroxy
sethoxydim
sulfone;
2­[
1­(
ethoxyimino)
butyl]­
5­[
2­
(
ethylsulfonyl)
propyl]­
3,5­
dihydroxy­
2­
cyclohexen­
1­
one
Page
63
of
71
M1S
5­
OH­
MSO
M1SO
MSO2
M1SO2
OH­
MSO2
Page
64
of
71
M2S
MGSO
M2SO
MGSO2
M2SO2
DME
Page
65
of
71
OH­
M2SO2
DME­
OH
10.2
Toxicology
Data
Requirements
The
requirements
(
40
CFR
158.340)
for
food
use
for
sethoxydim
are
in
Table
1.
Use
of
the
new
guideline
numbers
does
not
imply
that
the
new
(
1998)
guideline
protocols
were
used.

Test
Technical
Required
Satisfied
870.1100
Acute
Oral
Toxicity
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.1200
Acute
Dermal
Toxicity
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.1300
Acute
Inhalation
Toxicity
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.2400
Primary
Eye
Irritation
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.2500
Primary
Dermal
Irritation
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.2600
Dermal
Sensitization
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
yes
yes
yes
yes
yes
no
yes
yes
yes
yes
yes
­

870.3100
Oral
Subchronic
(
rodent)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.3150
Oral
Subchronic
(
nonrodent)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.3200
21­
Day
Dermal
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.3250
90­
Day
Dermal
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.3465
28­
Day
Inhalation
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
yes
yes
yes
­
yes
yes
no
yes
­
yes
870.3700a
Developmental
Toxicity
(
rodent)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.3700b
Developmental
Toxicity
(
nonrodent)
.
.
.
.
.
.
.
.
.
.
.
.
870.3800
Reproduction
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
yes
yes
yes
yes
yes
yes
870.4100a
Chronic
Toxicity
(
rodent)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.4100b
Chronic
Toxicity
(
nonrodent)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.4200a
Oncogenicity
(
rat)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.4200b
Oncogenicity
(
mouse)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.4300
Chronic/
Oncogenicity
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
­
yes
yes
yes
yes
­
yes
yes
yes
yes
Test
Technical
Required
Satisfied
Page
66
of
71
870.5100
Mutagenicity
 
Gene
Mutation
­
bacterial
.
.
.
.
.
.
.
.
870.5300
Mutagenicity
 
Gene
Mutation
­
mammalian
.
.
.
.
.
.
870.5915
Mutagenicity
 
Structural
Chromosomal
Aberrations
870.5550
Mutagenicity
 
Unscheduled
DNA
sythesis
(
rat
hepatocyte
cells)
.
.
.
.
.
.
.
.
.
.
.
.
yes
yes
yes
yes
yes
yes
yes
yes
870.6100a
Acute
Delayed
Neurotox.
(
hen)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.6100b
90­
Day
Neurotoxicity
(
hen)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.6200a
Acute
Neurotox.
Screening
Battery
(
rat)
.
.
.
.
.
.
.
.
.
870.6200b
90
Day
Neuro.
Screening
Battery
(
rat)
.
.
.
.
.
.
.
.
.
.
.
870.6300
Develop.
Neuro
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
no
no
no
no
no
­
­
­
­
­

870.7485
General
Metabolism
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.7600
Dermal
Penetration
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
yes
no
yes
­

Special
Studies
for
Ocular
Effects
Acute
Oral
(
rat)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
Subchronic
Oral
(
rat)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
Six­
month
Oral
(
dog)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
no
no
no
­
­
­

10.3
Non­
critical
Toxicology
Studies
STUDY
TYPE:
90­
Day
Oral
Toxicity
Feeding­
Mouse;
OPPTS
870.3100
[
81­
2];
OECD
408.

EXECUTIVE
SUMMARY:
In
a
14­
week
(
98­
day)
oral
toxicity
study
(
MRID
00045858)
NP­
55
(
sethoxydim
technical,
95.9%
a.
i.,
lot
#
PN­
1­
1)
was
administered
to
20
ICR
mice/
sex/
dose
in
the
diet
at
levels
of
0,
100,
300,
900,
or
2700
ppm
(
equivalent
to
0,
15.4,
45.6,
137.1,
or
373.6
mg/
kg
bw/
day
for
males
and
0,
17.2,
52.7,
164.4,
or
486.3
mg/
kg
bw/
day
for
females).

There
were
no
compound­
related
effects
on
mortality,
clinical
signs,
body
weight,
food
consumption,
hematology,
clinical
chemistry,
or
gross
pathology.
Absolute
liver
weights
of
males
in
the
900
and
2700
ppm
groups
and
of
females
in
the
2700
ppm
group
were
increased
by
13
and
33%
(
both,
p<
0.01)
and
32%
(
non­
significant),
respectively.
Hepatocellular
hypertrophy
was
observed
microscopically
in
the
livers
of
these
dose
groups.
Liver
weights
relative
to
body
weights
were
also
significantly
increased
in
both
males
and
females
in
the
900
and
2700
ppm
dietary
groups.
The
increased
liver
weights
accompanied
by
histopathological
evidence
hepatocellular
changes
are
considered
treatment­
related
effects.

The
NOAEL
for
NP­
55
in
mice
is
300
ppm
in
the
diet
(
males,
45.6
mg/
kg/
day;
females,
52.7
mg/
kg/
day).
The
LOAEL
is
900
ppm
(
males,
137.1
mg/
kg/
day;
females,
164.4
mg/
kg/
day)
based
on
increase
liver
weight
and
histopathological
evidence
of
hepatocellular
Page
67
of
71
hypertrophy.

This
90­
day
oral
toxicity
study
in
the
mouse
is
Acceptable/
Guideline
and
satisfies
the
guideline
requirement
for
a
90­
day
oral
toxicity
study
(
OPPTS
870.3100;
OECD
408)
in
the
rodent.
Although
many
guideline
requirements/
recommendations
were
not
fulfilled,
these
were
generally
minor
deviations
that
did
not
impact
the
results
of
the
study.

STUDY
TYPE:
90­
Day
Oral
Toxicity
[
Feeding]­
Rat;
OPPTS
870.3100
[
§
82­
la]
(
rodent);
OECD
408.

EXECUTIVE
SUMMARY:
In
a
subchronic
oral
toxicity
study
(
MRID
00045859)
NP­
55
(
Sethoxydim;
95.9%
a.
i.,
lot
#
PN­
1­
1)]
was
administered
to
20
Wistar
rats/
sex/
dose
in
the
diet
at
concentrations
of
0,
33,
100,
300,
900,
or
2700
ppm
(
equivalent
to
0,
2.25,
20.12,
60.43,
and
196.34
mg/
kg
bw/
day,
respectively,
in
males;
0,
2.42,
7.08,
21.43,
66.18,
and
200.45
mg/
kg
bw/
day,
respectively,
in
females)
for
98
days.

Treatment
with
the
high­
dose
(
2700
ppm)
of
NP­
55
resulted
in
suppressed
growth
in
both
males
and
females.
Statistically
significant
(
p<
0.05;
0.01)
decreases
in
mean
absolute
body
weights
were
observed
in
high­
dose
males
starting
at
week
6
and
continuing
throughout
treatment
(
92­
96%
of
controls,
terminal
body
weight
91%
of
controls),
and
in
high­
dose
females
at
weeks
12
and
14
(
96
and
94%
of
controls,
respectively;
terminal
body
weight
94%
of
controls).
High­
dose
males
and
females
also
had
decreases
in
overall
body
weight
gain
for
weeks
0­
14
(
83
and
86%
of
controls,
respectively;
p<
0.01).
Tbe
decreases
in
body
weights
were
accompanied
by
decreases
in
food
efficiency:
overall
food
efficiency
for
weeks
0­
14
was
decreased
by
26%
and
21%
in
high
dose
males
and
females,
respectively.
In
contrast,
food
consumption
did
not
appear
to
be
affected
by
treatment.
However,
comparable
or
greater
food
consumption
values
were
noted
at
various
intervals,
including
the
total
amount
of
food
consumed
over
the
entire
study
period
of
weeks
0­
14
(
105%
and
102%
of
controls
for
high­
dose
males
and
females,
respectively).
No
effects
on
body
weights
or
food
consumption
values
were
found
in
the
other
treated
males
or
females.
Treatment
with
up
to
2700
ppm
NP­
55
did
not
adversely
affect
survival,
clinical
signs,
water
consumption,
hematology
or
clinical
chemistry
parameters,
urinalysis
results,
or
gross
or
microscopic
findings.

The
LOAEL
is
2700
ppm
(
196.34
mg/
kg/
day
in
males;
200.45
mg/
kg/
day
in
females)
based
on
decreases
in
body
weight,
body
weight
gain,
and
food
efficiency.
The
NOAEL
is
900
ppm
(
60.43
mg/
kg/
day
for
males;
66.18
mg/
kg/
day
in
females).

This
90­
day
oral
toxicity
study
in
the
rat
is
Acceptable/
Guideline
and
does
satisfy
the
guideline
requirement
for
a
90­
day
oral
toxicity
study
(
OPPTS
870.3100;
OECD
408)
in
rats.
Few
deficiencies
were
noted
in
this
study,
to
include
mixing
procedure
used
in
the
diet
preparation
andocular
examination
following
dietary
exposure
to
NP­
55.
Page
68
of
71
STUDY
TYPE:
Subchronic
Oral
Toxicity
[
feeding]­[
dog]
[
OPPTS
870.3150
(
§
82­
l)]
(
non­
rodent);
OECD
409.

EXECUTIVE
SUMMARY:
In
a
26­
week
oral
toxicity
study
(
MRID
00045860)
NP­
55
(
91.6%
a.
i,,
lot
#
PN­
1­
2)
was
administered
to
6
beagle
dogs/
sex/
dose
in
the
diet
at
concentrations
of
0,
120,
600,
or
3000
ppm.
Approximate
doses
to
the
animals
in
the
treated
groups
were
3.2­
3.7,
16.6­
20.3,
and
82.8­
95.2
mg/
kg/
day,
for
males
and
3.2­
3.5,
14.4­
20.3,
and
73.2­
102
mg/
kg/
day
for
females.,
respectively.

No
dose­
or
treatment­
related
differences
in
absolute
body
weights
or
in
body
weight
gains,
food
consumption,
urinalysis
parameters,
or
ophthalmoscopic
examinations
were
observed
in
males
or
females
during
the
study.

Possible
treatment­
related
clinical
findings
were
limited
to
sanguineous
appearing
urine
in
one
low­
dose
male,
two
mid­
dose
males,
and
one
high­
dose
male;
apparent
urinary
calculi
were
found
in
these
animals
during
catheterization.
One
high­
dose
male
was
sacrificed
in
extremis
during
week
10
due
to
a
calculi­
blocked
urethra
resulting
in
severe
necrotizing
suppurative
cystitis.
All
remaining
animals
survived
to
scheduled
termination.

White
cell
counts
were
consistently
higher
for
all
treated
groups
compared
with
the
controls
with
statistical
significance
(
p
<
0.05)
attained
occasionally
for
mid­
and
high­
dose
females
and
high
dose
males.
Through
week
13
of
the
study,
LDH
values
for
the
mid­
and
high­
dose
males
were
41­
57%
and
44­
57%,
respectively,
of
the
controls
and
for
the
mid­
and
high­
dose
females
were52­
65%
and
54­
57%,
respectively,
of
the
controls.
By
week
26,
some
recovery
was
evident
with
LDH
values
72­
82%
of
the
control
levels
for
all
of
these
treated
groups.
Alkaline
phosphatase
levels
were
increased
throughout
the
study
for
the
high­
dose
males
and
females
to
155­
326%
and215­
240%,
respectively,
of
the
controls
and
for
the
mid­
dose
males
at
week
26
to
171%
of
the
control
level.
Total
albumin
levels
were
decreased
in
the
high­
dose
males
and
females
to
89­
91%
and
83­
91%,
respectively,
of
the
control
levels
which
resulted
in
corresponding
decreases
in
the
albumin:
globulin
ratio
for
these
groups
compared
with
the
controls.
PSP
excretion
rates
for
the
mid­
and
high­
dose
males
and
all
treated
females
generally
declined
over
time.
Excretion
rates
were
47­
52%
and
27­
45%
of
the
controls
for
the
mid­
and
high­
dose
males,
respectively,
and
67­
79%,
42­
48%,
and
24­
31%
of
the
controls
for
the
low­,
mid­,
and
high­
dose
females,
respectively.
Other
differences
in
hematology
and
clinical
chemistry
parameters
were
sporadic,
not
dose­
related,
or
not
sustained
over
time.

With
respect
to
the
control
values,
absolute
and
relative
liver
weights
were
112%
and
112%,
respectively,
for
the
mid­
dose
males,
144%
and
136%,
respectively,
for
the
high­
dose
males,
and
116%
and
115%,
respectively,
for
the
high­
dose
females.
Gross
necropsy
findings
among
animals
sacrificed
at
study
termination,
included
urinary
calculi
in
one
low­
dose
male,
two
mid­
dose
males
and
two
high­
dose
males.
Microscopically,
cystitis
of
the
urinary
bladder,
characterized
by
mucosal
hyperpiasia,
submucosal
edema,
hemorrhage,
and
inflammatory
infiltrate,
was
observed
Page
69
of
71
in
animals
from
all
treated
groups.
The
incidence
of
cystitis
in
the
control,
low­,
mid­,
and
highdose
groups
was
0/
6,
2/
6,
3/
6,
and
3/
6,
respectively,
for
males
and
0/
6,
3/
6,
2/
6,
and
3/
6,
respectively,
for
females.
Pyelitis
in
the
renal
pelvis
was
observed
in
2/
6
mid­
and
3/
6
high­
dose
males.
In
addition,
uroliths
were
seen
in
one
mid­
dose
and
two
high
dose
males.

The
tentative
LOAEL
is
120
ppm
(
3.183­
3.740
and
3.198­
3.460
mg/
kg/
day
for
male
and
female
dogs,
respectively)
based
on
cystitis
of
the
urinary
bladder.
The
NOAEL
is
not
identified.

This
26­
week
oral
toxicity
study
m
the
dog
is
Unacceptable/
Non­
guideline
and
does
not
satisfy
the
guideline
requirement
for
a
90­
day
oral
toxicity
study
(
OPPTS
870.3150;
OECD
409)
in
dogs.
The
dogs
were
fed
the
formulated
diet
once
weekly
for
six
weeks,
then
twice
weekly
for
the
remaining
26­
week
period.
They
were
observed
for
clinical
signs
daily
for
the
first
2
weeks,
then
biweekly.
The
results
of
feed
analysis
concentration
of
the
a.
i
deviated
widely.

STUDY
TYPE:
21­
Day
Dermal
Toxicity
Study
in
Rabbits;
OPPTS
870.3200
[
82­
2];
OECD
411
EXECUTIVE
SUMMARY:
In
a
21­
day
dermal
toxicity
study
(
MRID
41987203),
groups
of
5
male
and
5
female
New
Zealand
White
rabbits
were
dermally
dosed
with
sethoxydim
6
hours
per
day
over
21
consecutive
days
at
0
(
vehicle
control),
40,200,
and
1000
mg/
kg/
day.
The
only
doserelated
dosing
site
lesion
was
slight
epidermal
hyperplasia,
which
was
found
in
nearly
all
highdose
males
and
females,
and
was
probably
an
adaptive
response.
There
was
no
evidence
of
compound­
related
toxicity
onclinical
signs,
body
weights,
food
consumption,
food
efficiency,
eye
health,
clinical
pathology,
organ
weights,
or
gross
pathology.
The
NOAEL
is
>
1000
mg/
kg/
day
(
limit
dose)
and
the
systemic
LOAEL
is
not
identified.

This
study
is
Acceptable­
Guideline,
and
thus
satisfies
data
requirement
82­
2
for
a
21­
Day
Dermal
Toxicity
Study.
This
study
received
Quality
Assurance
review.

STUDY
TYPE:
Chronic
toxicity
­
dog
[
feeding];
OPPTS
870,4100
[
§
83­
l];
OECD
452.

EXECUTIVE
SUMMARY:
In
a
chronic
toxicity
study
(
MRIDs
00152669
and
40629001.)
NP­
55
(
96.86%
a,
i.,
lot
#
KK­
1240)
was
administered
to
6
beagle
dogs/
sex/
dose
in
the
diet
at
concentrations
of
0,
300,
600,
or
3600
ppm
for
12
months.
Overall
time­
weighted
average
doses
were
0,
8.7,
17.5,
and
110
mg/
kg/
day,
respectively,
for
males
and
0,
9.4,19.9,
and
129
mg/
kg/
day,
respectively,
for
females.

All
animals
survived
to
scheduled
termination.
No
adverse,
treatment­
related
effects
on
clinical
signs,
body
­
weight,
food
consumption,
or
gross
pathology,
were
observed.
Mild
to
moderate
changes
were
observed
in
hematology,
clinical
chemistry,
liver
weights,
and
microscopic
pathology.
In
males,
dose­
related
changes
in
red
cell
parameters
were
suggestive
of
a
hemolytic
Page
70
of
71
episode
and
correlated
with
increases
in
hemosiderosis
in
the
spleen
which
was
observed
microscopically
with
special
iron
staining.
However,
the
magnitude
of
the
changes
is
not
considered
to
be
adverse­
Evidence
of
hepatocyte
enzyme
induction
was
apparent
from
increased
liver
weights
(
both
absolute
and
relative)
of
high­
dose
males
and
females
and
histopathological
lesions
in
all
treated
male
groups
and
in
mid­
and
high­
dose
females.
However,
BSP
clearance
showed
no
effect
on
liver
excretion.
Dose­
related
increases
in
alkaline
phosphatase
in
both
sexes
(
up
to
4.0
fold
increase),
ALT
(
2­
fold
compared
to
controls),
slight
decrease
in
albumin
and
cholesterol
levels
were
observed
during
different
periods
of
the
study.

There
was
a
slight
increase
in
splenic
hemosiderosis
(
seen
in
iron­
stained
sections
only)
in
the
high­
dose
males
and
females,
and
a
slight
decrease
in
myeloid
erythropoiesis
in
the
sternal
bone
marrow
of
the
high­
dose
males,
but
in
the
absence
of
marked
anemia,
the
significance
and
the
cause
of
these
findings
are
uncertain.

The
NOAEL
is
600
ppm
(
17.5
and
19.9
mg/
kg/
day,
for
males
and
females,
respectively)
add
the
LOAEL
is
3600
ppm
(
110
and
129
nig/
kg/
day,
for
males
and
females,
respectively)
based
on
increased
hemosiderosis
in
the
spleen
and
depressed
myeloid
erythropoiesis
in
the
sternal
bone
marrow,
increased
absolute
and
relative
liver
weights,
increased
alkaline
phosphatase
and
ALT
levels.

This
chronic
toxicity
study
is
Acceptable/
Guideline
and
does
satisfy
the
guideline
requirement
for
a
chronic
oral
study
[
OPPTS
870.4100,
OECD
452]
in
dogs.

STUDY
TYPE:
Combined
Chronic
Toxicity/
Carcinogenicity
Study
in
Rats;
OPPTS
870.4300
[
§
83­
5];
OECD
453
EXECUTIVE
SUMMARY:
In
a
chronic
toxicity/
oncogenicity
study
(
MRID
43939101),
sethoxydim
(
96.8%
a.
i.)
was
administered
to
groups
of
50
male
and
50
female
Wistar
rats
at
dietary
concentrations
of
0,
264,
1000,
or
3000
ppm
(
0,
12,
48,
and
143
mg/
kg/
day
for
males
and
0,
17,
66,
204
mg/
kg/
day
for
females)
for
up
to
24
months
(
main
study
groups).
Additional
groups
of
10
rats
per
sex/
per
group
were
fed
the
same
concentrations
for
up
to
24
months
for
terminal
evaluation
(
satellite
groups).

No
treatment­
related
clinical
signs
of
toxicity
or
increases
in
mortality
rates
were
observed
for
either
the
main
study
or
satellite
groups.
Treatment­
related
effects
on
mean
body
weights
were
observed
in
male
rats
administered
diets
containing
1000
or
3000
ppm
of
the
test
material
and
in
females
administered
3000
ppm.
Body
weight
decreases
ranged
from
­
2%
to
­
6%
(
p<
0.01
or
<
0.05)
from
day
14
to
day
483
for
1000­
ppm
group
males,
­
3%
to
­
9%
from
day
7
to
day
483
and
on
day
707
for
3000­
ppm
group
males,
­
3%
on
day
7
and
­
8%
to
­
15%
from
day
14
to
651
for
3000­
ppm
group
females.
Satellite
males
also
showed
statistically
significant
decreases
in
body
weight,
but
not
satellite
females.
Male
rats
in
the
1000­
and
3000­
ppm
groups
(
main
study)
Page
71
of
71
gained
8
and
9%
less
(
p<
0.01)
weight
than
controls
during
the
entire
first
year
of
the
study,
10%
less
at
3000
ppm
or
45%
more
at
1000
ppm
during
the
second
year,
and
overall
9%
less
at
3000
ppm
or
2%
less
at
1000
ppm
for
the
entire
study.
Females
fed
the
3000­
ppm
diet
(
main
study)
gained
15%
less
weight
than
controls
(
p<
0.01)
during
the
first
year,
57%
more
during
the
second
year,
and
only
5%
less
overall
for
the
entire
study.
At
3000
ppm,
male
rats
consumed
slightly
but
significantly
less
(
up
to
­
6%)
food
than
controls
at
some
time
intervals
up
to
day
147,
and
females
consumed
significantly
less
(
up
to
­
8%)
food
than
controls
at
some
intervals
up
to
day
91.
Food
efficiency
was
decreased
by
up
to
15%
(
p<
0.01)
at
3000
ppm
and
11%
(
p<
0.01)
at
1000
ppm
for
the
first
28
or
35
days,
respectively
in
main
study
males
and
by
11­
25%
for
1000­
or
3000­
ppm
group
females.

No
treatment­
related
hematologic
changes
were
observed.
Decreases
in
alkaline
phosphatase,
increases
in
creatinine,
and
decreases
in
triglycerides
were
attributed
to
the
nutritional
status
of
the
animals
and
not
to
treatment
with
the
test
material.

Treatment­
related
pathologic
changes
occurred
in
the
lungs
and
liver.
Treatment­
related
effects
in
the
lungs
included
increased
incidences
of
interstitial
fibrosis
in
the
lungs
of
female
rats
fed
the
3000­
ppm
diet
(
9/
60
vs
2/
60
for
controls,
p<
0.05)
and
heart
failure
cells
in
the
lungs
of
3000­
ppm
group
male
(
16/
60
vs
4/
60
for
controls,
p<
0.01)
and
female
rats
(
10/
60
vs
3/
60,
p<
0/
05).
The
liver
was
the
primary
target
for
sethoxydim.
Serum
bilirubin
levels
were
elevated
up
to
194%
of
controls
in
males
and
up
to
377%
in
females
at
1000
or
3000
ppm.
Treatment­
related
histopathologic
effects
in
the
liver
included
increased
incidences
of
eosinophilic
foci
in
33/
60
(
p<
0.01)
males
fed
3000
ppm
compared
with
14/
60
controls,
centrilobular
hepatocellular
hypertrophy
in
38/
60
(
p<
0.01)
males
at
3000
ppm,
10/
60
(
p<
0.01)
males
at
1000
ppm,
33/
60
(
p<
0.01)
females
at
3000
ppm
compared
with
0/
60
controls
of
either
sex.
In
addition,
the
incidence
of
centrilobular
fatty
infiltration
in
the
liver
was
increased
in
male
rats
(
20/
60
vs
7/
60
controls,
p<
0.01)
at
3000
ppm,
and
the
incidence
of
zone
1
fatty
infiltration
in
the
liver
showed
a
negative
trend
in
males
(
6/
60
vs
41/
60
for
controls,
p<
0.01)
and
females
(
18/
60
vs
36/
60
for
controls,
p<
0.01)
at
3000
ppm.

The
lowest­
observed­
adverse­
effect
level
(
LOAEL)
for
Sethoxydim
is
1000
ppm
(
48
mg/
kg/
day)
for
male
rats
based
on
liver
toxicity
(
centrilobular
hepatocellular
hypertrophy)
and
3000
ppm
(
204
mg/
kg/
day)
for
female
rats
based
on
decreased
body
weight,
body
weight
gain,
liver
toxicity
(
centrilobular
hepatocellular
hypertrophy),
and
lung
lesions
(
heart
failure
cells
and
interstitial
fibrosis).
The
no­
observed­
adverse­
effect
level
(
NOAEL)
was
264
ppm
(
12
mg/
kg/
day)
for
male
rats
and
1000
ppm
(
66
mg/
kg/
day)
for
female
rats.

The
chronic
toxicity/
carcinogenicity
is
ACCEPTABLE­
GUIDELINE
and
satisfies
the
guideline
requirement
for
a
chronic
toxicity/
carcinogenicity
study
(
§
83­
5)
in
rats.
