1
of
66
UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
OFFICE
OF
PREVENTION,
PESTICIDES
AND
TOXIC
SUBSTANCES
Date:
7/
13/
06
MEMORANDUM
SUBJECT:
S­
metolachlor
Human
Health
Risk
Assessment
for
Proposed
Section
18
Uses
on
Cilantro,
Collards,
Kale,
and
Mustard
Greens;
Section
3
Use
on
Pumpkin;
and
Tolerance
on
Winter
Squash
without
a
US
Registration.
PC
Code:
108800
Smetolachlor
&
108801
Metolachlor,
ID#:
06OH05
&
PP#
5E7015,
DP
Numbers:
329117
&
326011.

Regulatory
Action:
Section
18,
Section
3,
and
Tolerance
without
US
Registration
Risk
Assessment
Type:
Single
Chemical
Aggregate
FROM:
W.
Cutchin,
Chemist
ARIA
Team/
Technical
Review
Branch
Registration
Division
(
7505P)

THROUGH:
Christina
Swartz,
Chief
Registration
Action
Branch
Health
Effects
Division
(
7509P)

TO:
Barbara
Madden/
A.
Ertman
PM­
5
Risk
Integration
Minor
Use
and
Emergency
Response
Branch
Registration
Division
(
7505P)
2
of
66
Table
of
Contents
1.0
Executive
Summary................................................................................................................................
3
2.0
Ingredient
Profile.........................................................................................................................................
11
2.1
Summary
of
Registered/
Proposed
Uses...................................................................................................
11
2.2
Structure
and
Nomenclature
...................................................................................................................
11
2.3
Physical
and
Chemical
Properties
...........................................................................................................
12
3.0
Hazard
Characterization/
Assessment
.........................................................................................................
12
3.1
Hazards
and
Dose­
Response
Characterization
.......................................................................................
12
3.2
FQPA
Considerations
..............................................................................................................................
17
3.3
Dose
Response
Assessment
......................................................................................................................
17
3.4
Endocrine
Disruption
..............................................................................................................................
21
4.0
Dietary
Exposure/
Risk
Characterization....................................................................................................
21
4.1
Pesticide
Metabolism
and
Environmental
Degradation..........................................................................
21
4.1.1
Metabolism
in
Primary
Crops
..........................................................................................................
21
4.1.2
Metabolism
in
Rotational
Crops
.......................................................................................................
22
4.1.3
Metabolism
in
Livestock
...................................................................................................................
22
4.1.4
Analytical
Methodology
....................................................................................................................
22
4.1.5
Environmental
Degradation..............................................................................................................
23
4.1.6
Comparative
Metabolic
Profile.........................................................................................................
23
4.1.8
Pesticide
Metabolites
and
Degradates
of
Concern............................................................................
23
4.1.9
Drinking
Water
Residue
Profile
.......................................................................................................
24
4.1.10
Food
Residue
Profile
.......................................................................................................................
25
4.2.11
International
Residue
Limits.......................................................................................................
27
4.3
Dietary
Exposure
and
Risk......................................................................................................................
27
5.0
Residential
(
Non­
Occupational)
Exposure/
Risk
Characterization.............................................................
29
5.1
Residential
Handler
Exposure.................................................................................................................
29
5.2
Residential
Postapplication
Exposure
.....................................................................................................
29
5.3
Other
(
Spray
Drift,
etc.)
..........................................................................................................................
30
6.0
Aggregate
Risk
Assessments
and
Risk
Characterization............................................................................
30
6.1
Acute
Aggregate
Risk
..............................................................................................................................
30
6.2
Short­
Term
Aggregate
Risk
....................................................................................................................
30
6.3
Intermediate­
Term
Aggregate
Risk
........................................................................................................
31
6.4
Chronic
Aggregate
Risk...........................................................................................................................
31
6.5
Cancer
Risk..............................................................................................................................................
32
7.0
Cumulative
Risk
Characterization/
Assessment
..........................................................................................
32
8.0
Occupational
Exposure/
Risk
Pathway........................................................................................................
32
8.1
Short/
Intermediate/
Long­
Term/
Cancer
Handler
Risk
...........................................................................
33
8.1.1
Data
and
Assumptions
for
Proposed
Handler
Exposure
Scenarios
.................................................
33
8.1.2
Summary
of
Exposure
Data
for
Handler
Exposure
Scenarios.........................................................
37
8.1.3
Non­
cancer
S­
metolachlor
Handler
Exposure
and
Risk...................................................................
38
9.0
Data
Needs
and
Label
Requirements
..........................................................................................................
51
9.1
Toxicology................................................................................................................................................
51
9.2
Residue
Chemistry...................................................................................................................................
51
9.3
Occupational
and
Residential
Exposure..................................................................................................
52
References
..........................................................................................................................................................
52
Appendix
A
Table
1:
Toxicity
Profile
for
Metolachlor
(
PC
Code
108801)........................................................
53
Appendix
A
Table
2:
Toxicity
Profile
for
S­
Metolachlor
(
PC
Code
108800)
....................................................
59
Appendix
A
Table
3:
Structure
of
S­
Metolachlor
(
PC
Code
108800)
and
Metabolites.....................................
66
Appendix
B
International
Residue
Status
Sheet...............................................................................................
67
3
of
66
1.0
Executive
Summary
Background
The
Ohio
Department
of
Agriculture
is
requesting
a
specific
exemption
for
the
use
of
Smetolachlor
formulated
as
Dual
Magnum
®
(
EPA
Reg.
No.:
100­
816)
for
control
of
common
purslane
and
prostrate
pigweed
on
cilantro,
collards,
kale,
and
mustard
greens.
The
Interregional
Research
Project
Number
4
(
IR­
4)
has
submitted
data
on
the
residues
of
S­
metolachlor
formulated
as
Dual
Magnum
®
(
EPA
Reg.
No.:
100­
816)
on
winter
squash
in
support
of
the
requested
tolerance
on
winter
squash,
without
a
US
registration,
and
the
use
on
pumpkin.

Metolachlor
is
a
racemic
herbicide
(
PC
Code
108801)
which
consists
of
50%
each
of
the
Renantiomer
(
CGA
77101)
and
the
S­
enantiomer
(
CGA
77102,
or
alpha
metolachlor).
The
Senantiomer
is
the
herbicidally
active
isomer.
An
isomer
enriched
formula
called
S­
metolachlor
(
88%
S­
isomer
and
12%
R­
isomer)(
PC
Code
108800)
was
submitted
for
reduced­
risk
status
based
on
similar
efficacy
at
decreased
application
rates
(
approximately
36
percent
lower
than
that
of
metolachlor).
In
1997,
the
EPA
approved
the
registration
of
S­
metolachlor
as
a
reducedrisk
product.

Use
Profile
Metolachlor
and
S­
metolachlor
are
selective,
chloroacetanilide
herbicides
used
primarily
for
grassy
weed
control
in
many
agricultural
food
and
feed
crops;
residential
lawns;
commercial
turf
(
including
golf
courses,
sports
fields,
recreation
areas,
and
sod
farms);
ornamental
plants,
trees,
and
shrubs,
and
vines;
hedge
rows;
and
horticultural
nurseries.
Corn,
sorghum,
and
soybean
account
for
the
majority
of
the
use
of
both
metolachlor
and
S­
metolachlor,
followed
by
cotton,
sweet
corn,
peanut,
potato,
and
other
minor
field
and
vegetable
crops.

Application
rates
for
metolachlor
and
S­
metolachlor
range
from
approximately
one
to
four
pounds
active
ingredient
(
ai)
per
acre.
Application
is
typically
made
pre­
emergence,
one
time
per
season.

The
registrant,
Syngenta,
does
not
currently
hold
any
active
end­
use
product
registrations
for
metolachlor.
S­
metolachlor
is
registered
by
Syngenta
under
the
trade
names
of
Dual
MAGNUM
®
,
Pennant
MAGNUM
®
,
Bicep
MAGNUM
®
,
Boundary
®
,
and
Medal
®
.
S­
metolachlor
is
formulated
mainly
as
an
emulsifiable
concentrate.
Other
formulations
include
flowable
concentrates,
granular,
and
ready­
to­
use
formulations.
Application
methods
for
agricultural
uses
includes
ground
application
(
the
most
common
application
method),
aerial
application,
irrigation
systems,
and
chemigation
(
center
pivot
only).
A
backpack
sprayer,
hose­
end
sprayer,
or
handgun
application
may
be
used
by
professional
applicators
for
application
to
residential
lawns
or
turf.
Residential
applications
to
lawns
and
turf
are
intended
for
use
by
professional
applicators
only.
The
only
currently
active
lawn/
turf
label
is
an
emulsifiable
concentrate
formulation
for
S­
metolachlor
(
Pennant
MAGNUM
®
,
EPA
Reg.
No.
100­
950).
4
of
66
The
Ohio
Department
of
Agriculture
requested
use
is
for
a
single
application,
pre­
emergence
using
a
ground
sprayer
on
cilantro,
collards,
kale,
and
mustard
greens,
at
0.95
lb
ai/
A
to
1500
A
in
the
state
of
Ohio.
A
total
of
1425
lb
ai
(
187
gal
formulation)
would
be
used
as
a
result
of
this
request.
In
order
to
harmonize
with
Pesticide
Management
Regulatory
Agency
(
PMRA),
Canada,
a
revised
Section
B
is
required
indicating
the
use
on
pumpkin
as
direct
seeded
treatment
(
soil
application,
pre­
emergent
to
crop
and
weed)
or
post
emergent
treatment
(
foliar
application
at
the
1­
2
leaf
crop
stage,
prior
to
weed
emergence)
at
a
rate
of
0.94
lb
ai/
A
(
1.05
kg
ai/
ha),
and
a
PHI
of
65
days.
No
US
registration
for
winter
squash
is
requested
at
this
time.

Toxicity/
Hazard
The
toxicology
database
for
metolachlor
is
complete
for
risk
assessment
purposes.
Metolachlor
is
moderately
acutely
toxic
(
toxicity
category
III)
by
the
oral,
dermal,
and
inhalation
routes
of
exposure.
It
is
not
irritating
to
the
skin
or
eyes,
but
is
a
dermal
sensitizer.
The
Agency
notes
that
recently
reviewed
acute
toxicity
studies
from
1994
show
metolachlor
to
be
moderately
acutely
toxic
(
toxicity
category
III)
by
the
oral
and
dermal
routes
of
exposure,
and
less
toxic
(
toxicity
category
IV)
by
the
inhalation
route
of
exposure.
These
1994
studies
also
show
metolachlor
to
be
a
mild
eye
irritant
(
toxicity
category
III)
and
a
minimal
skin
irritant
(
toxicity
category
IV).
In
the
subchronic
and
chronic
toxicity
studies,
decreased
body
weight
and
body
weight
gain
were
the
most
commonly
observed
effects.
There
was
no
evidence
that
metolachlor
was
a
reproductive
or
developmental
toxicant.
No
systemic
toxicity
was
observed
when
metolachlor
was
administered
dermally
at
doses
up
to
1000
mg/
kg/
day.
There
was
no
evidence
of
mutagenic
or
cytogenetic
effects
in
vivo
or
in
vitro.
Metolachlor
has
been
classified
as
a
Group
C,
possible
human
carcinogen
based
on
liver
tumors
in
rats
at
the
highest
dose
tested.
No
cancer
potency
factor
has
been
established,
as
risks
calculated
based
on
the
chronic
reference
dose
are
predictive
of
cancer
effects.

The
toxicology
database
for
S­
metolachlor,
when
bridged
with
the
metolachlor
database,
is
complete
for
risk
assessment
purposes.
Bridging
toxicology
data
from
metolachlor,
including
acute
toxicity,
subchronic
toxicity
in
rat
and
dog,
developmental
toxicity
in
rat
and
rabbit,
mutagenicity,
and
metabolism
studies
are
available.
S­
metolachlor
is
moderately
acutely
toxic
(
toxicity
category
III)
by
the
oral
and
dermal
route
and
relatively
non­
toxic
(
toxicity
category
IV)
by
the
inhalation
route
of
exposure.
It
causes
slight
eye
irritation,
and
is
non­
irritating
dermally
but
is
a
dermal
sensitizer.
In
the
subchronic
studies,
body
weight
and
body
weight
gain
decreases
were
the
most
commonly
observed
effects.
There
was
no
evidence
that
S­
metolachlor
was
a
developmental
toxicant.
There
was
no
evidence
of
mutagenic
or
cytogenetic
effects
in
vivo
or
in
vitro
with
S­
metolachlor.

Tolerances
are
established
for
the
combined
residues
(
free
and
bound)
of
metolachlor
and
its
metabolites,
determined
as
the
derivatives
2­[(
2­
ethyl­
6­
methylphenyl)
amino]­
1­
propanol
(
CGA­
37913)
and
4­(
2­
ethyl­
6­
methylphenyl)­
2­
hydroxy­
5­
methyl­
3­
morpholinone
(
CGA­
49751),
each
expressed
as
the
parent
compound,
in
or
on
raw
agricultural
commodities
(
40
CFR
§
180.368).
The
Metabolism
Assessment
Review
Committee
(
MARC)
determined
that
the
residues
of
concern
for
plant
and
animal
commodities
are
metolachlor
and
its
metabolites,
5
of
66
determined
as
the
derivatives
CGA­
37913
and
CGA­
49751.
Metabolites
of
metolachlor
are
assumed
to
be
toxicologically
equivalent
to
parent
metolachlor.
The
residues
of
concern
for
Smetolachlor
are
the
same
as
those
for
metolachlor.

Based
on
the
Hazard
Identification
Assessment
Review
Committee
(
HIARC)
decision
that
metolachlor
and
S­
metolachlor
are
of
comparable
toxicity,
studies
of
either
chemical
were
used
interchangeably
for
toxicology
endpoint
selection.
Toxicological
endpoints
selected
for
risk
assessment
purposes
are
based
on
clinical
signs
of
toxicity
and
decreased
body
weight
gain.
No
evidence
of
neurotoxicity
or
neuropathology
was
seen
in
any
of
the
available
studies.
A
developmental
neurotoxicity
study
is
not
required
for
metolachlor.
Dermal
absorption
is
calculated
to
be
58%,
based
on
a
dermal
absorption
study
in
rats,
and
inhalation
absorption
is
assumed
to
be
100%.

In
the
case
of
metolachlor/
S­
metolachlor,
risk
assessments
were
conducted
for
the
specific
exposure
scenarios
listed
below.
Short­
and
intermediate­
term
dermal
risk
assessments
were
not
conducted
as
no
systemic
toxicity
was
seen
at
the
limit
dose
of
1000
mg/
kg/
day.
A
total
uncertainty
factor
(
UF)
of
100X
was
applied
to
the
risk
assessment
to
account
for
interspecies
extrapolation
(
10X)
and
intraspecies
variability
(
10X).
The
reference
dose
(
RfD)
is
equal
to
the
No­
Observed­
Adverse­
Effect­
Level,
or
NOAEL,
divided
by
the
100X
uncertainty
factor.
The
FQPA
Safety
Factor
Committee
has
concluded
that
the
FQPA
safety
factor
for
the
protection
of
infants
and
children
may
be
reduced
to
1X
(
i.
e.,
removed)
for
the
dietary
and
residential
risk
assessments.
The
Population
Adjusted
dose
(
PAD)
is
equal
to
the
RfD
divided
by
the
FQPA
safety
factor.

Acute
Dietary
(
general
population):
NOAEL=
300
mg/
kg/
day
RfD=
3.0
mg/
kg/
day
aPAD=
3.0
mg/
kg/
day
Chronic
Dietary:
NOAEL=
9.7
mg/
kg/
day
RfD
=
0.1
mg/
kg/
day
cPAD=
0.1
mg/
kg/
day
Short­
term
Incidental
Oral:
NOAEL=
50
mg/
kg/
day
Target
MOE=
100
Dietary
Exposure
The
qualitative
nature
of
metolachlor
residues
in
plants
is
adequately
understood
based
upon
adequate
corn,
potato,
and
soybean
metabolism
studies.
Residues
of
concern
in
plants
include
metolachlor
and
its
metabolites,
determined
as
the
derivatives
CGA­
37913
and
CGA­
49751.
The
residues
of
concern
for
S­
metolachlor
are
the
same
as
for
metolachlor.

Adequate
studies
are
available
depicting
the
metabolism
of
metolachlor
in
ruminants
and
poultry.
Metolachlor
is
rapidly
metabolized
and
almost
totally
eliminated
in
the
urine
and
feces
of
ruminants
(
goats),
non­
ruminants
(
rats),
and
poultry.
Metolachlor
per
se
was
not
detected
in
any
of
the
excreta
or
tissues.
As
in
plants,
metolachlor
residues
of
concern
in
livestock
commodities
include
metolachlor
and
its
metabolites,
determined
as
the
derivatives
CGA­
37913
and
CGA­
49751.
The
residues
of
concern
for
S­
metolachlor
in
animals
are
the
same
as
for
metolachlor.
6
of
66
Adequate
methodology
is
available
for
enforcing
the
current
and
proposed
tolerances.
The
Pesticide
Analytical
Manual
(
PAM,
Vol.
II)
lists
a
GC/
NPD
method
(
Methods
I)
for
determining
residues
in/
on
plants
and
a
GC/
MSD
method
(
Method
II)
for
determining
residues
in
livestock
commodities.
These
methods
determine
residues
of
metolachlor
and
its
metabolites
as
either
CGA­
37913
or
CGA­
49751
following
acid
hydrolysis.
A
modified
version
of
this
method
(
Syngenta
Method
No.
1848­
01)
which
uses
LC/
MS/
MS
has
also
been
used.
Adequate
data
are
available
on
the
recovery
of
metolachlor
through
Multi­
residue
Method
Testing
Protocols.
The
FDA
PESTDATA
database
indicates
that
metolachlor
is
completely
recovered
through
Method
302,
PAM
Vol.
I
(
3rd
ed.,
revised
10/
97).

Cilantro,
Collards,
Kale,
and
Mustard
Greens:
Previously
submitted
data
from
crop
field
trials
conducted
on
spinach
show
that
the
combined
residues
of
CGA­
37913
and
CGA­
49751,
each
expressed
as
parent
metolachlor,
were
<
0.08­<
0.38
ppm
in/
on
samples
harvested
34­
69
days
following
a
single
pre­
emergence
soil
application
of
metolachlor
at
1.0
lb
ai/
A.
Combined
residues
were
also
<
0.08­
0.263
ppm
in/
on
spinach
harvested
41­
69
days
following
preemergence
application
at
2.0
lb
ai/
A.
These
data
would
support
a
similar
use
of
S­
metolachlor
on
spinach
at
a
maximum
rate
of
0.6
lb
ai/
A.
The
available
data
indicated
that
a
tolerance
level
of
0.5
ppm
would
be
appropriate
for
a
tolerance
on
spinach.
Considering
the
similarity
between
spinach
and
the
subject
crops
and
the
higher
proposed
application
rate
for
this
Section
18,
the
data
indicate
that
residues
of
S­
metolachlor
are
not
likely
to
exceed
1.0
ppm
as
a
result
of
the
proposed
use.
A
time­
limited
tolerance
of
1.0
ppm
for
the
residues
of
S­
metolachlor
on
cilantro,
collards,
kale,
and
mustard
greens
would
be
appropriate.

Pumpkins
and
Winter
Squash:
Residue
trials
conducted
jointly
by
IR­
4
and
the
Pest
Management
Centre
of
Agriculture
and
Agri­
Food
Canada
(
PMC,
AAFC)
on
behalf
of
the
Canadian
Horticultural
Council,
have
been
submitted
for
S­
metolachlor
on
winter
squash.
The
residue
study
was
arranged
into
four
treatment
scenarios:
1
pre­
emergent
(
PRE)
soil
application
at
0.64­
0.69
lb
ai/
A
(
Treatment
2);
1
pre­
emergent
soil
application
at
1.25­
1.37
lb
ai/
A
(
Treatment
3);
1
post­
emergent
(
POST)
foliar
application
at
0.63­
0.69
lb
ai/
A
(
Treatment
4);
and
1
post­
emergent
foliar
application
at
1.25­
1.43
lb
ai/
A
(
Treatment
5).
Winter
squash
fruit
was
harvested
at
pre­
harvest
intervals
(
PHIs)
of
43­
119
days
(
PRE
Treatments
2
and
3)
or
31­
105
days
(
POST
Treatments
4
and
5).
The
results
from
these
trials
show
that
maximum
total
residues
of
S­
metolachlor
(
determined
as
CGA­
37913
and
CGA­
49751)
were
<
0.08
ppm
(
below
the
Lowest
Limit
of
Method
Validation,
LLMV)
in
winter
squash
treated
with
either
one
preemergent
soil
application
(
0.72­
1.54
kg
ai/
ha
or
0.64­
1.37
lb
ai/
A)
or
one
post­
emergent
foliar
application
(
0.71­
1.60
kg
ai/
ha
or
0.63­
1.43
lb
ai/
A),
and
harvested
at
PHIs
of
31­
119
days.
Only
one
residue
was
detected
above
the
LLMV
(
CGA­
49751
at
0.061
ppm).
These
data
are
sufficient
to
indicate
that
residues
of
S­
metolachlor
on
winter
squash
are
not
likely
to
exceed
the
proposed
tolerance
of
0.1
ppm
as
a
result
of
the
proposed
use.
According
to
the
2002
Reviewer's
Guide,
if
winter
squash
data
are
submitted
and
found
acceptable
to
support
a
winter
squash
tolerance
then
tolerances
can
be
established
on
several
Cucurbita
spp.
including
pumpkin.
The
data
submitted
are
sufficient
to
support
the
request
for
a
tolerance
on
pumpkins.
Tolerances
of
0.1
ppm
for
the
residues
of
S­
metolachlor
on
pumpkins
and
winter
squash
are
appropriate.
The
tolerance
on
winter
squash
would
be
established
without
a
US
registration.
7
of
66
The
proposed
crop
tolerances
will
have
no
impact
on
the
maximum
theoretical
dietary
burden
(
MTDB)
for
livestock.
Therefore,
no
changes
are
required
in
the
tolerances
for
animal
commodities
as
a
result
of
the
proposed
Section
18s.

A
drinking
water
assessment
was
conducted
based
on
monitoring
data
from
several
sources,
as
well
as
on
Tier
1
FIRST
and
SCI­
GROW
modeling
results.
This
assessment
is
a
worst­
case
scenario
and
demonstrates
high
end
numbers.
EECs
for
metolachlor
and
S­
metolachlor
were
calculated
for
both
the
parent
compound
and
the
ethanesulfonic
acid
(
ESA)
and
oxanilic
acid
(
OA)
degradates.
Although
it
was
determined
by
the
MARC
that
the
ESA
and
OA
metabolites
appear
to
be
less
toxic
than
parent
metolachlor,
they
are
included
in
the
risk
assessment
since
they
were
found
in
greater
abundance
than
the
parent
in
water
monitoring
studies.

PRZM/
EXAMS
and
FIRST
models
were
used
to
calculate
the
maximum
peak
and
annual
average
concentrations
of
metolachlor/
S­
metolachlor
in
surface
water.
The
SCI­
GROW
screening
model
was
used
to
estimate
groundwater
concentrations.
As
a
result
of
the
modeling
results,
the
recommended
total
EEC's
for
surface
water
(
peak),
surface
water
(
average),
and
groundwater
(
peak
and
average)
are
322
ppb
(
199
parent
+
31.9
ESA+
91.4
OA),
97
ppb
(
9.2
parent
+
22.8
ESA
+
65.1
OA),
and
103
ppb
(
5.5
parent
+
65.8
ESA
+
31.7
OA),
respectively.

Acute
and
chronic
dietary
risk
assessments
were
conducted
using
the
Dietary
Exposure
Evaluation
Model
(
DEEM­
FCID
 
,
Version
2.03)
which
uses
food
consumption
data
from
the
USDA's
Continuing
Surveys
of
Food
Intakes
by
Individuals
(
CSFII)
from
1994­
1996
and
1998.
Both
the
acute
and
chronic
analyses
assume
tolerance­
level
residues
and
100
%
CT
data
on
all
crops
with
established,
pending,
or
proposed
tolerances
for
metolachlor
and/
or
S­
metolachlor.

The
acute
dietary
analysis
for
S­
metolachlor
was
conducted
using
the
highest
drinking
water
estimate
for
acute
exposure,
322
ppb.
The
dietary
exposure
estimate
to
the
U.
S.
population
was
<
1%
aPAD
and
the
most
highly
exposed
subgroup,
all
infants
<
1
yr
old,
at
2%
aPAD.
The
results
of
the
analysis
indicate
that
acute
risk
from
the
dietary
exposure
to
S­
metolachlor
from
the
existing
and
requested
uses
did
not
exceed
HED's
level
of
concern
for
the
U.
S.
population
or
any
population
subgroup.

A
chronic
dietary
analysis
for
S­
metolachlor
was
conducted
using
the
highest
drinking
water
estimate
for
chronic
exposure,
103
ppb.
The
dietary
exposure
estimate
to
the
U.
S.
population
was
4%
cPAD
and
the
most
highly
exposed
subgroup,
all
infants
<
1
yrs
old,
at
10%
cPAD.
The
results
of
the
analysis
indicate
that
chronic
risk
from
the
dietary
exposure
to
S­
metolachlor
from
the
existing
and
requested
uses
did
not
exceed
HED's
level
of
concern
for
the
U.
S.
population
or
any
population
subgroup.

Residential
Exposure
Metolachlor
is
a
selective
herbicide
that
was
first
registered
in
1976
and
consists
of
a
Renantiomer
and
S­
enantiomer
mixture
in
a
ratio
of
50:
50.
Based
on
the
enhanced
herbicidal
activity
of
the
S­
enantiomer,
metolachlor
has
recently
been
replaced
in
the
market
by
Smetolachlor
which
has
a
S­
to
R­
enantiomer
ratio
of
88:
12.
Efficacy
studies
conducted
by
the
registrant
(
Syngenta)
demonstrate
that
S­
metolachlor
is
needed
in
amounts
37%
less
than
the
8
of
66
original
metolachlor
and
this
difference
is
reflected
in
the
maximum
application
rates
used
in
this
assessment.

The
formulated
S­
metolachlor
end­
use
product
is
labeled
under
the
trade
name
Pennant
MAGNUMTM
(
EPA
Reg.
No.
100­
950)
to
distinguish
the
new
product
from
the
original
metolachlor
formulation
named
PennantTM
(
EPA
Reg.
No.
100­
691).
Pennant
MAGNUMTM
(
7.62
lbs.
active
ingredient
per
gallon)
is
labeled
for
use
on
commercial
(
sod
farm)
and
residential
warm­
season
turfgrasses
and
other
noncrop
land
including
golf
courses,
sports
fields,
and
ornamental
gardens.
Although
not
labeled
as
a
restricted­
use
pesticide,
Pennant
MAGNUMTM,
as
currently
marketed,
is
not
intended
for
homeowner
purchase
or
use
(
intended
for
use
by
professionals).
On
this
basis,
with
regard
to
the
requirements
of
FQPA,
metolachlor
and
S­
metolachlor
are
risk
assessed
for
postapplication
exposure
only.
Pennant
MAGNUMTM
and
PennantTM
are
both
emulsifiable
concentrates
(
EC).

For
this
risk
assessment,
small
children
are
the
population
group
of
concern.
Although
the
type
of
site
that
S­
metolachlor
may
be
used
on
varies
from
golf
courses
to
ornamental
gardens,
the
scenario
chosen
for
risk
assessment
(
residential
turf
use)
represents
what
the
Agency
considers
the
likely
upper­
end
of
possible
exposure.
Postapplication
exposures
from
various
activities
following
lawn
treatment
are
considered
to
be
the
most
common
and
significant
in
residential
settings.
Since
toxicity
was
not
observed
in
a
dermal
toxicity
study,
up
to
a
dose
level
of
1,000
mg/
kg/
day,
the
only
parameter
of
risk
necessarily
addressed
in
this
assessment
is
the
possible
oral
exposure
of
small
children
from
treated
turf,
or
soil.

The
following
postapplication
exposure
scenarios
resulting
from
lawn
treatment
were
assessed:
(
1)
the
incidental
ingestion
of
metolachlor
residues
on
lawns
from
a
"
hand­
to­
mouth"
transfer,
(
2)
the
incidental
ingestion
of
metolachlor
residues
from
"
object­
to­
mouth"
activities
(
in
this
case
treated
turfgrass),
and
(
3)
the
incidental
ingestion
of
metolachlor­
treated
soil
in
residential
areas.
The
term
"
incidental"
is
used
to
distinguish
the
inadvertent
(
irregular)
oral
exposure
of
small
children
from
the
expected
exposure
from
treated
foods,
or
residue
in
drinking
water.
The
exposure
estimates
of
the
three
oral
ingestion
scenarios
are
combined
to
establish
the
possible
(
if
not
likely)
upper­
end
of
oral
exposure
from
lawn
(
or
similar)
use.

The
current
label
specifies
a
6
week
interval
before
the
re­
application
of
metolachlor
and
the
registrant
(
Syngenta)
has
indicated
a
label
revision
to
limit
application
to
once
per
season.
On
this
basis,
metolachlor
risk
is
assessed
for
the
time
interval
referred
to
as
"
short­
term"
(
1­
30
days)
and
will
not
be
assessed
for
a
longer,
or
"
intermediate­
term"
duration.
Also,
since
residents
are
not
expected
to
re­
enter
treated
areas
until
the
spray
has
dried
(
as
labeled),
no
inhalation
exposure
is
expected,
or
assessed.

Based
on
the
short­
term
NOAEL
of
50
mg/
kg/
day,
the
risk
estimate
for
hand­
to­
mouth,
objectto
mouth,
and
soil
ingestion
combined
(
on
the
day
of
treatment)
is
0.046
mg/
kg/
day
(
MOE
=
1,100)
for
S­
metolachlor.
9
of
66
Aggregate
Risk
An
acute
aggregate
risk
assessment
addresses
potential
exposure
from
combined
residues
of
metolachlor/
S­
metolachlor
on
food
and
in
drinking
water
(
both
surface
and
ground
water).
Potential
residential
exposures
are
not
incorporated
into
an
acute
aggregate
risk
assessment.
Since
the
exposure
from
food
and
drinking
water
were
already
incorporated
into
the
acute
dietary
risk
assessment,
no
further
aggregation
is
required.
The
dietary
exposure
estimate
to
the
U.
S.
population
was
<
1%
aPAD
and
the
most
highly
exposed
subgroup,
all
infants
<
1
yr
old,
at
2%
aPAD.
The
results
of
the
analysis
indicate
that
acute
aggregate
exposure
risk
to
S­
metolachlor
from
the
existing
and
requested
uses
did
not
exceed
the
Agency's
level
of
concern
for
U.
S.
population
or
any
population
subgroup.

A
short­
term
aggregate
risk
assessment
considers
potential
exposure
from
food,
drinking
water,
and
short­
term,
non­
occupational
(
residential)
pathways
of
exposure
for
a
duration
of
1
to
30
days.
For
S­
metolachlor,
potential
short­
term,
non­
occupational
risk
scenarios
consist
of
oral
exposure
of
children
to
treated
lawns
only.
In
this
aggregate
short­
term
risk
assessment,
exposure
from
food,
drinking
water,
and
residential
lawns
has
been
considered.
The
exposure
to
food
and
water
has
already
been
considered
in
the
chronic
dietary
risk
assessment.
The
dietary
exposure
estimate
was
4%
cPAD
for
the
U.
S.
population
and
10%
cPAD
for
the
most
highly
exposed
subgroup,
all
infants
<
1
yrs
old.
Since
only
children
have
the
potential
for
nonoccupational
short­
term
risk,
they
are
the
only
population
subgroup
for
which
an
aggregate
short­
term
risk
assessment
was
conducted.
Toddlers'
S­
metolachlor
incidental
oral
exposure
is
assumed
to
include
hand­
to­
mouth
exposure,
object­
to­
mouth
exposure
and
exposure
through
incidental
ingestion
of
soil.
The
aggregate
short­
term
risk
for
exposure
to
S­
metolachlor
for
all
infants
<
1
yr
old,
the
subgroup
with
the
highest
exposure,
is
MOE
of
890,
which
does
not
reach
the
Agency's
level
of
concern.

An
intermediate­
term
aggregate
risk
assessment
considers
potential
exposure
from
food,
drinking
water,
and
non­
occupational
(
residential)
pathways
of
exposure
for
a
duration
of
30
to
180
days.
However,
for
metolachlor/
S­
metolachlor,
no
intermediate­
term
non­
occupational
exposure
scenarios
are
expected
to
occur;
therefore,
an
intermediate­
term
aggregate
risk
assessment
is
not
required.

A
chronic
aggregate
risk
assessment
considers
chronic
exposure
from
food,
drinking
water,
and
non­
occupational
(
residential)
pathways
of
exposure.
For
metolachlor
and
S­
metolachlor,
there
are
no
chronic
(
greater
than
180
days
of
exposure)
non­
occupational
exposure
scenarios.
Therefore,
the
chronic
aggregate
risk
assessment
considers
exposure
from
food
and
drinking
water
only.
Since
the
exposure
from
food
and
drinking
water
were
already
incorporated
into
the
chronic
dietary
risk
assessment,
no
further
aggregation
is
required.
The
chronic
dietary
exposure
estimate
to
the
U.
S.
population
was
4%
cPAD
and
the
most
highly
exposed
subgroup,
all
infants
<
1
yrs
old,
at
10%
cPAD.
The
results
of
the
analysis
indicate
that
chronic
aggregate
risk
from
exposure
to
S­
metolachlor
from
the
existing
and
requested
uses
did
not
exceed
the
Agency's
level
of
concern
for
the
U.
S.
population
or
any
population
subgroup.

Metolachlor
has
been
classified
as
a
Group
C,
possible
human
carcinogen
based
on
liver
tumors
in
rats
at
the
highest
dose
tested.
The
chronic
NOAEL
of
15
mg/
kg/
day
that
was
established
10
of
66
based
on
tumors
in
the
rat
(
seen
at
the
highest
dose
tested
of
150
mg/
kg/
day)
is
comparable
to
the
NOAEL
of
9.7
mg/
kg/
day
selected
for
establishing
the
chronic
reference
dose
for
metolachlor.
It
is
assumed
that
the
chronic
dietary
PAD
is
protective
for
cancer
dietary
risk.
Therefore,
a
separate
cancer
aggregate
risk
assessment
was
not
conducted.

Occupational
Exposure/
Risk
This
risk
assessment
incorporates
the
toxicological
endpoints
of
concern
as
presented
in
the
Report
of
the
Hazard
Identification
Assessment
Review
Committee
(
HIARC)
September
28,
2001.
No
short­
or
intermediate­
term
dermal
endpoint
of
concern
was
identified.
The
short­
term
inhalation
endpoint
of
concern
(
NOAEL
=
50
mg/
kg/
day)
is
based
on
increased
incidence
of
clinical
signs,
decreased
body
weight
and
body
weight
gain,
food
consumption,
and
food
efficiency
from
an
oral
prenatal
developmental
toxicity
study
in
rats
with
S­
metolachlor.
Since
an
oral
study
was
selected,
a
100%
absorption
factor
should
be
applied
and
since
the
endpoint
is
from
a
prenatal
developmental
toxicity
study,
a
body
weight
of
60
kilograms
 
the
weight
of
an
average
female
adult
 
was
used.
The
intermediate­
term
inhalation
endpoint
of
concern
(
NOAEL
=
8.8
mg/
kg/
day)
is
based
on
decreased
body
weight
gain
from
an
oral
subchronic
(
6
month)
toxicity
study
in
dogs
with
metolachlor.
Since
an
oral
study
was
selected,
a
100%
absorption
factor
should
be
applied
and
since
the
toxicological
endpoint
of
concern
is
not
sexspecific
a
body
weight
of
70
kilograms
 
the
weight
of
an
average
adult
 
was
used.
Only
inhalation
Margins
of
Exposure
(
MOE)
were
calculated,
therefore,
no
aggregation
of
dermal
and
inhalation
exposures
was
performed.

Occupational
handler
exposure
was
addressed
using
the
Pesticide
Handlers
Exposure
Database
(
PHED
ver.
1.1),
and
data
from
the
Outdoor
Residential
Exposure
Task
Force
(
ORETF).
PHED
data
for
mixing/
loading
liquid
formulations
using
closed
systems
were
used
as
a
surrogate
for
commercial
impregnation
of
dry
fertilizer
with
liquid
S­
metolachlor.
Dermal
risks
were
not
evaluated
since
no
hazard
was
identified
for
quantification
of
risk
following
dermal
exposure.

When
data
were
available
to
assess
risks,
short­
and
intermediate­
term
inhalation
risks
to
occupational
handlers
are
below
the
Agency's
level
of
concern
for
noncancer
risk
assessments
(
i.
e.,
MOE
<
100)
at
baseline
(
i.
e.,
no
respirator).
HED
has
insufficient
data
to
assess
baseline
and
PPE
levels
of
exposures
to
assess
risks
to
pilots
applying
sprays
with
aerial
equipment
and
assumes
commercial
mixer/
loaders
impregnating
dry
bulk
fertilizers
(
using
the
PHED
data)
are
using
engineering
controls.
Therefore
for
these
scenarios,
only
inhalation
risks
using
engineering
controls
are
assessed.
The
inhalation
risks
at
the
engineering
control
level
of
exposure
were
not
a
concern
for
these
scenarios.

Since
no
post­
application
dermal
risks
were
calculated,
the
default
restricted­
entry
interval
of
12
hours
should
be
established
for
S­
metolachlor.
EPA
notes
that
S­
metolachlor
does
not
qualify
for
consideration
for
a
4­
hour
restricted­
entry
interval
since
it
is
classified
as
a
dermal
sensitizer.

The
occupational
risk
assessment
applied
the
latest
exposure
data,
toxicology
information,
and
usage
data.
The
overall
results
indicate
that
the
Agency
has
no
risk
concerns
for
S­
metolachlor
use­
patterns
involving
agricultural
crops
or
commercial
uses.
Occupational
handler
and
11
of
66
postapplication
risks
were
not
a
concern
at
the
lowest
level
of
risk
mitigation
assessed
for
each
scenario.

Recommendations
Provided
a
revised
Section
B
is
received,
ARIA
concludes
that
there
is
a
reasonable
certainty
that
no
harm
will
result
to
the
U.
S.
Population,
including
infants
and
children,
from
acute,
short­
and
intermediate­
term,
and
chronic
aggregate
exposure
to
S­
metolachlor
residues.
ARIA
recommends
for
time­
limited
tolerances
for
the
residues
of
S­
metolachlor
on
cilantro,
collards,
kale,
and
mustard
greens
at
1.0
ppm
and
permanent
tolerances
on
pumpkin
and
winter
squash
at
0.1
ppm.
The
tolerance
on
winter
squash
does
not
have
a
US
registration.

2.0
Ingredient
Profile
S­
metolachlor
is
a
selective
herbicide
developed
for
the
control
of
a
large
number
of
grassy
weeds
in
corn,
soybeans,
sorghum
and
other
crops.
The
S­
diastereomer
of
metolachlor
has
been
shown
to
have
greater
biological
efficacy
than
the
R­
diastereomer.

2.1
Summary
of
Registered/
Proposed
Uses
Table
2.1
Summary
of
Directions
for
Use
of
S­
metolachlor.

Applic.
Timing,
Type,
and
Equip.
Formulation
[
EPA
Reg.
No.]
Applic.
Rate
(
lb
ai/
A)
Max.
No.
Applic.
per
Season
Max.
Seasonal
Applic.
Rate
(
lb
ai/
A)
PHI
(
days)
Use
Directions
and
Limitations
Cilantro,
Collards,
Kale,
and
Mustard
Greens
Pre­
emergence
by
broadcast
or
spot
treatment
ground
sprayer
Dual
Magnum
[
100­
816]
0.475­
0.95
1
0.95
60
Do
not
apply
through
any
type
of
irrigation
system.

Pumpkin
Broadcast
ground
sprayer
either
single
application
preemergence
or
post­
emergence.
Dual
Magnum
[
100­
816]
0.94
1
0.94
65
Do
not
apply
after
two­
true
leaf
stage.
Do
not
apply
through
any
type
of
irrigation
system.

Conclusions:
The
use
directions
for
cilantro,
collards,
kale,
and
mustard
greens
are
correct.
The
petitioner
must
correct
Section
B
to
a
single
application
at
0.94
lb
ai/
A
either
pre­
or
postemergence
with
a
65­
day
PHI.
A
revised
Section
B
is
required.

2.2
Structure
and
Nomenclature
TABLE
2.2
Test
Compound
Nomenclature
12
of
66
TABLE
2.2
Test
Compound
Nomenclature
Compound
S­
metolachlor
C
H
3
N
O
Cl
CH
3
O
C
H
3
CH
3
Common
name
S­
metolachlor
Company
experimental
name
CGA­
77102
IUPAC
name
2­
Chloro­
N­(
2­
ethyl­
6­
methylphenyl)­
N­{
S(
2­
methoxy­
1­
methylethyl)}
acetamide
CAS
name
Chloro­
N­(
2­
ethyl­
6­
methylphenyl)­
N­(
2­
methoxy­
1­
methylethyl)
acetamide
(
E)­
N{(
6­
chloro­
3­
pyridyl)
methyl}­
N'­
cyano­
N­
methylacetamidine
CAS
#
87392­
12­
9
End­
use
product/(
EP)
Dual
II
MAGNUM
®
(
EPA
Reg.
No.
100­
816),
Pennant
MAGNUMTM
(
EPA
Reg.
No.
100­
950)

2.3
Physical
and
Chemical
Properties
TABLE
2.3
Physicochemical
Properties
of
the
Technical
Grade
Test
Compound
Parameter
Value
Reference
Melting
point/
range
N/
A
pH
7.8
at
25
°
C
(
1%
aqueous
dispersion)

Density
1.117
g/
cm3
at
20
°
C
Water
solubility
(
25
°
C)
0.48
g/
L
Solvent
solubility
(
mg/
L
at
25
°
C)
Miscible
with
methanol,
acetone,
toluene,
n­
octanol,
nhexane
ethyl
acetate,
dichloromethane
Vapor
pressure
at
25
°
C
2.8
x
10­
5
mm
Hg
Dissociation
constant
(
pKa)
No
dissociation
constant
in
pH
range
2­
12
Octanol/
water
partition
coefficient
Log(
KOW)
3.0
at
25
°
C
UV/
visible
absorption
spectrum
Not
Provided
Registration
Division:
Physical
and
Chemical
Characteristics
(
DP
Num:
225258)

3.0
Hazard
Characterization/
Assessment
3.1
Hazards
and
Dose­
Response
Characterization
Metolachlor:
13
of
66
The
metolachlor
toxicology
database
is
complete
for
risk
assessment
purposes.
Metolachlor
is
moderately
acutely
toxic
(
toxicity
category
III)
by
the
oral,
dermal,
and
inhalation
routes
of
exposure.
It
is
not
irritating
to
the
skin
or
eyes,
but
is
a
dermal
sensitizer.
The
Agency
notes
that
the
reviewed
acute
toxicity
studies
from
1994
show
metolachlor
to
be
moderately
acutely
toxic
(
toxicity
category
III)
by
the
oral
and
dermal
routes
of
exposure,
and
less
toxic
(
toxicity
category
IV)
by
the
inhalation
route
of
exposure.
These
1994
studies
also
show
metolachlor
to
be
a
mild
eye
irritant
(
toxicity
category
III)
and
a
minimal
skin
irritant
(
toxicity
category
IV).

In
the
subchronic
oral
studies,
the
only
evidence
of
toxicity
was
decreased
body
weight/
body
weight
gain
at
259
mg/
kg/
day
in
female
rats
and
at
29
mg/
kg/
day
in
male
and
female
dogs.
The
respective
No
Observed
Adverse
Effect
Levels
(
NOAELs)
for
these
studies
were
23
mg/
kg/
day
and
9
mg/
kg/
day.
There
was
no
evidence
of
systemic
toxicity
when
1000
mg/
kg/
day
was
applied
topically
to
rabbits.
Dermal
irritation
was
observed
at
10
mg/
kg/
day
and
above.

Similar
effects
were
seen
after
long­
term
administration
of
metolachlor.
In
the
chronic
dog
study,
the
only
adverse
effect
was
decreased
body
weight
gain
in
females
at
33
mg/
kg/
day;
the
NOAEL
was
10
mg/
kg/
day.
In
the
mouse
carcinogenicity
study,
possible
treatment­
related
deaths
in
females
and
decreased
body
weight/
body
weight
gain
in
both
sexes
were
observed
at
450
mg/
kg/
day;
the
NOAEL
was
150
mg/
kg/
day.
In
the
rat
combined
chronic
toxicity/
carcinogenicity
study,
decreased
body
weight
gain
and
food
consumption
were
observed
at
150
mg/
kg/
day;
the
NOAEL
was
15
mg/
kg/
day.
There
was
no
evidence
of
carcinogenicity
in
mice;
however,
there
were
statistically
significant
increases
in
liver
adenomas
and
combined
adenomas/
carcinomas
in
female
rats.
In
male
rats,
there
was
a
statistically
significant
trend
but
not
pair­
wise
significance
for
liver
tumors.
There
was
no
evidence
of
a
mutagenic
or
cytogenetic
effects
in
vivo
or
in
vitro.

HED's
Cancer
Assessment
Review
Committee
has
classified
metolachlor
as
a
Group
C
carcinogen
with
risk
quantitated
using
a
non­
linear
approach.
The
NOAEL
of
15
mg/
kg/
day
from
the
rat
combined
chronic
toxicity/
carcinogenicity
study
is
based
on
neoplastic
nodules/
hepatocellular
carcinomas
seen
at
the
highest
dose
tested
of
150
mg/
kg/
day.
The
Agency
notes
that
the
tumor
NOAEL
of
15
mg/
kg/
day
is
comparable
to
the
NOAEL
of
9.7
mg/
kg/
day
selected
for
establishing
the
chronic
reference
dose
for
metolachlor.
The
recommendation
for
a
non­
linear
approach
should
be
followed
since
no
new
data
were
submitted
for
a
re­
evaluation
by
the
Cancer
Assessment
Review
Committee.

The
prenatal
developmental
studies
in
the
rat
and
rabbit
revealed
no
evidence
of
a
qualitative
or
quantitative
susceptibility
in
fetal
animals.
In
the
rabbit
prenatal
developmental
toxicity
study,
at
360
mg/
kg/
day,
maternal
animals
had
persistent
anorexia
and
decreased
body
weight
gain;
the
NOAEL
was
120
mg/
kg/
day.
In
the
rat
prenatal
developmental
toxicity
study,
frank
toxicity
[
death,
clinical
signs
(
clonic
and/
or
tonic
convulsions,
excessive
salivation,
urine­
stained
abdominal
fur
and/
or
excessive
salivation)
and
decreased
body
weight
gain]
was
observed
at
the
limit
dose
of
1000
mg/
kg/
day
in
maternal
animals;
the
NOAEL
was
300
mg/
kg/
day.
The
developmental
effects
at
1000
mg/
kg/
day
included
slightly
decreased
number
of
implantations
per
dam,
decreased
number
of
live
fetuses/
dam,
increased
number
of
resorptions/
dam
and
significant
decrease
in
mean
fetal
body
weight.
In
the
two­
generation
reproduction
study
in
rats,
there
was
no
evidence
of
parental
or
reproductive
toxicity
at
approximately
80
mg/
kg/
day,
the
14
of
66
highest
dose
tested.
At
this
dose,
there
was
a
minor
decrease
in
fetal
body
weight
beginning
at
lactation
day
4;
the
NOAEL
was
approximately
25
mg/
kg/
day.
Since
a
similar
body
weight
decrease
was
not
seen
on
lactation
day
zero,
the
cause
of
the
effect
on
later
lactation
days
is
most
likely
due
to
exposure
of
the
pups
to
metolachlor
in
the
diet
and/
or
milk
and
therefore
is
not
evidence
of
an
increased
quantitative
susceptibility
in
post­
natal
animals.

A
series
of
acute,
subchronic,
developmental
(
rat)
and
mutagenicity
studies
were
conducted
on
the
ethane
sulfonic
acid
(
ESA,
or
CGA
354743)
and
oxanilic
acid
(
OA,
or
CGA
51202)
metabolites
found
in
water.
The
MARC
concluded
that
the
ESA
and
OA
metabolites
appear
to
be
less
toxic
than
parent
metolachlor/
S­
metolachlor,
based
on
subchronic
studies
in
the
rat
and
dog
(
ESA
metabolite
only)
and
developmental
studies
in
the
rat.
No
toxicity
was
observed
in
any
of
these
studies
at
the
limit
dose(
s)
of
1000
mg/
kg/
day
or
greater.
Since
a
dose
for
toxicity
of
the
metabolites
was
not
demonstrated,
the
degree
of
difference
between
metabolite
and
parent
could
not
be
established.
Acute
toxicity
was
essentially
comparable,
except
both
metabolites
were
moderate
(
ESA)
or
severe
(
OA)
eye
irritants,
whereas
the
parent
compound
was
not.
However,
the
MARC
concluded
that
the
ESA
and
OA
metabolites
should
be
included
in
the
water
risk
assessment
(
not
in
the
tolerance
expression
and
not
in
the
dietary
food
assessment)
since
they
were
found
in
greater
abundance
than
the
parent(
s)
in
water
monitoring
studies
and
assuming
the
toxicity
of
the
degradates
are
equivalent
to
metolachlor.
In
addition,
parent
metolachlor
has
been
classified
as
a
Group
C
carcinogen.
Without
long­
term
studies
in
rats
and
mice
with
the
metabolites,
there
are
no
data
to
substantiate
that
the
metabolites
are
not
carcinogenic.

One
toxicology
data
gap
exists
for
metolachlor,
as
there
is
concern
for
toxicity
by
the
inhalation
route
following
exposure
on
multiple
days
in
a
commercial
setting.
A
28­
day
inhalation
study
in
rats
with
metolachlor
should
be
conducted.
Registrants
are
recommended
to
follow
the
protocol
provided
in
OPPTS
Guideline
870.3465
(
90­
day
inhalation
study)
but
cease
exposure
at
28
days.
15
of
66
The
acute
toxicity
profile
for
metolachlor
is
presented
in
Table
3.1.
a.
For
comparison
purposes,
the
acute
toxicity
profile
for
metolachlor,
based
on
the
reviewed
1994
acute
toxicity
studies,
is
presented
in
Table
3.1.
b.

Table
3.1.
a
Acute
Toxicity
Profile
of
Metolachlor
(
PC
Code
108801)

Guideline
No.
Study
Type
MRIDs
#
Results
Toxicity
Category
870.1100
Acute
Oral­
Rats
00015523
LD50
=
2780
mg/
kg
III
870.1200
Acute
Dermal­
Rabbit
00015526
LD50
=
>
10
mg/
kg
III
870.1300
Acute
Inhalation­
Rats
00015535
LC50
=
>
1.75
mg/
L
III
870.2400
Primary
Eye
Irritation­
Rabbits
00015528
non­
irritating
IV
870.2500
Primary
Skin
Irritation­
Rabbits
00015530
non­
irritating
IV
870.2600
Dermal
Sensitization­
Guinea
pigs
00015631
positive
870.6200
Acute
Neurotoxicity 
NA
NA 
study
not
required
Table
3.1.
b
Acute
Toxicity
Profile
of
Metolachlor
(
PC
Code
108801)
Based
on
1994
Studies
OPPTS
Guideline
No.
Study
Type
MRIDs
#
Results
Toxicity
Category
870.1100
Acute
Oral
­
Rat
43492001
LD50
=
3302
mg/
kg
(
males);
2000
mg/
kg
(
females);
2877
mg/
kg
(
combined
sexes)
III
870.1200
Acute
Dermal
­
Rabbit
43492002
LD50
=
>
2000mg/
kg
III
870.1300
Acute
Inhalation
­
Rat
43492003
LC50
=
>
4.33
mg/
L
IV
870.2400
Primary
Eye
Irritation
­
Rabbit
43492004
mild
irritant
III
870.2500
Primary
Skin
Irritation
­
Rabbit
43492005
minimal
irritant
IV
870.2600
Dermal
Sensitization
­
guinea
pig
43492006
positive
S­
metolachlor:
The
toxicology
database
for
S­
metolachlor,
when
bridged
with
the
metolachlor
database,
is
complete
for
risk
assessment
purposes.
Bridging
toxicology
data,
including
acute
toxicity,
subchronic
toxicity
in
the
rat
and
dog,
developmental
toxicity
in
the
rat
and
rabbit,
mutagenicity,
and
metabolism
studies
are
available.
S­
metolachlor
is
moderately
acutely
toxic
(
Toxicity
Category
III)
by
the
oral
and
dermal
routes
of
exposure
and
relatively
non­
toxic
(
Toxicity
Category
IV)
by
the
inhalation
route
of
exposure.
S­
metolachlor
causes
slight
eye
irritation
and
is
non­
irritating
dermally,
but
is
a
dermal
sensitizer.
16
of
66
In
one
subchronic
toxicity
study
in
rodents
with
S­
metolachlor,
no
effects
were
observed
in
male
and
female
rats
at
the
high
dose
of
approximately
225
mg/
kg/
day.
In
another
subchronic
toxicity
study
in
rats,
decreased
body
weight/
body
weight
gain,
reduced
food
consumption
and
food
efficiency
and
increased
kidney
weights
in
males
were
observed
at
150
mg/
kg/
day;
the
NOAEL
was
15
mg/
kg/
day.
In
the
subchronic
dog
study,
no
effects
were
observed
in
dogs
at
the
high
dose
of
approximately
70
mg/
kg/
day.

There
was
no
evidence
of
increased
quantitative
or
qualitative
fetal
susceptibility
in
the
prenatal
developmental
studies
in
rats
and
rabbits.
In
the
rat,
maternal
toxicity
[
increased
clinical
signs
of
toxicity
(
pushing
head
through
bedding)
and
decreased
body
weights/
body
weight
gains,
food
consumption
and
food
efficiency]
was
observed
at
500
mg/
kg/
day;
the
NOAEL
was
50
mg/
kg/
day.
There
were
no
developmental
effects
at
1000
mg/
kg/
day,
the
highest
dose
tested.
In
the
rabbit,
clinical
signs
of
toxicity
(
little/
none/
soft
stool)
were
observed
at
100
mg/
kg/
day;
the
NOAEL
was
20
mg/
kg/
day.
No
developmental
effects
were
observed
at
500
mg/
kg/
day,
the
highest
dose
tested.
There
was
no
evidence
of
mutagenic
or
cytogenic
effects
in
vitro
or
in
vivo
studies
with
S­
metolachlor.

S­
metolachlor
is
extensively
absorbed
and
metabolized
following
oral
administration.
Elimination
is
via
the
urine
and
feces.
Tissue
residues
were
highest
in
whole
blood.
Metabolism
studies
were
inadequate
for
comparing
the
metabolic
pathways
of
metolachlor
and
Smetolachlor
However,
based
on
a
comparison
of
the
findings
in
the
available
studies
with
both
chemicals,
it
appears
that
S­
metolachlor
is
of
comparable
toxicity
to
the
racemic
mixture
(
metolachlor).

One
toxicology
data
gap
exists
for
S­
metolachlor,
as
there
is
concern
for
toxicity
by
the
inhalation
route
following
exposure
on
multiple
days
in
a
commercial
setting.
A
28­
day
inhalation
study
in
rats
with
S­
metolachlor
should
be
conducted.
The
registrant
is
recommended
to
follow
the
protocol
provided
in
OPPTS
Guideline
870.3465
(
90­
day
inhalation
study)
but
cease
exposure
at
28
days.

The
acute
toxicity
profile
for
S­
metolachlor
is
presented
in
Table
3.1.
c.

Table
3.1.
c
Acute
Toxicity
Profile
of
S­
metolachlor
(
PC
Code
108800)

Guideline
No.
Study
Type
MRIDs
#
Results
Toxicity
Category
870.1100
Acute
Oral­
Rats
43928915
LD50
=
3267
mg/
kg
(%);
2577
mg/
kg/
day
(&);
2672
mg/
kg/
day
(
combined)
III
870.1200
Acute
Dermal­
Rabbit
43928916
LD50
=
>
2000
mg/
kg
III
870.1300
Acute
Inhalation­
Rats
43928917
LC50
=
>
2.91
mg/
L
IV
17
of
66
870.2400
Primary
Eye
Irritation­
Rabbits
43928918
slight
to
moderate
conjunctival
irritation
that
cleared
in
48
hours
III
870.2500
Primary
Skin
Irritation­
Rabbits
43928919
non­
irritating
IV
870.2600
Dermal
Sensitization­
Guinea
pigs
43928920
positive
870.6200
Acute
Neurotoxicity 
NA
NA 
study
not
required
3.2
FQPA
Considerations
The
FQPA
Safety
Factor
Committee
met
on
November
5,
2001
to
evaluate
the
hazard
and
exposure
data
for
metolachlor
and
S­
metolachlor,
and
recommended
that
the
FQPA
Safety
Factor
for
the
protection
of
infants
and
children
still
be
1x
(
based
on
the
2002
policy)
for
the
following
reasons
(
Memorandum:
Report
of
the
FQPA
Safety
Factor
Committee,
Carol
Christensen,
11/
14/
01):
i.
The
toxicology
database
is
complete
for
the
FQPA
assessment;

ii.
There
is
no
indication
of
quantitative
or
qualitative
increased
susceptibility
of
rats
or
rabbits
to
in
utero
and/
or
postnatal
exposure
to
metolachlor
in
the
available
toxicity
data;

iii.
A
developmental
neurotoxicity
study
is
not
required
for
metolachlor;

iv.
The
dietary
(
food
and
drinking
water)
and
non­
dietary
exposure
(
residential)
assessments
will
not
underestimate
the
potential
exposures
for
infants
and
children
from
the
use
of
metolachlor.

3.3
Dose
Response
Assessment
Rationale
for
Endpoint
Selection:
HED's
Hazard
Identification
Assessment
Review
Committee
(
HIARC)
met
on
September
6,
2001
and
reviewed
the
toxicology
databases
for
metolachlor
and
S­
metolachlor
with
regard
to
the
acute
and
chronic
reference
doses
(
RfDs)
and
the
toxicological
endpoint
selection
for
use
as
appropriate
in
occupational/
residential
risk
assessments.
The
HIARC
concluded
that
Smetolachlor
and
metolachlor
have
comparable
toxicity
profiles.
Studies
with
both
chemicals
were
used
interchangeably
for
toxicology
endpoint
selection.
This
endpoint
is
applicable
to
the
currently
proposed
uses.

A
complete
toxicology
profile
for
both
metolachlor
and
S­
metolachlor
can
be
found
in
Tables
1
and
2
of
Appendix
A.
A
summary
of
the
doses
and
endpoints
selected
for
human
health
risk
18
of
66
assessment
is
presented
in
Table
3.3
of
this
document.
A
more
thorough
explanation
of
the
rationale
for
endpoint
selection
is
included
below:

Acute
Dietary
Endpoint:
The
acute
RfD
of
3.0
mg/
kg/
day
is
based
on
a
prenatal
developmental
toxicity
study
in
rats
with
metolachlor,
and
is
calculated
as
the
NOAEL
(
300
mg/
kg/
day)
divided
by
the
total
uncertainty
factor
of
100X
(
10X
for
interspecies
extrapolation
and
10X
for
intraspecies
variability).
The
acute
endpoint
is
based
on
an
increased
incidence
of
death,
clinical
signs
of
toxicity
(
clonic
and/
or
tonic
convulsions,
excessive
salivation,
urine­
stained
abdominal
fur
and/
or
excessive
lacrimation)
and
decreased
body
weight
gain
seen
at
the
LOAEL
of
1000
mg/
kg/
day.
It
is
noted
that
although
increased
incidence
of
death
is
one
of
the
effects
seen,
it
was
seen
at
a
dose
(
1000
mg/
kg/
day)
approximately
three
times
higher
than
the
dose
(
300
mg/
kg/
day)
selected
for
risk
assessment;
therefore,
the
Agency
is
confident
that
adequate
safety
is
provided
to
protect
the
public
from
dietary
exposure
to
residues
of
metolachlor.
Since
the
FQPA
safety
factor
is
reduced
to
1X,
the
acute
RfD
is
equal
to
the
aPAD.
The
PAD
is
a
modification
of
the
acute
or
chronic
RfD
to
accommodate
the
FQPA
safety
factor,
and
is
calculated
as
the
RfD
divided
by
the
FQPA
safety
factor.

Since
clinical
signs
are
observed
after
a
single
oral
dose
of
metolachlor,
the
duration
and
route
of
administration
are
appropriate
for
the
risk
assessment.
Salivation
alone
is
seen
at
300
mg/
kg/
day;
however,
as
this
effect
is
most
likely
due
to
gastric
irritation
and
there
is
no
other
evidence
of
treatment­
related
toxicity,
the
finding
is
not
considered
toxicologically
significant.
Developmental
effects
observed
are
not
attributable
to
a
single
exposure
and
therefore,
a
separate
acute
endpoint
has
not
been
identified
for
females
13­
50.

Chronic
Dietary
Endpoint:
The
chronic
RfD
of
0.10
mg/
kg/
day
is
based
on
a
chronic
toxicity
study
in
dogs
with
metolachlor,
and
is
calculated
as
the
NOAEL
(
9.7
mg/
kg/
day)
divided
by
the
100X
UF.
The
chronic
endpoint
is
based
on
decreased
body
weight
gain
in
females
at
the
LOAEL
of
33.0
mg/
kg/
day.
Since
the
FQPA
safety
factor
is
reduced
to
1X,
the
chronic
RfD
is
equal
to
the
chronic
PAD.
The
study
duration
and
route
of
administration
are
appropriate
for
this
risk
assessment.

Short­
term
Incidental
Oral:
The
short­
term
incidental
oral
NOAEL
of
50
mg/
kg/
day,
from
a
prenatal
developmental
toxicity
study
in
rats
with
S­
metolachlor,
is
based
on
increased
incidence
of
clinical
signs,
decreased
body
weight/
body
weight
gain,
food
consumption
and
food
efficiency
seen
at
the
LOAEL
(
500
mg/
kg/
day)
in
maternal
animals.
The
endpoint
is
appropriate
for
the
population
of
concern
(
infants
and
children).
The
Committee
noted
that
the
NOAEL
(
20
mg/
kg/
day)
for
the
prenatal
developmental
toxicity
study
in
rabbits
with
S­
metolachlor
(
MRID
43928924)
was
lower
than
the
50
mg/
kg/
day
from
the
rat
developmental
study.
However,
the
endpoint
was
based
on
clinical
signs
of
toxicity
(
increase
in
little/
none/
soft
stool
observations)
at
100
mg/
kg/
day.
Although
there
was
a
dose­
related
increase
in
this
sign,
it
is
not
evidence
of
frank
toxicity
and
was
judged
not
be
appropriate
for
risk
assessment.
Therefore,
the
rabbit
study
with
S­
metolachlor
was
not
selected
for
this
exposure
scenario.

Intermediate­
term
Incidental
Oral:
The
intermediate­
term
incidental
oral
NOAEL
of
8.8
mg/
kg/
day,
from
a
subchronic
toxicity
study
in
dogs
with
metolachlor,
is
based
on
decreased
19
of
66
body
weight
gain
seen
at
the
LOAEL
of
29.4
mg/
kg/
day.
The
endpoint
and
study
duration
are
appropriate
for
the
population
of
concern
(
infants
and
children).

Dermal
Absorption:
A
dermal
absorption
value
of
58%
has
been
selected,
based
on
an
available
dermal
absorption
study
in
rats
with
metolachlor.
The
percentage
of
the
applied
dose
found
in
blood,
urine,
feces,
carcass
and
cage
was
increased
during
the
period
between
skin
wash
(
10
hours)
and
sacrifice
(
72
hours).
During
the
same
period,
the
levels
in
the
skin
decreased
by
a
similar
amount.
This
observation
suggested
that
metolachlor
retained
in
skin
was
absorbed
during
the
pre­
sacrifice
period.
Therefore,
the
HIARC
selected
58%
dermal
absorption
value
based
on
the
combined
values
at
10
hours
measurement
(
33%)
and
at
the
amount
remaining
on
the
skin
(
25%).

Short­
and
Intermediate­
Term
Dermal
Endpoints:
No
hazard
was
identified
for
quantification
of
risk
following
dermal
exposure.
In
a
21­
day
dermal
toxicity
study
(
MRID
41833101),
no
systemic
toxicity
was
seen
following
repeated
dermal
application
of
metolachlor
(
96.4%
ai)
to
the
intact
skin
of
five
New
Zealand
rabbits/
sex/
group
at
doses
of
0,
10,
100
or
1000
mg/
kg/
day
for
21
days.
No
prenatal
developmental
toxicity
studies
with
metolachlor
or
S­
metolachlor
were
appropriate
for
this
risk
assessment.
There
was
no
evidence
of
developmental
effects
in
rats
or
rabbits
at
maternally
toxic
doses
with
either
metolachlor
or
S­
metolachlor,
except
in
the
rat
prenatal
developmental
toxicity
study.
In
this
study,
there
were
slightly
decreased
number
of
implantations
per
dam,
decreased
number
of
live
fetuses/
dam,
increased
number
of
resorptions/
dam
and
significant
decrease
in
mean
fetal
body
weight
but
only
at
1000
mg/
kg/
day
which
was
extremely
toxic
to
dams
(
death,
clinical
signs
of
toxicity
and
decreased
body
weight
gain).

Long­
term
Dermal
Endpoint:
The
long­
term
dermal
NOAEL
of
9.7
mg/
kg/
day,
from
a
chronic
oral
toxicity
study
in
dogs
with
metolachlor,
is
based
on
decreased
body
weight
gain
in
females
at
the
LOAEL
of
33.0
mg/
kg/
day.
The
treatment
period
(
21­
days)
in
the
dermal
toxicity
study
with
metolachlor
was
not
considered
to
be
of
sufficient
duration
for
these
compounds
since
effects
seen
in
chronic
oral
studies
could
also
be
observed
with
long­
term
dermal
administration.
Therefore,
the
HIARC
selected
an
oral
NOAEL
for
this
exposure
scenario,
and
since
an
oral
study
was
selected,
the
dermal
absorption
factor
(
58%)
should
be
applied.

Short­
term
Inhalation
Endpoint:
The
short­
term
inhalation
NOAEL
of
50
mg/
kg/
day,
from
an
oral
prenatal
developmental
toxicity
study
in
rodents
with
S­
metolachlor,
is
based
on
increased
incidence
of
clinical
signs,
decreased
body
weight/
body
weight
gain,
food
consumption
and
food
efficiency
at
the
LOAEL
of
500
mg/
kg/
day
in
maternal
animals.
Since
an
oral
study
was
selected,
a
100%
absorption
factor
should
be
applied.

Intermediate­
Term
Inhalation
Endpoint:
The
intermediate­
term
inhalation
NOAEL
of
8.8
mg/
kg/
day,
from
a
subchronic
oral
toxicity
study
in
dogs
with
metolachlor,
is
based
on
decreased
body
weight
gain
at
the
LOAEL
of
29.4
mg/
kg/
day.
Since
an
oral
study
was
selected,
a
100%
absorption
factor
should
be
applied.

Long­
Term
Inhalation
Endpoint:
The
long­
term
inhalation
NOAEL
of
9.7
mg/
kg/
day,
from
a
chronic
toxicity
study
in
dogs
with
metolachlor,
is
based
on
decreased
body
weight
gain
in
20
of
66
females
at
the
LOAEL
of
33
mg/
kg/
day.
Since
an
oral
study
was
selected,
a
100%
absorption
factor
should
be
applied.

Target
MOE
for
residential
and
aggregate
exposure:
A
target
MOE
(
NOAEL/
exposure)
is
the
level
above
which
the
Agency
does
not
have
a
risk
concern.
For
metolachlor,
a
target
MOE
of
100
is
considered
adequate
for
dermal
and
inhalation
residential
exposure,
as
well
as
for
aggregate
exposure.
The
target
MOE
of
100
includes
the
FQPA
safety
factor
of
1X.

Table
3.3
Summary
of
Toxicological
Dose
and
Endpoints
for
Metolachlor
for
Use
in
Human
Risk
Assessment
Exposure
Scenario
Dose
(
mg/
kg/
day)
and
Uncertainty
Factor
(
UF)
Endpoint
for
Risk
Assessment
Study
NOAEL
=
300
UF
=
100x
FQPA
Safety
Factor
=
1x
death,
clinical
signs
of
toxicity
(
clonic
and/
or
tonic
convulsions,
excessive
salivation,
urinestained
abdominal
fur
and/
or
excessive
salivation)
and
decreased
body
weight
gain
Prenatal
developmental
toxicity
study
in
rats
with
metolachlor
Acute
Dietary
(
all
population
subgroups)

Acute
PAD
=
3.0
mg/
kg/
day
NOAEL=
9.7
UF
=
100
FQPA
Safety
Factor
=
1x
decreased
body
weight
gain
in
females
Chronic
study
in
dogs
with
metolachlor
Chronic
Dietary
(
all
population
subgroups)

Chronic
PAD
=
0.1
mg/
kg/
day
Incidental
Oral,
Short­
Term
(
one
to
30
days)
NOAEL
=
50
Target
MOE
=
100
increased
incidence
of
clinical
signs,
decreased
body
weight/
body
weight
gain,
food
consumption,
and
food
efficiency
Prenatal
developmental
toxicity
study
in
rats
with
S­
metolachlor
Incidental
Oral,
Intermediate­
Term
(
one
month
to
180
days)
NOAEL
=
8.8
Target
MOE
=
100
decreased
body
weight
gain
Subchronic
(
6
month)
toxicity
study
in
dogs
with
metolachlor
Dermal,
Short­
and
Intermediate­
Term
Hazard
was
not
identified
for
quantification
of
risk.
No
systemic
toxicity
was
seen
at
the
limit
dose
(
1000
mg/
kg/
day)
following
dermal
applications
and
there
is
no
concern
for
developmental
toxicity
in
rats
or
rabbits.

Dermal,
Long­
Terma
(
greater
than
180
days)
Oral
NOAEL
=
9.7
Target
MOE
=
100
decreased
body
weight
gain
in
females
chronic
toxicity
study
in
dogs
with
metolachlor
21
of
66
Table
3.3
Summary
of
Toxicological
Dose
and
Endpoints
for
Metolachlor
for
Use
in
Human
Risk
Assessment
Exposure
Scenario
Dose
(
mg/
kg/
day)
and
Uncertainty
Factor
(
UF)
Endpoint
for
Risk
Assessment
Study
Inhalation,
Short­
Termb
Oral
NOAEL
=
50
Target
MOE
=
100
increased
incidence
of
clinical
signs,
decreased
body
weight/
body
weight
gain,
food
consumption,
and
food
efficiency
Prenatal
development
toxicity
study
in
rats
with
S­
metolachlor
Inhalation,
Intermediate­
Termb
Oral
NOAEL
=
8.8
Target
MOE
=
100
decreased
body
weight
gain
subchronic
(
6
month)
toxicity
study
in
dogs
with
metolachlor
Inhalation,
Long­
Termb
Oral
NOAEL
=
9.7
Target
MOE
=
100
decreased
body
weight
gain
in
females
chronic
toxicity
study
in
dogs
with
metolachlor
*
The
reference
to
the
FQPA
Safety
Factor
refers
to
any
additional
safety
factor
retained
due
to
concerns
unique
to
the
FQPA.
a
Since
an
oral
NOAEL
was
selected,
a
dermal
absorption
factor
of
58%
should
be
used
in
route­
to­
route
extrapolation.

b
Since
an
oral
NOAEL
was
selected,
an
inhalation
factor
of
100%
should
be
used
in
route­
to­
route
extrapolation.

3.4
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
S­
metolachlor,
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
are
developed,
S­
metolachlor
may
be
subjected
to
further
screening
and/
or
testing
to
better
characterize
effects
related
to
endocrine
disruption.

4.0
Dietary
Exposure/
Risk
Characterization
4.1
Pesticide
Metabolism
and
Environmental
Degradation
4.1.1
Metabolism
in
Primary
Crops
22
of
66
The
qualitative
nature
of
metolachlor
residues
in
plants
is
adequately
understood
based
upon
adequate
corn,
potato,
and
soybean
metabolism
studies.
The
metabolism
of
metolachlor
involves
conjugation
with
glutathione,
breakage
of
this
bond
to
form
mercaptan,
conjugation
of
the
mercaptan
with
glucuronic
acid,
hydrolysis
of
the
methyl
ether,
and
conjugation
of
the
resultant
alcohol
with
a
neutral
sugar.
A
minor
pathway
may
involve
sugar
conjugation
of
metolachlor
directly
to
the
corresponding
oxo­
compounds.
Residues
of
concern
in
plants
include
metolachlor
and
its
metabolites,
determined
as
the
derivatives
CGA­
37913
and
CGA­
49751.
The
residues
of
concern
for
S­
metolachlor
are
the
same
as
for
metolachlor
(
DP
Num:
226780,
L.
Kutney,
11/
12/
96);
however,
the
Agency
is
currently
reviewing
additional
submitted
data
(
DP
Num:
278742
and
279110).
These
data
will
be
incorporated
into
future
assessments
for
metolachlor
and
S­
metolachlor.

4.1.2
Metabolism
in
Rotational
Crops
HED
has
concluded
that
the
confined
rotational
crop
study
for
metolachlor
was
inadequate
but
potentially
upgradable.
Additional
data
are
required
characterizing
the
14C­
residues
in
plants,
along
with
information
on
the
percentage
of
the
14C­
residues
measured
by
the
current
enforcement
method,
supporting
storage
stability
data,
and
sample
storage
conditions
and
intervals.
The
Agency
notes
that
additional
confined
accumulation
data
in
lettuce,
radish
and
wheat
rotational
crops
have
been
submitted
and
are
currently
under
review.
These
data
will
be
included
in
future
assessments.
Once
the
residue
data
requested
by
the
TRED
for
rotational
grains
are
submitted
through
the
reregistration
process,
HED
will
determine
whether
any
of
the
tolerances
should
be
revised
(
PP#
3E6787,
DP
Num:
304120,
R.
Loranger,
4/
17/
06).

4.1.3
Metabolism
in
Livestock
Adequate
studies
are
available
depicting
the
metabolism
of
metolachlor
in
ruminants
and
poultry.
Metolachlor
is
rapidly
metabolized
and
almost
totally
eliminated
in
the
urine
and
feces
of
ruminants
(
goats),
non­
ruminants
(
rats),
and
poultry.
Metolachlor
per
se
was
not
detected
in
any
of
the
excreta
or
tissues.
As
in
plants,
metolachlor
residues
of
concern
in
livestock
commodities
include
metolachlor
and
its
metabolites,
determined
as
the
derivatives
CGA­
37913
and
CGA­
49751.
The
residues
of
concern
for
S­
metolachlor
in
animals
are
the
same
as
for
metolachlor;
however,
the
Agency
is
currently
reviewing
additional
submitted
data
(
D278742
and
D279110).
These
data
will
be
incorporated
into
future
assessments
for
metolachlor
and
Smetolachlor

4.1.4
Analytical
Methodology
Adequate
methodology
is
available
for
enforcing
the
current
and
proposed
tolerances.
The
Pesticide
Analytical
Manual
(
PAM,
Vol.
II)
lists
a
GC/
NPD
method
(
Methods
I)
for
determining
residues
in/
on
plants
and
a
GC/
MSD
method
(
Method
II)
for
determining
residues
in
livestock
commodities.
These
methods
determine
residues
of
metolachlor
and
its
metabolites
as
either
CGA­
37913
or
CGA­
49751
following
acid
hydrolysis.
A
modified
version
of
this
method
(
Syngenta
Method
No.
1848­
01)
which
uses
LC/
MS/
MS
has
also
been
used.
Adequate
data
are
available
on
the
recovery
of
metolachlor
through
Multi­
residue
Method
Testing
Protocols.
The
23
of
66
FDA
PESTDATA
database
indicates
that
metolachlor
is
completely
recovered
through
Method
302,
PAM
Vol.
I
(
3rd
ed.,
revised
10/
97).

4.1.5
Environmental
Degradation
The
environmental
fate
database
is
complete
for
metolachlor.
Parent
metolachlor/
S­
metolachlor
appear
to
be
moderately
persistent
to
persistent,
and
range
from
mobile
to
highly
mobile
in
different
soils.
Metolachlor/
S­
metolachlor
have
reportedly
been
detected
as
far
as
the
36
to
48
inch
soil
layer
in
some
studies.
Degradation
appears
to
be
dependent
on
microbially
mediated
and
abiotic
processes.
The
frequency
of
detection
of
metolachlor/
S­
metolachlor
from
evaluated
monitoring
data
suggest
that
contamination
in
drinking
water
sources
is
widespread.

Environmental
fate
data
comparing
metolachlor
and
S­
metolachlor
indicate
that
both
are
expected
to
have
similar
degradation
pathways
and
rates
in
soil
and
water
environments,
and
both
are
expected
to
be
mobile
to
highly
mobile
in
soil
and
water
environments.

4.1.6
Comparative
Metabolic
Profile
S­
metolachlor
is
extensively
absorbed
and
metabolized
following
oral
administration.
Metolachlor
is
rapidly
metabolized
and
almost
totally
eliminated
in
the
urine
and
feces
of
ruminants
(
goats),
non­
ruminants
(
rats),
and
poultry.
Metolachlor
per
se
was
not
detected
in
any
of
the
excreta
or
tissues.
Tissue
residues
were
highest
in
whole
blood.
The
metabolism
of
metolachlor
in
plants
involves
conjugation
with
glutathione,
breakage
of
this
bond
to
form
mercaptan,
conjugation
of
the
mercaptan
with
glucuronic
acid,
hydrolysis
of
the
methyl
ether,
and
conjugation
of
the
resultant
alcohol
with
a
neutral
sugar.
A
minor
pathway
may
involve
sugar
conjugation
of
metolachlor
directly
to
the
corresponding
oxo­
compounds.
Residues
of
concern
in
plants
include
metolachlor
and
its
metabolites,
determined
as
the
derivatives
CGA­
37913
and
CGA­
49751.

4.1.8
Pesticide
Metabolites
and
Degradates
of
Concern
Table
4.1.8
Summary
of
Metabolites
and
Degradates
to
be
included
in
the
Risk
Assessment
and
Tolerance
Expression
Matrix
Residues
included
in
Risk
Assessment
Residues
included
in
Tolerance
Expression
Primary
Crop
Parent,
CGA­
37913
and
CGA­
49751
Parent,
CGA­
37913
and
CGA­
49751
Plants
Rotational
Crop
Parent,
CGA­
37913
and
CGA­
49751
Parent,
CGA­
37913
and
CGA­
49751
Ruminant
Parent,
CGA­
37913
and
CGA­
49751
Parent,
CGA­
37913
and
CGA­
49751
Livestock
Poultry
Parent,
CGA­
37913
and
CGA­
49751
Parent,
CGA­
37913
and
CGA­
49751
24
of
66
Table
4.1.8
Summary
of
Metabolites
and
Degradates
to
be
included
in
the
Risk
Assessment
and
Tolerance
Expression
Matrix
Residues
included
in
Risk
Assessment
Residues
included
in
Tolerance
Expression
Drinking
Water
Parent,
ethanesulfonic
acid
(
ESA)
and
oxanilic
acid
(
OA)
Not
Applicable
See
Appendix
A,
Table
3
for
chemical
structures.

4.1.9
Drinking
Water
Residue
Profile
A
drinking
water
assessment
was
conducted
based
on
monitoring
data
from
several
sources,
as
well
as
on
Tier
1
FIRST
and
SCI­
GROW
modeling
results.
This
assessment
is
a
worst­
case
scenario
and
demonstrates
high
end
numbers.
It
is
important
to
note
that
the
analytical
methods
used
to
obtain
the
monitoring
data
are
not
able
to
distinguish
between
metolachlor
and
S­
metolachlor;
therefore,
the
estimated
environmental
concentrations
(
EECs)
presented
in
this
risk
assessment
are
representative
of
both
racemic
metolachlor
and
S­
metolachlor.

EECs
for
metolachlor
and
S­
metolachlor
were
calculated
for
both
the
parent
compound
and
the
ethanesulfonic
acid
(
ESA)
and
oxanilic
acid
(
OA)
degradates.
Although
it
was
determined
by
the
MARC
that
the
ESA
and
OA
metabolites
appear
to
be
less
toxic
than
parent
metolachlor,
they
are
included
in
the
risk
assessment
since
they
were
found
in
greater
abundance
than
the
parent
in
water
monitoring
studies.

The
crops
with
the
highest
maximum
seasonal
application
rates
are
turf
(
S­
metolachlor
only)
and
corn
(
racemic
metolachlor
and
S­
metolachlor)
with
a
maximum
seasonal
application
rate
of
4.0
lbs
ai/
A.
Based
on
PRZM/
EXAMS
modeling
the
maximum
peak
and
annual
average
concentrations
of
metolachlor/
S­
metolachlor
in
surface
water
were
199
ug/
l
and
9.2
ug/
l,
respectively.
Based
on
FIRST
modeling
results
from
the
TRED,
the
estimate
of
the
drinking
water
concentration
from
surface
water
sources
of
metolachlor
ESA,
a
major
degradate
of
metolachlor,
is
not
likely
to
exceed
31.9
ug/
L
for
the
annual
peak
concentration
and
22.8
ug/
L
for
the
annual
average
exposure
for
use
on
turf/
corn
at
a
maximum
annual
application
rate
of
4.0
lbs
ai/
A.
Based
on
FIRST
modeling
results
from
the
TRED
the
estimate
of
the
drinking
water
concentration
from
surface
water
sources
of
metolachlor
OA,
another
major
degradate
of
metolachlor,
is
not
likely
to
exceed
91.4
ug/
L
for
the
annual
peak
concentration
and
65.1
ug/
L
for
the
annual
average
exposure
for
use
on
turf/
corn
at
a
maximum
annual
application
rate
of
4.0
lbs
ai/
A
(
ground
application
with
no
spray
drift).

SCI­
GROW
screening
model
was
used
to
estimate
groundwater
concentrations.
The
estimated
concentration
of
metolachlor/
S­
metolachlor
in
drinking
water
from
shallow
groundwater
sources
is
5.5
ug/
l
for
application
on
corn
at
a
seasonal
maximum
rate
of
4.0
lbs
ai/
A.
This
concentration
is
appropriate
for
both
the
peak
and
annual
average
exposures.
The
EEC
for
metolachlor
degradate
ESA
use
on
turf/
corn
is
not
expected
to
exceed
65.8
ug/
l
for
peak
and
annual
average
exposures.
The
EEC
for
metolachlor
OA
use
on
turf/
corn
is
not
expected
to
exceed
31.7
ug/
l
for
peak
and
annual
average
exposures.
25
of
66
As
a
result
of
the
above
modeling
results,
the
recommended
total
EEC's
for
surface
water
(
peak),
surface
water
(
average),
and
groundwater
(
peak
and
average)
are
322
ppb
(
199
parent
+
31.9
ESA+
91.4
OA),
97
ppb
(
9.2
parent
+
22.8
ESA
+
65.1
OA),
and
103
ppb
(
5.5
parent
+
65.8
ESA
+
31.7
OA),
respectively.

Table
4.1.9
Metolachlor
EEC's
Surface
Water
(
peak)
Surface
Water
(
average)
Ground
Water
Parent
199
9.2
5.5
metolachlor
ESA
31.9
22.8
65.8
metolachlor
OA
91.4
65.1
31.7
Total
EECs
(
ppb)
322.3
97.1
103.0
4.1.10
Food
Residue
Profile
S­
metolachlor
is
a
selective,
chloroacetanilide
herbicide
that
is
applied
to
a
variety
of
crops
as
a
preplant,
preplant­
incorporated
(
PPI),
pre­
emergence,
or
post­
emergence
application,
primarily
for
the
control
of
grass
weeds.
Permanent
tolerances
for
the
combined
S­
metolachlor
residues
have
been
established
in/
on
plant
commodities
ranging
from
0.1
ppm
in/
on
a
variety
of
plant
commodities
to
15
ppm
in/
on
sugar
beet
tops
[
40
CFR
§
180.368(
a)(
2)].

The
proposed
crop
tolerances
will
have
no
impact
on
the
maximum
theoretical
dietary
burden
(
MTDB)
for
livestock.
Therefore,
no
changes
are
required
in
the
tolerances
for
animal
commodities
as
a
result
of
the
proposed
Section
18s.

Cilantro,
Collards,
Kale,
and
Mustard
Greens
The
Ohio
Department
of
Agriculture
is
requesting
a
specific
exemption
for
the
use
of
Smetolachlor
formulated
as
Dual
Magnum
®
(
EPA
Reg.
No.:
100­
816)
for
control
of
common
purslane
and
prostrate
pigweed
on
cilantro,
collards,
kale,
and
mustard
greens.
The
requested
use
is
for
a
single
application,
pre­
emergence
using
a
ground
sprayer,
at
0.95
lb
ai/
A
to
1500
A
in
the
state
of
Ohio.
A
total
of
1425
lb
ai
(
187
gal
formulation)
would
be
used
as
a
result
of
this
request.

Previously
submitted
data
from
11
crop
field
trials
(
MRID
44615401)
conducted
on
spinach
during
1994
and
1995
show
that
the
combined
residues
of
CGA­
37913
and
CGA­
49751,
each
expressed
as
parent
metolachlor,
were
<
0.08­<
0.38
ppm
in/
on
22
samples
of
spinach
harvested
34­
69
days
following
a
single
pre­
emergence
soil
application
of
metolachlor
at
1.0
lb
ai/
A.
Combined
residues
were
also
<
0.08­
0.263
ppm
in/
on
10
samples
of
spinach
harvested
41­
69
days
following
an
pre­
emergence
application
at
2.0
lb
ai/
A.
These
data
would
support
a
similar
use
of
S­
metolachlor
on
spinach
at
a
maximum
rate
of
0.6
lb
ai/
A.
The
available
data
indicated
26
of
66
that
a
tolerance
level
of
0.5
ppm
would
be
appropriate
for
a
tolerance
on
spinach.
Considering
the
similarity
between
spinach
and
the
subject
crops
and
the
higher
proposed
application
rate
for
this
Section
18,
the
data
indicate
that
residues
of
S­
metolachlor
are
not
likely
to
exceed
1.0
ppm
as
a
result
of
the
proposed
use.
A
time­
limited
tolerance
of
1.0
ppm
for
the
residues
of
Smetolachlor
on
cilantro,
collards,
kale,
and
mustard
greens
would
be
appropriate.

Pumpkins
and
Winter
Squash
Residue
trials
conducted
jointly
by
the
Interregional
Research
Project
Number
4
(
IR­
4)
and
the
Pest
Management
Centre
of
Agriculture
and
Agri­
Food
Canada
(
PMC,
AAFC)
on
behalf
of
the
Canadian
Horticultural
Council,
have
been
submitted
for
S­
metolachlor
on
winter
squash
and
have
been
reviewed
(
MRID
46707501,
D.
Dotson,
in
process).

Eleven
trials
were
conducted
in
the
United
States
and
Canada.
The
residue
study
was
arranged
into
four
treatment
scenarios:
1
pre­
emergent
(
PRE)
soil
application
at
0.64­
0.69
lb
ai/
A
(
Treatment
2);
1
pre­
emergent
soil
application
at
1.25­
1.37
lb
ai/
A
(
Treatment
3);
1
postemergent
(
POST)
foliar
application
at
0.63­
0.69
lb
ai/
A
(
Treatment
4);
and
1
post­
emergent
foliar
application
at
1.25­
1.43
lb
ai/
A
(
Treatment
5).
An
adjuvant
was
not
added
to
the
spray
mixture
for
any
application.
Winter
squash
fruit
was
harvested
at
pre­
harvest
intervals
(
PHIs)
of
43­
119
days
(
PRE
Treatments
2
and
3)
or
31­
105
days
(
POST
Treatments
4
and
5).

Residue
analysis
for
S­
metolachlor
in/
on
winter
squash
was
conducted
using
an
analytical
method
entitled
"
Working
Method
for
Analysis
of
CGA­
37913
and
CGA­
49751
in
Winter
Squash."
The
working
method
(
HPLC/
MS/
MS)
was
adapted
and
modified
from
the
datagathering
enforcement
Method
AG­
612
(
GC
analysis)
which
was
previously
reviewed.
Briefly,
residues
were
extracted
by
reflux
with
hydrochloric
acid.
For
CGA­
37913,
acidified
extracts
were
cleaned­
up
by
partitioning
in
hexane
and
reconstituted
in
methanol.
For
CGA­
49751,
extracts
were
derivatized
in
10%
boron
trichloride
2­
chloroethanol
(
10%)
solution,
cleaned­
up
by
partitioning
in
dichloromethane
and
then
reconstituted
in
ethyl
acetate.
Residues
of
CGA­
37913
in
sample
extracts
were
analyzed
using
HPLC/
MS/
MS,
while
residues
of
CGA­
49751
were
analyzed
according
to
the
reference
method
No.
AG­
612
using
GC­
NPD.
Acceptability
of
the
working
method
was
confirmed
by
method
validation
and
concurrent
procedural
recoveries
of
70­
120%
(
±
20%
SD)
measured
during
the
residue
study.

A
freezer
storage
stability
test
was
conducted
in
conjunction
with
the
residue
study
in
order
to
demonstrate
residue
stability
for
the
trial
samples.
For
the
stability
test,
samples
were
fortified
at
0.990­
0.998
ppm
and
stored
frozen
(<­
14
°
C)
for
up
to
629
days
(
20
months).
Although
the
test
storage
period
(
629
days)
was
shorter
than
the
actual
sample
storage
period
(
720
days),
considering
stored
test
samples
were
stable
for
629
days
(
1.7
years),
it
is
expected
that
residues
remained
stable
up
to
720
days
(
2
years).

The
results
from
these
trials
show
that
maximum
total
residues
of
S­
metolachlor
(
determined
as
CGA­
37913
and
CGA­
49751)
were
<
0.08
ppm
(
below
the
Lowest
Limit
of
Method
Validation,
LLMV)
in
winter
squash
treated
with
either
one
pre­
emergent
soil
application
(
0.72­
1.54
kg
ai/
ha
or
0.64­
1.37
lb
ai/
A)
or
one
post­
emergent
foliar
application
(
0.71­
1.60
kg
ai/
ha
or
27
of
66
0.63­
1.43
lb
ai/
A),
and
harvested
at
PHIs
of
31­
119
days.
Only
one
residue
was
detected
above
the
LLMV
(
CGA­
49751
at
0.061
ppm).

TABLE
4.2.10
Summary
of
Residue
Data
from
Crop
Field
Trials
with
S­
metolachlor.

Residue
Levels
(
ppm)
Commodity
Total
Applic.
Rate
lb
ai/
A
(
kg
ai/
ha)
PHI
(
days)

n
Min.
Max.
HAFT*
Median
(
STMdR)**
Mean
(
STMR)**
Std.
Dev.

Total
combined
residues,
expressed
as
parent
equivalents
0.64
­
0.69
(
0.72
­
0.77)
PRE
43
­
119
22
<
0.08
<
0.08
<
0.08
<
0.08
<
0.08
­­

1.25
­
1.37
(
1.40
­
1.54)
PRE
43
­
119
20
<
0.08
<
0.08
<
0.08
<
0.08
<
0.08
­­

0.63
­
0.69
(
0.71
­
0.77)
POST
31
­
105
22
<
0.08
0.091
0.086
0.08
0.081
­­
Winter
squash,
fruit
1.25
­
1.43
(
1.40
­
1.60)
POST
31
­
105
22
<
0.08
<
0.08
<
0.08
<
0.08
<
0.08
­­

PRE
=
preemergent
(
to
crop),
POST
=
post­
emergent
(
to
crop)
*
HAFT
=
Highest
Average
Field
Trial.
**
STMdR
=
Supervised
Trial
Median
Residue;
STMR
=
Supervised
Trial
Mean
Residue
Conclusions:
In
order
to
harmonize
with
PMRA,
a
revised
Section
B
is
required
indicating
the
use
on
pumpkin
as
direct
seeded
treatment
(
soil
application,
pre­
emergent
to
crop
and
weed)
or
post
emergent
treatment
(
foliar
application
at
the
1­
2
leaf
crop
stage,
prior
to
weed
emergence)
at
a
rate
of
0.94
lb
ai/
A
(
1.05
kg
ai/
ha),
and
a
PHI
of
65
days
(
email:
Denise
MacGillivray
Evaluation
Officer,
HED,
PMRA,
6/
26/
06).
No
US
registration
for
winter
squash
is
requested
at
this
time.
The
submitted
data
with
the
revised
Section
B
are
sufficient
to
indicate
that
residues
of
S­
metolachlor
on
winter
squash
are
not
likely
to
exceed
the
proposed
tolerance
of
0.1
ppm.
According
to
the
2002
Reviewer's
Guide,
if
winter
squash
data
are
submitted
and
found
acceptable
to
support
a
winter
squash
tolerance
then
tolerances
can
be
established
on
several
Cucurbita
spp.
including
pumpkin.
The
data
submitted
are
sufficient
to
support
the
request
for
a
tolerance
on
pumpkins.
The
proposed
tolerances
of
0.1
ppm
for
the
residues
of
S­
metolachlor
on
pumpkins
and
winter
squash
are
appropriate.
The
tolerance
on
winter
squash
would
be
established
without
a
US
registration.

4.2.11
International
Residue
Limits
There
are
currently
no
Codex,
Canadian
or
Mexican
MRLs
for
S­
metolachlor;
therefore
there
are
no
international
harmonization
issues
for
these
actions.

4.3
Dietary
Exposure
and
Risk
Acute
and
chronic
dietary
risk
assessments
were
conducted
using
the
Dietary
Exposure
Evaluation
Model
(
DEEM­
FCID
 
,
Version
2.03)
which
uses
food
consumption
data
from
the
28
of
66
USDA's
Continuing
Surveys
of
Food
Intakes
by
Individuals
(
CSFII)
from
1994­
1996
and
1998.
The
analyses
were
performed
to
support
Section
18
requests
for
the
use
of
S­
metolachlor
on
cilantro,
collards,
kale,
mustard
greens,
a
Section
3
Use
on
Pumpkin;
and
Tolerance
on
Winter
Squash
without
a
US
Registration.

Both
the
acute
and
chronic
analyses
assume
tolerance­
level
residues
on
all
crops
with
established,
pending,
or
proposed
tolerances
for
metolachlor
and/
or
S­
metolachlor.
In
cases
where
separate
tolerance
listings
occur
for
both
metolachlor
and
S­
metolachlor
on
the
same
commodity,
the
higher
value
of
the
two
is
used
in
the
analyses.

An
acute
dietary
analysis
for
S­
metolachlor
was
conducted
using
tolerance
levels
and
100
%
CT
for
all
existing
and
proposed
uses.
The
highest
drinking
water
estimate
for
acute
exposure,
322
ppb,
was
used
in
the
analysis.
The
dietary
exposure
estimate
to
the
U.
S.
population
was
<
1%
aPAD
and
the
most
highly
exposed
subgroup,
all
infants
<
1
yr
old,
at
2%
aPAD.
The
results
of
the
analysis
indicate
that
acute
risk
from
the
dietary
exposure
to
S­
metolachlor
from
the
existing
and
requested
uses
did
not
exceed
HED's
level
of
concern
for
U.
S.
population
or
any
population
subgroup.

A
chronic
dietary
analysis
for
S­
metolachlor
was
conducted
using
tolerance
levels
and
100
%
CT
data
for
all
existing
and
proposed
uses.
The
highest
drinking
water
estimate
for
chronic
exposure,
103
ppb,
was
used
in
the
analysis.
The
dietary
exposure
estimate
to
the
U.
S.
population
was
4%
cPAD
and
the
most
highly
exposed
subgroup,
all
infants
<
1
yrs
old,
at
10%
cPAD.
The
results
of
the
analysis
indicate
that
chronic
risk
from
the
dietary
exposure
to
Smetolachlor
from
the
existing
and
requested
uses
did
not
exceed
HED's
level
of
concern
for
the
U.
S.
population
or
any
population
subgroup.

Table
4.3
Summary
of
Dietary
Exposure
and
Risk
for
S­
metolachlor
Acute
Dietary
(
95th
Percentile)
Chronic
Dietary
Cancer
Population
Subgroup
Dietary
Exposure
(
mg/
kg/
day)
%
aPAD
Dietary
Exposure
(
mg/
kg/
day)
%
cPAD
Dietary
Exposure
(
mg/
kg/
day)
Risk
General
U.
S.
Population
0.019972
<
1
0.004113
4
All
Infants
(<
1
year
old)
0.066430
2
0.010003
10
Children
1­
2
years
old
0.033427
1
0.007954
8
Children
3­
5
years
old
0.029665
<
1
0.007160
7
Children
6­
12
years
old
0.020708
<
1
0.004914
5
Youth
13­
19
years
old
0.016010
<
1
0.003352
3
Adults
20­
49
years
old
0.017578
<
1
0.003613
4
Adults
50+
years
old
0.015963
<
1
0.003597
4
Females
13­
49
years
old
0.017453
<
1
0.003521
4
N/
A
N/
A
29
of
66
5.0
Residential
(
Non­
Occupational)
Exposure/
Risk
Characterization
5.1
Residential
Handler
Exposure
There
are
no
residential
handler
uses
of
S­
metolachlor
and,
therefore,
no
residential
handler
exposure
assessment
is
required.

5.2
Residential
Postapplication
Exposure
The
formulated
S­
metolachlor
end­
use
product
is
labeled
under
the
trade
name
Pennant
MAGNUMTM
(
EPA
Reg.
No.
100­
950)
to
distinguish
the
new
product
from
the
original
metolachlor
formulation
named
PennantTM
(
EPA
Reg.
No.
100­
691).
Pennant
MAGNUMTM
(
7.62
lbs.
active
ingredient
per
gallon)
is
labeled
for
use
on
commercial
(
sod
farm)
and
residential
warm­
season
turfgrasses
and
other
noncrop
land
including
golf
courses,
sports
fields,
and
ornamental
gardens.
Although
not
labeled
as
a
restricted­
use
pesticide,
Pennant
MAGNUMTM,
as
currently
marketed,
is
not
intended
for
homeowner
purchase
or
use
(
intended
for
use
by
professionals).
On
this
basis,
with
regard
to
the
requirements
of
FQPA,
metolachlor
and
S­
metolachlor
are
risk
assessed
for
postapplication
exposure
only.
Pennant
MAGNUMTM
and
PennantTM
are
both
emulsifiable
concentrates
(
EC).

For
this
risk
assessment,
small
children
are
the
population
group
of
concern.
Although
the
type
of
site
that
S­
metolachlor
may
be
used
on
varies
from
golf
courses
to
ornamental
gardens,
the
scenario
chosen
for
risk
assessment
(
residential
turf
use)
represents
what
the
Agency
considers
the
likely
upper­
end
of
possible
exposure.
Postapplication
exposures
from
various
activities
following
lawn
treatment
are
considered
to
be
the
most
common
and
significant
in
residential
settings.
Since
toxicity
was
not
observed
in
a
dermal
toxicity
study,
up
to
a
dose
level
of
1,000
mg/
kg/
day,
the
only
parameter
of
risk
necessarily
addressed
in
this
assessment
is
the
possible
oral
exposure
of
small
children
from
treated
turf,
or
soil.

The
estimate
for
hand­
to­
mouth
exposure
on
the
day
of
treatment
is
0.037
mg/
kg/
day
(
MOE
=
1,400)
for
S­
metolachlor
and
0.06
mg/
kg/
day
(
MOE
=
840)
for
metolachlor.
(
MOE
estimates
are
based
on
the
short­
term
NOAEL
of
50
mg/
kg/
day).

The
estimate
for
object­
to­
mouth
exposure
on
the
day
of
treatment
is
0.0092
mg/
kg/
day
(
MOE
=
5,400)
for
S­
metolachlor
and
0.015
mg/
kg/
day
(
MOE
=
3,300)
for
metolachlor.
(
MOE
estimates
are
based
on
the
short­
term
NOAEL
of
50
mg/
kg/
day).

The
estimate
for
soil
ingestion
exposure
on
the
day
of
treatment
is
0.00012
mg/
kg/
day
(
MOE
=
400,000)
for
S­
metolachlor
and
0.0002
mg/
kg/
day
(
MOE
=
250,000)
for
metolachlor.
(
MOE
estimates
are
based
on
the
short­
term
NOAEL
of
50
mg/
kg/
day).

The
estimate
for
hand­
to­
mouth,
object­
to­
mouth,
and
soil
ingestion
combined
(
on
the
day
of
treatment)
is
0.046
mg/
kg/
day
(
MOE
=
1,100)
for
S­
metolachlor
and
0.075
mg/
kg/
day
(
MOE
=
670)
for
metolachlor.
(
MOE
estimates
are
based
on
the
short­
term
NOAEL
of
50
mg/
kg/
day).
30
of
66
The
MOE
estimates
above
are
greater
than
100
and
indicate
that
the
potential
metolachlor/
Smetolachlor
exposure
(
to
children)
associated
with
residential
use
is
not
sufficient
to
require
further
assessment.
Although
considered
an
upper­
bound,
the
exposure
estimate
for
the
three
scenarios,
combined,
is
recommended
for
aggregate
(
residential,
food,
and
drinking
water)
risk
estimates.

5.3
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
S­
metolachlor.
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.
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
database
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
and
risks
associated
with
aerial
as
well
as
other
application
types
where
appropriate.

Please
note
that
as
indicated
in
this
assessment,
S­
metolachlor
is
directly
applied
to
residential
turf
and
does
not
result
in
exposures
of
concern.
It
is
unlikely
that
the
potential
for
risk
of
exposure
to
spray
drift
from
agricultural
uses
would
be
higher
than
that
estimated
for
the
turf
use
of
this
chemical.

6.0
Aggregate
Risk
Assessments
and
Risk
Characterization
6.1
Acute
Aggregate
Risk
An
acute
aggregate
risk
assessment
addresses
potential
exposure
from
combined
residues
of
metolachlor/
S­
metolachlor
on
food
and
in
drinking
water
(
both
surface
and
ground
water).
Potential
residential
exposures
are
not
incorporated
into
an
acute
aggregate
risk
assessment.
Since
the
exposure
from
food
and
drinking
water
were
already
incorporated
into
the
acute
dietary
risk
assessment,
no
further
aggregation
is
required.
The
dietary
exposure
estimate
to
the
U.
S.
population
was
<
1%
aPAD
and
the
most
highly
exposed
subgroup,
all
infants
<
1
yr
old,
at
2%
aPAD.
The
results
of
the
analysis
indicate
that
acute
aggregate
exposure
risk
to
S­
metolachlor
from
the
existing
and
requested
uses
did
not
exceed
the
Agency's
level
of
concern
for
U.
S.
population
or
any
population
subgroup.

6.2
Short­
Term
Aggregate
Risk
A
short­
term
aggregate
risk
assessment
considers
potential
exposure
from
food,
drinking
water,
and
short­
term,
non­
occupational
(
residential)
pathways
of
exposure
for
a
duration
of
1
to
30
31
of
66
days.
For
S­
metolachlor,
potential
short­
term,
non­
occupational
risk
scenarios
consist
of
oral
exposure
of
children
to
treated
lawns
only.
In
this
aggregate
short­
term
risk
assessment,
exposure
from
food,
drinking
water,
and
residential
lawns
has
been
considered.
The
exposure
to
food
and
water
has
already
been
considered
in
the
chronic
dietary
risk
assessment.
The
dietary
exposure
estimate
was
4%
cPAD
for
the
U.
S.
population
and
10%
cPAD
for
the
most
highly
exposed
subgroup,
all
infants
<
1
yrs
old.
Since
only
children
have
the
potential
for
nonoccupational
short­
term
risk,
they
are
the
only
population
subgroup
for
which
an
aggregate
short­
term
risk
assessment
was
conducted.
Toddlers'
S­
metolachlor
incidental
oral
exposure
is
assumed
to
include
hand­
to­
mouth
exposure,
object­
to­
mouth
exposure
and
exposure
through
incidental
ingestion
of
soil.

Table
6.2.
Short­
Term
Aggregate
Risk
Calculations
Short
­
Term
Scenario
Population
NOAEL
mg/
kg/
day
LOC1
Average
Food
&
Water
Exposure
mg/
kg/
day
Residential
Exposure2
mg/
kg/
day
Aggregate
MOE
(
food
and
residential)
3
All
infants
<
1
yr
old
50
100
0.010003
0.046
890
1
The
level
of
concern
(
LOC)
MOE
is
100,
based
on
inter­
and
intra­
species
safety
factors
totaling
100.
2
Residential
Exposure
=
[
Incidental
Oral
exposure
from
all
possible
sources
­
combined
hand­
to­
mouth,
object­
tomouth
and
soil
ingestion
oral
exposure].
No
residential
oral
exposure
is
expected
for
adults
3
Aggregate
MOE
=
[
NOAEL
÷
(
Avg
Food
&
Water
Exposure
+
Residential
Exposure)]

The
aggregate
short­
term
risk
for
exposure
to
S­
metolachlor
for
all
infants
<
1
yr
old,
the
subgroup
with
the
highest
exposure,
is
MOE
of
890,
which
does
not
reach
the
Agency's
level
of
concern.

6.3
Intermediate­
Term
Aggregate
Risk
An
intermediate­
term
aggregate
risk
assessment
considers
potential
exposure
from
food,
drinking
water,
and
non­
occupational
(
residential)
pathways
of
exposure
for
a
duration
of
30
to
180
days.
However,
for
metolachlor/
S­
metolachlor,
no
intermediate­
term
non­
occupational
exposure
scenarios
are
expected
to
occur;
therefore,
an
intermediate­
term
aggregate
risk
assessment
is
not
required.

6.4
Chronic
Aggregate
Risk
A
chronic
aggregate
risk
assessment
considers
chronic
exposure
from
food,
drinking
water,
and
non­
occupational
(
residential)
pathways
of
exposure.
For
metolachlor
and
S­
metolachlor,
there
are
no
chronic
(
greater
than
180
days
of
exposure)
non­
occupational
exposure
scenarios.
Therefore,
the
chronic
aggregate
risk
assessment
considers
exposure
from
food
and
drinking
water
only.
Since
the
exposure
from
food
and
drinking
water
were
already
incorporated
into
the
chronic
dietary
risk
assessment,
no
further
aggregation
is
required.
The
chronic
dietary
exposure
estimate
to
the
U.
S.
population
was
4%
cPAD
and
the
most
highly
exposed
subgroup,
all
infants
32
of
66
<
1
yrs
old,
at
10%
cPAD.
The
results
of
the
analysis
indicate
that
chronic
aggregate
risk
from
exposure
to
S­
metolachlor
from
the
existing
and
requested
uses
did
not
exceed
the
Agency's
level
of
concern
for
the
U.
S.
population
or
any
population
subgroup.

6.5
Cancer
Risk
Metolachlor
has
been
classified
as
a
Group
C,
possible
human
carcinogen
based
on
liver
tumors
in
rats
at
the
highest
dose
tested.
The
chronic
NOAEL
of
15
mg/
kg/
day
that
was
established
based
on
tumors
in
the
rat
(
seen
at
the
highest
dose
tested
of
150
mg/
kg/
day)
is
comparable
to
the
NOAEL
of
9.7
mg/
kg/
day
selected
for
establishing
the
chronic
reference
dose
for
metolachlor.
It
is
assumed
that
the
chronic
dietary
PAD
is
protective
for
cancer
dietary
risk.
Therefore,
a
separate
cancer
aggregate
risk
assessment
was
not
conducted.

7.0
Cumulative
Risk
Characterization/
Assessment
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
S­
metolachlor
and
any
other
substances
and
S­
metolachlor
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
S­
metolachlor
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/.

8.0
Occupational
Exposure/
Risk
Pathway
S­
metolachlor
is
a
widely
used
herbicide
in
the
United
States
 
it
is
used
in
agricultural,
commercial,
and
residential
settings.
S­
metolachlor
is
formulated
as
an
emulsifiable
concentrate
and
is
applied
with
several
types
of
application
equipment.
The
major
wide­
area
methods
are
aerial,
groundboom,
and
chemigation
applications.
Applications
to
smaller
areas
may
be
made
with
handheld
equipment,
including
low­
pressure
handwand
sprayers,
high
pressure
handwand
sprayers,
and
handgun
sprayers.
S­
metolachlor
can
also
be
impregnated
into
dry
bulk
fertilizers.
There
is
a
potential
for
exposure
to
S­
metolachlor
in
occupational
scenarios
from
handling
Smetolachlor
products
during
the
application
process
(
i.
e.,
mixer/
loaders,
applicators,
flaggers,
and
mixer/
loader/
applicators)
and
a
potential
for
postapplication
worker
exposure
from
entering
into
areas
previously
treated
with
S­
metolachlor.
As
a
result,
risk
assessments
have
been
completed
for
occupational
handler
scenarios
as
well
as
occupational
postapplication
scenarios.

A
chemical
can
produce
different
effects
based
on
how
long
a
person
is
exposed,
how
frequently
exposures
occur,
and
the
level
of
exposure.
HED
classifies
exposures
up
to
30
days
as
shortterm
and
exposures
greater
than
30
days
up
to
several
months
as
intermediate­
term.
HED
completes
both
short­
and
intermediate­
term
assessments
for
occupational
scenarios
in
essentially
all
cases,
because
these
kinds
of
exposures
are
likely
and
acceptable
use/
usage
data
are
not
available
to
justify
deleting
intermediate­
term
scenarios.
Based
on
use
data
and
label
33
of
66
instructions,
HED
believes
that
occupational
S­
metolachlor
exposures
may
occur
over
a
single
day
or
up
to
weeks
at
a
time
for
many
use­
patterns
and
intermittent
exposures
over
several
weeks
also
may
occur.
Some
applicators
may
apply
S­
metolachlor
over
a
period
of
weeks,
because
they
are
custom
or
commercial
applicators
who
are
completing
a
number
of
applications
for
a
number
of
different
clients.
Long­
term
handler
exposures
are
not
expected
to
occur
for
Smetolachlor
Different
toxicological
endpoints
of
concern
have
been
selected
for
short­
and
intermediate­
term
inhalation
exposures
to
S­
metolachlor;
therefore
the
risk
results
for
all
inhalation
durations
of
exposure
are
numerically
distinct.

This
risk
assessment
incorporates
the
toxicological
endpoints
of
concern
as
presented
in
the
Report
of
the
Hazard
Identification
Assessment
Review
Committee
(
HIARC)
September
28,
2001.
No
short­
or
intermediate­
term
dermal
endpoint
of
concern
was
identified.
The
short­
term
inhalation
endpoint
of
concern
(
50
mg/
kg/
day)
is
based
on
increased
incidence
of
clinical
signs,
decreased
body
weight
and
body
weight
gain,
food
consumption,
and
food
efficiency
from
an
oral
prenatal
developmental
toxicity
study
in
rats
with
S­
metolachlor.
Since
an
oral
study
was
selected,
a
100%
absorption
factor
should
be
applied
and
since
the
endpoint
is
from
a
prenatal
developmental
toxicity
study,
a
body
weight
of
60
kilograms
 
the
weight
of
an
average
female
adult
 
was
used.
The
intermediate­
term
inhalation
endpoint
of
concern
(
8.8
mg/
kg/
day)
is
based
on
decreased
body
weight
gain
from
an
oral
subchronic
(
6
month)
toxicity
study
in
dogs
with
metolachlor.
Since
an
oral
study
was
selected,
a
100%
absorption
factor
should
be
applied
and
since
the
toxicological
endpoint
of
concern
is
not
sex­
specific,
a
body
weight
of
70
kilograms
 
the
weight
of
an
average
adult
 
was
used.
Only
inhalation
MOEs
were
calculated,
therefore,
no
aggregation
was
performed.

The
Agency's
level
of
concern
for
noncancer
risks
(
i.
e.,
target
level
for
MOEs)
is
defined
by
the
uncertainty
factors
that
are
applied
to
the
assessment.
The
Agency
applies
a
factor
of
100
to
account
for
inter­
species
extrapolation
to
humans
from
the
animal
test
species
and
to
account
for
intra­
species
sensitivity.
The
total
uncertainty
factor
that
has
been
applied
to
noncancer
risk
assessments
is
100
for
occupational
scenarios.

8.1
Short/
Intermediate/
Long­
Term/
Cancer
Handler
Risk
HED
uses
the
term
"
handlers"
to
describe
those
individuals
who
are
involved
in
the
pesticide
application
process.
HED
believes
that
there
are
distinct
job
functions
or
tasks
related
to
applications
and
that
exposures
can
vary
depending
on
the
specifics
of
each
task.
Job
requirements
(
e.
g.,
amount
of
chemical
to
be
used
in
an
application),
the
kinds
of
equipment
used,
the
target
being
treated,
and
the
level
of
protection
used
by
a
handler
can
cause
exposure
levels
to
differ
in
a
manner
specific
to
each
application
event.

8.1.1
Data
and
Assumptions
for
Proposed
Handler
Exposure
Scenarios
HED
uses
exposure
scenarios
to
describe
the
various
types
of
handler
exposures
that
may
occur
for
a
specific
active
ingredient.
The
anticipated
use
patterns
and
current
labeling
indicate
several
34
of
66
occupational
exposure
scenarios
based
on
the
types
of
equipment
and
techniques
that
can
potentially
be
used
for
S­
metolachlor
applications.

A
series
of
assumptions
and
exposure
factors
served
as
the
basis
for
completing
the
occupational
handler
risk
assessments.
Each
assumption
and
factor
is
detailed
below
on
an
individual
basis.
The
assumptions
and
factors
used
in
the
risk
calculations
include:

 
Occupational
handler
exposure
estimates
were
based
on
surrogate
data
from:
(
1)
the
Pesticide
Handlers
Exposure
Database
(
PHED)
and
(
2)
the
Outdoor
Residential
Exposure
Task
Force
(
ORETF).

 
The
adverse
effects
for
the
short­
term
inhalation
endpoint
are
based
on
an
inhalation
study
where
the
effects
were
observed
in
females,
therefore,
the
average
body
weight
of
an
adult
female
handler
(
i.
e.,
60
kg)
is
used
to
complete
the
short­
term
inhalation
noncancer
risk
assessment.

 
The
adverse
effects
for
the
intermediate­
term
inhalation
endpoint
are
based
on
an
inhalation
study
where
the
effects
were
observed
in
males
and
females,
therefore,
the
average
body
weight
of
an
adult
handler
(
i.
e.,
70
kg)
is
used
to
complete
the
intermediate­
term
inhalation
noncancer
risk
assessment.

 
Exposure
factors
used
to
calculate
daily
exposures
to
handlers
are
based
on
applicable
data,
if
available.

 
For
non­
cancer
assessments,
HED
assumes
the
maximum
application
rates
allowed
by
labels
in
its
risk
assessments
(
see
Table
3).

 
The
average
occupational
workday
is
assumed
to
be
8
hours.

 
The
daily
areas
treated
were
defined
for
each
handler
scenario
(
in
appropriate
units)
by
determining
the
amount
that
can
be
reasonably
treated
in
a
single
day
(
e.
g.,
acres,
square
feet,
cubic
feet,
or
gallons
per
day).
When
possible,
the
assumptions
for
daily
areas
treated
are
taken
from
the
Health
Effects
Division
Science
Advisory
Committee
on
Exposure
SOP
#
9:
Standard
Values
for
Daily
Acres
Treated
in
Agriculture,
which
was
completed
on
July
5,
2000.
However,
no
standard
values
are
available
for
numerous
scenarios.
Assumptions
for
these
scenarios
are
based
on
HED
estimates
and
could
be
further
refined
from
input
from
affected
sectors
(
see
Table
8.1.1).

Table
8.1.1
Summary
of
Maximum
Application
Rates
for
Proposed
S­
Metolachlor
Uses
from
Magnum
Herbicide
(
EPA
Reg
No.
100­
816)

Crop
or
Target
Application
Rate
(
lb
ai/
acre)
Application
Equipment
Area
Treated
Daily
(
acres)

Agricultural
Uses
Sodfarms
2.5
lb
ai/
acre
Aerial
350
acres
35
of
66
Table
8.1.1
Summary
of
Maximum
Application
Rates
for
Proposed
S­
Metolachlor
Uses
from
Magnum
Herbicide
(
EPA
Reg
No.
100­
816)

Crop
or
Target
Application
Rate
(
lb
ai/
acre)
Application
Equipment
Area
Treated
Daily
(
acres)

Chemigation
Groundboom
80
acres
Dry
Bulk
Fertilizers
(
on­
farm)
80
acres
320
acres
(
commercial
applicator)
50
lb
ai/
ton
(
based
on
label
recommendation
of
100
pounds
of
fertilizer
per
acre)
Dry
Bulk
Fertilizers
(
commercial)
500
­
960
tons
(
commercial
mixer/
loader)

Aerial
Chemigation
350
acres
Groundboom
80
acres
2.5
lb
ai/
acre
Dry
Bulk
Fertilizers
(
on­
farm)
80
acres
320
acres
(
commercial
applicator)
Tabasco
Peppers
25
lb
ai/
ton
(
based
on
label
recommendation
of
200
pounds
of
fertilizer
per
acre)
Dry
Bulk
Fertilizers
(
commercial)
500
­
960
tons
(
commercial
mixer/
loader)

Chemigation
60
acres
Dry
Bulk
Fertilizers
(
on­
farm)
60
acres
Handgun
Sprayer
5
acres
High
Pressure
Handwand
Sprayer
5acres
2.5
lb
ai/
acre
Low
Pressure
Handwand
Sprayer
2
acres
320
acres
(
commercial
applicator)
Nurseries
50
lb
ai/
ton
(
based
on
label
recommendation
of
100
pounds
of
fertilizer
per
acre)
Dry
Bulk
Fertilizers
(
commercial)
500
­
960
tons
(
commercial
mixer/
loader)

Aerial
1200
acres
Chemigation
350
acres
Groundboom
200
acres
1.9
lb
ai/
acre
Dry
Bulk
Fertilizers
(
on­
farm)
160
acres
320
acres
(
commercial
applicator)
Corn,
Soybeans
19
lb
ai/
ton
(
based
on
label
recommendation
of
200
pounds
of
fertilizer
per
acre)
Dry
Bulk
Fertilizers
(
commercial)
500
­
960
tons
(
commercial
mixer/
loader)

Pod
crops,
1.9
lb
ai/
acre
Aerial
350
36
of
66
Chemigation
Groundboom
80
Dry
Bulk
Fertilizers
(
on­
farm)
80
acres
320
acres
(
commercial
applicator)
Peanuts,
Potatoes,
Safflowers,
Brassica
head
and
stem,
Leaf
petioles
19
lb
ai/
ton
(
based
on
label
recommendation
of
200
pounds
of
fertilizer
per
acre)
Dry
Bulk
Fertilizers
(
commercial)
500
­
960
tons
(
commercial
mixer/
loader)

Aerial
1200
acres
Chemigation
350
acre
Groundboom
200
acres
1.6
lb
ai/
acre
Dry
Bulk
Fertilizers
(
on­
farm)
160
acres
320
acres
(
commercial
applicator)
Grain/
Forage
Sorghum
16
lb
ai/
ton
(
based
on
label
recommendation
of
200
pounds
of
fertilizer
per
acre)
Dry
Bulk
Fertilizers
(
commercial)
500
­
960
tons
(
commercial
mixer/
loader)

Aerial
Chemigation
350
acres
Groundboom
80
acres
1.6
lb
ai/
acre
Dry
Bulk
Fertilizers
(
on­
farm)
80
acres
320
acres
(
commercial
applicator)
Transplanted
and
Direct
Seeded
Vegetables
16
lb
ai/
ton
(
based
on
label
recommendation
of
200
pounds
of
fertilizer
per
acre)
Dry
Bulk
Fertilizers
(
commercial)
500
­
960
tons
(
commercial
mixer/
loader)

Aerial
1200
acres
Chemigation
350
acres
Groundboom
200
acres
1.3
lb
ai/
acre
(
based
on
label
recommendation
of
200
pounds
of
fertilizer
per
acre)
Dry
Bulk
Fertilizers
(
on­
farm)
160
acres
320
acres
(
commercial
applicator)
Cotton
13
lb
ai/
ton
Dry
Bulk
Fertilizers
(
commercial)
500
­
960
tons
(
commercial
mixer/
loader)

Chemigation
350
acres
Pumpkins
and
Winter
Squash
1.27
lb
ai/
A
Groundboom
80
acres
Aerial
Chemigation
350
acres
Groundboom
80
acres
Green
and
Dry
Bulb
onions,
Vegetable
root
(
except
sugar
beet)
1.3
lb
ai/
acre
Dry
Bulk
Fertilizers
(
on­
farm)
80
acres
37
of
66
320
acres
(
commercial
applicator)
13
lb
ai/
ton
(
based
on
label
recommendation
of
200
pounds
of
fertilizer
per
acre)
Dry
Bulk
Fertilizers
(
commercial)
500
­
960
tons
(
commercial
mixer/
loader)

Commercial
Uses
Residential
and
Commercial
Turfgrass
2.5
Handgun
Sprayer
5
acres
Handgun
Sprayer
5
acres
High
Pressure
Handwand
Sprayer
5
acres
Landscape
Plantings
2.5
Low
Pressure
Handwand
Sprayer
2
acres
8.1.2
Summary
of
Exposure
Data
for
Handler
Exposure
Scenarios
HED
uses
unit
exposure
to
assess
handler
exposures
to
pesticides.
Unit
exposures
are
estimates
of
the
amount
of
exposure
to
an
active
ingredient
a
handler
receives
while
performing
various
handler
tasks
and
are
expressed
in
terms
of
micrograms
or
milligrams
of
active
ingredient
per
pounds
of
active
ingredient
handled.
HED
has
developed
a
series
of
unit
exposures
that
are
unique
for
each
scenario
typically
considered
in
our
assessments
(
i.
e.,
there
are
different
unit
exposures
for
different
types
of
application
equipment,
job
functions,
and
levels
of
protection).
The
unit
exposure
concept
has
been
established
in
the
scientific
literature
and
also
through
various
exposure
monitoring
guidelines
published
by
the
U.
S.
EPA
and
international
organizations
such
as
Health
Canada
and
OECD
(
Organization
for
Economic
Cooperation
and
Development).

Pesticide
Handler
Exposure
Database
(
PHED)
Version
1.1
(
August
1998):
PHED
was
designed
by
a
task
force
of
representatives
from
the
U.
S.
EPA,
Health
Canada,
the
California
Department
of
Pesticide
Regulation,
and
member
companies
of
the
American
Crop
Protection
Association.
PHED
is
a
software
system
consisting
of
two
parts
 
a
database
of
measured
exposures
for
workers
involved
in
the
handling
of
pesticides
under
actual
field
conditions
and
a
set
of
computer
algorithms
used
to
subset
and
statistically
summarize
the
selected
data.
Currently,
the
database
contains
values
for
over
1,700
monitored
individuals
(
i.
e.,
replicates).

Occupational
handler
exposure
assessments
are
completed
by
HED
using
different
levels
of
risk
mitigation.
Typically,
HED
uses
a
tiered
approach.
The
lowest
tier
is
designated
as
the
baseline
exposure
scenario
(
i.
e.,
no
respirator).
If
risks
are
of
concern
at
baseline
attire,
then
increasing
levels
of
personal
protective
equipment
or
PPE
(
e.
g.,
respirators)
are
evaluated.
If
risks
remain
a
concern
with
maximum
PPE,
then
engineering
controls
(
e.
g.,
enclosed
cabs
or
cockpits,
watersoluble
packaging,
and
closed
mixing/
loading
systems)
are
evaluated.
This
approach
is
used
to
ensure
that
the
lowest
level
of
risk
mitigation
that
provides
adequate
protection
is
selected,
since
the
addition
of
PPE
and
engineering
controls
involves
an
additional
expense
to
the
user
and
 
in
the
case
of
PPE
 
also
involves
an
additional
burden
to
the
user
due
to
decreased
comfort
and
dexterity
and
increased
heat
stress
and
respiratory
stress.
38
of
66
Surrogate
Data:
HED
used
surrogate
data
for
some
exposure
scenarios.

HED
generated
MOEs
to
assess
risk
to
commercial
handlers
engaged
in
impregnating
Smetolachlor
onto
dry
bulk
fertilizer
using
inhalation
unit
exposure
data
from
the
Pesticide
Handlers
Exposure
Database
(
PHED),
Version
1.1
(
August
1998).
The
PHED
scenario
for
mixing/
loading
liquids
using
a
closed
system
were
used
as
a
surrogate
to
estimate
these
exposures.
However,
such
an
exposure
surrogate
is
less
appropriate
for
estimating
exposures
due
to
transferring
the
treated
dry
bulk
fertilizer
from
an
auger
truck
to
the
application
equipment.
There
are
no
data
or
reasonable
surrogate
data
available
for
this
operation.

HED
generated
MOEs
to
assess
risk
to
on­
farm
handlers
engaged
in
impregnating
S­
metolachlor
onto
dry
bulk
fertilizer
using
inhalation
unit
exposure
data
from
the
Pesticide
Handlers
Exposure
Database
(
PHED),
Version
1.1
(
August
1998).
The
PHED
scenario
for
mixing/
loading
liquids
using
an
open
system
was
used
as
a
surrogate
to
estimate
these
exposures.

HED
generated
MOEs
to
assess
risk
to
on­
farm
and
commercial
applicators
engaged
in
applying
impregnated
dry
bulk
fertilizer
using
inhalation
unit
exposure
data
from
the
Pesticide
Handlers
Exposure
Database
(
PHED),
Version
1.1
(
August
1998).
The
PHED
scenario
for
applying
granular
formulations
with
a
tractor­
drawn
spreader
using
an
open
cab
was
used
as
a
surrogate
to
estimate
these
exposures.

8.1.3
Non­
cancer
S­
metolachlor
Handler
Exposure
and
Risk
The
following
equations
and
calculations
were
used
in
determining
handler
exposure
and
risk:

Daily
Exposure:
Daily
inhalation
handler
exposures
are
estimated
for
each
applicable
handler
task
with
the
application
rate,
the
area
treated
in
a
day,
and
the
applicable
inhalation
unit
exposure
using
the
following
formula:

  
 

  
 

  
 

  
 

  
 

  
 

  
 

  
 
×
×
=
day
area
Treated
Area
Daily
area
ai
lb
Rate
n
Applicatio
handled
ai
lb
ai
mg
Exposure
Unit
day
ai
mg
Exposure
Dailey
Where:

Daily
Exposure
=
Amount
(
mg
ai/
day)
inhaled
that
is
available
for
inhalation
absorption;
Unit
Exposure
=
Unit
exposure
value
(
mg
ai/
lb
ai)
derived
from
August
1998
PHED
data,
from
ORETF
data,
and
from
Proprietary
data;
Application
Rate
=
Normalized
application
rate
based
on
a
logical
unit
treatment,
such
as
acres,
or
tons.
Maximum
values
are
generally
used
(
lb
ai/
A,
lb
ai/
ton);
and
Daily
Area
Treated
=
Normalized
application
area
based
on
a
logical
unit
treatment
such
as
acres
(
A/
day)
or
tons
(
tons/
day).

Daily
Dose:
The
daily
inhalation
dose
is
calculated
by
normalizing
the
daily
exposure
by
body
weight
and
adjusting,
if
necessary,
with
an
appropriate
inhalation
absorption
factor.
For
short­
term
inhalation
exposure
scenarios
for
S­
metolachlor,
an
average
adult
female
body
weight
of
60
kilograms
was
used,
since
the
toxicological
endpoint
is
sex­
specific.
For
intermediate­
term
inhalation
exposure
scenarios
for
S­
metolachlor,
an
average
adult
body
weight
of
70
kilograms
39
of
66
was
used,
since
the
toxicological
endpoint
is
not
sex­
specific.
Since
the
inhalation
toxicological
endpoints
of
concern
are
based
on
oral
studies,
an
inhalation
absorption
factor
of
100%
is
needed
for
the
inhalation
dose
calculations.
Daily
dose
was
calculated
using
the
following
formula:

(
)

 
 

 
 

 
 

 
 
×

 
 

 
 

 
 

 
 
=
(
kg)
h
Body
Weigt
(%/
100)
Factor
Absorption
day
ai
mg
Exposure
Daily
mg/
kg/
day
Dose
Daily
Average
Where:

Average
Daily
Dose
=
Absorbed
dose
received
from
exposure
to
a
pesticide
in
a
given
scenario
(
mg
pesticide
active
ingredient/
kg
body
weight/
day);
Daily
Exposure
=
Amount
(
mg
ai/
day)
inhaled
that
is
available
for
inhalation
absorption;
Absorption
Factor
=
A
measure
of
the
amount
of
chemical
that
crosses
a
biological
boundary
such
as
the
lungs
(%
of
the
total
available
absorbed);
and
Body
Weight
=
Body
weight
determined
to
represent
the
population
of
interest
in
a
risk
assessment
(
kg).

Margins
of
Exposure:
Non­
cancer
inhalation
risks
for
each
applicable
handler
scenario
are
calculated
using
a
Margin
of
Exposure
(
MOE),
which
is
a
ratio
of
the
daily
dose
to
the
toxicological
endpoint
of
concern.
All
MOE
values
were
calculated
for
inhalation
exposure
levels
using
the
formula
below:

)
(
mg/
kg/
day
Dose
Daily
Average
)
(
mg/
kg/
day
LOAEL
or
NOAEL
MOE=

Where:

MOE
=
Margin
of
Exposure,
value
used
by
HED
to
represent
risk
or
how
close
a
chemical
exposure
is
to
being
a
concern
(
unitless);
ADD
=
Average
Daily
Dose
or
the
absorbed
dose
received
from
exposure
to
a
pesticide
in
a
given
scenario
(
mg
pesticide
active
ingredient/
kg
body
weight/
day);
and
NOAEL
or
LOAEL
=
Dose
level
in
a
toxicity
study,
where
no
observed
adverse
effects
(
NOAEL)
or
where
the
lowest
observed
adverse
effects
(
LOAEL)
occurred
in
the
study
The
short­
and
intermediate­
term
non­
cancer
risk
calculations
for
occupational
S­
metolachlor
handlers
are
presented
in
Table
8.1.3.
Dermal
risks
were
not
evaluated
since
no
hazard
was
identified
for
quantification
of
risk
following
dermal
exposure.
For
both
short­
term
and
intermediate­
term
exposures,
the
following
scenarios
risks
were
not
a
concern
at
the
baseline
level
(
no
respirator)
of
exposure:

 
Mixing/
Loading
Emulsifiable
Concentrates
for
Aerial
Applications
 
Mixing/
Loading
Emulsifiable
Concentrates
for
Chemigation
Applications
 
Mixing/
Loading
Dry
Bulk
Fertilizers
(
on­
farm,
PHED)
 
Mixing/
Loading
Emulsifiable
Concentrates
for
Groundboom
Applications
 
Applying
Liquid
Sprays
via
Groundboom
Equipment
 
Applying
Dry
Bulk
Fertilizers
(
commercial,
PHED)
 
Applying
Dry
Bulk
Fertilizers
(
on­
farm,
PHED)
 
Flagging
for
Liquid
Sprays
via
Aerial
Equipment
 
Mixing/
Loading/
Applying
Emulsifiable
Concentrates
with
a
Handgun
Sprayer
40
of
66
 
Mixing/
Loading/
Applying
Emulsifiable
Concentrates
with
a
Low
Pressure
Handwand
HED
has
insufficient
data
to
assess
baseline
and
PPE
levels
of
exposures
to
assess
risks
to
pilots
applying
sprays
with
open­
cockpit
aerial
equipment
 
the
only
available
data
is
for
pilots
using
enclosed
cockpits.
In
addition,
HED
assumes
commercial
mixer/
loaders
impregnating
dry
bulk
fertilizers
(
using
the
PHED
data)
are
using
engineering
controls
(
i.
e.,
closed
systems).
Therefore
for
these
scenarios,
only
inhalation
risks
using
engineering
controls
are
assessed.
The
inhalation
risks
at
the
engineering
control
level
of
exposure
were
not
a
concern
for
these
scenarios:

 
Mixing/
Loading
Dry
Bulk
Fertilizers
(
commercial
­­
PHED)
 
Applying
Liquid
Sprays
via
Aerial
Equipment
For
most
of
the
occupational
handler
scenarios
for
S­
metolachlor
risks
were
not
found
to
be
a
concern
at
the
baseline
attire
exposure
level.
For
those
scenarios
with
only
engineering
control
exposure
data
available,
risks
were
not
found
to
be
a
concern
at
that
level
of
exposure.
Therefore,
the
short­
and
intermediate­
term
inhalation
handler
risk
assessment
for
S­
metolachlor
does
not
indicate
risk
concerns
for
any
of
the
handler
scenarios.

The
key
data
gap
identified
by
HED
for
occupational
handlers
is
exposures
while
transferring
just­
impregnated
dry
bulk
fertilizer
into
trucks.
After
impregnation,
the
treated
fertilizer
is
gravity­
fed
through
a
hopper
onto
a
conveyor
belt
leading
to
a
truck,
which
carries
it
to
the
field.
There
are
no
data
or
reasonable
surrogates
available
for
the
transfer
operation.
In
addition,
data
gaps
exist
for
mixing/
loading
and
applying
dry
bulk
fertilizers.
HED
has
no
data
for
these
scenarios
and
has
used
surrogate
PHED
data
from
scenarios
assumed
to
be
similar.

In
order
to
refine
this
occupational
risk
assessment,
data
on
actual
use
patterns
including
rates,
timing,
and
areas
treated
would
better
characterize
S­
metolachlor
risks.
Exposure
studies
for
many
equipment
types
that
lack
data
or
that
are
not
well
represented
in
PHED
(
e.
g.,
because
of
low
replicate
numbers
or
data
quality)
should
also
be
considered
based
on
the
data
gaps
identified
above
and
based
on
a
review
of
the
quality
of
the
data
used
in
this
assessment.
41
of
66
42
of
66
Table
8.1.3
S­
Metolachlor
Short­
term
and
Intermediate­
term
Inhalation
Risks
Unit
Exposures
(
Fg/
lb
ai)

Exposure
Scenario
Crop
or
Target
Application
Ratea
Area
Treated
Dailyb
No
Respiratorc
(
unless
noted)
No
Respirator
(
unless
noted)

Short­
term
Dose
(
mg/
kg/
day)
No
Respirator
(
unless
noted)

Short­
term
MOEd
No
Respirator
(
unless
noted)

Intermediate­
term
Dose
(
mg/
kg/
day)
No
Respirator
(
unless
noted)
Intermediate­
term
MOEe
Mixer/
Loader
Tabasco
Peppers,

Sodfarms
2.5
lb
ai/
acre
350
acres
1.2
0.018
2900
0.015
590
Corn,
Soybeans
1.9
lb
ai/
acre
1200
acres
1.2
0.046
1100
0.039
230
Peanuts,
Pod
crops,

Potatoes,
Safflowers,

Brassica
head
and
stem,
Leaf
petioles
1.9
lb
ai/
acre
350
acres
1.2
0.013
3800
0.011
770
Grain/
Forage
Sorghum
1.6
lb
ai/
acre
1200
acres
1.2
0.038
1300
0.033
270
Transplanted
and
Direct
Seeded
Vegetables
1.6
lb
ai/
acre
350
acres
1.2
0.011
4500
0.0096
920
Cotton
1.3
lb
ai/
acre
1200
acres
1.2
0.031
1600
0.027
330
Emulsifiable
Concentrates
(
Liquids)
for
Aerial
Applications
Green
and
Dry
Bulb
onions,
Vegetable
root
(
except
sugar
beet)
1.3
lb
ai/
acre
350
acres
1.2
0.0091
5500
0.0078
1100
Emulsifiable
Concentrates
Tabasco
Peppers,

Sodfarms
2.5
lb
ai/
acre
350
acres
1.2
0.018
2900
0.015
590
43
of
66
Table
8.1.3
S­
Metolachlor
Short­
term
and
Intermediate­
term
Inhalation
Risks
Unit
Exposures
(
Fg/
lb
ai)

Exposure
Scenario
Crop
or
Target
Application
Ratea
Area
Treated
Dailyb
No
Respiratorc
(
unless
noted)
No
Respirator
(
unless
noted)

Short­
term
Dose
(
mg/
kg/
day)
No
Respirator
(
unless
noted)

Short­
term
MOEd
No
Respirator
(
unless
noted)

Intermediate­
term
Dose
(
mg/
kg/
day)
No
Respirator
(
unless
noted)
Intermediate­
term
MOEe
(
Liquids)
for
Chemigation
Applications
Nurseries
2.5
lb
ai/
acre
60
acres
1.2
0.003
17000
0.0026
3400
44
of
66
Corn,
Peanuts,
Pod
crops,
Potatoes,

Safflowers,

Soybeans,
Brassica
head
and
stem,
Leaf
petioles
1.9
lb
ai/
acre
350
acres
1.2
0.013
3800
0.011
770
Grain/
Forage
Sorghum,

Transplanted
and
Direct
Seeded
Vegetables
1.6
lb
ai/
acre
350
acres
1.2
0.011
4500
0.0096
920
Cotton,
Green
and
Dry
Bulb
onions,

Vegetable
root
(
except
sugar
beet)
1.3
lb
ai/
acre
350
acres
1.2
0.0091
5500
0.0078
1100
Pumpkin
and
Winter
Squash
1.27
lb
ai/
acre
350
acres
1.2
0.0089
5,600
0.0076
1,200
Sodfarms,
Nurseries
50
lb
ai/
ton
960
tons
0.083
(
engineering
controls)
0.066
(
engineering
controls)
750
(
engineering
controls)
0.057
(
engineering
controls)
150
(
engineering
controls)

Sodfarms,
Nurseries
50
lb
ai/
ton
500
tons
0.083
(
engineering
controls)
0.035
(
engineering
controls)
1,400
(
engineering
controls)
0.03
(
engineering
controls)
300
(
engineering
controls)

Tabasco
Peppers
25
lb
ai/
ton
960
tons
0.083
(
engineering
controls)
0.033
(
engineering
controls)
1,500
(
engineering
controls)
0.028
(
engineering
controls)
310
(
engineering
controls)

Dry
Bulk
Fertilizers
(
commercial
­­

PHED)
Tabasco
Peppers
25
lb
ai/
ton
500
tons
0.083
(
engineering
controls)
0.017
(
engineering
controls)
2,900
(
engineering
controls)
0.015
(
engineering
controls)
590
(
engineering
controls)
45
of
66
Corn,
Peanuts,
Pod
crops,
Potatoes,

Safflowers,

Soybeans,
Brassica
head
and
stem,
Leaf
petioles
19
lb
ai/
ton
960
tons
0.083
(
engineering
controls)
0.025
(
engineering
controls)
2,000
(
engineering
controls)
0.022
(
engineering
controls)
410
(
engineering
controls)

Corn,
Peanuts,
Pod
crops,
Potatoes,

Safflowers,

Soybeans,
Brassica
head
and
stem,
Leaf
petioles
19
lb
ai/
ton
500
tons
0.083
(
engineering
controls)
0.013
(
engineering
controls)
3,800
(
engineering
controls)
0.011
(
engineering
controls)
780
(
engineering
controls)

Grain/
Forage
Sorghum,

Transplanted
and
Direct
Seeded
Vegetables
16
lb
ai/
ton
960
tons
0.083
(
engineering
controls)
0.021
(
engineering
controls)
2,400
(
engineering
controls)
0.018
(
engineering
controls)
480
(
engineering
controls)

Grain/
Forage
Sorghum,

Transplanted
and
Direct
Seeded
Vegetables
16
lb
ai/
ton
500
tons
0.083
(
engineering
controls)
0.011
(
engineering
controls)
4,500
(
engineering
controls)
0.0095
(
engineering
controls)
930
(
engineering
controls)

Cotton,
Green
and
Dry
Bulb
onions,

Vegetable
root
(
except
sugar
beet)
13
lb
ai/
ton
960
tons
0.083
(
engineering
controls)
0.017
(
engineering
controls)
2,900
(
engineering
controls)
0.015
(
engineering
controls)
590
(
engineering
controls)

Cotton,
Green
and
Dry
Bulb
onions,

Vegetable
root
(
except
sugar
beet)
13
lb
ai/
ton
500
tons
0.083
(
engineering
controls)
0.009
(
engineering
controls)
5,600
(
engineering
controls)
0.0077
(
engineering
controls)
1100
(
engineering
controls)

Tabasco
Peppers,

Sodfarms
2.5
lb
ai/
acre
80
acres
1.2
0.004
13000
0.0034
2600
Nurseries
2.5
lb
ai/
acre
60
acres
1.2
0.003
17000
0.0026
3400
Dry
Bulk
Fertilizers
(
on­
farm
­­
PHED)
Corn,
Peanuts,

Soybeans
1.9
lb
ai/
acre
160
acres
1.2
0.0061
8200
0.0052
1700
46
of
66
Pod
crops,
Potatoes,

Safflowers,
Brassica
head
and
stem,
Leaf
petioles
1.9
lb
ai/
acre
80
acres
1.2
0.003
16000
0.0026
3400
Grain/
Forage
Sorghum
1.6
lb
ai/
acre
160
acres
1.2
0.0051
9800
0.0044
2000
Transplanted
and
Direct
Seeded
Vegetables
1.6
lb
ai/
acre
80
acres
1.2
0.0026
20000
0.0022
4000
Cotton
1.3
lb
ai/
acre
160
acres
1.2
0.0042
12000
0.0036
2500
Green
and
Dry
Bulb
onions,
Vegetable
root
(
except
sugar
beet)
1.3
lb
ai/
acre
80
acres
1.2
0.0021
24000
0.0018
4900
Tabasco
Peppers,

Sodfarms
2.5
lb
ai/
acre
80
acres
1.2
0.004
13000
0.0034
2600
Corn,
Soybeans
1.9
lb
ai/
acre
200
acres
1.2
0.0076
6600
0.0065
1400
Peanuts,
Pod
crops,

Potatoes,
Safflowers,

Brassica
head
and
stem,
Leaf
petioles
1.9
lb
ai/
acre
80
acres
1.2
0.003
16000
0.0026
3400
Grain/
Forage
Sorghum
1.6
lb
ai/
acre
200
acres
1.2
0.0064
7800
0.0055
1600
Transplanted
and
Direct
Seeded
Vegetables
1.6
lb
ai/
acre
80
acres
1.2
0.0026
20000
0.0022
4000
Cotton
1.3
lb
ai/
acre
200
acres
1.2
0.0052
9600
0.0045
2000
Emulsifiable
Concentrates
(
Liquids)
for
Groundboom
Applications
Green
and
Dry
Bulb
onions,
Vegetable
root
(
except
sugar
beet)
1.3
lb
ai/
acre
80
acres
1.2
0.0021
24000
0.0018
4900
47
of
66
Pumpkin
and
Winter
Squash
1.27
lb
ai/
acre
80
acres
1.2
0.0020
25,000
0.0017
5,100
Applicator
Tabasco
Peppers,

Sodfarms
2.5
lb
ai/
acre
350
acres
0.068
(
engineering
controls)
0.00099
(
engineering
controls)
50,000
(
engineering
controls)
0.00085
(
engineering
controls)
10000
(
engineering
controls)

Corn,
Soybeans
1.9
lb
ai/
acre
1200
acres
0.068
(
engineering
controls)
0.0026
(
engineering
controls)
19,000
(
engineering
controls)
0.0022
(
engineering
controls)
4000
(
engineering
controls)

Peanuts,
Pod
crops,

Potatoes,
Safflowers,

Brassica
head
and
stem,
Leaf
petioles
1.9
lb
ai/
acre
350
acres
0.068
(
engineering
controls)
0.00075
(
engineering
controls)
66,000
(
engineering
controls)
0.00065
(
engineering
controls)
14000
(
engineering
controls)

Grain/
Forage
Sorghum
1.6
lb
ai/
acre
1200
acres
0.068
(
engineering
controls)
0.0022
(
engineering
controls)
23,000
(
engineering
controls)
0.0019
(
engineering
controls)
4700
(
engineering
controls)

Transplanted
and
Direct
Seeded
Vegetables
1.6
lb
ai/
acre
350
acres
0.068
(
engineering
controls)
0.00063
(
engineering
controls)
79,000
(
engineering
controls)
0.00054
(
engineering
controls)
16000
(
engineering
controls)

Cotton
1.3
lb
ai/
acre
1200
acres
0.068
(
engineering
controls)
0.0018
(
engineering
controls)
28,000
(
engineering
controls)
0.0015
(
engineering
controls)
5800
(
engineering
controls)

Applying
Liquid
Sprays
via
Aerial
Equipment
Green
and
Dry
Bulb
onions,
Vegetable
root
(
except
sugar
beet)
1.3
lb
ai/
acre
350
acres
0.068
(
engineering
controls)
0.00052
(
engineering
controls)
97,000
(
engineering
controls)
0.00044
(
engineering
controls)
20000
(
engineering
controls)

Tabasco
Peppers,

Sodfarms
2.5
lb
ai/
acre
80
acres
0.74
0.0025
20000
0.0021
4200
Corn,
Soybeans
1.9
lb
ai/
acre
200
acres
0.74
0.0047
11000
0.004
2200
Applying
Liquid
Sprays
via
Groundboom
Equipment
Peanuts,
Pod
crops,

Potatoes,
Safflowers,

Soybeans,
Brassica
head
and
stem,
Leaf
petioles
1.9
lb
ai/
acre
80
acres
0.74
0.0019
27000
0.0016
5500
48
of
66
Grain/
Forage
Sorghum
1.6
lb
ai/
acre
200
acres
0.74
0.0039
13000
0.0034
2600
Transplanted
and
Direct
Seeded
Vegetables
1.6
lb
ai/
acre
80
acres
0.74
0.0016
32000
0.0014
6500
Cotton
1.3
lb
ai/
acre
200
acres
0.74
0.0032
16000
0.0027
3200
Green
and
Dry
Bulb
onions,
Vegetable
root
(
except
sugar
beet)
1.3
lb
ai/
acre
80
acres
0.74
0.0013
39000
0.0011
8000
Pumpkin
and
Winter
Squash
1.27
lb
ai/
acre
80
acres
0.74
0.0013
40,000
0.0011
8,200
Tabasco
Peppers,

Sodfarms,
Nurseries
2.5
lb
ai/
acre
320
acres
1.2
0.016
3100
0.014
640
Corn,
Peanuts,
Pod
crops,
Potatoes,

Safflowers,

Soybeans,
Brassica
head
and
stem,
Leaf
petioles
1.9
lb
ai/
acre
320
acres
1.2
0.012
4100
0.01
840
Grain/
Forage
Sorghum,

Transplanted
and
Direct
Seeded
Vegetables
1.6
lb
ai/
acre
320
acres
1.2
0.01
4900
0.0088
1000
Applying
Dry
Bulk
Fertilizers
(
commercial
­­

using
PHED
tractor­
drawn
granular
spreader
data)
Cotton,
Green
and
Dry
Bulb
onions,

Vegetable
root
(
except
sugar
beet)
1.3
lb
ai/
acre
320
acres
1.2
0.0083
6000
0.0071
1200
Tabasco
Peppers,

Sodfarms
2.5
lb
ai/
acre
80
acres
1.2
0.004
13000
0.0034
2600
Applying
Dry
Bulk
Fertilizers
(
on­
farm
­­
using
PHED
tractor­
drawn
granular
spreader
data)
Nurseries
2.5
lb
ai/
acre
60
acres
1.2
0.003
17000
0.0026
3400
49
of
66
Corn,
Peanuts,

Soybeans
1.9
lb
ai/
acre
160
acres
1.2
0.0061
8200
0.0052
1700
Pod
crops,
Potatoes,
,

Safflower,
Brassica
head
and
stem,
Leaf
petioles
1.9
lb
ai/
acre
80
acres
1.2
0.003
16000
0.0026
3400
Grain/
Forage
Sorghum
1.6
lb
ai/
acre
160
acres
1.2
0.0051
9800
0.0044
2000
Transplanted
and
Direct
Seeded
Vegetables
1.6
lb
ai/
acre
80
acres
1.2
0.0026
20000
0.0022
4000
Cotton
1.3
lb
ai/
acre
160
acres
1.2
0.0042
12000
0.0036
2500
Green
and
Dry
Bulb
onions,
Vegetable
root
(
except
sugar
beet)
1.3
lb
ai/
acre
80
acres
1.2
0.0021
24000
0.0018
4900
Flagger
Tabasco
Peppers,

Sodfarms
2.5
lb
ai/
acre
350
acres
0.35
0.0051
9800
0.0044
2000
Corn,
Peanuts,
Pod
crops,
Potatoes,

Safflowers,

Soybeans,
Brassica
head
and
stem,
Leaf
petioles
1.9
lb
ai/
acre
350
acres
0.35
0.0039
13000
0.0033
2600
Flagging
for
Liquid
Sprays
via
Aerial
Equipment
Grain/
Forage
Sorghum,

Transplanted
and
Direct
Seeded
Vegetables
1.6
lb
ai/
acre
350
acres
0.35
0.0033
15000
0.0028
3100
50
of
66
Cotton,
Green
and
Dry
Bulb
onions,

Vegetable
root
(
except
sugar
beet)
1.3
lb
ai/
acre
350
acres
0.35
0.0027
19000
0.0023
3900
Mixer/
Loader/
Applicator
Mixing/
Loading/
Ap
plying
Emulsifiable
Concentrates
with
a
Handgun
Sprayer
(
LCO
ORETF
data)
Turfgrass/
Nurseries/

Landscape
plantings
2.5
lb
ai/
acre
5
acres
1.8
0.00038
130000
0.00032
27000
Mixing/
Loading/
Ap
plying
Emulsifiable
Concentrates
with
a
High
Pressure
Handwand
Nurseries/

Landscape
plantings
2.5
lb
ai/
acre
5
acres
120
0.025
2000
0.021
410
Mixing/
Loading/
Ap
plying
Emulsifiable
Concentrates
with
a
Low
Pressure
Handwand
(
Residential
ORETF
data)
Turfgrass/
Nurseries/

Landscape
plantings
2.5
lb
ai/
acre
2
acres
3.8
0.00032
160000
0.00027
32000
a
Application
rates
are
the
maximum
application
rates
determined
from
EPA
registered
labels
for
S­
metolachlor.

b
Amount
handled
per
day
values
are
HED
estimates
of
acres
or
tons
treated
applied
based
on
Exposure
SAC
SOP
#
9
"
Standard
Values
for
Daily
Acres
Treated
in
Agriculture,"
industry
sources,
and
HED
estimates.

c
No
Respirator:
indicates
baseline
level
risk
mitigation
with
no
respirator.
When
engineering
controls
are
noted:
closed
mixing/
loading
system
and
enclosed
cockpits
are
assumed.

d
Short­
term
inhalation
MOE
=
NOAEL
(
50
mg/
kg/
day)
/
inhalation
daily
dose
(
mg/
kg/
day),
where
inhalation
dose
=
daily
unit
exposure
(
Fg/
lb
ai)
x
application
rate
x
amount
handled
per
day
x
conversion
factor
(
1mg/
1,000
Fg)/
body
weight
(
60
kg
adult
female).

e
Intermediate­
term
inhalation
MOE
=
NOAEL
(
8.8
mg/
kg/
day)
/
inhalation
daily
dose
(
mg/
kg/
day),
where
inhalation
dose
=
daily
unit
exposure
(
Fg/
lb
ai)
x
application
rate
x
amount
handled
per
day
x
conversion
factor
(
1mg/
1,000
Fg)
/
body
weight
(
70
kg
adult
female).
51
9.0
Data
Needs
and
Label
Requirements
9.1
Toxicology
None
9.2
Residue
Chemistry
Deficiencies
described
in
the
last
HED
risk
assessment
remain
(
PP#
3E6787,
DP
Num:
304120,
R.
Loranger,
4/
17/
06):

°
Label
amendments
are
required
pertaining
to
the
proposed
uses
on
legume
vegetables
(
excluding
soybean).
Use
directions
on
legume
vegetables
should
be
amended
to
prohibit
applications
to
legume
cultivars
grown
for
the
production
of
succulent
shelled
peas
or
beans,
pending
submission
of
adequate
field
trial
data
covering
subgroup
6B.

°
Label
amendments
are
required
pertaining
to
the
proposed
uses
on
bulb
vegetables.
The
directions
for
bulb
vegetables
should
be
amended
to
indicate
the
correct
crop
group;
bulb
vegetables
are
in
crop
group
3,
not
crop
group
8.

°
Label
amendments
are
required
pertaining
to
the
proposed
uses
on
fruiting
vegetables.
The
use
directions
should
be
amended
as
two
different
maximum
seasonal
use
rates
are
specified
(
1.6
or
1.66
lb
ai/
A).
The
available
field
trial
data
will
support
a
maximum
seasonal
rate
of
1.66
lb
ai/
A,
which
is
equivalent
to
1.75
pt
product/
A.

°
In
addition,
a
revised
copy
of
the
7.6
lb/
gal
EC
label
should
be
submitted
including
all
the
proposed
changes
in
the
use
directions.

°
Field
trial
data
on
representative
succulent,
shelled
peas
and
beans
are
required
to
support
the
proposed
general
use
on
legume
vegetables,
except
soybeans.

°
The
requirements
pertaining
to
rotational
crops
cited
in
the
revised
Metolachlor
and
SMetolachlor
TRED
(
D292881,
S.
Kinard,
8/
15/
03)
remain
outstanding:

For
confined
rotational
crops,
additional
information
is
needed
on
the
percentage
of
the
14C­
residues
measured
by
the
current
enforcement
method,
supporting
storage
stability
data,
and
sample
storage
conditions
and
intervals.
With
regard
to
field
accumulation
in
rotational
crops,
"
Residue
data
are
required
for
both
metolachlor
and
S­
metolachlor
on
grain,
forage,
hay,
and
straw
of
representative
cereal
grains
(
wheat
and
oats)
supporting
the
4.5
month
plantback
interval."

In
addition,
a
revised
Section
B
for
the
use
on
pumpkin
is
required.
52
9.3
Occupational
and
Residential
Exposure
None.

References
TRED,
DP
Num:
288263,
S.
Kinard,
2/
12/
03
EFED,
DP
Num:
296726,
M.
Corbin,
6/
16/
04
HED
MARC,
TXR#
0052788,
DP
Num:
274326,
V.
Dobozy,
8/
14/
01
HED
ORE,
DP
Num:
296725,
M.
Collantes,
4/
10/
06
DP
Num:
226780,
L.
Kutney,
11/
12/
96
PP#
3E6787,
DP
Num:
304120,
R.
Loranger,
4/
17/
06
DP
Num:
279110,
S.
Kinard,
8/
15/
03
DP
Num:
280216;
MRID
44615401,
S.
Kinard,
2/
28/
02
MRID
46707501,
S­
Metolachlor:
Magnitude
of
the
Residue
on
Squash
(
Winter),
D.
Dotson,
in
process
Dietary
Analysis,
ID#
s:
06OH05,
DP
Num:
329632,
W,
Cutchin,
in
process
HED
ORE
for
the
New
Uses
on
Pumpkin
and
Winter
Squash,
DP
Num:
330187,
M.
Collantes,
6/
21/
06
Residential
Exposure,
DP
Num:
274331,
R.
Griffin,
2/
20/
02
Reviewer's
Guide
and
Summary
of
HED
ChemSAC
Approvals
for
Amending
Commodity
Definitions
[
40
CFR
§
180.1(
h)]
and
Crop
Group/
Subgroups
[
40
CFR
§
180.41],
B.
Schneider,
6/
14/
02
53
Appendix
A
Table
1:
Toxicity
Profile
for
Metolachlor
(
PC
Code
108801)

Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
870.3100
90­
Day
oral
toxicity
rodents
44775401
(
1999)
Acceptable/
guideline
0,
30,
300,
3000
ppm
(
M/
F:
0,
2.00/
2.32,
20.2/
23.4,
210/
259
mg/
kg/
day)
NOAEL
for
males
=
3000
ppm
LOAEL
for
males
not
established
NOAEL
for
females
=
300
ppm
LOAEL
for
females
=
3000
ppm
based
on
decreased
body
weight/
body
weight
gain
870.3150
180­
Day
oral
toxicity
in
nonrodents
00032174
(
1980),
43244001
acceptable/
guideline
0,
100,
300,
1000
ppm
(
M/
F:
0,
2.92/
2.97,
9.71/
8.77,
29.61/
29.42)
NOAEL
=
300
ppm
LOAEL
=
1000
ppm
based
on
decreased
body
weight
gain
870.3200
21/
28­
Day
dermal
toxicity
41833101
(
1987)
acceptable/
guideline
0,
10,
100
or
1000
mg/
kg/
day
systemic
NOAEL
=
1000
mg/
kg/
day.
systemic
LOAEL
was
not
established
dermal
irritation
NOAEL
was
not
established
dermal
irritation
LOAEL
=
10
mg/
kg/
day
based
on
very
slight
erythema,
dry
skin
and
fissuring
(
one
animal)

870.3700a
Prenatal
developmental
in
rodents
00151941
(
1985)
acceptable/
guideline
0,
30,
100,
300
or
1000
mg/
kg/
day
maternal
toxicity
NOAEL
=
300
mg/
kg/
day.
maternal
toxicity
LOAEL
=
1000
mg/
kg/
day
based
on
an
increased
incidence
of
death,
clinical
signs
of
toxicity
(
clonic
and/
or
toxic
convulsions,
excessive
salivation,
urine­
stained
abdominal
fur
and/
or
excessive
lacrimation)
and
decreased
body
weight
gain.

developmental
toxicity
NOAEL
=
300
mg/
kg/
day
developmental
toxicity
LOAEL
=
1000
mg/
kg/
day
based
on
slightly
decreased
number
of
implantations
per
dam,
decreased
number
of
live
fetuses/
dam,
increased
number
of
resorptions/
dam
and
significant
decrease
in
mean
fetal
body
weight
870.3700b
Prenatal
developmental
in
nonrodents
00041283
(
1980)
acceptable/
guideline
0,
36,
120
or
360
mg/
kg/
day
maternal
toxicity
NOAEL
=
120
mg/
kg/
day.
maternal
toxicity
LOAEL
=
360
mg/
kg/
day
based
on
an
increased
incidence
of
clinical
observations
(
persistent
anorexia)
and
decreased
body
weight
gain
developmental
toxicity
NOAEL
=
360
mg/
kg/
day
developmental
toxicity
LOAEL
was
not
established.
54
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
870.3800
Reproduction
and
fertility
effects
00080897
(
1981)
acceptable/
guideline
0,
30,
300
or
1000
ppm
(
F0
males:
0,
2.4,
23.5
and
75.8
mg/
kg/
day;
F0
females:
0,
2.5,
26.0
and
85.7
mg/
kg/
day;
F1males:
0,
2.3,
23.7
and
76.6
mg/
kg/
day;
F1
females:
0,
2.6,
25.7
and
84.5
mg/
kg/
day).
Parental
toxicity
NOAEL
=
1000
ppm
(
F0
males/
females:
75.8/
85.7
mg/
kg/
day;
F1males/
females:
76.6/
84.5
mg/
kg/
day).
Parental
toxicity
LOAEL
was
not
established
Reproduction
toxicity
NOAEL
=
1000
ppm
(
F0
males/
females:
75.8/
85.7
mg/
kg/
day;
F1males/
females:
76.6/
84.5
mg/
kg/
day).
Reproduction
toxicity
LOAEL
was
not
established
Offspring
NOAEL
=
300
ppm
(
F0
males/
females:
23.5/
26.0
mg/
kg/
day;
F1males/
females:
23.7/
25.7
mg/
kg/
day).
Offspring
LOAEL
=
1000
ppm
(
F0
males/
females:
75.8/
85.7
mg/
kg/
day;
F1males/
females:
76.6/
84.5
mg/
kg/
day)
based
on
decreased
body
weight.

870.4100b
Chronic
toxicity
dogs
40980701,
41164501,
42218601
and
42218602.
(
1989)
acceptable/
guideline
0,
100,
300
or
1000
ppm
(
males:
0,
3.5,
9.7
and
32.7
mg/
kg/
day,
respectively;
females:
0,
3.6,
9.7
and
33.0
mg/
kg/
day,
respectively)
for
one
year.
NOAEL
=
300
ppm
(
9.7
mg/
kg/
day)
for
females
LOAEL
=
1000
ppm
for
females
(
33.0
mg/
kg/
day)
based
on
decreased
body
weight
gain
LOAEL
for
males
was
not
established;
NOAEL
=
1000
ppm
(
32.7
mg/
kg/
day).

870.4300
Chronic
toxicity/
carcinogenicity
rodents
00129377
(
1983)
acceptable/
guideline
0,
30,
300
or
3000
ppm
(
0,
1.5,
15
or
150
mg/
kg/
day
based
on
1
ppm
in
food
equals
0.05
mg/
kg/
day)
NOAEL
=
300
ppm
(
15
mg/
kg/
day)
for
females
LOAEL
=
3000
ppm
(
150
mg/
kg/
day)
for
females
based
on
slightly
decreased
body
weight
gain
and
food
consumption.

The
LOAEL
was
not
established
for
males.
The
NOAEL
was
3000
ppm
(
150
mg/
kg/
day).

Administration
of
doses
up
to
3000
ppm
was
associated
with
statistically
significant
increases
in
liver
adenomas
and
combined
adenoma/
carcinoma
in
female
rats.
In
male
rats,
there
was
a
statistically
significant
trend
but
not
pair­
wise
significance
for
liver
tumors.

870.4300
Carcinogenicity
mice
00117597
(
1982)
acceptable/
guideline
0,
300,
1000
or
3000
ppm
(
0,
45,
150
or
450
mg/
kg/
day
based
on
1
ppm
in
food
equals
0.150
mg/
kg/
day)
NOAEL
=
1000
ppm
(
150
mg/
kg/
day)
LOAEL
=
3000
ppm
(
450
mg/
kg/
day)
based
on
possible
treatmentrelated
deaths
in
females
and
decreased
body
weight/
body
weight
gain
in
males
and
females
no
evidence
of
carcinogenicity
Gene
Mutation
870.5100
­
bacterial
reverse
mutation
00015397
(
1976)
acceptable/
guideline
10,
100,
1000
and
10,000
ug/
plate
negative
up
to
cytotoxic
doses
(
1000
ug/
plate)
55
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
Gene
Mutation
870.5300
­
mouse
lymphoma
00158929
(
1984)
acceptable/
guideline
9.5­
190
nl/
ml
without
activation;
10.5­
280
nl/
ml
with
activation
no
effect
on
the
incidence
of
mutations
in
the
presence
or
absence
of
metabolic
activation
Cytogenetics
870.5395
­
micronucleus
assay
in
Chinese
hamsters
00158925
(
1984)
acceptable/
guideline
0,
1250,
2500
or
5000
mg/
kg
no
effect
of
treatment
on
incidence
of
micronuclei
induction
Cytogenetics
870.5450
­
dominant
lethal
assay
in
mice
00015630
(
1978)
acceptable/
guideline
100
or
300
mg/
kg
no
effect
on
embryonic
death,
pre­
and
post­
implantation
or
fertility
rates
in
mated
females
Other
Effects
870.5550
­
DNA
Damage/
Repair
in
rat
hepatocytes
00142828
(
1984)
acceptable/
guideline
0.25,
1.25,
6.25,
or
31.25
nl/
ml
negative
Other
Effects
870.5550
­
DNA
Damage/
Repair
in
human
fibroblasts
00142827
acceptable/
guideline
0.125,
0.625,
3.125
or
15.625
nl/
ml
negative
Other
Effects
870.5550
­
Unscheduled
DNA
synthesis
in
rat
hepatocytes
43244003
(
1994)
acceptable/
guideline
1250,
2500
or
4000
mg/
kg
to
males;
500,
1000
or
1500
mg/
kg
to
females
negative
for
induction
of
UDS;
however,
significant
increases
in
percentage
of
cells
in
S­
phase
were
observed
in
females
dosed
at
500
mg/
kg
(
but
not
at
1000
or
1500
mg/
kg)
and
sacrificed
at
15
hours
56
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
870.7485
Metabolism
and
pharmacokinetics
MRID
00015425
(
1974)
unacceptable
52,
28
or
33
mg/
kg
to
male
rats
Conclusions:
Urinary
metabolites
of
CGA
24705
(
N­(
2­
methoxy­
1­
methylethyl)­
2­
ethyl­
6­
methyl­
chloroacetanilide)
were
identified
following
oral
administration
of
52
mg/
kg,
28
mg/
kg,
and
33
mg/
kg
to
male
rats.
Two
metabolites,
each
comprising
approximately
5%
of
chloroform
extractable
urinary
radioactivity,
were
identified
from
oral
administration
of
CGA
24705.
These
were
the
products
CGA
37735
(
2­
ethyl­
6­
methyl­
hydroxyacetanilide),
in
which
Ndealkylation
of
R1
(
the
N­(
2­
methoxy­
1­
methylethyl
side
chain)
and
side
chain
dechlorination
and
oxidation
of
R2
(
the
N­
chloroacetyl
side
chain)
have
occurred,
and
CGA
46129
(
N­(
1­
carboxy­
ethyl)­
2­
ethyl­
6­
methyl
hydroxyacetanilide)
in
which
the
ether
bond
of
R1
has
been
split
and
oxidized
to
the
corresponding
carboxylic
acid,
while
R2
is
similar
to
R2
found
in
CGA
37735.
In
study
#
7/
74,
these
2
metabolites
each
represented
approximately
5%
of
organic
extractable
urinary
radioactivity,
while
in
study
#
12/
74,
the
percentage
found
as
CGA
46129
was
between
20­
25%
of
urinary
radioactivity,
and
CGA
37735
represented
between
3­
5%
of
organic
extractable
radioactivity.

The
major
metabolic
pathway
proposed
from
analysis
of
urinary
as
well
as
fecal
metabolites
is
one
of
cleavage
of
the
ether
bond
and
subsequent
oxidation
to
the
carboxylic
acid,
as
well
as
hydrolytic
removal
of
the
chlorine
atom.
Conjugation
of
CGA
24705
or
metabolites
with
gluronic
acid
or
sulfate
does
not
appear
to
occur.

Aqueous
extractable
urinary
radioactivity
contained
58%
of
the
total
urinary
radioactivity
and
was
composed
of
5
different
radioactive
fractions,
which
were
not
identified.

Current
guideline
recommendations
as
to
dose
levels
and
use
of
both
sexes
in
metabolism
studies
were
not
followed.
Thus,
whether
the
metabolic
pattern
is
altered
with
dose
or
repeated
exposure
cannot
be
evaluated
from
these
data.
57
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
870.7485
Metabolism
and
pharmacokinetics
40114401
(
1987)
unacceptable
Single
low
(
1.5
mg/
kg),
single
high
(
300
mg/
kg)
and
repeated
low
(
1.5
mg/
kg/
day
for
15
days)
Conclusions:
Single
low
(
1.5
mg/
kg),
single
high
(
300
mg/
kg)
and
repeated
low
(
1.5
mg/
kg/
day
for
15
days)
oral
doses
of
metolachlor
were
readily
absorbed
and
eliminated
by
male
and
female
rats.
Urinary
and
fecal
elimination
of
radioactivity
associated
with
orally
administered
[
14C]
metolachlor
was
essentially
complete
within
48
to
72
hours
after
dosing.
Low­
and
high­
dose
females
eliminated
14C
more
rapidly
(
p<
0.003,
half­
lives
of
elimination,
16.6
and
15.6
hours,
respectively)
than
low­
and
high­
dose
males
and
repeateddose
animals
of
both
sexes
(
half­
lives,
18.2
and
20.0
hours).
Elimination
by
all
animals
followed
first­
order
kinetics.
Approximately
one­
half
to
two­
thirds
(
48
to
64
percent)
of
the
14C
administered
was
recovered
from
the
urine
within
7
days;
similar
amounts
were
present
in
the
feces.
Low­
dose
males
eliminated
slightly
more
of
the
radioactive
dose
in
the
feces
(
55
percent)
than
the
urine
(
48
percent).
The
opposite
trend
was
seen
in
the
low­
dose
females
and
repeated­
dose
rats
of
both
sexes;
these
animals
excreted
approximately
58
to
64
percent
of
the
14C
dose
in
the
urine
and
42.5
to
46.5
percent
in
the
feces
within
7
days
after
dosing.
High­
dose
animals
excreted
similar
amounts
(
58
to
60
percent)
of
the
radioactive
dose
in
the
urine
and
feces.
Total
recoveries
of
14C
(
urine,
feces,
and
tissues)
tended
to
be
high
and
were
between
105
and
122.5
percent.

Relatively
low
levels
of
radioactivity
were
present
in
the
tissues
of
all
animals
at
7
days
postdosing.
Tissues
of
low­
and
repeated­
dose
rats
contained
approximately
1.6
to
2.5
percent
of
the
14C
dose;
tissues
of
high­
dose
rats
accounted
for
3.2
(
females)
and
4.2
(
males)
percent.
For
all
groups,
most
of
the
tissue
radioactivity
(
1.1
to
3.0
percent
of
the
dose)
was
associated
with
red
blood
cells
(
RBCs);
RBCs
also
contained
the
highest
concentrations
of
radio
labeled
compound
(
0.6
to
0.9
ppm,
low­
and
repeated­
dose
rats;
232
and
247
ppm,
high­
dose
females
and
males,
respectively),
indicating
that
[
14C]
metolachlor
and/
or
its
metabolites
bind
extensively
to
these
cells.
The
next
highest
concentrations
of
radiolabel
(
0.03
to
0.13
ppm,
low­
and
repeated­
dose
rats;
7.3
to
37
ppm,
high­
dose
animals)
were
present
in
metabolically
active
tissues,
including
the
heart,
lung,
kidney,
liver
and
spleen.
Brain,
bone
and
muscle
contained
the
smallest
amounts
of
radioactivity
(
0.004
to
0.015
ppm,
low­
and
repeated­
dose
rats;
1.7
to
3.5
ppm,
high­
dose
rats).
Tissue
14C
residues
in
high­
dose
males
were
approximately
250
to
500
times
greater
than
those
of
low­
dose
males,
indicating
that
the
ratio
of
tissue
concentrations
(
high
dose:
low
dose)
was
much
larger
than
the
corresponding
dose
ratio
of
200:
1
(
300
mg/
kg:
1.5
mg/
kg).
In
contrast,
tissue
14C
levels
of
females
were,
in
general,
proportionate
to
dose.
Tissues
of
low­
and
repeated­
dose
rats
contained
similar
amounts
of
radioactivity.
These
data
indicate
that
some
14C
was
retained
by
all
animals
and
that
the
greatest
potential
for
accumulation
of
radioactivity
was
in
male
rats
given
a
single
high
oral
dose
of
[
14C]
metolachlor.
58
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
870.7485
Metabolism
and
pharmacokinetics
43164201
(
1992)
acceptable/
guideline
low
oral
dose
(
1.5
mg/
kg
x
14
days),
and
a
single
high
dose
(
300
mg/
kg)
In
a
rat
metabolism
study
(
MRID
#
431642­
01),
14C­
Metolachlor
was
administered
orally
in
PEG­
200
[
HWI
6117­
208]
or
corn
oil
[
ABR­
94001]
to
groups
(
5
sex/
dose)
of
male
and
female
Sprague­
Dawley
rats
at
a
low
oral
dose
(
1.5
mg/
kg),
repeated
low
oral
dose
(
1.5
mg/
kg
x
14
days),
and
a
single
high
dose
(
300
mg/
kg).
Control
animals
(
1/
sex)
received
blank
formulation.

Comparison
of
oral
and
intravenous
data
showed
that
of
the
administered
dose,
between
69.6%
and
93.2%
was
absorbed.
Distribution
data
showed
that
the
only
significant
sites
of
residual
radioactivity
at
7
days
post­
dose
were
residual
carcass
(
0.9
­
2.2%
of
the
administered
dose)
and
red
blood
cells
(
0.95­
1.53
Fg
equivalents/
gram
in
blood
cells
for
all
low
dose
male
and
female
rats).
Dosing
regimen
did
not
result
in
any
apparent
accumulation
of
residual
radioactivity.

Excretion
data
showed
that
urine
and
feces
were
both
significant
routes
for
elimination
of
metolachlor
derived
radioactivity.
In
the
low
dose
groups,
the
urine
appeared
more
of
a
predominant
route
for
excretion
in
female
rats
than
in
males,
whereas
fecal
excretion
was
slightly
higher
in
males.
However,
at
the
high
oral
dose,
there
were
no
apparent
sex­
related
differences
in
the
pattern
of
urinary
excretion.
Examination
of
urinary
excretion
data
as
presented
in
graphical
format
indicated
that
at
the
300
mg/
kg
dose,
excretion
was
delayed
vs
the
low
oral
dose,
suggesting
saturation
of
elimination.

Metabolism
of
metolachlor
in
this
study
was
complex,
with
up
to
32
metabolites
identified
in
urine
and/
or
feces.
The
"
major"
urinary
metabolite
found
in
all
dose
groups
was
the
metabolite
designated
CGA­
46129.
This
metabolite
was
present
as
5.6­
13.1%
of
the
total
radioactive
residue
(
TRR)
in
rat
urine
across
all
dose
groups,
and
was
highest
in
the
intravenously
dosed
group.
In
the
orally
dosed
rats,
the
percentage
of
this
metabolite
decreased
from
approximately
13%
of
TRR
to
between
5.6­
9.2%
of
TRR.
Other
metabolites
identified
in
urine
which
constituted
near
or
at
5%
of
TRR
were
U10
(
CGA­
37735),
U13,
U17,
U1,
"
polar
1",
and
"
polar
2."
The
radioactivity
constituting
the
`
polar
1'
and
`
polar
2'
regions
was
further
broken
down
to
at
least
12
components
by
TLC,
but
the
identity
of
the
metabolites
in
these
regions
was
not
demonstrated.

In
feces,
a
similarly
complex
metabolite
profile
was
obtained.
The
"
major"
metabolite
observed
in
feces,
F9,
was
identical
to
U7,
or
CGA­
46129.
Except
for
intravenously
dosed
rats,
where
the
percentage
of
this
metabolite
in
feces
was
equivalent
in
male
and
female
rats
(
11.6
and
13.2%
of
TRR,
respectively),
the
percentage
of
F9
in
feces
of
orally
dosed
rats
was
always
higher
in
males
than
in
females.
Other
fecal
metabolites
identified
at
or
near
5%
of
TRR
in
feces
included
F2
(
CGA­
41638),
F3
(
CGA­
133275),
F7,
F8
and
F8',
F16,
F14,
and
F17.

Based
on
these
data,
a
scheme
for
metabolism
of
metolachlor
was
proposed.
59
Appendix
A
Table
2:
Toxicity
Profile
for
S­
Metolachlor
(
PC
Code
108800)

Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
870.3100
90­
Day
oral
toxicity
rodents
43928923
(
1995)
acceptable/
guideline
0,
30,
300,
3000
or
10000
ppm
(
0,
1.5,
15,
150
or
500
mg/
kg/
day)
NOAEL
=
300
ppm
LOAEL
=
3000
ppm
based
on
lower
body
weights/
body
weight
gains,
reduced
food
consumption
and
food
efficiency
and
increased
kidney
weights
in
males
870.3100
90­
Day
oral
toxicity
rodents
44775402
(
1999)
unacceptable/
guideline
0,
30,
300,
3000
ppm
(
M/
F:
0,
1.90/
2.13,
20.4/
23.9
and
208.0/
236.0
mg/
kg/
day0
NOAEL
=
3000
ppm
(
equivalent
to
208
mg/
kg/
day
in
males
and
236
mg/
kg/
day
in
females
LOAEL
cannot
be
defined
870.3150
90­
Day
oral
toxicity
in
nonrodents
43928922
(
1995)
acceptable/
nonguideline
0,
300,
500,
1000
or
2000
ppm
(
M/
F:
0,
9/
10,
15.1/
17.2,
31.1/
31.5
or
62/
74
mg/
kg/
day)
NOAEL
=
2000
ppm
(
M/
F:
62/
74
mg/
kg/
day)
LOAEL
=
not
established
870.3700a
Prenatal
developmental
in
rodents
43928925
(
1995)
acceptable/
guideline
0,
5,
50,
500
or
1000
mg/
kg/
day
Maternal
NOAEL
=
50
mg/
kg/
day
LOAEL
=
500
mg/
kg/
day
based
on
increased
clinical
signs
of
toxicity,
decreased
body
weights/
body
weight
gains,
food
consumption
and
food
efficiency.
Developmental
NOAEL
=
1000
mg/
kg/
day
LOAEL
=
not
established
870.3700b
Prenatal
developmental
in
nonrodents
43928924
(
1995)
acceptable/
guideline
0,
20,
100
or
500
mg/
kg/
day
Maternal
NOAEL
=
20
mg/
kg/
day
LOAEL
=
100
mg/
kg/
day
based
on
clinical
signs
of
toxicity
Developmental
NOAEL
=
500
mg/
kg/
day
LOAEL
=
not
established
Gene
Mutation
870.5100
Salmonella
&
Escherichia/
Mammalia
n
Microsome
Mutagenicity
Test
43928927
(
1995)
acceptable/
guideline
78.13­
1250.0
ug/
plate
In
independently
performed
microbial
mutagenicity
assays,
Salmonella
typhimurium
TA1535,
TA1537,
TA98,
TA100
and
TA102
and
Escherichia
coli
WP2
uvrA
were
initially
exposed
to
312.5­
5000.0
Fg/
plate
CGA­
77102
technical
(
95.6%)
in
the
presence
and
absence
of
S9
activation.
For
the
confirmatory
trial,
doses
of
78.13­
1250.0
Fg/
plate
±
S9
were
evaluated
with
S.
typhimurium
strains
TA1535,
TA1537,
TA100
and
TA102;
concentrations
of
312.5­
5000.0
Fg/
plate
±
S9
were
examined
with
S.
typhimurium
TA
98
and
E.
coli
WP2
uvrA.

In
general,
doses
$
1250.0
Fg/
plate
±
S9
were
cytotoxic
for
S.
typhimurium
TA1535,
TA1537,
TA100
and
TA102
and
5000.0
Fg/
plate
±
S9
was
slightly
cytotoxic
for
S.
typhimurium
TA98
and
E.
coli
WP2
uvrA.
There
was,
however,
no
indication
that
CGA­
77102
technical
induced
of
a
mutagenic
effect
in
any
tester
strain
either
in
the
presence
or
the
absence
of
S9
activation.
60
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
Cytogenetics
870.5395
Micronucleus
test
43928926
(
1995)
acceptable/
guideline
500,
1000
or
2000
mg/
kg
Groups
of
five
male
and
five
female
Tif:
MAGf(
SPF)
mice
received
single
oral
gavage
administrations
of
500,
1000
or
2000
mg/
kg
CGA
77102
technical
(
95.6%).

Toxic
signs,
similar
to
those
seen
in
the
preliminary
range­
finding
studies
(
i.
e.,
ataxia,
tremors
and/
or
hunched
posture)
were
recorded
for
high­
dose
males
and
females
throughout
the
48­
hour
postexposure.
No
bone
marrow
cytotoxicity
was
seen
at
any
dose
or
sacrifice
time.
The
positive
control
induced
the
expected
high
yield
of
MPEs
in
males
and
females.
There
was,
however,
no
evidence
that
CGA
77102
technical
induced
a
clastogenic
or
aneugenic
effect
in
either
sex
at
any
dose
or
sacrifice
time.

Other
Effects
870.5550
Unscheduled
DNA
synthesis
43928928
(
1995)
acceptable/
guideline
500,
1500,
3200
(
females),
5000
(
males)
mg/
kg
Groups
consisting
of
three
to
four
rats
per
sex
received
single
oral
gavage
administrations
of
CGA­
77102
Technical
(
95.6%)
at
doses
of
500,
1500
or
5000
mg/
kg
(
males)
or
500,
1500
or
3200
mg/
kg
(
females).
Hepatocytes
harvested
at
15
and
38
hours
were
evaluated
for
viability
and
replicative
DNA
synthesis
(
RDS).
For
the
UDS
determination,
additional
groups
(
3/
sex/
dose)
were
exposed
to
500
or
1500
mg/
kg
and
the
recovered
hepatocytes
were
scored
at
2
or
15
hours
postexposure.

Two
of
four
females
in
the
3200­
mg/
kg
group
and
2
of
4
males
in
the
5000­
mg/
kg
group
died
prior
to
the
scheduled
sacrifice
at
38
hours.
Severe
cytotoxicity
was
seen
in
the
hepatocytes
recovered
from
1
of
2
surviving
males
and
both
female
survivors
in
the
highdose
groups.
Lower
levels
were
neither
toxic
to
the
animals
nor
cytotoxic
to
the
target
cells.
A
clear
dose­
related
increase
in
the
percentage
of
cells
in
S­
phase
(
RDS)
was
obtained
from
hepatocytes
harvested
38
hours
posttreatment
of
the
male
rats.
The
response
ranged
from
a
5.3­
fold
increase
at
1500
mg/
kg
to
a
16.1­
fold
increase
at
the
high
dose
(
5000
mg/
kg).
In
females,
a
marked
increase
in
RDS
was
initially
seen
at
1500
mg/
kg
but
the
response
declined
over
time
with
a
24.4­
fold
increase
at
15
hours
and
a
12.2­
fold
increase
at
38
hours.
There
was,
however,
no
evidence
that
the
CGA
77102
Technical
at
doses
of
500
or
1500
mg/
kg
induced
a
genotoxic
response
at
2
or
15
hours
posttreatment.
We
conclude,
therefore,
that
the
data
indicate
that
CGA
77102
Technical
was
negative
for
genotoxicity
but
positive
for
cellular
proliferation
when
tested
up
to
overtly
toxic
and
cytotoxic
doses
in
this
in
vivo/
in
vitro
rat
hepatocyte
RDS/
UDS
assay.
61
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
870.7485
Metabolism
and
pharmacokinetics
44491401
(
1996)
acceptable/
guideline
single
dose
of
0.5
(
group
B1)
or
100
mg/
kg
(
group
D1)
radio
labeled
CGA­
77102;
100
mg/
kg/
day
non­
radio
labeled
CGA
77102
for
14
days
followed
by
0.5
mg/
kg
radio
labeled
CGA­
77102
(
Group
V1);
single
dose
of
0.5
or
100
mg/
kg
radio
labeled
CGA­
77102
for
bilecannulation
study
In
all
three
dose
groups
(
B1,
D1,
and
V1),
the
seven
day
combined
levels
of
radioactivity
in
urine
were
31.1
­
36.5%
for
males
and
40.8
­
45.5%
for
females;
the
fecal
levels
were
60.2
­
62.5%
for
males
and
48.9
­
55.0%
for
females.
Only
0.1%
or
less
was
eliminated
in
the
expired
air.
The
total
recovery
ranged
from
96.5
±
2.3%
to
99.3
±
0.9%.
The
route
or
extent
of
excretion
was
slightly
influenced
by
the
sex
of
the
animal
but
not
by
pretreatment
with
non­
radio
labeled
CGA­
77102
or
by
the
dose
level.
The
degree
of
absorption,
based
on
adding
the
cumulative
urinary
excretion
to
the
total
residues
in
tissues,
was
35
­
39%
in
males
and
43
­
49%
in
females
of
both
dose
groups.
However,
based
on
the
bile
duct
cannulation
study,
most
of
CGA­
77102
was
absorbed
from
the
gastrointestinal
tract
since
85%
of
the
dose
was
recovered
in
urine,
bile
fluid,
and
tissues
during
the
48
hours
study
period.
Therefore,
the
biliary
excretion
and
enterohepatic
circulation
play
a
significant
role
in
the
elimination
process
of
CGA­
77102.

Irrespective
of
the
dose
and
sex,
there
seems
to
be
a
biphasic
plasma
profile
with
two
concentration
maxima
(
Cmax);
a
fast
rising
first
Cmax
was
reached
at
0.25
­
1
hour
post
dosing
which
was
succeeded
by
a
second
Cmax
at
8
and
at
12
­
24
hours
following
administration
of
the
low
and
high
dose,
respectively.
In
the
low
dose
group
(
B1),
the
first
and
second
Cmax
were
nearly
identical
(~
0.03
Fg/
ml);
in
the
high
dose
group
(
D1),
the
first
and
second
Cmax
were,
respectively,
4.6
and
>
3.9
Fg/
ml
in
males
and
2.2
and
4.5
Fg/
ml
in
females.
The
time
to
half
maximum
plasma
concentration
(
tcmax/
2)
in
males/
females
was
31/
24
hours
at
the
low
dose
and
44/
32
hours
at
the
high
dose.
Bioavailability,
or
the
area
under
the
plasma
concentration
curve
(
AUC0­
48hr),
was
nearly
identical
(~
0.8
mg/
kg.
hr)
among
males
and
females
of
the
low
dose
group.
Also,
both
sexes
in
the
high
dose
group
had
similar
plasma
AUC0­
48hr
(
M/
F:
143/
125
mg/
kg.
hr)
which
increased
almost
proportionately
with
the
200­
fold
increase
in
the
dose
level.
The
residues
in
RBC
increased
steadily
with
time
reaching
peak
levels
(
at
24
­
48
hours
post­
dosing)
of
0.5­
0.6
and
90
ppm
(
or
Fg/
g)
CGA­
77102
equivalents
for
the
low
(
B1)
and
high
(
D1)
dose
groups,
respectively.
The
peak
levels
in
RBC
remained
high
and
were
nearly
20
fold
higher
than
the
respective
plasma
Cmax
levels.
62
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
The
kinetics
of
tissue
distribution
and
depletion
in
both
sexes
were
also
followed
for
up
to
144
hours
following
a
single
low
or
high
oral
dose
(
Groups
F1
­
F4).
Peak
residue
levels
were
reached
within
12
­
24
hours
and
ranged
from
0.007
ppm
(
female
muscle)
to
0.123
ppm
(
male
kidneys)
at
the
low
dose,
and
from
1.29
ppm
(
male
brain)
to
16.82
ppm
(
male
liver)
at
the
high
dose,
with
the
highest
levels
being
among
some
of
the
well­
perfused
tissues
(
e.
g.,
liver,
kidneys,
spleen,
and
lungs).
The
extent
of
residue
depletion
was
variable
among
the
tissue
types
but
was
minimally
affected
by
the
dose
or
the
sex
of
the
animal.
The
radiolabel
was
most
persistent
in
some
of
the
well­
perfused
organs
(
e.
g.,
the
heart,
lungs,
and
spleen)
in
addition
to
the
brain
and
bone
where,
after
144
hours,
the
levels
were
decreased
to
only
45
­
94%
of
their
maximal
concentrations.
In
Groups
F1
­
F4,
peak
residue
concentration
in
the
whole
blood
(
0.2
and
42
­
47
Fg/
ml
in
the
low
and
high
dose
groups,
respectively)
was
reached
at
24
hours
and
was
maintained
throughout
the
study.
Overall,
the
high/
low
dose
peak
tissue
levels
(
including
blood)
ranged
from
132
to
282
which
approximates
the
200­
fold
increase
in
dosage.

CGA­
77102
has
a
high
affinity
for
and
a
long
half­
life
in
blood
(
especially
RBC)
which
might
contribute
to
the
retarded
depletion
of
tissue
residues.
63
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
870.7485
Metabolism
and
pharmacokinetics
44491402
(
1996)
unacceptable/
guideline
single
dose
of
0.5
(
group
B1)
or
100
mg/
kg
(
group
D1)
radio
labeled
CGA­
77102;
100
mg/
kg/
day
non­
radio
labeled
CGA
77102
for
14
days
followed
by
0.5
mg/
kg
radio
labeled
CGA­
77102
(
Group
V1);
single
dose
of
0.5
or
100
mg/
kg
radio
labeled
CGA­
77102
for
bilecannulation
study
(
from
MRID
44491401)
single
oral
low
dose
(
0.5
mg/
kg,
Group
B2)
of
[
Phenyl­
U­
14C]
CGA­
24705
(
R/
S­
metolachlor,
racemate)
The
72
hour
mean
recovery
of
radioactivity
in
urine,
feces,
and
carcass
following
administration
of
0.5
mg/
kg
of
[
Phenyl­
U­
14C]
CGA­
24705
was
43.1%,
47.0%,
and
7.4%
in
males
and
54.0%,
39.4%,
and
4.1%
in
females,
respectively.
In
contrast,
both
sexes
excreted
more
of
the
label
in
the
feces
(
M:
F
59.7%:
53.4%)
than
in
the
urine
(
M:
F
29.4%:
39.8%)
during
the
same
period
following
administration
of
the
same
dose
of
[
Phenyl­
U­
14C]
CGA­
77102
(
the
S­
enantiomer)
(
MRID
44491401).

The
urinary
and
fecal
metabolite
profiles,
with
31
and
15
metabolite
fractions,
respectively,
were
qualitatively
similar
among
all
groups;
however,
there
were
large
quantitative
differences,
based
on
the
dosing
formulation,
on
one
hand,
and
the
sex
of
the
animal,
on
the
other.
Based
on
a
percentage
of
the
dose,
several
of
the
major
urinary
metabolite
fractions
(
e.
g.,
U1,
U2,
U3,
U18,
U24,
and
U30)
were
more
abundant
in
the
case
of
the
racemic­
Metolachlor
(
CGA­
24705)
than
the
S­
metolachlor
(
CGA­
77102);
in
contrast,
several
fecal
metabolite
fractions
(
e.
g.,
F9,
F10,
F12,
and
F13)
were
present
at
higher
levels
in
the
case
of
CGA­
77102
than
CGA­
24705.
On
the
other
hand,
there
were
sex­
related
differences
regardless
of
the
dosing
formulation
where,
for
instance,
females
had
greater
urinary
concentrations
than
males
of
several
metabolite
fractions,
including
U3,
U4,
U8,
U9,
U18,
U20,
and
U30;
the
males,
however,
excreted
more
of
fractions
U1
and
U24
than
the
females.
Also,
several
fecal
fractions
including
F1,
F3,
F5,
F6,
F7,
F8,
and
F13
were
influenced
by
the
sex
regardless
of
the
dose
level
(
e.
g.
B1
vs.
D1)
or
the
stereochemical
make­
up
of
Metolachlor
(
B1
vs.
B2).
Other
metabolite
fractions
were
dependent
on
both
the
sex
and
the
chemical
formulation
as,
for
instance,
in
the
case
of
metabolite
U2
which,
relative
to
the
opposite
sex
within
the
same
group,
was
more
abundant
in
the
urine
of
the
females
of
Group
B2
(
CGA­
24705)
and
in
the
urine
of
the
males
of
Group
B1
(
CGA­
77102).

The
bile
fluid
accounted
for
79.8%
of
the
administered
low
or
high
dose
of
CGA­
77102
(
Groups
G1
and
G2)
where
the
2D­
TLC
showed
14
biliary
metabolite
fractions
(
G1­
G14)
in
the
high
dose
Group
and
only
six
metabolites
in
the
low
dose
Group.
The
two
metabolite
fractions
G7
and
G8
accounted,
respectively,
for
33.3%
and
9.6%
of
the
administered
low
dose
and
31.3%
and
14.6%
of
the
administered
high
dose.
Other
major
biliary
metabolites
were
G3,
G9,
and
G10
which
accounted
for
about
5%,
5­
7%,
and
3­
5%,
respectively,
of
either
dose
group.
64
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
The
results
clearly
show
that
the
metabolite
profile
in
excreta
and
bile
fluid
is
very
complex
and
that
Metolachlor
(
racemate
or
Senantiomer
is
extensively
metabolized.
This
was
also
shown
earlier
by
another
rat
metabolism
study
on
the
absorption,
distribution,
excretion,
and
metabolite
identification
of
racemic
CGA­
24705
(
MRID
43164201,
reviewed
by
T.
McMahon,
HED
doc.
no.
010990
dated
May
23,
1994).
No
actual
metabolites
or
pathways
were
identified
in
the
current
study
and
there
were
no
data
to
support
or
refute
the
previous
findings
of
four
major
degradation
pathways
with
more
than
30
metabolites.
However,
knowing
the
enantiomeric
stereospecific
reactions/
metabolites
is
not
likely
to
help
in
making
comparative
risk
assessments
between
R/
Smetolachlor
(
CGA­
24705)
and
S­
metolachlor
(
CGA­
77102)
since
the
contribution
of
each
metabolite
to
the
overall
toxicity
of
Metolachlor
is
not
well
understood.
Furthermore,
other
bridging
animal
studies
with
CGA­
77102
should
highlight
possible
toxicity
differences
from
the
well­
studied
CGA­
24705
due
to
variations
in
the
metabolite
profiles.

The
Registrant
is
requested
to
comment
on
or
provide
information
on
a
number
of
issues
including:
1)
The
stereoisomeric
purity
of
CGA­
24705
and
CGA­
77102.
2)
The
adequacy
of
the
storage
conditions
and
the
validity
of
the
metabolite
profile
results
in
light
of
the
storage­
related
results
variability.
3)
Explain
why,
relative
to
the
other
dosing
formulation,
some
metabolite
fractions
(
e.
g.,
F10,
F12,
and
F13)
were
up
to
7­
fold
higher
in
the
case
of
the
S­
enantiomer
(
CGA­
77102)
while
some
urinary
metabolite
fractions
(
e.
g.,
U1,
U2,
and
U3)
were
up
to
4­
fold
higher
in
the
case
of
CGA­
24705.
4)
Provide
rational
for
dose
selection.
5)
The
Registrant
might
also
have
to
comment
on
the
possible
formation
and
the
level
of
methylethylaniline
from
either
dosing
formulation
and
the
possible
contribution
of
this
metabolite
to
the
carcinogenicity
of
Metolachlor.
This
issue
was
raised
earlier
by
T.
McMahon
(
HED
document
no.
010990
dated
May
23,
1994)
and
might
need
to
be
followed
up
by
HED's
risk
assessors
who
are
in
charge
of
Smetolachlor
65
Appendix
A
Table
3:
Structure
of
S­
Metolachlor
(
PC
Code
108800)
and
Metabolites
S­
metolachlor
and
Metabolites
Chemical
Structure
S­
metolachlor
(
2­
Chloro­
N­(
2­
ethyl­
6­
methylphenyl)­
N­{
S(
2­
methoxy­
1­
methylethyl)}
acetamide)

CGA­
37913
(
2­[(
2­
ethyl­
6­
methylphenyl)
amino]­
1­
propanol)

C
H
3
NH
CH
3
O
H
CH
3
CGA­
49751
(
4­(
2­
ethyl­
6­
methylphenyl)­
2­
hydroxy­
5­
methyl­
3­
morpholinone)

C
H
3
CH
3
N
O
O
OH
C
H
3
ESA
(
metolachlor
ethane
sulfonic
acid)

OA
(
metolachlor
oxanilic
acid)
66
Appendix
B
International
Residue
Status
Sheet
INTERNATIONAL
RESIDUE
LIMIT
STATUS
Chemical
Name:
Common
Name:
Smetolachlor
Proposed
tolerance
Reevaluated
tolerance
Other
Date:
6/
12/
06
Codex
Status
(
Maximum
Residue
Limits)
U.
S.
Tolerances
X
No
Codex
proposal
step
6
or
above
No
Codex
proposal
step
6
or
above
for
the
crops
requested
Petition
Numbers:
06NY08
DP
Barcodes:
D329176
Other
Identifier:
108800
Reviewer/
Branch:
W.
Cutchin
Residue
definition
(
step
8/
CXL):
N/
A
Proposed
Residue
definition:
S­
metolachlor
[
S­
2­
chloro­
N­
(
2­
ethyl­
6­
methylphenyl)­
N­(
2­
methoxy­
1­
methylethyl)
acetamide],
its
R­
enantiomer,
and
its
metabolites,
determined
as
the
derivatives,
2­[
2­
ethyl­
6­
methylphenyl)
amino]­
1­
propanol
and
4­(
2­
ethyl­
6­
methylphenyl)­
2­
hydroxy­
5­
methyl­
3­
morpholinone,
each
expressed
as
the
parent
compound
Crop
(
s)
MRL
(
mg/
kg)
Crop(
s)
Tolerance
(
ppm)

Cilantro
1.0
Kale
1.0
Collards
1.0
Mustard
greens
1.0
Pumpkins
0.1
Limits
for
Canada
Limits
for
Mexico
No
Limits
X
No
Limits
for
the
crops
requested
No
Limits
X
No
Limits
for
the
crops
requested
Residue
definition:
2­
chloro­
N­(
2­
ethyl­
6­
methylphenyl)­
N­[(
1S)­
2­
methoxy­
1­
methylethyl)
acetamide
and
2­
chloro­
N­(
2­
ethyl­
6­
methylphenyl)­
N­[(
1R)­
2­
methoxy­
1­
methylethyl)
acetamide,
including
the
metabolites2­[(
2­
ethyl­
6­
methylphenyl)
amino]­
1­
propanol
and
4­(
2­
ethyl­
6­
methylphenyl)­
2­
hydroxy­
5­
methyl­
3­
morpholinone
Residue
definition:
metolaclor
Crop(
s)
MRL
(
mg/
kg)
Crop(
s)
MRL
(
mg/
kg)

Notes/
Special
Instructions:
S.
Funk,
25/
06/
2006.
