Document ID: EPA-HQ-OPP-2002-0223-0020
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2002-10-23T04:00Z

UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
OFFICE
OF
PREVENTION,
PESTICIDES
AND
TOXIC
SUBSTANCES
May
23,
2002
MEMORANDUM
SUBJECT:
Metolachlor.
Revised
HED
Science
Assessment
for
Tolerance
Reassessment
Eligibility
Decision.
PC
Code
108801.
DP
Barcode
D282964.

FROM:
Christina
Jarvis,
Risk
Assessor
Reregistration
Branch
II
Health
Effects
Division
(7509C)

THROUGH:
Alan
Nielsen,
Branch
Senior
Scientist
Reregistration
Branch
II
Health
Effects
Division
(7509C)

TO:
Anne
Overstreet,
Chemical
Review
Manager
Reregistration
Branch
III
Special
Review
and
Reregistration
Division
(7508W)

Attached
is
the
revised
tolerance
reassessment
eligibility
decision
document
for
metolachlor
and
s­
metolachlor,
prepared
by
the
Health
Effects
Division
(HED).
This
assessment
has
been
revised
to
take
into
consideration
comments
made
by
Syngenta
Crop
Protection
during
the
30­
day
registrant
comment
period.
HED
notes
that
no
changes
to
the
toxicological
endpoint
selection
have
been
made
in
this
revised
assessment,
nor
have
any
of
Syngenta's
comments
resulted
in
a
significant
change
to
the
risk
picture
for
metolachlor
and
s­
metolachlor.
New
estimated
environmental
concentrations
of
metolachlor/
s­
metolachlor
in
drinking
water
have
not
resulted
in
a
significant
change
to
the
aggregate
risk
assessment.
This
assessment
includes
the
hazard
characterization
from
Virginia
Dobozy,
residential
exposure
assessment
from
Richard
Griffin,
dietary
exposure
and
residue
chemistry
assessments
from
Sherrie
Kinard,
product
chemistry
from
Ken
Dockter,
drinking
water
assessment
from
Mark
Corbin,
and
aggregate
exposure
assessment
and
risk
characterization
from
Christina
Jarvis.
The
disciplinary
science
chapters
and
other
supporting
documents
referenced
in
this
document
are
as
follows:

°
Revised
Estimated
Drinking
Water
Concentrations
for
Metolachlor/
S­
Metolachlor
and
its
Degradation
Products
for
Use
in
the
Human
Health
Drinking
Water
Risk
Assessment.
M.
Corbin,
05/
22/
02.
°
Product
Chemistry
Chapter
for
the
Tolerance
Reassessment
Eligibility
Decision
(TRED)
Document.
K.
Dockter,
2/
06/
02.
D274330.
°
Response
to
"SCAN
[only]
of
PMRA's
Review
of
Product
Chemistry.
K.
Dockter,
04/
19/
02.
D281758.
°
S­
metolachlor.
Supplemental
Product
Chemistry
[Storage
Stability;
OPPTS
Guideline
No.
830.6317].
MRID
44183001
[Addendum
to
MRID
43928903].
K.
Dockter,
05/
22/
02.
D283040.
°
Report
of
the
Hazard
Identification
Assessment
Review
Committee.
V.
Dobozy,
9/
28/
01.
°
Results
of
the
HED
Metabolism
Assessment
Review
Committee
Meeting
Held
on
8/
14/
01.
V.
Dobozy;
8/
14/
01.
D274326.
°
Report
of
the
FQPA
Safety
Factor
Committee.
C.
Christensen;
11/
14/
01.
°
Revised
Metolachlor
and
S­
Metolachlor
Residue
Chemistry
Chapter
for
the
Tolerance
Reassessment
Eligibility
Decision
(TRED)
Document.
S.
Kinard;
05/
22/
02.
D282931.
°
Revised
Toxicology
Chapter
for
Metolachlor/
S­
Metolachlor.
V.
Dobozy,
05/
13/
02.
D282934.
°
Metolachlor.
Review
of
Six
Acute
Toxicity
Studies.
V.
Dobozy,
05/
21/
02.
D283039.
°
Revised
Metolachlor
and
S­
Metolachlor.
Acute
and
Chronic
Dietary
Exposure
Assessments
for
the
Tolerance
Reassessment
Eligibility
Decision
(TRED).
S.
Kinard;
05/
22/
02.
D282933.
°
Metolachlor/
S­
Metolachlor:
Residential
Risk
Assessment.
R.
Griffin,
2/
20/
02.
D274331.

°
Review
of
Metolachlor
Incident
Reports.
J.
Blondell
and
M.
Spann,
8/
15/
97.
D238112.

°
Replacement
of
Metolachlor
Technical
(Racemic
Metolachlor)
with
Alpha­
Metolachlor
Technical;
Review
of
Bridging
Data.
L.
Kutney,
11/
12/
96.
D226780.
TABLE
OF
CONTENTS
1.
0
Executive
Summary......................................................................
­2­

2.
0
Physical/
Chemical
Properties
Characterization
.................................................
­7­

3.0
Hazard
Characterization
..................................................................
­8­
3.1
Hazard
Profile
...................................................................
­8­
3.
2
FQPA
Considerations
............................................................
­12­
3.3
Dose
Response
Assessment
.......................................................
­12­
3.4
Endocrine
Disruption
............................................................
­18­

4.0
Exposure
Assessment
and
Characterization
..................................................
­18­
4.
1
Summary
of
Registered
Uses
......................................................
­18­
4.2
Dietary
Exposure/
Risk
Pathway
....................................................
­19­
4.
2.
1
Residue
Profile
........................................................
­19­
4.2.2
Dietary
Exposure
.......................................................
­23­
4.
2.
2.
1
Acute
Dietary
Risk
Estimates.....................................
­24­
4.
2.
2.
2
Chronic
Dietary
Risk
Estimates
...................................
­25­
4.2.2.3
Cancer
Dietary
Exposure/
Risk
....................................
­26­
4.3
Water
Exposure/
Risk
Pathway
.....................................................
­26­
4.4
Residential
Exposure/
Risk
Pathway
.................................................
­29­
4.
4.
1
Home
Uses
............................................................
­29­
4.4.1.1
Residential
Handler
Exposure
.....................................
­29­
4.4.1.2
Residential
Postapplication
Exposure
...............................
­30­
4.
4.
2
Recreational
Uses.......................................................
­31­
4.
4.
3
Other
(Spray
Drift
etc.)...................................................
­32­
4.
5
Incidents
Reports.........................................................
­32­

5.
0
Aggregate
Risk
Assessments
and
Risk
Characterizations
.......................................
­32­
5.
1
Acute
Risk
....................................................................
­32­
5.
1.
1
Aggregate
Acute
Risk
Assessment
.........................................
­32­
5.
1.
2
Acute
DWLOC
Calculations..............................................
­34­
5.
2
Short­
Term
Risk
................................................................
­35­
5.
2.
1
Aggregate
Short­
Term
Risk
Assessment.....................................
­35­
5.
2.
2
Short­
Term
DWLOC
Calculations..........................................
­35­
5.
3
Intermediate­
Term
Risk
........................................................
­37­
5.
3.
1
Aggregate
Intermediate­
Term
Risk
Assessment
...............................
­37­
5.
4
Chronic
Risk...................................................................
­37­
5.
4.
1
Aggregate
Chronic
Risk
Assessment
........................................
­37­
5.
4.
2
Chronic
DWLOC
Calculations.............................................
­37­
5.
5
Cancer
Risk
....................................................................
­38­
5.
5.
1
Aggregate
Cancer
Risk
Assessment
.........................................
­38­

6.
0
Cumulative............................................................................
­38­

7.
0
Data
Needs/
Label
Requirements...........................................................
­39­
­2­
Background
Metolachlor
is
a
chloroacetanilide
herbicide
that
was
first
registered
for
use
in
1976.
Racemic
metolachlor
consists
of
50%
each
of
the
R­
enantiomer
(CGA
77101)
and
the
S­
enantiomer
(CGA
77102,
or
alpha
metolachlor).
The
S­
enantiomer
is
the
herbicidally
active
isomer.
In
1996,
the
registrant
(originally
Ciba­
Geigy,
now
Syngenta)
proposed
a
process
to
produce
a
higher
ratio
of
CGA
77102:
CGA
77101
(88:
12
instead
of
50:
50)
and
applied
for
reduced
risk
status
based
on
similar
efficacy
at
decreased
application
rates
(the
application
rate
of
smetolachlor
is
approximately
36
percent
lower
than
that
of
metolachlor).
In
1997,
the
EPA
approved
the
registration
of
s­
metolachlor
as
a
reduced
risk
product.

Syngenta
no
longer
holds
any
active
registrations
for
(racemic)
metolachlor
end­
use
products;
however,
a
search
of
the
Agency's
REFS
system
on
5/
9/
2002
shows
that
there
is
a
registration
for
a
(racemic)
metolachlor
technical
product
that
is
still
held
by
Syngenta
(EPA
Reg.
No.
100­
587).
Until
this
technical
registration
is
revoked,
the
Agency
will
proceed
with
a
tolerance
reassessment
decision
for
racemic
metolachlor,
based
on
all
crops
that
metolachlor
may
be
used
on,
as
allowed
for
by
the
technical
label.
The
Agency
notes,
however,
that
since
the
use
pattern
of
s­
metolachlor
is
identical
to
that
of
racemic
metolachlor,
and
since
the
Agency
has
determined
that
s­
metolachlor
has
either
comparable
or
decreased
toxicity
as
compared
to
racemic
metolachlor,
this
document
is
reflective
of
s­
metolachlor
as
well.

1.0
Executive
Summary
The
Agency
has
conducted
a
revised
human
health
risk
assessment
for
the
active
ingredient
metolachlor
[2­
chloro­
N­(
2­
ethyl­
6­
methylphenyl)­
N­(
2­
methoxy­
1­
methylethyl)
acetamide]
for
the
purpose
of
making
a
tolerance
reassessment
eligibility
decision.
Since
the
Reregistration
Eligibility
Decision
(RED)
document
for
metolachlor
was
completed
prior
to
the
passage
of
the
Food
Quality
Protection
Act
(FQPA)
of
1996,
a
tolerance
reassessment
eligibility
decision,
or
TRED,
is
now
required.
This
assessment
only
discusses
the
human
health
risk
assessment
required
for
reassessment
of
tolerances,
and
does
not
include
an
occupational
risk
assessment
required
for
reregistration
of
products.
As
noted
above,
this
TRED
for
metolachlor
is
also
representative
of
the
uses
of
s­
metolachlor.

Usage
Information
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
soybeans
account
for
the
majority
of
the
use
of
both
metolachlor
and
s­
metolachlor,
followed
by
cotton,
sweet
corn,
peanuts,
potatoes,
and
other
minor
field
and
vegetable
crops.

Application
rates
for
metolachlor
and
s­
metolachlor
range
from
approximately
one
to
four
pounds
active
ingredient
(a.
i.)
per
acre.
Application
is
typically
made
preemergence,
one
time
per
season.
­3­
Syngenta
does
not
currently
hold
any
active
end­
use
product
registrations
for
metolachlor.
Smetolachlor
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).

Hazard
Identification
and
FQPA
Considerations
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.
A
linear
risk
assessment
is
not
required.

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
CGA37913
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
­4­
residues
of
concern
for
plant
and
animal
commodities
are
metolachlor
and
its
metabolites,
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
(L.
Kutney
memo,
11/
12/
96).

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.
The
reference
dose
(RfD)
is
equal
to
the
No­
Observed­
Adverse­
Effect­
Level,
or
NOAEL,
divided
by
the
100X
uncertainty
factor.

–
acute
dietary(
general
population):
NOAEL=
300
mg/
kg/
day
RfD=
3.0
mg/
kg/
day
–
chronic
dietary:
NOAEL=
9.7
mg/
kg/
day
RfD
=
0.1
mg/
kg/
day
–
short­
term
incidental
oral:
NOAEL=
50
mg/
kg/
day
Target
MOE=
100
A
total
uncertainty
factor
(UF)
of
100X
was
applied
to
the
risk
assessment
to
account
for
interspecies
extrapolation
(10X)
and
intraspecies
variability
(10X).
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.

Dietary
Exposure
An
upper­
end
Tier
1
acute
dietary
risk
assessment
was
conducted
for
combined
exposure
to
residues
of
metolachlor
and
s­
metolachlor
found
on
various
field
and
vegetable
crops.
The
assessment
used
tolerance
level
residues
values
and
assumed
that
100%
of
labeled
crops
were
treated
with
metolachlor/
s­
metolachlor.
Since
it
is
not
possible
to
distinguish
between
residues
of
metolachlor
and
s­
metolachlor
using
currently
available
enforcement
methods,
and
since
the
tolerances
for
metolachlor
presently
cover
residues
resulting
from
the
use
of
s­
metolachlor,
acute
dietary
risk
estimates
are
applicable
to
both
metolachlor
and
s­
metolachlor.
Acute
dietary
risk
estimates
are
not
of
concern
(i.
e.,
below
100%
of
the
acute
population
adjusted
dose,
or
aPAD)
at
the
95
th
exposure
percentile,
for
any
population
subgroup.

An
upper­
end
Tier
1
chronic
dietary
risk
assessment
was
also
conducted
for
combined
exposures
to
metolachlor
and
s­
metolachlor.
Tolerance
level
residue
values
and
100%
crop
treated
were
assumed.
As
with
the
acute
dietary
risk
assessment,
chronic
dietary
risk
estimates
are
applicable
to
both
metolachlor
and
s­
metolachlor.
Chronic
dietary
risk
estimates
are
not
of
concern
(i.
e.,
­5­
below
100%
of
the
chronic
population
adjusted
dose,
or
cPAD)
for
any
population
subgroup.

The
Agency
notes
that
the
Tier
1
acute
and
chronic
dietary
assessments
could
be
further
refined
using
available
percent
crop
treated
information,
field
trial
and
monitoring
data,
and
processing
factors;
however,
the
estimated
acute
and
chronic
dietary
risks
are
not
of
concern
for
any
population
subgroup.
Further
refinements
are
not
warranted
at
this
time.
A
separate
cancer
dietary
risk
assessment
was
not
conducted,
as
it
was
determined
that
the
chronic
dietary
endpoint
would
be
protective
of
any
cancer
dietary
risks.

In
conjunction
with
a
March
22,
2002
Federal
Register
notice
that
cancelled
the
existing
use
of
metolachlor
on
stone
fruits
and
almonds,
stone
fruits
have
been
removed
from
this
revised
risk
assessment.
Almonds
will
remain
in
the
dietary
assessment,
as
there
is
a
crop
group
tolerance
that
exists
for
tree
nuts,
and
almonds
are
part
of
the
tree
nut
crop
group.

The
Agency
has
agreed
to
include
sunflower,
sugar
beets,
tomatoes,
spinach,
and
grass
grown
for
seed
in
the
tolerance
reassessment.
The
residue
chemistry
data
for
sunflower
and
sugar
beets
are
currently
under
review;
however,
a
decision
on
permanent
tolerances
for
these
commodities
cannot
be
made
until
an
occupational
assessment
has
been
conducted.
Residue
chemistry
data
support
permanent
tolerances
for
tomatoes,
spinach,
and
grass
grown
for
seed.
However,
a
permanent
tolerance
may
not
be
granted
until
a
full
occupational
assessment
has
been
conducted.
Since
this
is
a
tolerance
reassessment
document
and
not
a
reregistration
eligibility
decision
document,
an
occupational
assessment
will
not
be
done
as
part
of
this
document.
Asparagus,
carrots,
Swiss
chard,
all
peppers,
horseradish,
and
rhubarb
are
pending
tolerances
that
will
be
reviewed
by
the
Agency's
Registration
Division
at
a
future
date
and
will
not
be
included
in
the
tolerance
reassessment
eligibility
decision
document.

Residential
Exposure
Syngenta
has
no
remaining
residential
end­
use
product
labels
for
racemic
metolachlor.
Smetolachlor
may
be
applied
as
an
emulsifiable
concentrate
to
residential
lawns
or
turf
by
a
professional
applicator
only.
Therefore,
residential
handlers
are
not
expected
to
be
exposed
to
residues
of
s­
metolachlor.
A
residential
handler
risk
assessment
was
not
conducted.

There
is
a
potential
for
residential
postapplication
exposure
to
residues
of
s­
metolachlor
that
may
remain
on
lawns
after
treatment
by
professional
applicators.
However,
no
short­
and
intermediate­
term
dermal
endpoints
were
selected
(there
was
no
systemic
toxicity
seen
at
the
limit
dose
of
1000
mg/
kg/
day)
and
inhalation
exposure
is
expected
to
be
minimal
as
labels
specify
that
residents
should
not
enter
treated
areas
until
after
sprays
have
dried.
Therefore,
the
only
residential
postapplication
scenarios
that
were
assessed
were
potential
oral
exposure
to
children
from
contact
with
treated
lawn
and
soil
(i.
e.,
object­
to­
mouth,
hand­
to­
mouth,
and
incidental
soil
ingestion
scenarios).
These
exposure
scenarios
are
considered
short­
term
in
duration
(one
to
30
days
of
exposure),
based
on
label
specifications
of
a
six
week
interval
before
the
re­
application
of
s­
metolachlor.
The
registrant
has
also
indicated
a
label
revision
to
limit
application
to
one
application
per
season.
­6­
Postapplication
oral
risk
estimates
are
based
on
a
single
application
of
s­
metolachlor
at
the
maximum
label
rate
of
2.47
lb
ai/
acre
(EPA
Reg.
No.
100­
950).
The
exposure
values
of
the
three
scenarios
(object­
to­
mouth,
hand­
to­
mouth,
and
incidental
soil
ingestion)
were
combined
to
establish
the
possible,
if
not
likely,
upper­
end
estimate
of
oral
exposure
to
children
from
lawn
(or
similar)
use.
Combined
oral
MOE
estimates
are
1100
for
s­
metolachlor.
Postapplication
oral
exposure
from
s­
metolachlor
is
not
of
concern.
The
Agency
acknowledges
that
Syngenta
has
no
remaining
residential
end­
use
product
labels
for
racemic
metolachlor;
however,
for
informational
purposes,
the
combined
oral
MOE
estimates
for
metolachlor
(based
on
EPA
Reg.
No.
100­
691
and
a
maximum
label
application
rate
of
4
lb
ai/
acre)
are
670
and
not
of
concern.

Drinking
Water
Exposure
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.
It
is
important
to
note
that
the
analytical
methods
used
in
the
drinking
water
assessment
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
Metabolism
Assessment
Review
Committee
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.

Revised
surface
water
EEC
values
for
parent
metolachlor/
s­
metolachlor
range
from
4.3
ppb
(chronic)
to
77.6
ppb
(acute)
in
monitoring
data.
The
ground
water
EEC
value
for
parent
metolachlor/
s­
metolachlor
is
5.5
ppb,
based
on
modeled
estimates.
The
EEC
values
of
the
ESA
and
OA
degradates
range
from
22.8
ppb
to
91.4
ppb
in
surface
water,
and
from
31.7
ppb
to
65.8
ppb
in
ground
water,
based
on
modeled
estimates.
These
values
are
all
below
the
Agency's
estimated
drinking
water
levels
of
comparison
(DWLOCs),
and
therefore
do
not
pose
an
unreasonable
risk
of
concern
to
human
health.

Aggregate
Exposure
Aggregate
risk
assessments
for
metolachlor/
s­
metolachlor
consider
the
combined
risk
from
exposure
to
residues
via
the
food,
drinking
water,
and
residential
pathways
of
exposure.
In
the
case
of
metolachlor/
s­
metolachlor,
food,
drinking
water,
and
postapplication
oral
exposure
to
children
(post­
application
oral
exposure
values
are
from
the
use
of
s­
metolachlor
only)
will
be
considered
in
the
aggregate
assessment.
The
acute
aggregate
risk
assessment
is
based
on
combined
exposure
to
food
and
drinking
water
only,
and
is
not
of
concern.
The
short­
term
aggregate
risk
assessment
is
based
on
food,
drinking
water,
and
short­
term
postapplication
oral
exposure
to
children
(s­
metolachlor
only).
Short­
term
aggregate
risks
are
not
of
concern.
The
chronic
aggregate
risk
assessment
is
based
on
food
and
drinking
water
exposure
only,
as
there
are
no
long­
term
postapplication
exposure
scenarios.
Chronic
aggregate
risks
are
not
of
concern.
­7­
Occupational
Exposure
Occupational
exposures
and
risks
are
not
considered
under
FQPA;
therefore,
an
occupational
risk
assessment
is
not
included
in
this
FQPA
tolerance
reassessment
document.

Data
Needs
Toxicology
data
gaps
for
metolachlor
and
s­
metolachlor
include
a
28­
day
inhalation
study
in
rats.
Submission
of
these
studies
would
allow
the
Agency
to
improve
characterization
regarding
the
concern
for
toxicity
via
the
inhalation
route
of
exposure.
Registrants
are
recommended
to
follow
the
protocol
for
the
90­
day
inhalation
study
provided
in
OPPTS
Guideline
870.3465,
but
cease
exposure
at
28
days.

Numerous
residue
chemistry
data
gaps,
as
well
as
several
product
chemistry
data
gaps,
have
been
identified
for
metolachlor
and/
or
s­
metolachlor.
These
are
identified
in
Section
7.0
of
this
document.

2.0
Physical/
Chemical
Properties
Characterization
Metolachlor
[2­
chloro­
N­(
2­
ethyl­
6­
methylphenyl)­
N­(
2­
methoxy­
1­
methylphenyl)
acetamide],
a
List
A
chemical,
and
its
enriched
isomer
s­
metolachlor
are
registered
for
selective
weed
control
in
many
field
and
vegetable
crops,
ornamentals,
lawns,
and
turf.

Metolachlor
is
a
pale
yellow
to
light
brown
liquid
with
a
boiling
point
of
334
C;
density
of
1.117
g/
cm
3
at
20
C;
log
Pow
of
3.05
at
25
C;
and
a
low
vapor
pressure
of
2.8
x
10
­5
mm
Hg
at
25
C.
Metolachlor
is
completely
miscible
in
n­
hexane,
methanol,
acetone,
toluene,
and
n­
octanol
at
25
C.

No
impurities
of
toxicological
concern
have
been
identified
for
metolachlor
or
s­
metolachlor.

Product
chemistry
data
requirements
are
essentially
complete
for
both
metolachlor
and
smetolachlor
Any
product
chemistry
data
gaps
that
have
been
identified
in
the
product
chemistry
chapter
are
listed
in
Section
7.0
of
this
document
(K.
Dockter
memo,
2/
06/
02;
revised
by
K.
Dockter
memo,
4/
19/
02).

Empirical
formula:
C15
H22
NO2
Cl
Molecular
weight:
283.8
CAS
Registry
Nos.:
51218­
45­
2
and
87392­
12­
9
PC
Codes:
108801
&
108800
­8­
N
O
O
Cl
3.0
Hazard
Characterization
3.1
Hazard
Profile
Metolachlor:
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
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
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
­9­
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
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
compounds
were
not.
However,
the
MARC
concluded
that
the
ESA
and
OA
metabolites
should
be
included
in
the
water
risk
assessment
since
they
were
found
in
greater
abundance
than
the
parent(
s)
in
water
monitoring
studies.
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
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.

The
acute
toxicity
profile
for
metolachlor
is
presented
in
Table
1a.
For
comparison
purposes,
the
­10­
acute
toxicity
profile
for
metolachlor,
based
on
the
recently
reviewed
1994
acute
toxicity
studies,
is
presented
in
Table
1b.

Table
1a:
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
LD50
=
>
1.75
mg/
L
III
870.2400
Primary
Eye
Irritation­
Rabbits
00015528
non­
irritating
IV
870.2500
Primary
Skin
IrritationRabbits
00015530
non­
irritating
IV
870.2600
Dermal
Sensitization­
Guinea
pigs
00015631
positive
870.6200
Acute
Neurotoxicity–
NA
NA–
study
not
required
Table
1b:
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.

In
one
subchronic
toxicity
study
in
rodents
with
s­
metolachlor,
no
effects
were
observed
in
male
­11­
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
a
mutagenic
or
cytogenic
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
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
1c:
­12­
Table
1c:
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
LD50
=
>
2.91
mg/
L
IV
870.2400
Primary
Eye
Irritation­
Rabbits
43928918
slight
to
moderate
conjunctival
irritation
that
cleared
in
48
hours
III
870.2500
Primary
Skin
IrritationRabbits
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
be
reduced
to
1x
(removed)
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
Background:
Metolachlor
(CGA
24705)
consists
of
50%
each
of
the
R­
enantiomer
(CGA
77101)
and
the
S­
­13­
enantiomer
(CGA
77102,
also
referred
to
as
alpha
metolachlor).
CGA
77102
is
the
isomer
that
is
responsible
for
the
herbicidal
activity
of
metolachlor.
The
registrant
developed
a
process
to
produce
a
higher
ratio
of
CGA
77102:
CGA
77101
(88:
12)
and
applied
for
reduced
risk
status
based
on
decreased
application
rates
in
1996.
To
support
the
registration
of
s­
metolachlor,
bridging
toxicology
data
were
submitted,
including
the
following
studies:
six
acute
toxicity,
subchronic
toxicity
in
rat
and
dog,
developmental
toxicity
in
rat
and
rabbit
and
three
mutagenicity
studies.
The
registrant
made
the
argument
that
CGA
77102
was
already
tested
as
part
of
the
racemate.
Based
on
the
additional
studies
with
CGA
77102,
the
quantitative
doseeffect
relationship
of
the
racemate
and
the
S­
enantiomer
were
very
similar.
The
HED
RfD
Peer
Review
Committee
met
on
April
10,
1997
to
determine
whether
the
limited
toxicological
data
were
adequate
to
demonstrate
that
both
s­
metolachlor
and
metolachlor
have
identical
properties
and
if
so,
the
applicability
of
the
data
base
for
metolachlor
in
the
safety
evaluation
of
smetolachlor
and
whether
a
separate
RfD
was
required.
The
Committee
concluded
that,
without
metabolism
studies
and
side­
by­
side
subchronic
studies
conducted
in
the
same
strain
of
rat
using
comparable
dose
levels
of
test
materials,
the
identification
of
any
qualitative
or
quantitative
differences
in
the
toxicological
properties
of
CGA
77012
and
metolachlor
was
not
possible.

The
data
(metabolism
and
subchronic
toxicity
studies)
requested
by
the
1997
RfD
Committee
were
submitted
and
reviewed.
On
August
14,
2001,
the
HED's
Metabolism
Assessment
Review
Committee
met
to
determine
if
there
is
comparable
metabolism
of
metolachlor
and
smetolachlor
The
MARC
concluded
that
there
are
some
deficiencies
in
the
metabolism
databases
for
metolachlor
and
s­
metolachlor
that
prohibit
a
definitive
conclusion
about
the
comparable
metabolism
of
the
two
chemicals.
First,
the
study
(MRID
44491402)
in
which
there
were
side­
byside
metabolic
assays
was
conducted
with
only
a
single
oral
dose
(0.5
mg/
kg).
Therefore,
there
are
no
data
on
high
dose
or
repeated
low­
dose
metabolism
under
the
same
study
conditions.
Second,
a
metabolic
pathway
was
proposed
for
metolachlor
(MRID
43164201)
but
not
s­
metolachlor.
Third,
most
of
the
metabolites
of
both
metolachlor
and
s­
metolachlor
have
not
been
identified.

The
MARC
concluded
that,
given
the
lack
of
certain
data,
such
as
proposed
metabolic
pathway
for
s­
metolachlor
and
identification
of
metabolites
for
both
chemicals,
and
uncertainties
about
findings
in
some
studies,
such
as
quantitative
differences
in
metabolites,
it
was
not
possible
to
determine
if
the
metabolism
of
the
racemic
mixture
and
s­
metolachlor
are
comparable.
However,
the
Committee
questioned
how
much
this
information
contributed
to
assessing
the
relative
toxicity
of
metolachlor
and
s­
metolachlor.
Given
inherent
variabilities
in
the
results
of
the
available
metabolism
studies,
it
was
concluded
that
additional
metabolism
studies
might
not
add
more
understanding
than
the
current
information.

The
MARC
has
determined
that
the
residues
of
toxicological
concern
are
the
same
for
both
metolachlor
and
s­
metolachlor.

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
­14­
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.

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
assessment
is
presented
in
Table
2
of
this
document.
A
more
thorough
explanation
of
the
rationale
for
endpoint
selection
is
included
below:

Acute
Dietary
Endpoint:
The
acute
reference
dose
(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,
urinestained
abdominal
fur
and/
or
excessive
lacrimation)
and
decreased
body
weight
gain
seen
at
the
Lowest­
Observed­
Adverse­
Effect­
Level
(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)
that
caused
these
deaths;
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
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
­15­
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
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%
a.
i.)
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
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
­16­
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
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.
­17­
Table
2.
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
Acute
Dietary
(all
population
subgroups)
NOAEL
=
300
UF
=
100x
FQPA
Safety
Factor
=
1x
death,
clinical
signs
of
toxicity
(clonic
and/
or
tonic
convulsions,
excessive
salivation,
urine­
stained
abdominal
fur
and/
or
excessive
salivation)
and
decreased
body
weight
gain
Prenatal
developmental
toxicity
study
in
rats
with
metolachlor
Acute
PAD
=
3.0
mg/
kg/
day
Chronic
Dietary
(all
population
subgroups)
NOAEL=
9.7
UF
=
100
FQPA
Safety
Factor
=
1x
decreased
body
weight
gain
in
females
Chronic
study
in
dogs
with
metolachlor
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
Term
a
(greater
than
180
days)
Oral
NOAEL
=
9.7
Target
MOE
=
100
decreased
body
weight
gain
in
females
chronic
toxicity
study
in
dogs
with
metolachlor
Inhalation,
Short
Term
b
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
Term
b
Oral
NOAEL
=
8.8
Target
MOE
=
100
decreased
body
weight
gain
subchronic
(6
month)
toxicity
study
in
dogs
with
metolachlor
Exposure
Scenario
Dose
(mg/
kg/
day)
and
Uncertainty
Factor
(UF)
Endpoint
for
Risk
Assessment
Study
­18­
Inhalation,
Long
Term
b
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
Federal
Food,
Drug,
and
Cosmetic
Act
(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
the
recommendations
of
its
Endocrine
Disruptor
Screening
and
Testing
Advisory
Committee
(EDSTAC),
EPA
determined
that
there
was
scientific
bases
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).

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

4.0
Exposure
Assessment
and
Characterization
4.1
Summary
of
Registered
Uses
Metolachlor
and
s­
metolachlor
are
broad­
spectrum
herbicides
that
are
a
member
of
the
chloroacetanilide
group
of
pesticides.
They
are
used
primarily
for
grassy
weed
control
in
many
agricultural
food
and
feed
crops
(major
crop
uses
include
corn,
soybeans,
and
sorghum);
residential
lawns
(by
certified
applicator
only);
commercial
turf
(including
golf
courses,
sports
fields,
recreation
areas,
and
sod
farms);
ornamental
plants,
trees,
and
shrubs,
and
vines;
hedge
rows;
and
horticultural
nurseries.
Types
of
weeds
controlled
by
metolachlor
and
s­
metolachlor
include,
but
are
not
limited
to,
the
following:
pigweed,
carpetweed,
waterhemp,
chickweed,
goosefoot,
ragweed,
broomweed,
morning
glory,
crabgrass,
witchgrass,
foxtail,
and
nightshade.

[NOTE:
That
Agency
acknowledges
that
Syngenta
no
longer
holds
any
active
registrations
for
­19­
(racemic)
metolachlor
end­
use
products;
however,
a
search
of
the
Agency's
REFS
system
on
5/
9/
2002
shows
that
there
is
a
registration
for
a
(racemic)
metolachlor
technical
product
that
is
still
held
by
Syngenta
(EPA
Reg.
No.
100­
587).
Until
this
registration
is
revoked,
the
Agency
will
proceed
with
a
tolerance
reassessment
decision
for
racemic
metolachlor,
based
on
all
crops
that
metolachlor
may
be
used
on,
as
allowed
for
by
the
technical
label].

Metolachlor
and
s­
metolachlor
are
formulated
as
emulsifiable
concentrates
(most
common),
flowable
concentrate,
soluble
concentrates,
ready­
to­
use
formulations,
and
as
granular
formulations.
Application
methods
may
include
the
following:
ground
application
(most
common),
aerial
application,
irrigation
systems,
and
chemigation
(center
pivot
only).
For
residential
lawns,
a
hose­
end
sprayer,
backpack
sprayer,
or
handgun
application
may
be
used.
Application
timing
is
as
follows:
pre­
plant,
at
plant,
preemergence,
and
postemergence.
Metolachlor
and
s­
metolachlor
are
generally
applied
one
time
per
year.
Application
rates
range
from
approximately
one
to
four
pounds
a.
i.
per
acre,
with
the
application
rate
of
s­
metolachlor
being
approximately
35
percent
less
than
that
used
historically
for
metolachlor.

This
risk
assessment
is
a
tolerance
reassessment
only;
therefore,
exposures
to
occupational
handlers
of
metolachlor/
s­
metolachlor
are
not
assessed
in
this
document.
Potential
sources
of
non­
occupational
exposure
to
metolachlor/
s­
metolachlor
include
exposure
from
residues
in
food
and
drinking
water,
and
postapplication
exposure
of
homeowners
and
infants/
children
to
residues
of
s­
metolachlor
remaining
on
treated
lawns
or
turf.
Non­
occupational
exposure
from
spray­
drift
is
also
discussed
in
this
tolerance
reassessment
eligibility
decision
document.

4.2
Dietary
Exposure/
Risk
Pathway
4.2.1
Residue
Profile
Tolerances
for
residues
of
both
metolachlor
and
s­
metolachlor
in
or
on
raw
agricultural
commodities
include
the
combined
residues
of
(free
and
bound)
metolachlor
and
its
metabolites,
determined
as
the
derivatives,
CGA­
37913
and
CGA­
47951,
each
expressed
as
parent
compound.
Permanent
tolerances
for
metolachlor
residues
have
been
established
on
various
plant
commodities
ranging
from
0.1
ppm
in/
on
numerous
commodities
to
30.0
ppm
in/
on
peanut
forage
and
hay
[40
CFR
§180.368(
a)].
Time­
limited
tolerances
associated
with
section
18
emergency
exemptions
have
been
established
for
metolachlor
residues
in/
on
grass
forage
and
hay,
spinach,
and
tomato
commodities
[40
CFR
§180.368(
b)].
Tolerances
associated
with
regional
registrations
have
also
been
established
for
metolachlor
residues
in/
on
dry
bulb
onions,
cabbage,
and
various
peppers
(chili,
Cubanelle,
and
tabasco)
[40
CFR
§180.368(
c)].

Tolerances
for
metolachlor
currently
cover
residues
of
s­
metolachlor
on
the
same
commodities
for
the
same
use
pattern
when
the
maximum
use
rate
of
s­
metolachlor
is
approximately
35
percent
less
than
the
historical
use
rate
of
metolachlor.
Although
smetolachlor
is
applied
at
lower
application
rates
than
metolachlor,
there
are
currently
no
data
available
to
reassess
the
s­
metolachlor
tolerances
at
lower
levels
than
metolachlor.
However,
HED
does
recommend
that
a
separate
tolerance
section
be
established
under
§180.368
for
s­
­20­
C
H
3
NH
CH
3
HO
CH
3
C
H
3
CH
3
N
O
O
OH
C
H
3
metolachlor.
Tolerances
for
metolachlor
should
be
listed
under
§180.368(
a)(
1)
through
(d)(
1),
and
tolerances
for
s­
metolachlor
should
be
listed
under
§180.368(
a)(
2)
through
(d)(
2).
A
summary
of
the
tolerance
reassessment
and
recommended
modifications
in
commodity
definitions
for
metolachlor
and
s­
metolachlor
are
presented
in
Appendix
A,
Tables
3
and
4,
respectively.

Nature
of
the
Residue
in
Plants
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
structures
of
the
metabolites
are
shown
in
Figure
1
below.
The
residues
of
concern
for
smetolachlor
are
the
same
as
for
metolachlor
(L.
Kutney
memo,
D226780,
11/
12/
96);
however,
the
Agency
is
currently
reviewing
additional
submitted
data
(D278742
and
D279110).
These
data
will
be
incorporated
into
future
assessments
for
metolachlor
and
s­
metolachlor.

Figure
1.
Chemical
names
and
structures
of
metolachlor
residues
of
concern
in
plants
and
animals.

Common
names/(
Codes)
Chemical
name
Chemical
Structure
CGA­
37913
2­[(
2­
ethyl­
6­
methylphenyl)
amino]­
1­
propanol
CGA­
49751
4­(
2­
ethyl­
6­
methylphenyl)­
2­
hydroxy­
5­
methyl­
3­
morpholinone
Nature
of
the
Residue
in
Livestock:
­21­
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

Residue
Analytical
Methods
The
Pesticide
Analytical
Manual
(PAM)
Vol.
II,
lists
a
GC/
NPD
method
(Method
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.
Residue
data
from
the
most
recent
field
trials
and
processing
studies
were
obtained
using
an
adequate
GC/
NPD
method
AG612
which
is
a
modification
of
Method
I.

Multi­
residue
Method
Testing
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
(3
rd
ed.,
revised
10/
97).

Storage
Stability
Data
Adequate
storage
stability
data
are
available
to
support
the
crop
field
trials
and
processing
studies.
In
plant
commodities,
the
parent
compound
and
all
residues
convertible
to
CGA­
37913
are
stable
at
#
­10
C
for
at
least
2
years
in
corn
(grain
and
forage),
peanuts,
potatoes
(tubers,
wet
peel
and
flakes),
soybeans
(hulls
and
meal)
and
tomatoes,
for
at
least
29
months
in
cottonseed
oil,
and
for
at
least
37
months
in
cottonseed
and
corn
oil.
The
derivative
CGA­
49751
is
also
stable
at
#
­10
C
for
at
least
2
years
in
corn
(grain,
forage,
and
oil),
peanuts,
potatoes
(tubers,
wet
peel
and
flakes),
soybeans
(hulls
and
meal)
and
tomatoes,
and
for
at
least
37
months
in
cottonseeds
and
cottonseed
oil.

For
livestock
commodities,
data
are
available
indicating
that
CGA­
49751
is
stable
at
­15
C
for
up
to
25
months
in
milk,
eggs,
beef
liver
and
muscle.
The
derivative
CGA­
37913
is
stable
at
­15
C
for
up
to
25
months
in
milk
and
eggs,
12
months
in
beef
liver,
and
2
months
in
beef
muscle.
More
recent
storage
stability
data
for
CGA­
37913
indicated
that
it
is
stable
at
­20
C
in
beef
muscle
for
up
to
12
months;
however,
HED
has
concluded
that
the
original
storage
stability
studies
for
beef
muscle
were
more
representative
of
the
conditions
encountered
during
the
feeding
study;
therefore,
the
original
studies
would
be
assumed
to
be
valid
and
residues
of
CGA­
37913
in
beef
muscle
will
be
corrected
for
loss
during
frozen
storage.
­22­
Magnitude
of
the
Residue
in
Crops
Adequate
metolachlor
residue
data
are
available
for
both
metolachlor
and
s­
metolachlor
in/
on
celery,
corn
(field
and
sweet),
cottonseed,
grasses
grown
for
seed,
potatoes,
safflower,
and
sorghum.
An
adequate
number
of
field
trials
have
been
conducted
on
these
crops
and
depict
residues
resulting
from
the
application
of
metolachlor
at
the
maximum
labeled
or
proposed
use
rate.
Adequate
metolachlor
and
s­
metolachlor
data
are
also
available
for
legume
vegetable
foliage,
peanuts,
soybeans,
spinach,
and
tree
nuts
provided
the
specified
metolachlor
and
smetolachlor
label
amendments
are
made.
There
are
adequate
metolachlor
data
available
for
tomatoes;
however,
copies
of
the
labels
must
be
provided
specifying
a
PHI
of
90
days
and
a
maximum
of
one
post­
emergence
application
of
3.0
lb
ai/
A
for
metolachlor,
and
1.9
lb
ai/
A
for
smetolachlor
The
available
residue
data
for
metolachlor
are
summarized
on
a
crop­
by­
crop
basis
in
the
residue
chemistry
chapter
(S.
Kinard
memo,
D282931,
5/
22/
2002).

To
support
current
or
proposed
tolerances
for
metolachlor
and
s­
metolachlor,
residue
data
are
required
reflecting
the
maximum
use
rates
on
the
following
crops
or
commodities:
(i)
representative
succulent,
shelled
peas
and
beans,
to
support
the
use
on
legume
vegetables;
(ii)
bell
peppers,
to
support
a
pending
tolerance
on
peppers;
and
(iii)
corn,
sorghum,
and
soybean
aspirated
grain
fractions.

Maximum
use
rates
for
s­
metolachlor
are
­
35
percent
less
than
the
use
rate
for
metolachlor
on
comparable
crops.
The
available
bridging
studies
on
corn
and
soybeans
indicate
that
residues
resulting
from
the
application
of
s­
metolachlor
are
likely
to
be
lower
than
for
metolachlor;
therefore,
the
available
metolachlor
residue
data
will
support
comparable
uses
of
s­
metolachlor
provided
that
the
labeled
use
rates
for
s­
metolachlor
are
­
35
percent
lower
than
the
metolachlor
use
rates.
However,
for
those
uses
that
result
in
residues
well
above
the
method
LOQ
(0.08
ppm),
such
as
corn
forage,
residue
data
for
s­
metolachlor
will
be
required
to
reassess
tolerances
if
s­
metolachlor
completely
replaces
a
particular
use
of
metolachlor.
Current
examples
of
this
include
the
special
local
need
(SLN)
uses
on
cabbage
and
dry
bulb
onions.
Tolerances
for
both
cabbage
and
dry
bulb
onion
are
1.0
ppm,
and
all
metolachlor
SLN
labels
for
these
uses
have
been
replaced
by
SLNs
associated
with
s­
metolachlor.
Accordingly,
residue
data
are
required
for
s­
metolachlor
on
cabbage
and
onions.
For
cases
in
which
the
current
tolerance
for
metolachlor
is
set
at
or
near
the
method
LOQ,
such
as
celery
(0.1
ppm),
additional
s­
metolachlor
residue
data
will
not
be
required
if
the
comparable
use
of
metolachlor
is
canceled.

Magnitude
of
the
Residue
in
Processed
Food/
Feed
Adequate
processing
studies
are
available
for
corn,
cottonseed,
peanuts,
potatoes,
safflower,
soybeans
and
tomatoes.
The
data
from
the
corn,
cottonseed
and
safflower
studies
indicate
that
metolachlor
residues
do
not
concentrate
in
processed
commodities
from
these
crops;
however,
the
peanut,
potato,
soybean,
and
tomato
processing
studies
indicated
that
there
is
the
potential
for
concentration
of
metolachlor
residues
in
several
commodities.
These
data
can
be
translated
to
support
the
use
of
s­
metolachlor.
A
summary
of
the
residue
data
by
crop
may
be
found
in
the
residue
chemistry
chapter
(S.
Kinard
memo,
D282931,
5/
22/
2002).
­23­
Magnitude
of
the
Residue
in
Meat,
Milk,
Poultry,
and
Eggs
Tolerance
reassessment
requirements
for
magnitude
of
the
residue
in
meat,
milk,
poultry,
and
eggs
are
fulfilled.
Adequate
ruminant
and
poultry
feeding
studies
are
available
for
metolachlor,
and
these
data
will
also
support
the
use
of
s­
metolachlor.

Confined
Accumulation
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
14
C­
residues
in
plants,
along
with
information
on
the
percentage
of
the
14
C­
residues
measured
by
the
current
enforcement
method,
supporting
storage
stability
data,
and
sample
storage
conditions
and
intervals.

Codex/
International
Harmonization
No
maximum
residue
limits
(MRLs)
for
either
metolachlor
or
s­
metolachlor
have
been
established
or
proposed
by
Codex,
Canada,
or
Mexico
for
any
agricultural
commodity;
therefore,
no
compatibility
questions
exist
with
respect
to
U.
S.
tolerances.

4.2.2
Dietary
Exposure
Metolachlor
and
s­
metolachlor
acute
and
chronic
dietary
exposure
assessments
were
conducted
using
the
Dietary
Exposure
Evaluation
Model
(DEEM™)
software
Version
7.73,
which
incorporates
consumption
data
from
USDA's
Continuing
Surveys
of
Food
Intake
by
Individuals
(CSFII),
1989­
1992.
The
1989­
92
data
are
based
on
the
reported
consumption
of
more
than
10,000
individuals
over
three
consecutive
days,
and
therefore
represent
more
than
30,000
unique
"person
days"
of
data.
Foods
"as
consumed"
(e.
g.,
apple
pie)
are
linked
to
raw
agricultural
commodities
and
their
food
forms
(e.
g.,
apples­
cooked/
canned
or
wheat­
flour)
by
recipe
translation
files
internal
to
the
DEEM
software.
Consumption
data
are
averaged
for
the
entire
US
population
and
within
population
subgroups
for
chronic
exposure
assessment,
but
are
retained
as
individual
consumption
events
for
acute
exposure
assessment.

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

For
acute
exposure
assessments,
individual
one­
day
food
consumption
data
are
used
on
an
individual­
by­
individual
basis.
The
reported
consumption
amounts
of
each
food
item
can
be
multiplied
by
a
residue
point
estimate
and
summed
to
obtain
a
total
daily
pesticide
exposure
for
a
­24­
deterministic
(Tier
1
or
Tier
2)
exposure
assessment.
The
resulting
distribution
of
exposures
is
expressed
as
a
percentage
of
the
aPAD
on
both
a
user
(i.
e.,
those
who
reported
eating
relevant
commodities/
food
forms)
and
a
per­
capita
(i.
e.,
those
who
reported
eating
the
relevant
commodities
as
well
as
those
who
did
not)
basis.
In
accordance
with
HED
policy,
per
capita
exposure
and
risk
are
reported
for
all
Tiers
of
analysis;
however,
for
Tiers
1
and
2,
significant
differences
in
user
vs.
per
capita
exposure
and
risk
are
identified.

The
DEEM™
analyses
estimated
the
acute
and
chronic
dietary
exposure
for
the
general
U.
S.
population
and
26
population
subgroups.
The
results
reported
in
Table
3
are
for
the
U.
S.
Population
(total),
all
infants
(<
1
year
old),
children
1­
6,
children
7­
12,
females
13­
50,
males
13­
19,
males
20
and
older,
and
seniors
55
and
older.
The
results
for
the
other
population
subgroups
are
not
reported
in
Table
3.
This
is
because
the
numbers
of
respondents
in
the
other
subgroups
were
not
sufficient,
and
thus
the
exposure
estimates
for
these
subgroups
contained
higher
levels
of
uncertainty;
however,
the
respondents
in
these
subgroups
were
also
part
of
larger
subgroups
which
are
listed
in
Table
3.
For
example,
nursing
and
non­
nursing
infants
are
included
in
all
infants.
Subgroups
broken
down
by
region,
season,
and
ethnicity
are
also
not
included
in
Table
3.
4.2.2.1
Acute
Dietary
Risk
Estimates
A
conservative
Tier
1
acute
dietary
exposure
assessment
was
conducted
for
all
labeled
metolachlor
and
s­
metolachlor
food
uses.
Inputs
for
this
assessment
included
tolerance­
level
residue
values
and
an
assumption
that
100%
of
all
labeled
crops
were
treated
with
metolachlor/
smetolachlor
For
all
supported
registered
commodities,
the
acute
dietary
exposure
estimates
are
below
the
Agency's
level
of
concern
(<
100%
aPAD)
at
the
95
th
exposure
percentile
for
the
general
U.
S.
population
and
all
population
subgroups.
The
acute
dietary
risk
estimate
for
the
highest
exposed
population
subgroup,
children
1­
6
years
of
age,
is
<1%
of
the
aPAD.
Acute
dietary
risk
estimates
are
not
of
concern.
Results
of
the
acute
dietary
risk
assessment
are
presented
in
Table
3.

4.2.2.2
Chronic
Dietary
Risk
Estimates
A
conservative
Tier
1
chronic
dietary
exposure
assessment
was
conducted
for
all
supported
metolachlor
and
s­
metolachlor
food
uses.
For
all
supported
registered
commodities,
the
chronic
dietary
exposure
estimates
are
below
the
Agency's
level
of
concern
(<
100%
cPAD)
for
the
general
U.
S.
population
and
all
population
subgroups.
The
chronic
dietary
risk
estimate
for
the
highest
exposed
population
subgroup,
children
1­
6
years
of
age,
is
3%
of
the
cPAD.
Chronic
dietary
risk
estimates
are
not
of
concern.
Results
of
the
chronic
dietary
risk
assessment
are
presented
in
Table
3.

The
Agency
notes
that
the
conservative
Tier
1
dietary
assessments
for
metolachlor
and
smetolachlor
could
be
refined
for
more
realistic
dietary
exposure
estimates
by
using
available
percent
crop
treated
estimates,
field
trial
and
monitoring
data,
and
processing
factors;
however,
the
estimated
dietary
risk
to
metolachlor
and
s­
metolachlor
is
not
of
concern
for
all
populations
in
both
the
acute
and
chronic
assessments.
Further
refinements
are
not
warranted
at
this
time.
­25­
­26­
Table
3.
Summary
of
Dietary
Exposure
Estimates
for
Metolachlor
and
S­
metolachlor
Population
Subgroup
Acute
Dietary
Chronic
Dietary
Dietary
Exposure
(mg/
kg/
day)
%
aPAD
Dietary
Exposure
(mg/
kg/
day)
%
cPAD
U.
S.
Population
(total)
0.
003822
<1
0.001454
2
All
Infants
(<
1
year)
0.
005245
<1
0.001872
2
Children
1­
6
years
0.
006876
<1
0.003171
3
Children
7­
12
years
0.
004636
<1
0.002153
2
Females
13­
50
0.002699
<1
0.001121
1
Males
13­
19
0.003489
<1
0.001541
2
Males
20+
years
0.
002747
<1
0.001191
1
Seniors
55+
0.002578
<1
0.001072
1
4.2.2.3
Cancer
Dietary
Exposure/
Risk
Metolachlor
has
been
classified
as
a
Group
C,
possible
human
carcinogen,
based
on
liver
tumors
in
rats
seen
at
the
highest
dose
tested
of
150
mg/
kg/
day.
The
Cancer
Assessment
Review
Committee
met
on
July
27,
1994,
and
determined
that
carcinogenic
risks
to
metolachlor
should
be
quantitated
using
a
non­
linear
approach,
with
a
NOAEL
of
15
mg/
kg/
day
based
on
neoplastic
nodules/
hepatocellular
carcinomas
seen
at
150
mg/
kg/
day
in
the
chronic
toxicity/
carcinogenicity
study
in
rats.
The
Cancer
Assessment
Review
Committee
notes
that
the
NOAEL
used
for
calculating
the
cancer
MOE
values
(15
mg/
kg/
day)
is
comparable
to
the
NOAEL
of
9.7
mg/
kg/
day
selected
for
establishing
the
chronic
reference
dose
for
metolachlor.
Therefore,
a
separate
cancer
dietary
risk
assessment
was
not
conducted
as
it
is
assumed
that
the
chronic
dietary
endpoint
is
protective
for
cancer
dietary
exposure.

4.3
Water
Exposure/
Risk
Pathway
A
drinking
water
assessment
for
metolachlor
and
s­
metolachlor
was
conducted
by
the
Environmental
Fate
and
Effects
Division
(EFED)
and
involved
the
analysis
of
surface
and
ground
water
monitoring
data,
prospective
ground
water
study
data,
and
Tier
I
(FIRST
and
SCIGROW
and
Tier
II
(PRZM/
EXAMS)
modeling
results.
This
assessment
includes
concentrations
of
parent
metolachlor/
s­
metolachlor
and
the
degradates
metolachlor
ethanesulfonic
acid
(ESA)
and
metolachlor
oxanilic
acid
(OA).
Although
it
was
determined
by
the
Metabolism
Assessment
Review
Committee
that
the
ESA
and
OA
metabolites
appear
to
be
less
toxic
than
parent
metolachlor/
s­
metolachlor,
they
are
included
in
this
risk
assessment
since
they
were
found
in
greater
abundance
than
the
parent
in
water
monitoring
studies.
­27­
The
Agency
notes
that
a
key
assumption
of
the
drinking
water
assessment
is
that
reported
monitoring
data
represent
both
racemic
metolachlor
and
s­
metolachlor.
The
analytical
methods
for
surface
and
ground
water
monitoring
data
used
in
this
assessment
are
unable
to
distinguish
between
metolachlor
and
s­
metolachlor.
However,
EFED
believes
that
the
fate
properties
of
racemic
metolachlor
and
s­
metolachlor
are
similar.
Therefore,
the
EECs
used
in
this
risk
assessment
are
representative
of
both
racemic
metolachlor
and
s­
metolachlor.

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.

EECs
for
Parent
Metolachlor/
S­
Metolachlor:
No
surface
or
ground
water
monitoring
studies
that
specifically
target
metolachlor/
s­
metolachlor
were
available
for
the
drinking
water
assessment.
As
a
result,
the
drinking
water
assessment
for
parent
metolachlor/
s­
metolachlor
is
based
primarily
on
monitoring
data
from
the
following
sources:
the
United
States
Geological
Survey
(USGS)
National
Water
Quality
Assessment
(NAWQA)
database,
the
US
EPA
STORET
database,
the
Acetochlor
Registration
Partnership
(ARP)
database,
and
two
USGS
Reservoir
Monitoring
studies.

The
acute
estimated
environmental
concentration
(EEC)
of
77.6
ppb
was
selected
from
the
NAWQA
database,
and
the
chronic
EEC
of
4.3
ppb
was
selected
from
the
maximum
annual
time
weighted
mean
from
the
NAWQA
data.
These
values
represent
the
estimated
concentration
of
parent
metolachlor/
s­
metolachlor
in
surface
water,
and
are
supported
by
the
metolachlor
concentrations
from
the
National
Contaminant
Occurrence
Database
representing
analysis
of
treated
drinking
water,
as
well
as
from
model
predictions
using
PRZM/
EXAMS.
When
the
monitoring
data
and
modeling
data
are
considered
together,
there
is
a
general
agreement
between
the
various
sources
of
information
used
in
the
assessment.

Acute
and
chronic
concentrations
of
parent
metolachlor/
s­
metolachlor
in
ground
water
were
modeled
using
SCI­
GROW.
SCI­
GROW
estimates
the
upper
bound
ground
water
concentrations
of
pesticides
likely
to
occur
when
the
pesticide
is
used
at
the
maximum
allowable
rate
in
areas
with
ground
water
vulnerable
to
contamination.
Estimates
were
based
on
two
applications
to
corn/
turf
for
a
total
of
4
lbs
ai/
acre
(the
maximum
application
rate).
In
comparison
to
the
SCI­
GROW
estimate
of
5.5
ppb
in
shallow
ground
water,
the
Iowa
NAWQA
data
have
a
maximum
concentration
of
15.4
ppb.
However,
it
should
be
noted
that
the
second
highest
concentration
of
parent
metolachlor/
s­
metolachlor
in
the
Iowa
NAWQA
data
is
1.7
ppb.
Additionally,
recent
data
collected
by
the
Suffolk
Country,
New
York
Department
of
Health
­28­
Services,
Bureau
of
Groundwater
Resources
indicate
that
both
metolachlor
and
s­
metolachlor,
and
its
degradates,
have
been
detected
in
ground
water.
In
data
collected
between
1997
and
2001,
metolachlor/
s­
metolachlor
was
detected
in
60
well
samples
with
a
maximum
concentration
of
83
ppb.
No
information
was
available
on
frequency
of
detection
and
only
summary
statistics
were
provided
on
these
data;
therefore,
these
data
were
not
used
quantitatively
in
the
risk
assessment.
However,
these
data
suggest
that
the
SCI­
GROW
estimates
for
metolachlor/
smetolachlor
are
not
overestimating
the
potential
impact
of
metolachlor/
s­
metolachlor
use
on
ground
water.
Of
note,
parent
metolachlor/
s­
metolachlor
was
not
detected
in
two
prospective
ground
water
studies
that
have
been
completed.
The
SCI­
GROW
estimate
of
5.5
ppb
in
ground
water
is
appropriate
for
risk
assessment
purposes.

EECs
for
Metolachlor
ESA
and
OA
Degradates:
Only
two
small
data
sets
were
available
on
the
ESA
and
OA
degradates
from
the
Iowa
and
Illinois
NAWQA
data.
In
the
absence
of
more
robust
monitoring
data
for
the
degradates,
upperbound
Tier
I
estimates
for
ESA
and
OA
based
on
FIRST
and
SCI­
GROW
modeling
were
used
to
calculate
EECs
for
the
degradates.
The
modeling
used
conservative
assumptions
of
selected
fate
parameters
(aerobic
soil
metabolism
rate
constant
and
soil
partitioning
coefficient)
as
well
as
the
maximum
application
rate
of
4
lbs
ai/
acre
on
turf/
corn.

Acute
and
chronic
estimates
of
metolachlor
ESA
in
surface
water
(based
on
FIRST
modeling)
are
31.9
ppb
and
22.8
ppb,
respectively.
Acute
and
chronic
estimates
of
metolachlor
OA
in
surface
water
are
91.4
ppb
and
65.1
ppb,
respectively.
The
Agency
notes
that
the
application
rate
used
for
metolachlor
ESA
and
OA
in
the
model
runs
was
estimated
by
converting
maximum
label
rates
for
each
use
by
the
maximum
percentage
of
degradate
found
in
fate
studies.
In
addition,
each
application
rate
was
corrected
for
molecular
weight
differences
of
each
degradate.
However,
EFED
could
not
establish
a
statistically
significant
relationship
between
parent
metolachlor
and
degradates;
therefore,
the
amount
of
degradate
is
an
uncertainty
in
this
assessment.

Acute
and
chronic
estimates
of
metolachlor
ESA
in
ground
water
(based
on
SCI­
GROW
modeling,
turf/
corn
scenario)
are
not
expected
to
exceed
65.8
ppb.
This
value
is
considered
representative
of
both
peak
and
long­
term
average
concentrations
because
of
the
inherent
transport
nature
of
ground
water
(generally
slow
movement
from
the
source
of
contamination
both
laterally
and
horizontally).
Acute
and
chronic
estimates
of
metolachlor
OA
in
ground
water
(also
based
on
the
turf
/corn
scenario)
are
not
expected
to
exceed
31.7
ppb.
The
Agency
notes
that
these
values
exceed
those
detected
in
the
Iowa
NAWQA
study
(63.7
ppb
for
metolachlor
ESA
and
4.4
ppb
for
metolachlor
OA),
and
also
exceed
those
values
detected
in
two
PGW
studies
(metolachlor
ESA
was
detected
at
a
maximum
concentration
of
24
ppb
while
metolachlor
OA
was
detected
at
a
maximum
concentration
of
15.6
ppb).
In
addition,
recent
data
collected
by
the
Suffolk
Country,
New
York
Department
of
Health
Services,
Bureau
of
Groundwater
Resources
indicate
that
both
metolachlor
and
s­
metolachlor,
and
its
degradates,
have
been
detected
in
ground
water.
In
data
collected
between
1997
and
2001,
metolachlor
ESA
was
detected
in
296
well
samples
with
a
maximum
concentration
of
39.7
ppb,
while
metolachlor
OA
was
detected
in
228
wells
with
a
maximum
concentration
of
49.6
ppb.
No
information
was
­29­
available
on
frequency
of
detection
and
only
summary
statistics
were
provided
on
these
data;
therefore,
these
data
were
not
used
quantitatively
in
the
risk
assessment.
However,
these
data
suggest
that
the
SCI­
GROW
estimates
for
metolachlor
ESA
and
OA
are
slightly
overestimating
the
potential
impact
of
metolachlor/
s­
metolachlor
use
on
ground
water.

Drinking
Water
Levels
of
Comparison
(DWLOCs):
In
the
absence
of
chemical­
specific
monitoring
data,
the
Agency
uses
drinking
water
levels
of
comparison
to
calculate
aggregate
risk.
A
drinking
water
level
of
comparison,
or
a
DWLOC,
is
a
theoretical
upper
limit
on
a
pesticide's
concentration
in
drinking
water
in
light
of
total
aggregate
exposure
to
a
pesticide
in
food,
drinking
water,
and
through
residential
uses.
In
other
words,
the
DWLOC
value
represents
the
maximum
theoretical
exposure
a
person
may
have
to
pesticide
residues
through
drinking
water,
after
their
exposure
to
the
pesticide's
residues
through
food
and
residential
exposure
have
been
taken
into
consideration.
The
Office
of
Pesticide
Programs
uses
DWLOCs
internally
in
the
risk
assessment
process
as
a
surrogate
measure
of
potential
exposure
associated
with
pesticide
exposure
through
drinking
water.
DWLOC
values
are
not
regulatory
standards
for
drinking
water;
however,
they
do
have
an
indirect
regulatory
impact
through
aggregate
exposure
and
risk
assessments.

DWLOCs
are
calculated
for
each
type
of
risk
assessment
as
appropriate
(acute,
short­
term,
intermediate­
term,
chronic,
and
cancer)
and
compared
to
the
appropriate
estimated
concentration
of
a
pesticide
in
surface
and
ground
water,
as
provided
by
EFED.
If
the
DWLOC
is
greater
than
the
estimated
surface
and
ground
water
concentration,
(i.
e.,
if
the
DWLOC
>
EEC),
the
Agency
concludes
with
reasonable
certainty
there
is
no
drinking
water
risk
of
concern.

A
summary
of
aggregate
exposure
and
risk,
including
DWLOC
calculations,
may
be
found
in
Section
5.0
of
this
document.

4.4
Residential
Exposure/
Risk
Pathway
4.4.1
Home
Uses
4.4.1.1
Residential
Handler
Exposure
The
Agency
notes
that
Syngenta
does
not
currently
hold
any
active
end­
use
product
registrations
for
metolachlor.
S­
metolachlor
is
registered
(as
an
emulsifiable
concentrate
formulation)
for
use
on
lawn,
turf
(including
sod
farms),
golf
courses,
sports
fields,
and
ornamental
gardens.
Although
not
labeled
as
a
restricted­
use
pesticide,
the
label
as
it
is
currently
marketed
is
not
intended
for
homeowner
purchase
or
use.
On
this
basis,
a
residential
handler
is
not
expected
to
be
exposed
to
residues
of
s­
metolachlor.
Therefore,
a
residential
handler
assessment
was
not
conducted.

4.4.1.2
Residential
Postapplication
Exposure
There
is
potential
for
postapplication
exposure
to
adults
and
children
resulting
from
the
use
of
s­
­30­
metolachlor
on
residential
lawns.
Although
the
use
sites
for
s­
metolachlor
vary
from
golf
courses
to
ornamental
gardens,
the
residential
lawn
scenario
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.

Postapplication
exposure
is
considered
to
be
short­
term
(one
to
30
days
of
exposure)
only,
based
on
a
label
specification
of
a
six
week
interval
before
the
re­
application
of
s­
metolachlor.
The
registrant
has
also
indicated
a
label
revision
to
limit
application
to
one
time
per
season.

A
short­
term
dermal
endpoint
was
not
selected,
since
no
systemic
toxicity
was
seen
at
the
limit
dose
of
1000
mg/
kg/
day;
therefore,
a
dermal
risk
assessment
was
not
conducted
and
dermal
exposures
are
assumed
to
be
minimal.
Postapplication
inhalation
exposure
is
also
expected
to
be
minimal
since
s­
metolachlor
is
only
applied
in
an
outdoor
setting,
the
vapor
pressure
is
low
(2.8
x
10
­5
mm
Hg
at
25
C),
and
the
label
specifies
that
residents
should
not
re­
enter
treated
areas
until
after
sprays
have
dried.

The
following
postapplication
incidental
oral
scenarios
following
application
to
lawns
and
turf
have
been
identified:
1)
short­
term
oral
exposure
to
toddlers
and
children
following
hand­
tomouth
exposure;
2)
short­
term
oral
exposure
to
toddlers
and
children
following
object­
to­
mouth
exposure;
and
3)
short­
term
oral
exposure
to
toddlers
and
children
following
soil
ingestion.
The
term
"incidental"
is
used
to
distinguish
the
inadvertent
oral
exposure
of
small
children
from
exposure
that
may
be
expected
from
treated
foods
or
residues
in
drinking
water.

Since
the
FQPA
safety
factor
for
the
protection
of
children
and
infants
was
reduced
to
1X,
a
target
MOE
value
of
100
has
been
identified
for
residential
assessments.
MOE
values
greater
than
100
are
not
considered
to
be
of
concern
to
the
Agency.
MOE
estimates
are
based
on
the
dose
level
of
50
mg/
kg/
day
established
for
short­
term
oral
risk
assessment.

The
HED
Standard
Operating
Procedures
for
Residential
Exposure
Assessments
(Draft,
December
18,
1997)
were
used
as
a
guideline
for
the
residential
postapplication
assessment.
Also,
standard
values
for
turf
transferable
residues,
turf
transfer
coefficients,
and
hand­
to­
mouth
activities
were
used
as
amended
by
Exposure
Policy
12
(Science
Advisory
Panel
on
Exposure,
February
22,
2001).
The
exposure
and
risk
estimates
for
the
three
residential
exposure
scenarios
are
assessed
for
the
day
of
application
(day
"0")
since
children
will
likely
contact
the
lawn
immediately
following
application.

The
following
estimates/
assumptions
were
used
in
the
risk
assessment:

°
A
single
application
at
the
maximum
label
rate
of
2.47
lb
ai/
acre
for
s­
metolachlor.

°
Exposure
duration
for
children
is
assumed
to
be
2
hours
per
day.

°
The
exposed
child's
weight
is
15
kg
(33
pounds).
­31­
°
Turf
transferable
residue
(TTR)
value
of
5%,
and
object­
to­
mouth
residue
value
of
20%
of
the
application
rate
assumed.

An
explanation
of
the
exposure
calculations
and
formula
used
in
the
assessment
may
be
found
in
the
Residential
Risk
Assessment
chapter
(R.
Griffin
memo,
2/
20/
2002).

The
exposure
estimates
for
the
three
postapplication
scenarios
(object­
to­
mouth,
hand­
to­
mouth,
and
incidental
soil
ingestion)
were
combined
to
represent
the
possible
(if
not
likely)
high­
end
oral
exposure
resulting
from
lawn
(or
similar
use).
Combined
post­
application
oral
risk
estimates
for
s­
metolachlor
are
not
of
concern.
Table
4
summarizes
the
results
of
the
residential
postapplication
assessment:

Table
4:
Summary
of
Residential
Postapplication
MOE
Values
Exposure
Scenario
a
S­
Metolachlor
b
Oral
Dose
(mg/
kg/
day)
Oral
Short­
term
MOE
c
Object­
to­
mouth
S­
metolachlor
0.
0092
5400
Hand­
to­
mouth
S­
metolachlor
0.
037
1400
Soil
ingestion
S­
metolachlor
0.
00012
400,000
Combined
exposure
S­
metolachlor
0.
046
1100
a
Exposure
scenario
represents
oral
exposure
of
children,
with
an
assumed
body
weight
of
15
kg.
b
S­
metolachlor
application
rate
is
2.47
lb
ai/
acre.
c
Short­
term
oral
MOE
=
NOAEL/
Dose,
where
short­
term
oral
NOAEL
=
50
mg/
kg/
day.

The
Agency
acknowledges
that
Syngenta
has
no
remaining
residential
end­
use
product
labels
for
racemic
metolachlor;
however,
for
informational
purposes,
the
combined
oral
MOE
estimates
for
metolachlor
(based
on
EPA
Reg.
No.
100­
691
and
a
label
rate
of
4
lb
ai/
acre)
are
670
and
not
of
concern.

4.4.2
Recreational
Uses
S­
metolachlor
may
be
used
on
sports
and
recreational
fields,
as
well
as
golf
courses.
However,
the
Agency
believes
that
children's
exposure
to
residues
of
s­
metolachlor
remaining
on
residential
lawns
after
treatment
represents
the
likely
upper­
end
of
exposure.
Furthermore,
since
dermal
and
inhalation
risks
are
not
of
concern,
and
oral
exposures
from
sports
and
recreational
fields,
as
well
as
golf
courses,
are
expected
to
be
minimal,
risks
for
these
other
non­
occupational
settings
are
expected
to
be
insignificant.

4.4.3
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
groundboom
application
methods.
The
Agency
has
been
working
with
the
Spray
Drift
Task
Force,
EPA
Regional
Offices
and
State
Lead
Agencies
for
­32­
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
data
base
submitted
by
the
Spray
Drift
Task
Force,
a
membership
of
U.
S.
pesticide
registrants,
and
is
developing
a
policy
on
how
to
appropriately
apply
the
data
and
the
AgDRIFT
computer
model
to
its
risk
assessments
for
pesticides
applied
by
air,
orchard
airblast
and
ground
hydraulic
methods.
After
the
policy
is
in
place,
the
Agency
may
impose
further
refinements
in
spray
drift
management
practices
to
reduce
off­
target
drift
and
risks
associated
with
aerial
as
well
as
other
application
types
where
appropriate.

HED
has
conducted
a
direct
exposure
assessment
for
the
use
of
s­
metolachlor
on
lawns,
and
determined
that
there
is
no
risk
of
concern
from
this
use.
No
additional
risk
to
s­
metolachlor
is
expected
from
spray
drift.

4.5
Incidents
Reports
A
review
of
metolachlor
incident
reports
was
conducted
by
HED
in
August,
1997.
The
following
incident
data
bases
were
consulted:
the
OPP
Incident
Data
System
(IDS),
Poison
Control
Centers,
California
Department
of
Pesticide
Regulation;
and
the
National
Pesticide
Telecommunications
Network
(NPTN).
HED
determined
that
no
serious
illnesses
that
could
be
attributed
to
metolachlor
have
been
reported
in
data
sources
available
to
the
EPA.

Although
more
cases
of
incidents
involving
metolachlor
have
been
reported
in
Poison
Control
Center
data
and
the
Incident
Data
System
since
1997,
most
of
the
cases
were
minor,
involving
skin
and
eye
irritation.
Two
ingestions
reported
in
the
literature
(one
in
a
pregnant
woman)
did
not
result
in
significant
effects.
These
findings
do
not
alter
the
conclusions
reached
in
the
August,
1997
incident
report
memo
(personal
communication
between
C.
Jarvis
and
J.
Blondell
on
10/
29/
2001).

5.0
Aggregate
Risk
Assessments
and
Risk
Characterizations
5.1
Acute
Risk
5.1.1
Aggregate
Acute
Risk
Assessment
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.
As
show
in
Table
5a,
EFED's
EECs
are
below
the
Agency's
back­
calculated
DWLOC
values
for
the
parent
compound,
the
ESA
degradate,
and
the
OA
degradate.
The
combined
value
of
the
parent
plus
the
degradates
is
also
below
the
acute
DWLOC
value.
The
Agency
concludes
that
acute
aggregate
risk
estimates
are
not
of
concern
for
any
population
subgroup.
­33­
5.1.2
Acute
DWLOC
Calculations
Table
5a.
Acute
DWLOC
Calculations
Population
Subgroup
1
Acute
Scenario
aPAD
mg/
kg/
d
Acute
Food
Exp
mg/
kg/
d
Max
Acute
Water
Exp
mg/
kg/
day
2
Ground
Water
EEC
(ppb)
3
Surface
Water
EEC
(ppb)
3
Acute
DWLOC
(
F
g/
L)
4
Parent
ESA
OA
Total
5
Parent
ESA
OA
Total
5
U.
S.
Population
3.0
0.
003822
3.0
5.
5
65.8
31.7
103
77.6
31.9
91.4
200.9
1.
0
x
10
5
Females
13­
50
3.0
0.
002699
3.0
5.
5
65.8
31.7
103
77.6
31.9
91.4
200.9
9.
0
x
10
4
Children
1­
6
3.0
0.
006876
3.0
5.
5
65.8
31.7
103
77.6
31.9
91.4
200.9
3.
0
x
10
4
Males
13­
19
3.0
0.
003489
3.0
5.
5
65.8
31.7
103
77.6
31.9
91.4
200.9
1.
0
x
10
5
1
Population
subgroups
are
representative
of
those
with
the
highest
dietary
exposure
values.
Standard
body
weights
and
water
consumption
values
are
as
follows:
70
kg/
2L
per
day
(adult
male/
general
population);
60
kg/
2L
per
day
(adult
female);
10
kg/
1L
per
day
(child).
2
Maximum
acute
water
exposure
(mg/
kg/
day)
=
[(
acute
PAD
(mg/
kg/
day)
­
acute
food
exposure
(mg/
kg/
day)]
3
The
crop
producing
the
highest
level
was
used.
4
Acute
DWLOC(
F
g/
L)
=
[maximum
acute
water
exposure
(mg/
kg/
day)
x
body
weight
(kg)]
[water
consumption
(L)
x
10
­3
mg/
F
g]
5
"Total"
represents
the
combined
value
of
parent
plus
the
ESA
and
OA
degradates.
­34­

5.2
Short­
Term
Risk
5.2.1
Aggregate
Short­
Term
Risk
Assessment
A
short­
term
aggregate
risk
assessment
considers
potential
exposure
from
food,
drinking
water,
and
short­
term,
non­
occuapational
(residential)
pathways
of
exposure.
For
s­
metolachlor,
potential
short­
term,
non­
occupational
risk
scenarios
include
oral
exposure
of
children
to
treated
lawns.
In
this
aggregate
short­
term
risk
assessment,
exposure
from
food,
drinking
water,
and
residential
lawns
s

metolachlor
use
only)
has
been
considered.
Since
only
children
have
the
potential
for
non­
occupational,
short­
term
risk,
they
are
the
only
population
subgroup
included
below.
Short­
term
DWLOC
values
have
been
calculated
for
s­
metolachlor
only,
since
Syngenta
no
longer
holds
any
[racemic]
metolachlor
residential
end­
use
products.
As
shown
in
Table
5b,
EFED's
EECs
for
the
parent
compound,
the
ESA
degradate,
and
the
OA
degradate
are
below
the
short­
term
s­
metolachlor
DWLOC
value
for
children.
The
combined
value
of
the
parent
plus
the
degradates
is
also
below
the
short­
term
s­
metolachlor
DWLOC
value.
The
Agency
concludes
that
short­
term
aggregate
risks
from
s­
metolachlor
are
not
of
concern.

For
informational
purposes,
it
is
noted
that
the
EEC
values
for
the
parent
compound,
ESA
degradate,
and
the
OA
degradate
are
below
the
metolachlor
short­
term
DWLOC
value
for
children.
The
combined
value
of
the
parent
plus
the
degradates
is
also
below
the
metolachlor
short­
term
DWLOC
value.

5.2.2
Short­
Term
DWLOC
Calculations
Table
5b.
Short­
Term
Aggregate
Risk
and
DWLOC
Calculations
Population
Short­
Term
Scenario
Chemical
Target
MOE
1
MOE
food
2
MOE
oral
3
Aggregate
MOE
(food
and
residential)
6
MOE
water
7
Allowable
water
exposure
8
(mg/
kg/
day)
Ground
Water
EEC
9
(ppb)
Surface
Water
EEC
9
(ppb)
DWLOC
10
(
F
g/
L)

Parent
ESA
OA
Total
11
Paren
t
ESAOA
Total
1
1
Children
(1­
6)
S­
moc
100
1.6
x
10
4
1100
1000
110
0.45
5.5
65.8
32
103.3
4.
3
22.8
65.1
92.2
4500
1
The
target
MOE
of
100
is
based
on
the
100x
uncertainty
factor,
and
the
1x
FQPA
safety
factor.
Aggregate
risks
above
100
are
not
of
concern.

2
MOE
food
=
[short­
term
oral
NOAEL
(50
mg/
kg/
day)/
chronic
dietary
exposure
of
children
(0.003171
mg/
kg/
day)]

3
MOE
oral
=
[short­
term
oral
NOAEL
(50
mg/
kg/
day)/
combined
hand­
to­
mouth,
object­
to­
mouth,
and
soil
ingestion
oral
exposure
(0.
046
mg/
kg/
day
s­
moc)]
­35­

4
MOE
dermal
=
not
applicable
(n/
a).
No
dermal
toxicity
seen
at
the
limit
dose.

5
MOE
inhalation
=
not
applicable.
Postapplication
inhalation
exposure
is
expected
to
be
minimal.

6
Aggregate
MOE
(food
and
residential)
=
1÷[
[(
1÷
MOE
food)
+
(1÷
MOE
oral)]]

7
Water
MOE
=
1÷
[[(
1÷
Target
Aggregate
MOE)
­
(1÷
Aggregate
MOE
(food
and
residential)]]

8
Allowable
water
exposure
=
Short­
term
Oral
NOAEL
÷
MOE
water
9
The
crop
producing
the
highest
level
was
used
(i.
e.,
turf)

10
DWLOC(
F
g/
L)
=
[allowable
water
exposure
(mg/
kg/
day)
x
body
weight
(kg)]

[water
consumption
(L)
x
10
­3
mg/
F
g]

11
"Total"
represents
the
combined
value
of
the
parent
plus
the
ESA
and
OA
degradates.
­36­
5.3
Intermediate­
Term
Risk
5.3.1
Aggregate
Intermediate­
Term
Risk
Assessment
An
intermediate­
term
aggregate
risk
assessment
considers
potential
exposure
from
food,
drinking
water,
and
non­
occupational
(residential)
pathways
of
exposure.
However,
for
metolachlor/
s­
metolachlor,
no
intermediate­
term
non­
occupational
exposure
scenarios
(greater
than
30
days
exposure)
are
expected
to
occur.
Therefore,
intermediate­
term
DWLOC
values
were
not
calculated
and
an
intermediate­
term
aggregate
risk
assessment
is
not
required.

5.4
Chronic
Risk
5.4.1
Aggregate
Chronic
Risk
Assessment
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
will
consider
exposure
from
food
and
drinking
water
only.
As
shown
in
Table
5c,
EFED's
EECs
for
the
parent
compound,
the
ESA
degradate,
and
the
OA
degradate
are
below
the
Agency's
chronic
DWLOC
values
for
all
population
subgroups.
The
combined
value
of
the
parent
plus
degradates
is
also
below
the
chronic
DWLOC
value.
The
Agency
concludes
that
chronic
aggregate
risks
are
not
of
concern.

5.4.2
Chronic
DWLOC
Calculations
Table
5c.
Chronic
DWLOC
Calculations
Population
Subgroup
1
Chronic
Scenario
cPAD
mg/
kg/
day
Chronic
Food
Exp
mg/
kg/
day
Max
Chronic
Water
Exp
mg/
kg/
day
2
Ground
Water
EEC
(ppb)
3
Surface
Water
EEC
(ppb)
3
Chronic
DWLOC
4
(
F
g/
L)
Parent
ESA
OA
Total
5
Parent
ESA
OA
Total
5
U.
S.
Population
0.1
0.
001454
0.0985
5.5
65.8
31.7
103
4.3
22.8
65.1
92.2
3400
Females
13­
50
0.1
0.
001121
0.0989
5.5
65.8
31.7
103
4.3
22.8
65.1
92.2
3000
Children
1­
6
0.1
0.
003171
0.0968
5.5
65.8
31.7
103
4.3
22.8
65.1
92.2
1000
Males
13­
19
0.1
0.
001541
0.0985
5.5
65.8
31.7
103
4.3
22.8
65.1
92.2
3400
1
Population
subgroups
are
representative
of
those
with
the
highest
dietary
exposure
values.
Standard
body
weights
and
water
consumption
values
are
as
follows:
70
kg/
2L
per
day
(adult
male/
general
population);
60
kg/
2L
per
day
(adult
female);
10
kg/
1L
per
day
(child).
2
Maximum
Chronic
Water
Exposure
(mg/
kg/
day)
=
[Chronic
PAD
(mg/
kg/
day)
­
Chronic
Dietary
Exposure
(mg/
kg/
day)]
3
The
crop
producing
the
highest
level
was
used.
4
Chronic
DWLOC(
F
g/
L)
=
[maximum
chronic
water
exposure
(mg/
kg/
day)
x
body
weight
(kg)]
[water
consumption
(L)
x
10
­3
mg/
F
g]
1
Guidance
for
Identifying
Pesticide
Chemicals
and
Other
Substances
that
Have
a
Common
Mechanism
of
Toxicity,
Office
of
Pesticide
Programs,
USEPA
(issued
for
public
comment
in
August,
1998;
issued
in
revised
form
January
29,
1999).

2
SAP
Report,
April
28,
1997.
Report
of
the
FIFRA
Scientific
Advisory
Panel
Meeting,
March
19­
20,
1997.
Held
at
the
Crystal
Gateway
Marriott,
1700
Jefferson
Davis
Highway,
Arlington,
VA
22202.

­37­
5
"Total"
represents
combined
value
of
parent
plus
ESA
and
OA
degradates.

5.5
Cancer
Risk
5.5.1
Aggregate
Cancer
Risk
Assessment
An
aggregate
cancer
risk
assessment
considers
potential
carcinogenic
exposure
from
food,
drinking
water,
and
non­
occupational
(residential)
pathways
of
exposure.
However,
as
noted
earlier
in
this
risk
assessment,
the
NOAEL
that
was
established
based
on
tumors
in
the
rat
(15
mg/
kg/
day,
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
endpoint
is
protective
for
cancer
dietary
exposure.
Therefore,
a
separate
cancer
aggregate
risk
assessment
was
not
conducted,
and
cancer
DWLOC
values
were
not
calculated.

6.0
Cumulative
The
chloroacetanilide
pesticides
represent
a
class
of
food
use
pesticides
that
have
been
given
high
priority
by
OPP
for
the
reassessment
of
tolerances
in
accordance
with
the
mandates
of
FQPA.
The
group
of
chloroacetanilide
pesticides
covered
by
this
review
consists
of
Acetochlor,
Alachlor,
Butachlor,
Metolachlor
and
Propachlor.
Various
members
of
this
group
of
chloroacetanilide
pesticides
have
been
shown
to
result
in
several
different
types
of
tumor
responses
in
laboratory
animals
(e.
g.,
nasal,
thyroid,
liver,
and
stomach
tumors).
Therefore,
as
part
of
the
reassessment,
OPP
scientists
considered
several
different
potential
common
mechanism
of
toxicity
groupings
for
these
chemicals.

In
reviewing
this
issue,
OPP
scientists
were
guided
by
several
relevant
Agency
science
policies,
including
Guidance
for
Identifying
Pesticide
Chemicals
and
Other
Substances
that
Have
a
Common
Mechanism
of
Toxicity
1
.
Additionally,
on
March
19,
1997,
the
Agency
presented
to
the
FIFRA
Scientific
Advisory
Panel
(SAP)
a
draft
case
study
illustrating
the
application
of
the
Common
Mechanism
Guidance
to
the
grouping
of
chloroacetanilide
pesticides
based
on
a
common
mechanism
of
toxicity.
The
SAP
agreed
with
the
Agency's
conclusion
that
there
is
sufficient
evidence
to
support
the
grouping
of
certain
chloroacetanilides
that
cause
nasal
turbinate
tumors
by
a
common
mechanism
of
toxicity
2
.

Upon
consideration
of
the
SAP
comments,
OPP's
own
reviews
and
the
data
underlying
these
3
The
Grouping
of
a
Series
of
Chloroacetanilide
Pesticides
Based
on
a
Common
Mechanism
of
Toxicity,
Office
of
Pesticide
Programs,
USEPA
(June
7,
2001).

­38­
reviews,
as
well
as
additional
information
received
by
the
Agency
from
registrants
or
presented
in
the
open
literature
since
the
1997
draft
document,
OPP
has
revised
its
science
document
discussing
the
potential
grouping
of
chloroacetanilide
pesticides,
or
a
subgroup
of
them,
based
on
a
common
mechanism
of
toxicity.

In
the
revised
document
entitled
The
Grouping
of
a
Series
of
Chloroacetanilide
Pesticides
Based
on
a
Common
Mechanism
of
Toxicity
3
,
OPP
has
concluded
that
only
some
of
the
pesticides
that
comprise
the
class
of
chloroacetanilides
should
be
designated
as
a
"Common
Mechanism
Group"
based
on
the
development
of
nasal
turbinate
tumors
by
metabolism
to
a
highly
tissue
reactive
moiety,
i.
e.,
quinoneimine.
Thus,
only
Acetochlor,
Alachlor,
and
Butachlor
should
be
grouped
based
on
a
common
mechanism
of
toxicity
for
nasal
turbinate
tumors.
Although
Metolachlor
does
distribute
to
the
nasal
turbinates,
and
might
produce
a
quinoneimine,
it
is
not
apparent
from
currently
available
data
that
it
shares
the
same
target
site
in
the
nasal
tissue
as
Acetochlor,
Alachlor
and
Butachlor.
Although
Propachlor
does
produce
a
precursor
of
a
quinoneimine,
the
available
data
do
not
support
its
tumorigenicity
to
the
nasal
turbinates.

In
conclusion,
it
is
OPP's
position,
at
this
stage
in
the
tolerance
reassessment
process,
that
only
some
chloroacetanilides,
namely
Acetochlor,
Alachlor,
and
Butachlor
should
be
considered
as
a
Common
Mechanism
Group
due
to
their
ability
to
cause
nasal
turbinate
tumors.
For
purposes
of
a
cumulative
risk
assessment
as
a
part
of
the
tolerance
reassessment
process
for
Acetochlor,
Alachlor,
and
Butachlor,
these
three
pesticides
will
be
considered
as
a
Common
Mechanism
Group.
Following
the
initiation
of
a
cumulative
risk
assessment,
further
analyses
of
new
or
existing
data
may
occur
which
could
impact
the
Agency's
evaluation
of
specific
members
of
this
group
or
the
group
as
a
whole.

7.0
Data
Needs/
Label
Requirements
Toxicology
Data
Needs:

The
need
for
a
28­
day
inhalation
study
has
been
identified
for
both
metolachlor
and
smetolachlor
Submission
of
this
study
would
allow
the
Agency
to
improve
characterization
regarding
the
concern
for
toxicity
via
the
inhalation
route
of
exposure
following
application
of
metolachlor/
s­
metolachlor
on
multiple
days
in
a
commercial
setting.
Registrants
are
recommended
to
follow
the
protocol
for
the
90­
day
inhalation
study
provided
in
OPPTS
Guideline
870.3465,
but
cease
exposure
at
28
days.

Residue
Chemistry
Data
Needs:

The
following
residue
chemistry
data
deficiencies
have
been
identified:
°
Residue
data
supporting
the
use
of
S­
metolachlor
(EC)
on
cabbage
are
required
and
the
­39­
registrant
should
pursue
a
section
3
registration
for
s­
metolachlor
on
cabbage.
°
Residue
data
on
corn
aspirated
grain
fractions
are
required
for
both
metolachlor
and
smetolachlor
°
A
revised
Section
F
proposing
appropriate
tolerances
for
metolachlor
residues
in/
on
grass
forage
and
grass
hay
should
be
submitted.
°
Residue
data
supporting
shelled,
succulent
peas,
and
beans
are
required.
°
Label
amendments
are
required
for
both
metolachlor
and
s­
metolachlor
use
on
legume
vegetable
foliage.
°
Residue
data
supporting
the
use
of
s­
metolachlor
(EC)
on
dry
bulb
onions
are
required
and
the
registrant
should
pursue
a
section
3
registration
for
s­
metolachlor
on
onion.
°
Label
amendments
are
required
for
both
metolachlor
and
s­
metolachlor
use
on
peanut.
°
Additional
residue
data
supporting
bell
peppers
are
required.
°
Residue
data
on
sorghum
aspirated
grain
fractions
are
required
for
both
metolachlor
and
s­
metolachlor.
°
Residue
data
on
soybean
aspirated
grain
fractions
are
required
for
both
metolachlor
and
s­
metolachlor.
°
Label
amendments
are
required
for
both
metolachlor
and
s­
metolachlor
use
on
soybean.
°
Label
amendments
are
required
for
metolachlor
(EC)
use
on
spinach.
If
the
petitioner
intends
to
support
the
3.0
lb
ai/
A
seasonal
rate,
then
data
would
be
required
reflecting
pre­
emergence
applications
at
1.0
lb
ai/
A/
crop
to
three
successive
spinach
crops.
°
The
registrant
must
provide
copies
of
labels
including
the
proposed
use
on
tomatoes.
°
Label
amendments
are
required
for
metolachlor
use
on
tree
nuts.
°
Additional
data
are
required
characterizing
the
14
C­
residues
in
rotated
crops,
along
with
information
on
the
percentage
of
the
14
C­
residues
measured
by
the
current
enforcement
method,
supporting
storage
stability
data,
and
sample
storage
conditions
and
intervals.
°
Residue
data
are
required
depicting
residues
in/
on
representative
rotated
cereal
grains
planted
4.5
months
following
a
single
application
of
metolachlor
at
the
maximum
rate
for
corn.
°
Analytical
grade
reference
standards
are
required
as
requested
by
the
repository
for
metolachlor,
s­
metolachlor,
and
all
metabolites
of
concern.

Product
Chemistry
Data
Needs:

The
following
product
chemistry
data
deficiencies
have
been
identified:

°
830.1700
Preliminary
Analysis
(metolachlor;
Syngenta
95%
Technical)
°
830.1800
Enforcement
Analytical
Method
(metolachlor;
Syngenta
95%
Technical)
°
830.7050
UV/
Visible
Absorption
(metolachlor;
Syngenta
95%
Technical)
­40­
APPENDIX
A
­41­
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.
Guideline
No./
Study
Type
MRID
No.
(year)/
Classification
/Doses
Results
­42­
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;
F1
males:
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;
F1
males/
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;
F1
males/
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;
F1
males/
females:
23.7/
25.7
mg/
kg/
day).
Offspring
LOAEL
=
1000
ppm
(F0
males/
females:
75.8/
85.7
mg/
kg/
day;
F1
males/
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)
Guideline
No./
Study
Type
MRID
No.
(year)/
Classification
/Doses
Results
­43­
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
Guideline
No./
Study
Type
MRID
No.
(year)/
Classification
/Doses
Results
­44­
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
methylhydroxyacetanilide
in
which
N­
dealkylation
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.
Guideline
No./
Study
Type
MRID
No.
(year)/
Classification
/Doses
Results
­45­
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
[
14
C]
metolachlor
was
essentially
complete
within
48
to
72
hours
after
dosing.
Low­
and
high­
dose
females
eliminated
14
C
more
rapidly
(p<
0.003,
half­
lives
of
elimination,
16.6
and
15.6
hours,
respectively)
than
low­
and
high­
dose
males
and
repeated­
dose
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
14
C
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
14
C
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
14
C
(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
14
C
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
[
14
C]
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
14
C
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
14
C
levels
of
females
were,
in
general,
proportionate
to
dose.
Tissues
of
lowand
repeated­
dose
rats
contained
similar
amounts
of
radioactivity.
These
data
indicate
that
some
14
C
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
[
14
C]
metolachlor.
Guideline
No./
Study
Type
MRID
No.
(year)/
Classification
/Doses
Results
­46­
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),
14
C­
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
F
g
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.
­47­
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/
Mammali
an
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
F
g/
plate
CGA­
77102
technical
(95.6%)
in
the
presence
and
absence
of
S9
activation.
For
the
confirmatory
trial,
doses
of
78.13­
1250.0
F
g/
plate
±S9
were
evaluated
with
S.
typhimurium
strains
TA1535,
TA1537,
TA100
and
TA102;
concentrations
of
312.5­
5000.0
F
g/
plate
±S9
were
examined
with
S.
typhimurium
TA
98
and
E.
coli
WP2
uvrA.

In
general,
doses
$
1250.0
F
g/
plate
±S9
were
cytotoxic
for
S.
typhimurium
TA1535,
TA1537,
TA100
and
TA102
and
5000.0
F
g/
plate
±S9
was
slightly
cytotoxic
for
S.
typhimurium
TA98
and
E.
coli
WP2
uvrA.
There
was,
however,
no
indication
that
CGA77102
technical
induced
of
a
mutagenic
effect
in
any
tester
strain
either
in
the
presence
or
the
absence
of
S9
activation.
Guideline
No./
Study
Type
MRID
No.
(year)/
Classification
/Doses
Results
­48­
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.
Guideline
No./
Study
Type
MRID
No.
(year)/
Classification
/Doses
Results
­49­
870.7485
Metabolism
and
pharmacokinetics
44491401
(1996)
acceptable/
guideline
single
dose
of
0.5
(group
B1)
or
100
mg/
kg
(group
D1)
radio
labeled
CGA77102
100
mg/
kg/
day
nonradio
labeled
CGA
77102
for
14
days
followed
by
0.5
mg/
kg
radio
labeled
CGA77102
(Group
V1);
single
dose
of
0.5
or
100
mg/
kg
radio
labeled
CGA­
77102
for
bile­
cannulation
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
F
g/
ml);
in
the
high
dose
group
(D1),
the
first
and
second
Cmax
were,
respectively,
4.6
and
>3.9
F
g/
ml
in
males
and
2.2
and
4.5
F
g/
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
F
g/
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.
Guideline
No./
Study
Type
MRID
No.
(year)/
Classification
/Doses
Results
­50­
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
F
g/
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.
Guideline
No./
Study
Type
MRID
No.
(year)/
Classification
/Doses
Results
­51­
870.7485
Metabolism
and
pharmacokinetics
44491402
(1996)
unacceptable/
guideline
single
dose
of
0.5
(group
B1)
or
100
mg/
kg
(group
D1)
radio
labeled
CGA77102
100
mg/
kg/
day
nonradio
labeled
CGA
77102
for
14
days
followed
by
0.5
mg/
kg
radio
labeled
CGA77102
(Group
V1);
single
dose
of
0.5
or
100
mg/
kg
radio
labeled
CGA­
77102
for
bile­
cannulation
study
(from
MRID
44491401)
single
oral
low
dose
(0.5
mg/
kg,
Group
B2)
of
[Phenyl­
U­
14
C]
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
14
C]
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
14
C]
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
racemicMetolachlor
(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.
Guideline
No./
Study
Type
MRID
No.
(year)/
Classification
/Doses
Results
­52­
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/
S­
Metolachlor
(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
CGA77102
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
­53­
Appendix
A
Table
3:
Tolerance
Reassessment
Summary
for
Metolachlor
(PC
Code
108801)

Commodity
Current
Tolerance
(ppm)
a
Range
of
residues
(ppm)
Tolerance
Reassessment
(ppm)
Comment/
Correct
Commodity
Definition
Tolerances
listed
under
40
CFR
§180.368(
a):

Almond,
hulls
0.3
Data
were
not
available
for
review
(DNA)
TBD
Barley,
fodder
0.
5
Not
applicable
(NA)
Reassign
to
180.368(
d)
To
be
determined
(TBD)
Additional
data
are
required.
The
definition
for
fodder
should
be
changed
to
Barley,
straw
Barley,
grain
0.
1
Buckwheat,
grain
0.
1
Cabbage
1.0
NA
Revoke
Registered
uses
(SLNs)
on
cabbage
have
been
canceled.

Cattle,
fat
0.
02
Extrapolating
to
a
1x
feeding
level,
maximum
combined
residues
would
be
<0.011
ppm
in
fat,
<0.016
ppm
in
meat,
0.035
ppm
in
liver,
and
0.11
ppm
in
kidney.
0.04
Tolerances
for
fat,
meat,
and
meat
byproducts
(except
kidney)
should
be
set
at
the
method
LOQ
of
0.04
ppm.
The
tolerance
for
liver
should
be
revoked,
and
the
tolerance
for
kidney
should
remain
at
0.2
ppm.
Cattle,
kidney
0.
2
0.
20
Cattle,
liver
0.05
Revoke
Cattle,
meat
0.
02
0.
04
Cattle,
meat
byproducts
(exc.
liver
and
kidney)
0.02
0.04
Celery
0.1
NA
Revoke
Registered
uses
(SLNs)
on
celery
have
been
canceled.

Corn,
fodder
8.
0
field
(0.11­
2.81)
sweet
(0.24­
5.54)
6.0
Corn,
Stover.
The
available
metolachlor
residue
data
indicate
that
the
tolerance
can
be
lowered
to
6.0
ppm
Corn,
forage
8.0
field
(<
0.12­
3.02)
sweet
(0.27­
5.75)
6.0
The
available
metolachlor
residue
data
indicate
that
the
tolerance
can
be
lowered
to
6.0
ppm
Corn,
fresh
(inc.
sweet)
(K+
CWHR)
0.1
<0.08­<
0.10
0.
10
Corn,
sweet
(K+
CWHR)

Corn,
grain
0.
1
<0.08
0.
10
Cotton,
undelinted
seed
0.1
<0.08
0.10
Egg
0.
02
Residues
were
not
detected
in
eggs
of
hens
dosed
at
up
to
5.7x
the
MTDB
0.04
The
tolerance
for
eggs
should
be
set
at
the
combined
LOQ
for
the
enforcement
method.

Goat,
fat
0.
02
See
cattle
above
0.04
See
cattle
above.
Goat,
kidney
0.
2
0.20
Goat,
liver
0.05
Revoke
Commodity
Current
Tolerance
(ppm)
a
Range
of
residues
(ppm)
Tolerance
Reassessment
(ppm)
Comment/
Correct
Commodity
Definition
­54­
Goat,
meat
0.02
0.04
Goat,
meat
byproducts
(exc.
liver
and
kidney)
0.02
0.04
Hog,
fat
0.
02
NA
Revoke
Based
on
the
results
of
the
ruminant
feeding
study
and
a
MTDB
for
swine
of
0.315
ppm,
there
is
no
reasonable
expectation
of
finding
quantifiable
residues
in
hog
tissues
[40
CFR
180.6(
a)(
3)].
Hog,
kidney
0.
2
Hog,
liver
0.05
Hog,
meat
0.02
Hog,
meat
byproducts
(exc.
liver
and
kidney)
0.02
Horse,
fat
0.
02
See
cattle
above
0.04
See
cattle
above.
Horse,
kidney
0.
2
0.20
Horse,
liver
0.05
Revoke
Horse,
meat
0.02
0.04
Horse,
meat
byproducts
(exc.
liver
and
kidney)
0.02
0.04
Legume
vegetables
group
foliage
(exc.
soybean
forage
and
hay)
15.0
forage
(0.44­
11.5)
hay
(0.31­
2.2)
15
Residue
data
for
forage
(vines)
reflect
a
­
60­
day
PHI
and
residue
data
on
hay
reflect
at
120
day
PHI.

Milk
0.02
Extrapolating
to
a
1x
feeding
level,
maximum
combined
residues
in
milk
would
be
0.004
ppm
0.02
Millet,
fodder
0.
5
NA
Reassign
to
180.368(
d)
TBD
Additional
data
are
required.
The
definition
for
fodder
should
be
changed
to
millet,
straw.
Millet,
forage
0.
5
Millet,
grain
0.
1
Milo,
fodder
0.
5
NA
Revoke
Residues
on
milo
commodities
are
covered
by
tolerances
on
sorghum.
Milo,
forage
0.5
Milo,
grain
0.
1
Nongrass
animal
feed
(forage,
fodder,
straw,
hay)
group
3.0
forage
­
<0.08­
0.54
hay
­
<0.08­<
0.47
1.0
Reassign
to
180.368(
d)
The
available
alfalfa
and
clover
data
indicate
that
the
tolerance
can
be
reduced
to
1.0
ppm.
Commodity
Current
Tolerance
(ppm)
a
Range
of
residues
(ppm)
Tolerance
Reassessment
(ppm)
Comment/
Correct
Commodity
Definition
­55­
Oats,
fodder
0.5
NA
Reassign
to
180.368(
d)
TBD
Additional
data
are
required.
The
definition
for
fodder
should
be
changed
to
oats,
straw.
Oats,
forage
0.5
Oats,
grain
0.
1
Peanut
0.5
<0.08­
0.19
0.20
Peanut,
nutmeats.
New
residue
data
indicate
that
the
tolerance
can
be
lowered
to
0.2
ppm.

Peanut,
forage
30.0
NA
Revoke
Peanut
forage
is
no
longer
listed
a
regulated
commodity
of
peanuts
Peanut,
hay
30.0
1.
04­
16.5
20.0
New
residue
data
indicate
that
the
tolerance
can
be
lowered
to
20.0
ppm.

Peppers,
bell
0.1
<0.02­
0.108
Revoke
Registered
uses
(SLNs)
on
peppers
have
been
canceled.

Potato
0.2
<0.08­
0.14
0.20
Poultry,
fat
0.
02
Residues
were
not
detected
in
tissues
of
hens
dosed
at
up
to
5.7x
the
MTDB
0.04
Tolerances
for
poultry
tissues
should
be
set
at
the
combined
LOQ
for
the
enforcement
method,
and
the
separate
tolerance
for
liver
should
be
revoked.
Poultry,
liver
0.05
Revoke
Poultry,
meat
0.02
0.04
Poultry,
meat
byproducts
(exc.
liver)
0.02
0.04
Rice,
fodder
0.
5
NA
Reassign
to
180.368(
d)
TBD
Additional
data
are
required.
The
tolerance
for
rice
forage
should
be
revoked
as
it
is
not
a
regulated
commodity,
and
the
definition
for
fodder
should
be
changed
to
rice,
straw.
Rice,
forage
0.5
Revoke
Rice,
grain
0.
1
Reassign
to
180.368(
d)
TBD
Rye,
fodder
0.
5
NA
Reassign
to
180.368(
d)
TBD
Additional
data
are
required.
The
tolerance
for
rye
fodder
should
be
changed
to
rye,
straw.
Rye,
forage
0.5
Rye,
grain
0.
1
Safflower,
seed
0.1
<0.08
0.10
Commodity
Current
Tolerance
(ppm)
a
Range
of
residues
(ppm)
Tolerance
Reassessment
(ppm)
Comment/
Correct
Commodity
Definition
­56­
Seed
and
pod
vegetables
(exc.
soybean)
0.3
<0.08­
0.44
0.50
Edible­
podded
legume
vegetables
subgroup.
The
available
data
support
a
tolerance
of
0.5
ppm
on
this
subgroup.

<0.08­<
0.11
0.
10
Dried
shelled
pea
and
bean
(except
soybean)
subgroup
The
available
data
support
a
tolerance
of
0.1
ppm
on
this
subgroup.

NA
TBD
Succulent
shelled
pea
and
bean
subgroup
Data
are
required
for
this
subgroup.

Sheep,
fat
0.
02
see
cattle
above
0.04
See
cattle
above
Sheep,
kidney
0.
2
0.20
Sheep,
liver
0.05
revoke
Sheep,
meat
0.02
0.04
Sheep,
meat
byproduct
(exc.
liver
and
kidney)
0.02
0.04
Sorghum
grain,
fodder
2.
0
<0.11­
3.19
4.0
Sorghum
grain,
stover
The
available
data
support
increasing
the
tolerance
on
stover
to
4.0
ppm
and
decreasing
the
tolerance
on
forage
to
1.0
ppm
Sorghum
grain,
forage
2.0
<0.08­
0.45
1.0
Sorghum
grain,
grain
0.
3
0.08­
0.19
0.30
Soybean
0.2
<0.08­<
0.18
0.
20
Soybean,
seed
Soybean,
forage
8.0
0.
15­
4.37
5.0
The
available
data
indicate
that
the
tolerance
on
forage
can
be
lowered
to
5.0
ppm
Soybean,
hay
8.
0
0.38­
6.90
8.0
Fruit,
stone,
group
0.1
<0.08­
0.08
Revoke
The
registrant
no
longer
wishes
to
support
the
use
on
stone
fruits.
Nuts,
tree,
group
0.1
<0.08­
0.08
0.10
Wheat,
fodder
0.
5
NA
Reassign
to
180.368(
d)
TBD
Additional
data
are
required.
The
definition
for
fodder
should
be
changed
to
wheat,
straw.
Wheat,
forage
0.5
Wheat,
grain
0.
1
Time­
limited
Tolerances
Listed
under
40
CFR
§180.368(
b):
Commodity
Current
Tolerance
(ppm)
a
Range
of
residues
(ppm)
Tolerance
Reassessment
(ppm)
Comment/
Correct
Commodity
Definition
­57­
Grass,
forage
10.0
b
0.04­
8.4
10
Permanent
tolerances
are
pending.
Grass,
hay
0.
2
b
<0.08­
0.11
0.20
Spinach
0.3
b
<0.08­
0.38
0.50
New
data
support
an
increased
permanent
tolerance
for
metolachlor
residues
of
0.5
ppm
in/
on
spinach
(PP#
8E5011).

Tomato
0.1
c
<0.08­
0.08
0.10
New
data
support
a
permanent
tolerance
for
metolachlor
residues
of
0.1
ppm
in/
on
tomatoes
(PP#
6F4751).

Tomato,
puree
0.3
c
<0.10
Revoke
New
data
indicate
that
the
tolerances
for
metolachlor
residues
in/
on
tomato
paste
and
puree
are
not
necessary.
Tomato,
paste
0.
6
c
<0.10
Revoke
Tolerances
with
Regional
Registrations
Listed
under
40
CFR
§180.368(
c):

Onion,
dry
bulb
1.
0
<0.08­<
0.43
ppm
Revoke
Registered
uses
(SLNs)
of
metolachlor
on
onions
and
various
peppers
have
been
canceled.
Pepper,
chili
0.5
<0.02­
0.03
Revoke
Pepper,
tabasco
0.
5
0.09­
0.45
Revoke
Pepper,
cubanelle
0.1
0.
03­
0.04
Revoke
Tolerances
Needed
under
40
CFR
§180.368(
a)(
1):

Cotton,
gin
byproducts
None
0.08­
3.2
4.
0
New
residue
data
indicates
that
a
tolerance
of
4.0
ppm
may
be
established.

Peanut,
meal
None
<3.85
0.
40
The
available
processing
data
indicates
that
residues
concentrate
in
presscake
(1.75x).

a
Expressed
in
terms
of
metolachlor
b
Time
limited
tolerances
on
grass
forage
and
hay
and
spinach
were
set
to
expire
on
12/
31/
01.
c
Time
limited
tolerances
on
tomato
commodities
are
set
to
expire
on
6/
30/
02.
d
Based
on
current
residue
data
for
peanuts,
additional
data
are
required
to
support
the
current
lower
use
rate.
­58­
Appendix
A
Table
4:
Tolerance
Reassessment
Summary
for
s­
Metolachlor
(PC
Code
108800)

Commodity
Current
Tolerance
(ppm)
a
Range
of
residues
(ppm)
Tolerance
Reassessment
(ppm)
Comment/
Correct
Commodity
Definition
Tolerances
needed
under
40
CFR
§180.368(
a)(
2):

Cabbage
1.0
NA
TBD
Additional
data
are
required
to
support
the
use
of
S­
metolachlor
on
cabbage
and
the
registrant
should
pursue
a
section
3
registration.

Cattle,
fat
0.
02
Extrapolating
to
a
1x
feeding
level,
maximum
combined
residues
would
be
<0.011
ppm
in
fat,
<0.016
ppm
in
meat,
0.035
ppm
in
liver,
and
0.11
ppm
in
kidney.
0.04
Tolerances
for
fat,
meat,
and
meat
byproducts
(except
kidney)
should
be
set
at
the
method
LOQ
of
0.04
ppm,
but
the
tolerance
for
kidney
should
remain
at
0.2
ppm.
Cattle,
kidney
0.
2
0.
20
Cattle,
meat
0.
02
0.
04
Cattle,
meat
byproducts
(exc.
kidney)
0.02
0.04
Celery
0.1
<0.08
0.10
The
available
metolachlor
data
support
a
tolerance
of
0.10
ppm
for
s­
metolachlor.

Corn,
fodder
8.
0
field
(0.11­
2.81)
sweet
(0.24­
5.54)
6.0
Corn,
Stover.
The
available
metolachlor
residue
data
indicate
that
the
tolerance
can
be
lowered
to
6.0
ppm
Corn,
forage
8.0
field
(<
0.12­
3.02)
sweet
(0.27­
5.75)
6.0
The
available
metolachlor
residue
data
indicate
that
the
tolerance
can
be
lowered
to
6.0
ppm
Corn,
fresh
(inc.
sweet)
(K+
CWHR)
0.1
<0.08­<
0.10
0.
10
Corn,
sweet
(K+
CWHR)
Supported
by
the
available
metolachlor
data.

Corn,
grain
0.
1
<0.08
0.
10
Corn,
Field,
grain.
Supported
by
the
available
metolachlor
data.

Cotton,
undelinted
seed
0.1
<0.08
0.10
Supported
by
the
available
metolachlor
data.

Cotton,
gin
byproducts
NA
0.08­
3.2
4.
0
New
metolachlor
residue
data
indicates
that
a
tolerance
of
4.0
ppm
may
be
established.

Egg
0.
02
Residues
were
not
detected
in
eggs
of
hens
dosed
at
up
to
5.7x
the
MTDB
0.04
The
tolerance
for
eggs
should
be
set
at
the
combined
LOQ
for
the
enforcement
method.

Goat,
fat
0.
02
See
cattle
above
0.04
See
cattle
above
Goat,
kidney
0.
2
0.20
Commodity
Current
Tolerance
(ppm)
a
Range
of
residues
(ppm)
Tolerance
Reassessment
(ppm)
Comment/
Correct
Commodity
Definition
­59­
Goat,
meat
0.02
0.04
Goat,
meat
byproducts
(exc.
kidney)
0.02
0.04
Horse,
fat
0.
02
See
cattle
above
0.04
See
cattle
above.
Horse,
kidney
0.
2
0.20
Horse,
meat
0.02
0.04
Horse,
meat
byproducts
(exc.
kidney)
0.02
0.04
Legume
vegetables
group
foliage
(exc.
soybean
forage
and
hay)
15.0
forage
(0.44­
11.5)
hay
(0.31­
2.2)
15
Residue
data
for
forage
(vines)
reflect
a
­
60­
day
PHI
and
residue
data
on
hay
reflect
at
120
day
PHI.

Milk
0.02
Extrapolating
to
a
1x
feeding
level,
maximum
combined
residues
in
milk
would
be
0.004
ppm
0.02
Peanut
0.5
<0.09
0.20
Peanut,
nutmeats.
New
metolachlor
residue
data
indicate
that
the
tolerance
can
be
lowered
to
0.2
ppm.

Peanut,
hay
30.0
­4.19
20.0
New
metolachlor
residue
data
indicate
that
the
tolerance
can
be
lowered
to
20.0
ppm.

Peppers,
bell
0.1
<0.02­
0.108
TBD
Additional
data
are
required
for
a
general
tolerance
on
peppers.

Potato
0.2
<0.08­
0.14
0.20
Supported
by
the
available
metolachlor
data.

Poultry,
fat
0.
02
Residues
were
not
detected
in
tissues
of
hens
dosed
at
up
to
5.7x
the
MTDB
0.04
Tolerances
for
poultry
tissues
should
be
set
at
the
combined
LOQ
for
the
enforcement
method,
and
the
separate
tolerance
for
liver
should
be
revoked.
Poultry,
meat
0.02
0.04
Poultry,
meat
byproducts
(exc.
liver)
0.02
0.04
Safflower,
seed
0.1
<0.08
0.10
Supported
by
the
available
metolachlor
data.
Commodity
Current
Tolerance
(ppm)
a
Range
of
residues
(ppm)
Tolerance
Reassessment
(ppm)
Comment/
Correct
Commodity
Definition
­60­
Seed
and
pod
vegetables
(exc.
soybean)
0.3
<0.08­
0.44
0.50
Edible­
podded
legume
vegetables
subgroup.
The
available
data
support
a
tolerance
of
0.5
ppm
on
this
subgroup.

<0.08­<
0.11
0.
10
Dried
shelled
pea
and
bean
(except
soybean)
subgroup
The
available
data
support
a
tolerance
of
0.1
ppm
on
this
subgroup.

NA
TBD
Succulent
shelled
pea
and
bean
subgroup
Data
are
required
for
this
subgroup.

Sheep,
fat
0.
02
see
cattle
above
0.04
See
cattle
above
Sheep,
kidney
0.
2
0.20
Sheep,
meat
0.02
0.04
Sheep,
meat
byproducts
(exc.
kidney)
0.02
0.04
Sorghum
grain,
fodder
2.
0
<0.11­
3.19
4.0
Sorghun,
stover.
The
available
data
support
increasing
the
tolerance
on
stover
to
4.0
ppm
and
decreasing
the
tolerance
on
forage
to
1.0
ppm
Sorghum
grain,
forage
2.0
<0.08­
0.45
1.0
Sorghum
grain,
grain
0.
3
0.08­
0.19
0.30
Soybean
0.2
<0.08­<
0.18
0.
20
Soybean,
seed.
Supported
by
the
available
metolachlor
and
s­
metolachlor
data.

Soybean,
forage
8.0
0.
15­
4.37
5.0
The
available
metolachlor
data
indicate
that
the
tolerance
on
forage
can
be
lowered
to
5.0
ppm.
Soybean,
hay
8.
0
0.38­
6.90
8.0
Soybean,
hulls
None
<0.14
None
New
s­
metolachlor
data
indicate
that
s­
metolachlor
residues
in/
on
soybean
hulls
will
not
exceed
the
established
tolerance
on
soybean
seeds.

Time­
limited
Tolerances
needed
under
40
CFR
§180.368(
b)(
2):
Commodity
Current
Tolerance
(ppm)
a
Range
of
residues
(ppm)
Tolerance
Reassessment
(ppm)
Comment/
Correct
Commodity
Definition
­61­
Grass,
forage
10.0
b
0.04­
8.4
10
Permanent
tolerances
are
pending.
Grass,
hay
0.
2
b
<0.08­
0.11
0.20
Spinach
0.3
b
<0.08­
0.38
0.50
New
metolachlor
data
support
an
increased
permanent
tolerance
for
s­
metolachlor
residues
of
0.5
ppm
in/
on
spinach.

Tomato
0.1
c
<0.08­
0.08
0.10
New
metolachlor
data
support
a
permanent
tolerance
for
smetolachlor
residues
of
0.1
ppm
in/
on
tomatoes.

Tomato,
puree
0.3
c
<0.10
revoke
New
metolachlor
residue
data
indicate
that
the
tolerances
for
s­
metolachlor
residues
in/
on
tomato
paste
and
puree
are
not
necessary.
Tomato,
paste
0.
6
c
<0.10
revoke
Tolerances
with
Regional
Registrations
needed
under
40
CFR
§180.368(
c)(
2):

Onion,
dry
bulb
1.
0
<0.08­<
0.43
ppm
0.50
The
available
metolachlor
residue
data
support
lowering
the
tolerance
to
0.
5
ppm;
however,
additional
data
are
required
to
support
the
use
of
s­
metolachlor
and
the
registrant
should
pursue
a
section
3
registration.

Pepper,
chili
0.5
<0.02­
0.03
0.10
With
the
exception
of
chili
peppers,
the
available
residue
data
support
the
current
tolerances.
Tolerances
for
chili
peppers
could
be
lowered
to
0.1
ppm.
If
a
general
tolerance
on
peppers
is
established
at
0.5
ppm,
than
these
separate
tolerances
should
be
revoked.
Pepper,
tabasco
0.
5
0.09­
0.45
0.50
Pepper,
cubanelle
0.1
0.
03­
0.04
0.10
Tolerances
Needed
under
40
CFR
§180.368(
d)(
2):

Barley,
grain
0.
5
NA
TBD
Additional
data
are
required.
Barley,
hay
None
Barley,
straw
0.
1
Buckwheat,
grain
0.
1
NA
TBD
Additional
data
are
required
Millet,
forage
0.
5
NA
TBD
Additional
data
are
required.
Millet,
grain
0.
1
Millet,
hay
None
Commodity
Current
Tolerance
(ppm)
a
Range
of
residues
(ppm)
Tolerance
Reassessment
(ppm)
Comment/
Correct
Commodity
Definition
­62­
Millet,
straw
0.
5
Nongrass
animal
feed
(forage,
fodder,
straw,
hay)
group
3.0
forage
­
<0.08­
0.54
hay
­
<0.08­<
0.47
1.0
The
available
alfalfa
and
clover
data
indicate
that
the
tolerance
can
be
reduced
to
1.0
ppm.

Oats,
forage
0.5
NA
TBD
Additional
data
are
required.
Oats,
grain
0.
1
Oats,
hay
None
Oats,
straw
0.5
Peanut,
meal
None
<3.85
0.
40
The
available
metolachlor
processing
data
indicates
that
residues
concentrate
in
presscake
(1.75x).

Rice,
grain
0.
1
NA
TBD
Additional
data
are
required.
Rice,
straw
0.
5
Rye,
forage
0.5
NA
TBD
Additional
data
are
required.
Rye,
grain
0.1
Rye,
straw
0.
5
Wheat,
forage
0.5
NA
TBD
Additional
data
are
required.
Wheat,
grain
0.
1
Wheat,
hay
None
Wheat,
straw
0.
5
a
Expressed
in
terms
of
s­
metolachlor
b
Time
limited
tolerances
on
grass
forage
and
hay
and
spinach
were
set
to
expire
on
12/
31/
01.
c
Time
limited
tolerances
on
tomato
commodities
are
set
to
expire
on
6/
30/
02.