Page
1
of
118
UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
OFFICE
OF
PREVENTION,
PESTICIDES
AND
TOXIC
SUBSTANCES
Date:
March
1,
2006
MEMORANDUM
SUBJECT:
ACETOCHLOR.
Revised
HED
Chapter
of
the
Tolerance
Reassessment
Eligibility
Decision
(
TRED)
Document.
PC
Code:
121601,
DP
Barcode:
D292336
Regulatory
Action:
Tolerance
Reassessment
Risk
Assessment
Type:
Single
Chemical
/
Aggregate
FROM:
Alberto
Protzel,
Ph.
D.,
Branch
Senior
Scientist,
Risk
Assessor
Toxicology
Branch
Health
Effects
Division
(
7509C)
AND
Linnea
Hansen,
Ph.
D.,
Toxicologist
Toxicology
Branch
AND
Samuel
Ary,
Chemist
Reregistration
Branch
2
Health
Effects
Division
(
7509C)
AND
Michael
R.
Barrett,
Ph.
D,
Senior
Chemist
Ronald
Parker,
Ph.
D.,
Senior
Environmental
Scientist
Environmental
Risk
Branch
V
Environmental
Fate
and
Effects
Division
(
7507C)

THROUGH:
Louis
Scarano,
Ph.
D.,
Chief
Toxicology
Branch
Health
Effects
Division
(
7509C)

TO:
Felicia
Fort,
Chemical
Review
Manager
Reregistration
Branch
III
Special
Review
and
Reregistration
Division
(
7508W)
Page
2
of
118
Table
of
Contents
1.0
Executive
Summary
.
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5
2.0
Ingredient
Profile
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8
2.1
Summary
of
Registered/
Proposed
Uses
.
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8
2.2
Structure
and
Nomenclature
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9
2.3
Physical
and
Chemical
Properties
.
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10
3.0
Metabolism
Assessment
.
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11
3.1
Comparative
Metabolic
Profile
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.
11
3.2
Nature
of
the
Residue
in
Foods
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13
3.2.1.
Description
of
Primary
Crop
Metabolism
.
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13
3.2.2
Description
of
Livestock
Metabolism
.
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.
14
3.2.3
Description
of
Rotational
Crop
Metabolism,
including
identification
of
major
metabolites
and
specific
routes
of
biotransformation
.
.
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.
17
3.3
Environmental
Degradation
.
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19
3.4
Tabular
Summary
of
Metabolites
and
Degradates
.
.
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19
3.5
Toxicity
Profile
of
Major
Metabolites
and
Degradates
.
.
.
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21
3.6
Summary
of
Residues
for
Tolerance
Expression
and
Risk
Assessment
.
.
.
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.
.
.
25
3.6.1
Tabular
Summary
.
.
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26
3.6.2
Rationale
for
Inclusion
of
Metabolites
and
Degradates
.
.
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.
26
3.6.3
Rationale
for
Exclusion
of
Degradates
.
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26
4.0
Hazard
Characterization/
Assessment
.
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27
4.1
Hazard
Characterization
.
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27
4.1.1
Database
Summary
.
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27
4.1.2
Mode
of
Action,
Metabolism,
Toxicokinetics
Data
.
.
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27
4.1.3
Sufficiency
of
Studies
/
Data
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29
4.1.4.
Toxicological
Effects
.
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29
4.1.5
Dose
Response
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45
4.1.6
FQPA
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46
4.2
FQPA
Hazard
Considerations
.
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46
4.2.1
Adequacy
of
the
Toxicity
Data
Base
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46
4.2.2
Evidence
of
Neurotoxicity
.
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46
4.2.3
Developmental
Toxicity
Studies
.
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48
4.2.4
Reproductive
Toxicity
Study
.
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51
4.2.5
Additional
Information
from
Literature
Sources
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55
Page
3
of
118
4.2.6
Pre­
and/
or
Postnatal
Toxicity
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55
4.2.6.1
Determination
of
Susceptibility
.
.
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.
55
4.2.6.2
Degree
of
Concern
Analysis
and
Residual
Uncertainties
for
Pre
and/
or
Post­
natal
Susceptibility
.
.
.
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.
55
4.3
Recommendation
for
a
Developmental
Neurotoxicity
Study
.
.
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.
55
4.3.1
Evidence
that
supports
requiring
a
Developmental
Neurotoxicity
study
.
.
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55
4.3.2
Evidence
that
supports
not
requiring
for
a
Developmental
Neurotoxicity
study
.
.
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56
4.3.2.1
Rationale
for
the
UF
DB
(
when
a
DNT
is
recommended)
56
4.4
Hazard
Identification
and
Toxicity
Endpoint
Selection
.
.
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.
56
4.4.1
Acute
Reference
Dose
(
aRfD)
­
General
Population
including
Females
age
13­
49
.
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56
4.4.2
Chronic
Reference
Dose
(
cRfD)
.
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58
4.4.3
Incidental
Oral
Exposure
(
Short
and
Intermediate
Term)
.
.
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.
58
4.4.4
Dermal
Absorption
.
.
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58
4.4.5
Dermal
Exposure
(
Short,
Intermediate
and
Long
Term)
.
.
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.
58
4.4.6
Inhalation
Exposure
(
Short,
Intermediate
and
Long
Term)
.
.
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.
62
4.4.7
Margins
of
Exposure
.
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63
4.4.8
Recommendation
for
Aggregate
Exposure
Risk
Assessments
.
.
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.
64
4.4.9
Classification
of
Carcinogenic
Potential
.
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64
4.5
Special
FQPA
Safety
Factor
.
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75
4.6
Endocrine
disruption
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75
5.0
Public
Health
Data
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76
5.1
Incident
Reports
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76
5.2
Other
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76
6.0
Exposure
Characterization/
Assessment
.
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76
6.1
Dietary
Exposure/
Risk
Pathway
.
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76
6.1.1
Residue
Profile
.
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76
6.1.2
Acute
and
Chronic
Dietary
Exposure
and
Risk
.
.
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78
6.2
Water
Exposure/
Risk
Pathway
.
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80
6.3
Residential
(
Non­
Occupational)
Exposure/
Risk
Pathway
.
.
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.
81
7.0
Aggregate
Risk
Assessments
and
Risk
Characterization
.
.
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.
81
7.1
Acute
Aggregate
Risk
.
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.
82
7.2
Short­
Term
Aggregate
Risk
.
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.
82
7.3
Intermediate­
Term
Aggregate
Risk
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82
7.4
Long­
Term
Aggregate
Risk
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82
7.5
Cancer
Risk
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82
8.0
Cumulative
Risk
Characterization/
Assessment
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83
Page
4
of
118
9.0
Occupational
Exposure/
Risk
Pathway
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83
10.0
Data
Needs
and
Label
Requirements
.
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83
10.1
Toxicology
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83
10.2
Residue
Chemistry
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83
References:
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84
Appendices
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107
Appendix
1.
Toxicology
Data
Requirements
.
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107
Appendix
2.
MOE
Assessment
of
Acetochlor
Water
Degradates
.
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.
108
Appendix
3.
Tolerance
Reassessment
Summary
for
Acetochlor
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117
Page
5
of
118
1.0
Executive
Summary
This
assessment
provides
information
to
support
the
issuance
of
a
risk
management
decision
document
known
as
a
Tolerance
Reassessment
Eligibility
Decision
(
TRED)
Document
for
acetochlor.
EPA's
pesticide
reregistration
process
provides
for
the
review
of
older
pesticides
(
those
initially
registered
prior
to
November
1984)
under
the
Federal
Insecticide,
Fungicide,
and
Rodenticide
Act
(
FIFRA)
to
ensure
that
they
meet
current
scientific
and
regulatory
standards.
The
process
considers
the
human
health
and
ecological
effects
of
pesticides
and
incorporates
a
reassessment
of
tolerances
(
pesticide
residue
limits
in
food)
to
ensure
that
they
meet
the
safety
standard
established
by
the
Food
Quality
Protection
Act
(
FQPA)
of
1996.

Acetochlor,
2­
chloro­
N­(
ethoxymethyl)­
N­(
2­
ethyl­
6­
methylphenyl)
acetamide,
is
a
chloroacetanilide
herbicide
used
for
preemergence
control
of
weeds
in
corn.
In
the
United
States,
acetochlor
is
conditionally
registered
for
use
on
field
corn
to
the
Acetochlor
Registration
Partnership
(
ARP),
which
is
comprised
of
Dow
AgroSciences,
LLC
(
Dow)
and
Monsanto
Company
(
Monsanto).
In
addition
to
the
ARP
members,
Drexel
Chemical
Company
(
Drexel),
Syngenta
Crop
Protection,
Inc.
(
Syngenta)
and
Tenkoz,
Inc.
(
Tenkoz)
also
have
end­
use
products
containing
acetochlor.
Acetochlor
is
formulated
as
a
variety
of
emulsifiable
concentrate
(
EC),
soluble
concentrate
(
SC),
microencapsulated
(
Mcap),
or
granular
(
G)
formulations
that
can
be
applied
to
field
corn
as
a
preplant,
preemergence,
or
early
postemergence
application
using
only
ground
equipment.

Acetochlor
has
low
acute
toxicity
by
the
oral,
dermal
and
inhalation
routes
and
it
is
mildly
irritating
to
the
eyes.
Acetochlor
has
shown
mild
skin
irritation
in
one
study,
however
in
another
study
it
has
been
a
strong
skin
irritant.
Acetochlor
is
a
strong
dermal
sensitizer.
Acetochlor
is
well
absorbed
by
the
oral
route,
undergoes
extensive
biotransformation
in
the
organism
leading
to
chemical
reactive
species
that
are
responsible
for
its
mode
of
action
in
nasal
tissue
carcinogenesis.

The
major
target
organs
affected
in
rats,
dogs
and
mice
exposed
to
acetochlor
appear
to
be
the
liver,
thyroid
(
secondary
to
liver),
nervous
system,
kidney,
testes,
and
erythrocytes.
Speciesspecific
target
organs
include
the
nasal
olfactory
epithelium
in
rats
and
the
lungs
in
mice.
Chronic
studies
showed
that
the
dog
was
more
sensitive
than
the
rat.
Chronic
toxicity
in
the
dog
appeared
in
the
form
of
testicular,
hepatic,
and
renal
histopathology,
and
at
high
doses,
brain
histopathology.
Evidence
of
neurotoxicity
has
been
observed
in
several
studies.
In
general,
dogs
appear
to
be
somewhat
more
sensitive
than
rats
to
effects
on
the
nervous
system.
There
is
no
evidence
that
acetochlor
is
teratogenic
or
that
offspring
are
more
susceptible
than
adults,
but
acetochlor
does
cause
developmental
toxicity
in
rats
(
but
not
in
rabbits)
at
maternally
toxic
doses.

Available
developmental
toxicity
studies
in
two
species
and
three
two­
generation
reproductive
toxicity
studies
in
the
rat
do
not
show
evidence
of
increased
susceptibility
of
the
offspring.
It
is
recommended
that
the
special
FQPA
SF
be
reduced
to
1X
because
there
are
no/
low
concerns
and
no
residual
uncertainties
with
regard
to
pre­
and/
or
postnatal
toxicity.
Based
on
neurotoxicity
Page
6
of
118
findings
in
two
species,
the
HED
HIARC
recommended
that
a
developmental
neurotoxicity
toxicity
(
DNT)
study
be
submitted
by
the
registrant.
Pending
submission
of
this
study,
a
10X
database
uncertainty
factor
(
UF
DB
)
has
been
proposed
for
acetochlor
to
account
for
the
absence
of
the
DNT
study.

Endpoints
for
risk
assesment
were
selected
as
follows:

!
An
acute
dietary
endpoint
for
females
13­
49
years
of
age
was
selected
from
an
oral
developmental
toxicity
study
in
rats,
based
on
decreased
fetal
weights,
increased
resorptions
and
post
implantation
loss.

!
An
acute
dietary
endpoint
for
the
general
population
was
chosen
based
on
acute
oral
neurotoxicity
in
female
rats.

!
The
chronic
dietary
endpoint
(
all
populations),
long­
term
dermal
(>
6
months)
and
inhalation
(>
6
months)
were
selected
from
a
chronic
dog
feeding
study
based
on
increased
salivation
and
histopathology
in
the
testes,
liver
and
kidney.

!
Incidental
oral
short­
term
(
1­
30
days)
and
intermediate
(
1­
6
months)
were
not
selected
because
there
are
no
registered
residential
uses
for
acetochlor.

!
The
short
term
dermal
(
1­
30
days)
endpoint
was
chosen
from
a
21­
day
dermal
toxicity
study
in
rabbits
based
on
mortality
and
clinical
signs
of
toxicity.

!
The
short­
term
inhalation
(
1­
30
days)
endpoint
was
selected
from
a
rabbit
oral
developmental
toxicity
study,
based
on
decreased
fetal
weights,
increased
resorptions
and
post
implantation
loss.

!
Intermediate­
term
(
1­
6
months)
dermal
and
inhalation
endpoints
were
selected
from
a
two­
generation
reproductive
toxicity
study
in
the
rat
based
on
decreased
Day
21
mean
pup
weight
and
pup
weight
gain
during
lactation;
focal
hyperplasia
and
polypoid
adenomata
in
nasal
epithelium
of
adult
F1
offspring
at
study
termination.

Acetochlor
is
classified
as
"
likely
to
be
carcinogenic
to
humans,"
based
on
increased
incidence
of
lung
tumors
in
male
and
female
mice,
histiocytic
sarcoma
in
female
mice
and
nasal
epithelial
tumors
and
thyroid
follicular
cell
adenomas
in
male
and
female
rats.
A
non
mutagenic
(
with
threshold)
mode
of
action
was
established
for
the
nasal
and
thyroid
tumors;
no
mode
of
action
was
established
for
the
other
observed
tumors.

Acute,
chronic,
and
cancer
dietary
risk
assessments
(
food
+
water)
were
conducted
for
all
supported
acetochlor
food
uses
and
were
performed
to
support
the
tolerance
reassessment
eligibility
decision.
The
acute,
chronic,
and
cancer
dietary
exposure
assessment
incorporated
tolerance
level
residues
for
all
crops
and
percent
crop
treated
data
provided
by
the
Acetochlor
Page
7
of
118
Registration
Partnership
(
ARP).
Processing
data
were
available
for
numerous
commodities
and
incorporated
into
the
assessment.
Water
values
were
generated
from
the
ARP
acetochlor
water
monitoring
program.

!
The
acute
dietary
risk
estimates
do
not
exceed
HED's
level
of
concern
(
less
than
100%
of
the
aPAD)
at
the
99.9th
exposure
percentile
for
the
U.
S.
population
at
2%
of
the
aPAD
and
all
population
subgroups,
with
the
highest
exposed
population
subgroup
being
infants
less
than
1
year
old
at
6%
of
the
aPAD
!
The
chronic
dietary
risk
estimates
do
not
exceed
HED's
level
of
concern
(
less
than
100%
of
the
cPAD)
for
the
U.
S.
population
and
all
population
subgroups
(
all
were
less
than
1%
of
the
cPAD).

!
The
estimated
exposure
of
the
general
U.
S.
population
to
acetochlor
is
0.000026
mg/
kg/
day.
Applying
the
Q
1
*
of
3.27
x
10­
2
(
mg/
kg/
day)­
1
to
the
exposure
value
results
in
a
cancer
risk
estimate
of
8.40
x
10­
7.
Therefore,
the
cancer
dietary
risk
estimate
does
not
exceed
HED's
level
of
concern
of
1.0
x
10­
6.

There
are
no
residential
uses
that
might
contribute
to
aggregate
risks,
and
occupational
exposure
is
not
assessed
in
this
TRED.
Acetochlor
is
part
of
a
Common
Mode
of
Action
group
with
the
related
chloroacetanilides
butachlor
and
alachlor.
A
cumulative
risk
assessment
is
currently
underway
for
acetochlor
and
alachlor.

Given
that
both
the
ESA
and
OXA
degradates
have
been
detected
in
water
samples
(
both
groundwater
and
surface
water)
­
in
many
cases
at
concentrations
higher
than
the
parent
acetochlor
­
worst­
case
non­
carcinogenic
margin­
of­
exposure
(
MOE)
calculations
were
done
for
the
two
water
degradates
to
better
support
the
MARC
conclusion.
The
values
were
found
to
be
not
of
concern
to
HED.
The
detailed
results
are
presented
in
Appendix
2.
Page
8
of
118
2.0
Ingredient
Profile
Acetochlor,
2­
chloro­
N­(
ethoxymethyl)­
N­(
2­
ethyl­
6­
methylphenyl)
acetamide,
is
a
chloroacetanilide
herbicide
used
for
preemergence
control
of
annual
grasses,
yellow
nutsedge,
and
certain
broadleaf
weeds
in
corn.
In
the
United
States,
acetochlor
is
conditionally
registered
for
use
on
field
corn
to
the
Acetochlor
Reregistration
Partnership
(
ARP).
The
ARP
was
originally
composed
of
Monsanto
and
Zeneca
(
ICI);
however,
Zeneca's
interest
in
the
partnership
was
purchased
by
Dow
in
2000.
Acetochlor
is
formulated
as
Emulsifiable
Concentrate
(
EC),
SC,
Mcap,
or
G
formulations
and
is
marketed
by
members
of
the
ARP
under
the
trade
names
Harness
®
,
TopHand
®
,
Degree
®
,
Field
Master
®
,
Surpass
 
,
TopNotch
 
,
Keystone
®
,
and
FulTime
 
.
These
formulations
can
be
applied
to
field
corn
as
a
preplant,
preemergence,
or
early
postemergence
application
using
only
ground
equipment.

Under
the
terms
of
the
conditional
registration,
the
Agency
stipulated
that
the
continued
registration
of
acetochlor
depended
on
a
significant
reduction
in
the
total
use
of
U.
S.
corn
herbicides
of
concern,
including
alachlor,
metolachlor,
atrazine,
and
2,4­
D.
The
registration
can
also
be
cancelled
or
suspended
if
there
is
evidence
of
groundwater
contamination
by
acetochlor.
In
addition,
the
Agency
restricted
the
use
of
acetochlor
to
certified
applicators,
prohibited
aerial
application,
restricted
the
types
of
soils
on
which
acetochlor
could
be
used,
and
prohibited
application
to
water.

2.1
Summary
of
Registered/
Proposed
Uses
Although
there
are
numerous
acetochlor
EPs
registered
for
use
on
corn,
the
use
directions
are
similar
among
the
various
labels.
Acetochlor
is
restricted
for
direct
use
only
on
field
corn
and
corn
grown
only
for
silage
or
seed.
Labels
allowing
direct
application
to
pop
corn
should
be
amended
to
prevent
such
application
until
the
registrant
formally
petitions
for
the
use.
Although
several
of
the
labels
also
allow
for
a
fall
application
to
soybean
stubble
after
crop
harvest,
replanting
the
following
spring
is
restricted
to
field
corn.
Generally,
acetochlor
can
be
applied
as
either
a
single
broadcast
or
banded
application,
preplant,
preemergence,
or
early
post­
emergence.
Preplant
applications
can
be
made
as
either
a
single
or
split
application
that
is
either
surface
applied
or
incorporated.
The
early
post­
emergence
application
is
allowed
only
on
corn
up
to
eleven
inches
in
height.
For
application,
acetochlor
may
be
either
diluted
with
water
or
liquid
fertilizers
or
impregnated
onto
dry
bulk
fertilizers.
Only
applications
using
ground
equipment
are
allowed;
applications
through
irrigation
systems
and
using
aerial
equipment
are
prohibited.
Due
to
concerns
about
ground
water
contamination,
use
of
acetochlor
is
restricted
near
water
sources
and
on
sands,
loamy
sands,
and
sandy
loam
soils
with
shallow
water
tables.

Application
rates
for
acetochlor
are
dependent
on
the
soil
type
and
the
type
of
weeds
to
be
controlled.
However,
the
maximum
single
use
rate
for
any
soil
type
is
3.0
lb
ai/
A,
which
is
also
the
maximum
seasonal
use
rate.
Formulations
containing
only
acetochlor
do
not
specify
pregrazing
(
PGI)
or
preharvest
intervals
(
PHI);
however,
the
multiple
active
ingredient
formulations
contain
PGI
and
PHI
restrictions
that
are
based
on
the
other
AIs
included
in
the
Page
9
of
118
formulation.
Following
application
with
acetochlor,
the
labels
only
allow
for
rotation
to
soybeans,
corn
(
all
types),
grain
sorghum
(
milo),
wheat,
or
tobacco.

The
ARP
has
previously
agreed
to
prohibit
use
in
certain
areas
with
ground
water
that
is
highly
vulnerable
to
contamination
by
pesticides
such
as
acetochlor.
Acetochlor
product
use
is
restricted
on
coarse­
textured,
low­
organic­
matter
soils
where
groundwater
is
within
30
feet
of
the
surface.
The
following
language
is
included
with
all
acetochlor
product
labels:

Acetochlor
products
may
not
by
applied
to
the
following
soils,
if
depth
to
groundwater
is
30
feet
or
less:

°
Sands
with
less
than
3%
organic
matter.
°
Loamy
sands
with
less
than
2%
organic
matter.
°
Sandy
loams
with
less
than
1%
organic
matter.
°
Acetochlor
herbicides
may
be
applied
to
the
above
soils
if
depth
to
groundwater
is
more
than
30
feet.

2.2
Structure
and
Nomenclature
The
PC
Code
and
nomenclature
of
acetochlor
are
listed
below
in
Table
2.2
and
the
physicochemical
properties
of
acetochlor
are
listed
in
Table
2.3
The
structure
of
acetochlor
and
selected
classes
of
metabolites
are
presented
in
Table
3.1.
Page
10
of
118
N
Cl
O
O
CH
3
C
H
3
C
H
3
Table
2.2.
Acetochlor
Nomenclature.

Chemical
structure
Common
name
Acetochlor
Molecular
formula
C14H20ClNO2
IUPAC
name
2­
chloro­
N­
ethoxymethyl­
6'­
ethylacet­
o­
toluidide
CAS
name
2­
chloro­
N­(
ethoxymethyl)­
N­(
2­
ethyl­
6­
methylphenyl)
acetamide
CAS
number
34256­
82­
1
PC
Code
121601
Current
food/
feed
site
registration
Corn,
field,
forage;
Corn,
field,
grain;
Corn,
field,
stover
2.3
Physical
and
Chemical
Properties
Table
2.3
Physicochemical
Properties
of
Acetochlor.

Parameter
Value
Reference
Molecular
weight
269.77
g/
mol
Merck
Index
Online
Boiling
point/
range
163
°
C
at
10
mm
Hg;
decomposition
occurs
before
the
boiling
point
at
atmospheric
pressure;
(
calculated
by
extrapolation
of
vapor
pressure
at
lower
temperature)
M.
Flood,
DEB
7474,
2/
6/
91
pH
4.41,
1%
solution
in
acetone:
water
(
1:
1,
v:
v)
M.
Flood,
DEB
7474,
2/
6/
91
Density
at
20
°
C
1.123
g/
mL
M.
Flood,
DEB
7474,
2/
6/
91
Water
solubility
at
25
°
C
223
mg/
L
2001
Farm
Chem
Handbook
Solvent
solubility
at
25
°
C
Infinitely
soluble
in
acetone,
benzene,
carbon
tetrachloride,
ethanol,
chloroform,
and
toluene
M.
Flood,
HED
Memo,
1/
21/
94
Vapor
pressure
at
25
°
C
0.045
µ
Hg
(
4.5
x
10­
5
mm
Hg)
M.
Flood,
DEB
7474,
2/
6/
91
Dissociation
constant,
pKa
Not
applicable
because
acetochlor
is
neither
an
acid
nor
a
base.
M.
Flood,
DEB
7474,
2/
6/
91
Octanol/
Water
partition
coefficient
970
or
1082
M.
Flood,
DEB
7474,
2/
6/
91
UV/
Visible
absorption
spectrum
Not
available
Page
11
of
118
3.0
Metabolism
Assessment
3.1
Comparative
Metabolic
Profile
Table
3.1
lists
the
acetochlor
metabolites
discussed
in
this
risk
assessment.

Studies
in
rats
indicate
that
acetochlor
is
extensively
absorbed
by
the
oral
route
(
at
least
70%
of
the
oral
dose),
and
its
metabolites
undergo
extensive
enterohepatic
circulation.
After
oral
administration,
acetochlor
and
its
metabolites
undergo
extensive
distribution
throughout
the
organism,
with
binding
to
the
nasal
olfactory
epithelium
in
rats
but
not
in
mice
and
monkeys.

As
summarized
in
Figure
3.1,
acetochlor
in
rats
undergoes
extensive
biotransformation
involving
enterohepatic
recirculation
leading
to
the
precursors
of
a
quinone­
imine
(
e.
g.
the
sulfoxide
metabolite,
Figure
3.1)
which
can
bind
to
tissue
macromolecules.
When
the
mouse
was
studied
it
was
found
that
the
major
in
vivo
metabolic
route
was
glucuronidation
and
excretion
of
the
chloramide.
Thus,
glutathione
conjugation,
enterohepatic
circulation
and
formation
of
quinone
imine
precursors
was
not
a
major
metabolic
pathway
in
mice
and
this
interspecies
difference
is
consistent
with
the
absence
of
nasal
tumors
in
the
mouse.

Adequate
studies
are
available
on
the
acetochlor
metabolism
in
plants
and
on
the
metabolism
of
various
plant
metabolites
in
ruminants
and
poultry.
The
major
plant
metabolites
from
studies
with
14C­
acetochlor
are
EMA­
containing
or
HEMA­
containing
metabolites
and
Metabolite
57
(
See
Table
3.1
for
Structures).
Goats
given
HEMA­
containing
or
EMA­
containing
plant
metabolites,
or
Metabolite
57
show
that
the
HEMA
moiety,
the
EMA
moiety,
or
metabolite
57
are
essentially
not
metabolically
transformed
(
i.
e.,
the
major
radioactive
residues
identified
are
either
EMAcontaining
HEMA­
containing,
or
Metabolite
57,
the
test
substances
for
the
studies).
Hens
given
plant
metabolites
containing
the
EMA
moiety
in
the
feeding
studies
show
that
transformation
to
the
HEMA
moiety
occurs.
When
hens
are
fed
Metabolite
57
the
major
metabolite
identified
was
the
test
substance
Page
12
of
118
N
C
CH
2
Cl
O
CH
2
OC
2
H
5
N
C
O
H
CH
2
SG
N
C
O
H
CH
2
SCH
3
N
H
H
N
C
O
H
CH
2
SOCH
3
N
H
H
O
H
N
C
O
H
CH
2
SOCH
3
O
H
N
O
H
N
C
O
CH
2
SOCH
3
O
Acetochlor
GSH
Conjugate
S­
Methyl
metabolite
Sulfoxide
p­
Hydroxy­
EMA
p­
Hydroxy­
sulfoxide
Quinone­
imine
Sulfoxide
quinone­
imine
Binding
to
Tissue
Macromolecules
Reaction
with
Tissue
Nucleophiles
(
e.
g.
GSH)
Binding
to
Tissue
Macromolecules
Reaction
with
Tissue
Nucleophiles
(
e.
g.
GSH)
2­
Ethyl­
6­
methylaniline
(
EMA)

Path
A
Path
B
Figure
3.1.
Summary
of
acetochlor
biotransformatiom,
leading
to
either
methylethylquinone
imine
(
MEQI)
or
methylethylquinone
imine
sulfoxide
in
the
rat
Page
13
of
118
3.2
Nature
of
the
Residue
in
Foods
3.2.1.
Description
of
Primary
Crop
Metabolism
The
qualitative
nature
of
acetochlor
residues
in
plants
is
understood
based
on
the
adequate
corn
metabolism
studies.
The
HED
Metabolism
Committee
concluded
that
the
regulated
residues
of
concern
in
corn
include
parent
and
any
metabolites
containing
the
EMA
or
HEMA
moiety
(
See
Table
3.1
for
Structures),
expressed
in
acetochlor
equivalents
(
M.
Flood,
9/
30/
1993).
With
regards
to
Metabolite
57,
which
was
identified
at
slightly
higher
levels
in
corn
forage
and
fodder
than
other
metabolites
in
one
metabolism
study
(
ICI
study),
the
Metabolism
Committee
concluded
that
this
metabolite
need
not
be
included
in
the
tolerance
expression
after
further
toxicity
testing
showed
that
it
was
not
mutagenic
(
A.
Protzel,
TXR
No.
0052813,
8/
31/
2004).

Adequate
plant
metabolism
studies
have
been
independently
submitted
by
both
Monsanto
and
ICI.
Monsanto's
corn
and
soybean
metabolism
studies
were
reviewed
in
1984
(
R.
Cook,
PP#
3F2966,
7/
20/
1984)
and
determined
to
be
adequate.
In
the
earlier
corn
metabolism
study
from
Monsanto,
14C­
acetochlor
was
applied
preemergence
to
greenhouse­
grown
corn
at
1.5
lb
ai/
A
and
harvested
3.5
months
later
at
maturity.
Total
radioactive
residues
were
0.2
ppm
in
corn
grain
and
26.7
ppm
in
corn
foliage.
Solvent
extraction
released
81%
and
37%
of
the
TRR
from
foliage
and
grain,
respectively.
Parent
was
not
detected
in
either
grain
or
foliage
extracts.
Approximately
65
metabolites
were
observed
in
corn
grain
and
foliage
with
individual
metabolites
each
accounting
for
<
10%
of
the
TRR.
However,
upon
strong
acid
hydrolysis,
the
majority
of
14C­
residues
were
converted
to
either
2­
ethyl­
6­
methylaniline
(
EMA)
or
2­
hydroxyethyl­
6­
methylaniline
(
HEMA).

In
the
later
corn
metabolism
study
from
ICI,
which
more
closely
conforms
to
current
guideline
requirements,
14C­
acetochlor
(
EC)
was
applied
preplant
to
greenhouse­
grown
corn
at
2.5
lb
ai/
A.
Samples
of
forage
were
collected
55
days
after
treatment
(
DAT)
and
samples
of
grain,
fodder,
and
cobs
were
collected
at
maturity
(
134
DAT).
Initial
TRRs
were
4.6­
4.7ppm
in
forage
and
fodder
and
0.06­
0.08
ppm
in
grain
and
cobs.
Acetochlor
was
not
detected
in
forage,
fodder
or
grain.
Analyses
of
fodder
(
5.27
ppm)
identified
up
to
eight
EMA­
type
metabolites
each
accounting
for
#
5.8%
TRR
and
totaling
23.2%
of
the
TRR,
along
with
isomers
of
two
ringhydroxylated
metabolites,
Metabolite
55
(
3.2%
TRR)
and
Metabolite
57
(
12.7%
TRR).
Results
from
forage
were
similar
to
fodder.
Analyses
of
grain
(
0.069
ppm)
identified
up
to
four
EMAtype
metabolites
each
accounting
for
#
3.6%
TRR,
along
with
Metabolites
55
(
3.0%
TRR)
and
Metabolite
57
(
8.8%
TRR).
As
in
the
earlier
Monsanto
study,
no
HEMA­
type
metabolites
were
directly
identified,
but
HEMA
metabolites
were
released
by
strong
base
hydrolysis.
Analysis
of
corn
commodities
using
the
common
moiety
method
with
base
hydrolysis
did
not
detect
quantifiable
residues
(<
0.02
ppm)
of
EMA
or
HEMA
metabolites
in
grain.
However,
EMA
type
metabolites
accounted
for
27.9%
of
the
TRR
in
forage
and
17.1%
of
the
TRR
in
fodder,
and
HEMA
metabolites
accounted
for
4.6­
4.8%
TRR
in
forage
and
fodder.
Metabolites
57
and
55
were
the
single
major
metabolites
in
forage
and
fodder
and
are
likely
formed
following
uptake
from
the
soil
of
Metabolite
17,
N­
ethoxymethyl­
N­(
2N­
ethyl­
6N­
methylphenyl)
oxamic
acid.
The
fact
that
these
isomers
were
not
identified
in
Monsanto's
earlier
corn
study
was
attributed
by
the
Page
14
of
118
registrants
to
the
methyl
bromide
fumigation
of
the
soil
in
the
earlier
study,
which
may
have
damaged
soil
microbes
active
in
acetochlor
metabolism.
Metabolites
57
and
55
are
not
detected
by
the
current
common
moiety
method.

3.2.2
Description
of
Livestock
Metabolism
The
qualitative
nature
of
acetochlor
residues
in
livestock
is
adequately
understood,
although
the
available
studies
dosing
goats
and
hens
with
14C­
acetochlor
are
not
fully
acceptable.
Adequate
studies
have
been
independently
submitted
by
Monsanto
and
ICI/
Zeneca
examining
the
metabolism
of
various
plant
metabolites
(
EMA­
type,
HEMA­
type,
and
Metabolite
57)
in
both
ruminants
and
poultry.
Based
on
these
studies,
the
Agency
concluded
that
acetochlor
residues
in
ruminants
and
poultry
include
EMA­
and
HEMA­
type
metabolites
and
Metabolite
57.
The
HED
Metabolism
Committee
(
M.
Flood,
9/
30/
1993)
concluded
that
tolerances
are
not
required
for
livestock
commodities
to
support
the
use
on
corn.

Ruminants.
The
available
ruminant
metabolism
studies
summarized
below
include:
two
studies
from
Monsanto
and
ICI/
Zeneca
dosing
goats
with
14C­
EMA­
type
metabolites
(
MRIDs
00118950
and
41963323);
a
study
from
Monsanto
dosing
goats
with
an
14C­
HEMA­
type
metabolite
(
MRID
41633601);
a
study
from
ICI/
Zeneca
dosing
a
cow
with
14C­
Metabolite
57
(
MRID
42549905);
and
two
studies
from
ICI/
Zeneca
dosing
goats
with
14C­
acetochlor
(
MRIDs
41565157
and
42549903).
Based
on
the
recommended
tolerance
of
3.0
ppm
for
field
corn
forage,
the
maximum
theoretical
dietary
burden
for
dairy
cattle
is
3.77
ppm
for
the
combined
residues
of
EMA­
type
and
HEMA­
type
metabolites.

In
the
earliest
Monsanto
study,
two
goats
were
dosed
for
five
days
with
a
combination
of
four
14C­
ring­
labeled,
EMA­
type
metabolites
at
a
level
equivalent
to
approximately
20
ppm
in
the
diet.
TRR
were
0.007
ppm
in
milk,
0.025
ppm
in
kidneys,
0.046
ppm
in
liver
and
<
0.001
ppm
in
muscle
and
fat.
Analysis
of
urine
and
feces
using
a
common
moiety
method
indicated
that
EMAtype
metabolites
accounted
for
83%
and
77%
of
the
radioactivity
in
urine
and
feces,
respectively.

In
the
similar
ICI/
Zeneca
study,
goats
were
dosed
for
seven
days
with
a
combination
of
four
14C­
ring­
labeled,
EMA­
type
metabolites
at
a
levels
equivalent
to
10
ppm
(
two
goats)
or
50
ppm
(
one
goat)
in
the
diet.
For
the
goats
dosed
at
10
ppm,
TRR
were
#
0.003
ppm
in
milk,
0.008
ppm
in
kidneys,
0.136
ppm
in
liver,
0.006
ppm
in
muscle,
and
<
0.005
ppm
in
fat.
For
the
goat
dosed
at
50
ppm,
TRR
were
0.013­
0.014
ppm
in
milk,
0.160
ppm
in
kidneys,
0.097
ppm
in
liver,
0.010
ppm
in
muscle,
and
<
0.005
ppm
in
fat.
Milk
and
tissue
samples
from
the
50
ppm
goat
were
extracted
for
analysis
releasing
54­
100%
of
the
TRR,
and
the
resulting
extracts
were
analyzed
for
EMA
and
HEMA
residues
using
the
common
moiety
method.
EMA­
type
metabolites
were
detected
at
0.04
and
0.13
ppm
in
liver
and
kidney,
respectively,
and
were
<
0.01
ppm
in
fat,
muscle,
and
milk.
HEMA­
type
metabolites
were
<
0.01
ppm
in
milk
and
all
tissues.
Analysis
of
urine
using
a
common
moiety
method
indicated
that
the
majority
of
residues
were
EMA
type
metabolites
($
83%
TRR);
HEMA
type
metabolites
accounted
for
#
1%
of
the
radioactivity
in
urine
indicating
that
oxidation
of
EMA
to
HEMA
metabolites
was
limited.
Page
15
of
118
In
conjunction
with
a
feeding
study
conducted
by
Monsanto,
four
goats
were
dosed
for
28
days
with
a
14C­
ring­
labeled,
HEMA­
type
metabolite
at
a
levels
equivalent
to
0.5,
1.5,
or
5
ppm
in
the
diet.
At
each
dosing
level,
TRR
were
<
0.001
ppm
in
milk
and
tissues.
Analysis
of
milk
and
tissues
using
a
common
moiety
method
did
not
detect
(<
0.01
ppm)
any
EMA
or
HEMA
residues.
The
metabolism
of
the
major
oxamic
acid
plant
metabolite
was
examined
in
a
study
from
ICI/
Zeneca
in
which
a
single
cow
was
dosed
with
14C­
ring­
labeled
Metabolite
57
for
seven
days
at
a
level
equivalent
to
approximately
25
ppm
in
the
diet.
TRR
levels
peaked
on
Day
6
in
milk
at
0.0063
ppm,
and
TRR
in
tissues
were
<
0.004
ppm
in
muscle,
#
0.004
ppm
in
fat,
0.008
ppm
in
liver,
and
0.015
ppm
in
kidneys.
Metabolite
57
comprised
80%
of
the
TRR
in
urine
and
88%
of
the
TRR
in
feces,
and
was
the
only
14C­
residue
identified
in
kidneys
at
43%
of
the
TRR.

In
the
first
ICI/
Zeneca
study
examining
the
direct
metabolism
of
14C­
acetochlor
in
ruminants,
goats
were
dosed
for
four
days
with
14C­
ring­
labeled
acetochlor
at
levels
equivalent
to
either
1
ppm
(
two
goats)
or
90
ppm
(
one
goat)
in
the
diet.
At
both
dose
levels,
the
majority
of
the
dose
was
excreted
in
the
urine
(
57­
62%
dose)
and
feces
(
21­
25%
dose).
For
the
high­
dose
goat,
TRR
were
0.15­
0.19
ppm
in
milk,
4.55
ppm
in
liver,
4.16
ppm
in
kidneys,
0.23­
0.25
ppm
in
muscle,
and
0.10
ppm
in
fat.
Characterization
was
attempted
in
urine,
liver,
and
kidneys,
but
milk,
muscle,
and
fat
samples
were
not
further
analyzed.
Acetochlor
was
not
detected
(<
0.1%
TRR)
in
any
samples.
The
principal
14C­
residue
identified
was
the
cysteine
conjugate
of
acetochlor
(
Metabolite
44)
at
37%,
15%,
and
18%
of
the
TRR
in
urine,
liver,
and
kidneys,
respectively.

In
the
subsequent
14C­
acetochlor
metabolism
study,
two
goats
were
dosed
for
four
days
with
14C­
ring­
labeled
acetochlor
at
levels
equivalent
to
10
ppm
in
the
diet.
TRR
in
milk
plateaued
within
two
days
at
0.016
ppm,
and
TRR
at
sacrifice
were
0.588
ppm
in
liver,
0.479
ppm
in
kidneys,
0.020­
0.024
ppm
in
muscle,
and
#
0.008
ppm
in
fat.
Characterization
was
attempted
in
urine,
feces,
milk,
muscle,
liver,
and
kidneys.
Acetochlor
was
detected
at
low
levels
(
0.8%
TRR)
in
feces,
but
was
not
detected
in
urine,
milk,
or
tissues.
Metabolite
44
was
identified
as
the
principal
14C­
residue
in
urine
(
23.6%
TRR)
and
milk
(
18.6%
TRR).
The
remaining
components
in
urine
and
milk
each
accounted
for
<
5%
of
the
TRR.
No
metabolites
were
identified
in
muscle,
liver
or
kidney.
Analysis
of
muscle,
kidney,
and
liver
using
the
common
moiety
method
detected
residues
of
EMA
and
HEMA­
type
metabolites
at
combined
levels
of
0.007
ppm
in
muscle,
0.04
ppm
in
kidney
and
0.08
ppm
in
liver.

The
Agency
noted
that
both
14C­
acetochlor
goat
metabolism
studies
are
inadequate
due
to
insufficient
characterization
of
14C­
residues
in
liver
and
kidneys.

Poultry.
The
available
poultry
metabolism
studies
summarized
below
include:
two
studies
from
Monsanto
and
ICI/
Zeneca
dosing
hens
with
14C­
EMA­
type
metabolites
(
MRIDs
40365602
and
41963324);
a
study
from
ICI/
Zeneca
dosing
hens
with
14C­
Metabolite
57
(
MRID
42549904);
and
a
study
from
ICI/
Zeneca
dosing
hens
with
14C­
acetochlor
(
MRIDs
41565158
and
41565159).
Based
on
reassessed
tolerances,
the
maximum
theoretical
dietary
burden
for
poultry
is
0.044
ppm
for
the
combined
residues
of
EMA­
and
HEMA­
type
metabolites.
Page
16
of
118
In
the
first
Monsanto
study,
groups
of
hens
were
dosed
for
six
days
with
a
combination
of
four
14C­
ring­
labeled,
EMA­
type
metabolites
at
a
levels
equivalent
to
either
15
or
100
ppm
in
the
diet.
At
both
dosing
levels,
95­
98%
of
the
administered
dose
was
recovered
in
the
excreta
and
0.02%
of
the
dose
was
recovered
in
eggs.
For
the
15
ppm
dose
groups,
maximum
TRR
levels
were
0.009
ppm
in
egg
whites,
0.027
ppm
in
yolks,
0.010
ppm
in
muscle,
0.045
ppm
in
liver
and
0.005
ppm
in
fat.
For
the
100
ppm
dose
groups,
TRR
levels
were
0.107
ppm
in
egg
whites,
0.173
ppm
in
yolks,
0.032
ppm
in
muscle,
0.266
ppm
in
liver
and
0.007
ppm
in
fat.
Eggs
and
tissues
were
analyzed
using
the
common
moiety
method.
EMA­
type
metabolites
accounted
for
63%
of
the
TRR
in
liver,
20­
48%
of
the
TRR
in
muscle,
and
86%
of
the
TRR
in
fat.
Analyses
of
muscle
also
detected
HEMA
type
metabolites
at
10­
1%
of
the
TRR
and
2­(
1­
hydroxyethyl­
6­
hydroxymethylaniline
(
HEHMA)
type
metabolites
at
3­
6%
of
the
TRR.
Analyses
of
egg
whites
detected
both
EMA
and
HEMA
type
metabolites
together
accounting
for
45­
52%
of
the
TRR,
with
the
HEMA
type
metabolites
being
2­
4x
more
abundant
than
the
EMA
type
metabolites.
Analyses
of
egg
yolks
detected
both
EMA
(
65%
TRR)
and
HEMA
(
27%
TRR)
type
metabolites
together
accounting
for
92%
of
the
TRR.

In
the
ICI/
Zeneca
study,
a
group
of
hens
was
dosed
for
seven
days
with
a
combination
of
four
14C­
ring­
labeled,
EMA­
type
metabolites
at
a
level
equivalent
to
10
ppm
in
the
diet.
Excreta
and
cage
wash
together
accounted
for
92%
of
the
administered
dose.
The
mean
TRR
in
egg
whites
was
0.006
ppm
(
Days
3,
5
and
7),
with
a
single
highest
value
of
0.009
ppm
from
one
sample
on
Day
7.
The
mean
TRR
in
egg
yolks
on
Day
7
was
0.015
ppm,
with
a
maximum
of
0.017
ppm.
Maximum
TRR
levels
were
0.013
ppm
in
kidney,
0.031
ppm
in
liver,
0.002
ppm
in
muscle,
and
0.010
ppm
in
fat.
Samples
of
liver,
egg
yolks,
and
excreta
were
analyzed
using
the
common
moiety
method.
In
excreta,
EMA­
and
HEMA­
type
metabolites
accounted
for
84%
and
8%
of
the
TRR,
respectively.
EMA­
type
metabolites
were
also
detected
at
0.015
ppm
in
yolks
and
0.01
ppm
in
liver,
but
HEMA­
type
metabolites
were
not
detected.

In
the
ICI/
Zeneca
study
examining
metabolism
of
Metabolite
57,
a
group
of
hens
were
dosed
for
10
days
with
14C­
ring­
labeled
Metabolite
57
at
a
level
equivalent
to
10
ppm
in
the
diet.
Radioactivity
in
excreta
accounted
for
>
98%
of
the
administered
dose.
Maximum
residues
in
eggs
yolks
were
attained
on
Day
8
at
0.016
ppm;
TRR
in
egg
whites
were
generally
<
0.003
ppm
although
a
value
of
0.007
ppm
was
obtained
from
one
sample.
Maximum
TRR
in
tissues
were
0.025
ppm
in
fat,
0.005
ppm
in
muscle,
and
0.006
ppm
in
liver.
Samples
of
excreta,
fat
and
egg
yolks
were
used
for
analysis.
Metabolite
57
comprised
77%
of
the
TRR
in
excreta,
41%
of
the
TRR
in
fat,
and
36%
of
the
TRR
in
egg
yolks.
No
other
components
were
identified.

In
the
ICI/
Zeneca
study
examining
the
direct
metabolism
of
14C­
acetochlor,
two
group
of
hens
were
dosed
for
four
days
with
14C­
ring­
labeled
acetochlor
at
levels
equivalent
to
either
1
or
90
ppm
in
the
diet.
At
both
dose
levels,
the
majority
of
the
dose
was
recovered
in
the
excreta
and
cage
wash
(
76­
89%
dose).
For
hens
dosed
at
1
ppm,
TRR
were
<
0.004
ppm
in
eggs,
0.041­
0.055
ppm
in
liver,
0.053­
0.062
ppm
in
kidneys,
0.004­
0.006
ppm
in
muscle,
and
<
0.010
ppm
in
fat.
For
hens
dosed
at
90
ppm,
TRR
were
0.16
ppm
in
eggs
(
Day
4),
2.48­
5.13
ppm
in
liver,
3.48­
7.48
ppm
in
kidneys,
0.30­
0.63
ppm
in
muscle,
and
0.16­
0.46
ppm
in
fat.
Characterization
Page
17
of
118
was
attempted
only
on
liver
and
excreta.
Acetochlor
was
detected
at
5.6%
of
the
TRR
in
liver,
and
analysis
using
the
common
moiety
method
indicated
that
EMA­
type
metabolites
accounted
for
12%
of
the
TRR.
In
excreta,
the
principal
14C­
residue
identified
was
N­(
2­
ethyl­
6­
methylphenyl)
oxamic
acid
(
Metabolite
27)
at
10%
of
the
TRR.
Analysis
of
excreta
using
the
common
moiety
method
detected
EMA
type
metabolites
at
19%
of
the
TRR.
This
study
was
deemed
inadequate
due
to
insufficient
characterization
of
14C­
residues.

3.2.3
Description
of
Rotational
Crop
Metabolism,
including
identification
of
major
metabolites
and
specific
routes
of
biotransformation
The
requirement
for
confined
accumulation
in
rotational
crops
is
satisfied.
The
requirements
for
field
accumulation
in
rotational
crops
are
satisfied.

Confined
Accumulation
in
Rotational
Crops.
The
requirement
for
confined
accumulation
in
rotational
crops
is
satisfied
(
Guideline
860.1850).
Following
an
application
of
14C­
acetochlor
to
a
sandy
loam
soil
at
3.0
lb
ai/
A
(
1x
rate),
TRR
were
>
0.01
ppm
in
all
commodities
of
lettuce,
radish,
and
wheat
that
were
planted
30,
120,
and
365
DAT,
with
14C­
residues
generally
being
the
highest
at
the
120­
day
plant
back
interval
(
PBI).
Extraction
and
analysis
of
the
rotational
crop
commodities
identified
or
characterized
$
63%
of
the
TRR
in
each
commodity
from
each
interval.
Acetochlor
was
detected
only
in
radish
foliage
from
one
interval
(
120­
DAT)
accounting
for
4%
of
the
TRR
(
0.03
ppm).
A
total
of
17
metabolites
were
identified
in
rotational
crops,
including
12
EMA­
producing
metabolites,
3
HEMA­
producing
metabolites,
and
2
HMEA­
producing
metabolites.
In
each
commodity,
the
EMA
producing
metabolites
were
present
at
the
highest
concentrations,
followed
by
the
HEMA­
and
HMEA­
type
metabolites,
respectively.
Metabolism
in
the
rotational
crops
was
similar
to
corn
except
that
HMEA­
type
metabolites
were
not
observed
in
corn,
and
Metabolite
57
was
not
observed
in
rotational
crops,
possibly
of
the
same
reason
indicated
for
one
of
the
earlier
corn
studies.

Based
on
the
above
results
and
the
data
from
the
extensive
rotational
crop
field
trials
discussed
below,
the
HED
MARC
concluded
that
tolerances
for
rotational
crops
should
be
expressed
as
acetochlor
and
its
EMA­
and
HEMA­
producing
metabolites
(
M.
Flood,
MARC
Memorandum,
9/
30/
93).
Residues
of
HMEA­
containing
metabolites,
expressed
in
acetochlor
equivalents,
should
not
be
included
in
the
tolerance
expression,
but
will
be
used
for
purposes
of
risk
assessment.

Field
Accumulation
in
Rotational
Crops.
The
requirements
for
field
accumulation
in
rotational
crops
are
satisfied
(
Guideline
860.1900).
The
available
extensive
rotational
crop
field
trials
are
adequate
and
support
the
current
tolerances
on
sorghum,
soybean,
and
wheat
commodities.
Labels
for
EPs
registered
to
members
of
the
ARP
currently
include
the
following
rotational
crop
restriction:
do
not
rotate
to
crops
other
than
soybeans,
corn
(
all
types),
milo
(
sorghum),
wheat
or
tobacco.

Extensive
rotational
field
crop
trials
were
conducted
on
sorghum,
soybean,
and
wheat
rotated
Page
18
of
118
with
treated
corn.
Acetochlor
(
EC)
was
applied
as
a
single
broadcast
preemergence
application
to
a
primary
crop
of
corn
at
3
lb
ai/
A
(
1x
maximum
rate)
at
19
test
locations
throughout
the
corn
growing
regions
of
the
U.
S.
After
corn
harvest,
rotational
crops
of
winter
wheat,
soybeans,
and
sorghum
were
planted
on
the
test
plots
at
PBIs
of
3.0­
5.9
months
for
wheat
and
10.4­
14.2
months
for
soybeans
and
sorghum.
Duplicate
samples
of
sorghum,
soybean,
and
wheat
commodities
were
collected
from
each
test
at
the
appropriate
harvest
intervals.

Samples
were
analyzed
for
residues
of
acetochlor
and
its
EMA­,
HEMA­,
and
HMEA­
containing
metabolites
using
an
adequate
HPLC/
OCED
method.
The
LOQ
for
each
analyte
is
0.01
ppm,
expressed
in
acetochlor
equivalents.
Residue
values
were
corrected
for
average
concurrent
recoveries.
The
field
trials
are
supported
by
the
available
storage
stability
data.
For
all
three
rotational
crops,
concentrations
of
EMA­
type
metabolites
were
highest,
followed
by
HEMA­
and
HMEA­
type
metabolites,
respectively.

For
rotated
wheat,
the
combined
residues
of
EMA­,
HEMA­,
and
HMEA­
yielding
compounds,
expressed
in
acetochlor
equivalents,
were
<
0.03
ppm
(<
LOQ)
in
38
samples
of
grain,
<
0.03­
0.531
ppm
in
44
forage
samples,
and
<
0.03­
0.124
ppm
in
38
straw
samples.
Considering
only
the
currently
regulated
EMA
and
HEMA
containing
compounds,
maximum
residues
were
<
0.02
ppm
in
grain,
0.457
ppm
in
forage,
and
0.104
ppm
in
straw.
No
data
were
provided
on
hay,
which
is
a
RAC
of
wheat.

For
rotated
sorghum,
the
combined
residues
of
EMA­,
HEMA­,
and
HMEA­
yielding
compounds
were
<
0.03
ppm
(<
LOQ)
in
34
samples
of
grain,
<
0.03­
0.103
ppm
in
36
forage
samples,
<
0.03­
0.082
ppm
in
34
fodder
(
stover)
samples,
<
0.03­
0.206
ppm
in
34
hay
samples,
and
<
0.03­
0.068
ppm
in
36
silage
samples.
Considering
only
the
currently
regulated
EMA­
and
HEMA­
containing
compounds,
maximum
residues
were
<
0.02
ppm
in
grain,
0.093
ppm
in
forage,
0.068
ppm
in
fodder,
0.186
ppm
in
hay,
and
0.057
ppm
in
silage.

For
rotated
soybeans,
the
combined
residues
of
EMA­,
HEMA­,
and
HMEA­
yielding
compounds
were
<
0.03­
0.128
ppm
in
32
samples
of
seed,
<
0.03­
0.769
ppm
in
36
forage
samples,
and
<
0.034­
1.217
ppm
in
32
hay
samples.
Considering
only
the
currently
regulated
EMA­
and
HEMA­
containing
compounds,
maximum
residues
were
0.101
ppm
in
seed,
0.648
ppm
in
forage,
and
1.064
ppm
in
hay.

3.3
Environmental
Degradation
The
major
routes
of
dissipation
for
acetochlor
appear
to
be
microbially­
mediated
degradation,
runoff,
and
leaching.
Although
acetochlor
generally
degrades
rapidly
when
applied
to
soil,
in
some
field
situations
it
can
be
relatively
persistent
(
e.
g.
field
dissipation
half­
lives
were
up
to
36
days)
and
it
has
been
found
in
groundwater
at
numerous
locations.
There
is
variable
evidence
as
to
the
persistence
of
acetochlor
in
subsoil
horizons
with
a
published
study
by
the
registrant
reporting
only
a
modest
increase
in
persistence
from
surface
soils
at
two
sites
using
in
situ
Page
19
of
118
N
Cl
O
O
CH
3
C
H
3
C
H
3
N
R2
O
R1
CH
3
C
H
3
methods
(
Mills
et
al.
2001).
Lavy
et
al.
(
1996)
have
reported
a
much
more
substantial
increase
in
persistence
at
two
sites
for
alachlor,
a
herbicide
that
is
chemically
related
to
acetochlor
and
tends
to
have
a
very
similar
environmental
fate
profile.

Laboratory
degradation
data
indicate
that
acetochlor
does
not
degrade
by
abiotic
processes
(
hydrolysis
and
photolysis).
While
acetochlor
has
relatively
short
half­
lives
in
fine­
textured
aerobic
soil,
it
may
be
moderately
persistent
in
coarser
soils
(
this
may
be
related
to
the
lower
rate
of
microbial
activity
in
sandy,
low
organic
matter
soils).

The
aerobic
soil
metabolism
degradates
oxanilic
acid
(
oxamic
acid),
and
sulfonic
acid
are
the
major
environmental
degradates
of
acetochlor.
Another
metabolite
is
thioacetic
acid
sulfoxide.

3.4
Tabular
Summary
of
Metabolites
and
Degradates
Table
3.1.
presents
presents
the
structures
of
major
residues
and
environmental
degradates
of
acetochlor.
Acetochlor
ESA
and
acetochlor
OXA
are
environmental
degradates.
All
other
compounds
in
Table
3.1
were
reported
in
plants
or
animals.

Table
3.1
Chemical
Names
and
Structures
of
Acetochlor
and
Major
Metabolites
and
Degradates.

Company
Name
(
Codes)
Chemical
Name
Structure
1
Acetochlor
MON
097
2­
chloro­
N­(
ethoxymethyl)­
N­(
2­
ethyl­
6­
methylphenyl)
acetamide
EMA­
type
metabolites
N/
A
=
not
applicable
Table
3.1
Chemical
Names
and
Structures
of
Acetochlor
and
Major
Metabolites
and
Degradates.

Company
Name
(
Codes)
Chemical
Name
Structure
1
Page
20
of
118
N
R2
O
R1
CH
3
C
H
3
OR
3
N
R2
O
R1
CH
2
OH
C
H
3
N
H
O
COOH
C
H
3
CH
3
OH
N
CH
3
SO
3
H
O
O
CH
3
C
H
3
HEMA­
type
metabolites
N/
A
HMEA­
type
metabolites
N/
A
Metabolite
57
N­(
6­
ethyl­
3­
hydroxy­
2­
methylphenyl)
oxamic
acid
Table
3.1
Chemical
Names
and
Structures
of
Acetochlor
and
Major
Metabolites
and
Degradates
(
Contd).

Company
Name
(
Codes)
Chemical
Name
Structure
1
Acetochlor
ESA
MON
52754
R290131
Acetochlor
ethane
sulfonic
acid
(
ESA)
Table
3.1
Chemical
Names
and
Structures
of
Acetochlor
and
Major
Metabolites
and
Degradates
(
Contd).

Company
Name
(
Codes)
Chemical
Name
Structure
1
Page
21
of
118
N
CH
3
O
CH
3
C
H
3
O
O
H
O
Acetochlor
OXA
MON
52755
R290130
Acetochlor
oxanilic
acid
(
OXA)

1.
For
the
EMA,
HEMA,
and
HMEA
type
metabolites
the
R1
functional
group
can
consist
of
­
H
or
­
CH2OCH2CH3
and
the
R2
functional
group
can
consist
of
many
different
moieties.
The
R3
functional
for
HEMA
type
metabolites
can
consist
of
­
H
or
a
variety
of
components
such
as
sugars.

3.5
Toxicity
Profile
of
Major
Metabolites
and
Degradates
Based
on
their
structures,
the
Metabolism
Assessment
Review
Committee
(
MARC)
was
unable
to
conclude
that
the
metabolites
in
raw
agricultural
commodities
(
RACs)
containing
the
EMA,
HEMA
or
HMEA
moieties
(
See
Table
3.1)
will
be
significantly
less
toxic
than
the
parent
and
therefore
recommended
that
for
risk
assessment
purposes
the
residues
of
concern
in
plants
are
the
parent
and
the
metabolites
containing
the
EMA
or
HEMA
moiety.
In
rotational
crops,
for
risk
assessment
purposes,
the
residues
of
concern
are
the
parent
and
the
metabolites
containing
the
EMA,
HEMA,
or
HMEA
moiety.

In
the
case
of
water,
the
MARC
concluded,
based
on
toxicity
data,
that
the
water
degradates
acetochlor
ESA
and
acetochlor
OXA
are
significantly
less
toxic
than
the
parent
and
should
not
be
included
in
the
risk
assessment.
The
ESA
and
OXA
degradates
have
been
monitored
in
water
samples
(
both
groundwater
and
surface
water)
­
and
in
many
cases
were
found
at
concentrations
higher
than
the
parent
acetochlor.
Thus,
to
support
the
MARC's
conclusion
on
the
water
degradates,
Margin­
of­
Exposure
(
MOE)
calculations
were
done
to
estimate
acute
and
chronic
risk
of
acetochlor
ESA
and
acetochlor
OXA
(
See
Appendix
2).

3.5.1
Summary
of
Available
Toxicity
Studies
on
Acetochlor
Degradates
The
toxicity
data
used
to
evaluate
the
relative
toxicities
of
the
ESA
degradate
relative
to
acetochlor
is
presented
below
in
Table
3.2.
Data
for
the
OXA
degradate
is
presented
in
Table
3.3.
Mutagenicity
data
for
the
ESA
and
OXA
degradates
(
and
a
mixture
of
compounds
57
and
55)
are
presented
below
in
Table
3.4:

Table
3.2.
Comparison
of
Toxicity
of
Acetochlor
and
Acetochlor
ESA
Page
22
of
118
Test
Acetochlor
Acetochlor
ESA
Acute
oral
LD50
LD50(
M&
F)
=
4124
(
3557­
4691)
mg/
kg
(
MRID
41565104)
LD50(
M&
F)
>
2000
mg/
kg
(
no
mortality
at
limit
dose)
(
MRID
44632704)

Metabolism
>
80%
oral
absorption,
extensive
biotransformation,
precursors
of
quinonone
imine,
binding
to
nasal
turbinates
(
MRIDs
41565125,
­
26,
­
27;
41592007,
­
08;
44496203,
­
10,
­
12)
Poorly
absorbed
by
the
oral
route
(
about
10­
12%
of
the
dose).
Limited
biotransformation
(
75­
79%)
excreted
untransformed.
Does
not
bind
to
nasal
turbinates.
(
MRID
45300504)

4­
Week
feeding
range
finding
(
ESA)/
thyroid
mechanistic
(
acetochlor)
(
rats)
Males
administered
acetochlor
in
diet
at
100.6
or
280.9
mg/
kg/
day
for
14,
28
or
56
days:
increased
liver
and
thyroid
weights,
hepatic
UDPGT
activity,
circulating
serum
TSH,
T4;
decreased
T3,
some
or
all
time
points.
Males
administered
acetochlor
at
10.4,
91.9
or
270.3
mg/
kg/
day
for
90
or
160
days:
increased
liver
weight
(
slight
increase
in
thyroid
wt)
at
91.9
mg/
kg/
day,
increased
hepatic
UDPGT
at
270.3
mg/
kg/
day.
(
MRID
44496208)
NOAEL
=
370.3
/
374.6
mg/
kg/
day
[
M/
F]
LOAEL
=
766.6/
762.3
mg/
kg/
day
[
M/
F],
based
on
decreased
body
weights
and
body
weight
gain
and
increased
TSH
and
free
T3
in
males.
At
1578.7
mg/
kg/
day
(
HDT)
there
was
a
statistically
significant
increase
in
T4­
UDPGT
(
microsomal
enzyme)
(
MRID
45300503)

90­
Day
feeding
(
rats)
Study
1:
NOAEL
=
16.1
/
19.1
mg/
kg/
day
[
M/
F]
LOAEL
=
161
/
191
mg/
kg/
day
[
M/
F]
based
on
hematology,
small
but
significant
increases
relative
liver,
kidney
&
brain
weights.
(
MRID
41565115)
Study
2:
NOAEL
=
40
mg/
kg/
day
LOAEL
=
100
mg/
kg/
day,
based
on
body
weight
loss
&
food
consumption.
(
MRID
00050933)
NOAEL
=
225.4
/
259.1
mg/
kg/
day
[
M/
F]
LOAEL
=
919.4
/
1073.2
mg/
kg/
day
[
M/
F],
based
on
reduced
body
weights,
body
weight
gains
and
food
utilization
in
both
sexes.
Decreased
cell
proliferation
in
nasal
passages
was
seen
at
the
LOAEL,
but
not
statistically
significantly
diff.
with
controls
because
of
variability.
(
MRID
45313801)

Developmental
toxicity
Study
1(
rats):
NOAEL(
maternal
&
developmental)
=
150
mg/
kg/
day,
LOAEL
(
mat
&
dev)
=
600
mg/
kg/
day;
Maternal:
based
on
clinical
signs
&
decr.
b.
wt.
gain.
Developmental:
based
on
incr.
resorptions
&
decr.
fetal
body
weights
(
MRID
41592005)
Study
2
(
rats):
NOAEL(
maternal
&
developmental)
=
200
mg/
kg/
day,
LOAEL
(
mat
&
dev)
=
400
mg/
kg/
day;
Maternal:
based
on
clinical
signs
&
decr.
b.
wt.
gain.
Developmental:
based
on
decr.
fetal
body
weights.
(
MRID
00050929)
No
data
for
Acetochlor
ESA.
Data
are
for
Alachlor
ESA.
Rats:
NOAEL
(
maternal
&
developmental):
greater
than
or
equal
to
900
(
HDT)
mg/
kg/
day
LOAEL
(
maternal
&
developmental):
greater
than
900
mg/
kg/
day
(
MRID
43908101)

Mutagenicity
No
Concern
(
See
Table
3.4)
No
Concern
(
See
Table
3.4)

Table
3.3.
Comparison
of
toxicity
of
Acetochlor
and
Acetochlor
OXA
Test
Acetochlor
Acetochlor
OXA
Acute
oral
LD50
LD50(
M&
F)
=
4124
(
3557­
4691)
mg/
kg
(
MRID
41565104)
LD50(
M&
F)
>
2000
mg/
kg
(
MRID
44632703)
Page
23
of
118
Metabolism
Rats:
>
80%
oral
absorption,
extensive
biotransformation,
precursors
of
quinone
imine,
binding
to
nasal
turbinates
(
MRIDs
41565125,
­
26,
­
27
;
41592007,
­
08;
44496203,
­
10,
­
12)
Rats:
About
33.9­
38.6%
of
the
dose
absorbed
by
the
oral
route
(
as
seen
in
urine)
Limited
biotransformation:
(
81.4­
84.9%
excreted
untransformed.
Two
unidentified
metabolites
(
5
&
2%
of
dose,
resp.
).
Does
not
bind
to
nasal
turbinates.
No
data
for
mouse.
(
MRID
45300507)

4­
Week
feeding
range
finding
(
OXA)/
mechani
stic
thyroid
toxicity
(
acetochlor)
(
rats)
Males
administered
acetochlor
in
diet
at
100.6
or
280.9
mg/
kg/
day
for
14,
28
or
56
days:
increased
liver
and
thyroid
weights,
hepatic
UDPGT
activity,
circulating
serum
TSH,
T4;
decreased
T3,
some
or
all
time
points.
Males
administered
acetochlor
at
10.4,
91.9
or
270.3
mg/
kg/
day
for
90
or
160
days:
increased
liver
weight
(
slight
increase
in
thyroid
wt)
at
91.9
mg/
kg/
day,
increased
hepatic
UDPGT
at
270.3
mg/
kg/
day.
(
MRID
44496208)
NOAEL
=
372.6
/
367.2
mg/
kg/
day
[
M/
F]
LOAEL
=
768.5
/
737.3
mg/
kg/
day
[
M/
F],
based
on
decr.
TSH
&
T3
and
incr.
absolute
&
relative
thyroid
weights
in
males
and
decr.
TSH
&
T3
in
females.
(
MRID
45300506)

90­
Day
feeding
(
rats)
Study
1:
NOAEL
=
16.1
/
19.1
mg/
kg/
day
[
M/
F]
LOAEL
=
161
/
191
mg/
kg/
day
[
M/
F]
based
on
hematology,
small
but
significant
increases
relative
liver,
kidney
&
brain
weights.
(
MRID
41565115)
Study
2:
NOAEL
=
40
mg/
kg/
day
LOAEL
=
100
mg/
kg/
day,
based
on
body
weight
loss
&
food
consumption.
(
MRID
00050933)
NOAEL
=
230.2
/
268.0
mg/
kg/
day
[
M/
F]
LOAEL
=
955.2/
1082.7
mg/
kg/
day
[
M/
F],
based
on
reduced
body
weights,
body
weight
gains
and
food
utilization
in
both
sexes.
Thyroid
weight
increases
were
not
seen
in
this
study.
T4­
UDPGT
activity
was
slightly,
but
not
significantly,
increased
in
high­
dose
males
and
was
statistically
significantly
decreased
in
high­
dose
females
(
MRID
45313805)

Developmental
toxicity
Study
1(
rats):
NOAEL(
maternal
&
developmental)
=
150
mg/
kg/
day,
LOAEL
(
mat
&
dev)
=
600
mg/
kg/
day;
Maternal:
based
on
clinical
signs
&
decr.
b.
wt.
gain.
Developmental:
based
on
incr.
resorptions
&
decr.
fetal
body
weights.
(
MRID
41592005)
Study
2
(
rats):
NOAEL(
maternal
&
developmental)
=
200
mg/
kg/
day,
LOAEL
(
mat
&
dev)
=
400
mg/
kg/
day;
Maternal:
based
on
clinical
signs
&
decr.
b.
wt.
gain.
Developmental:
based
on
decr.
fetal
body
weights
(
MRID
00050929)
Rats:
NOAEL
(
maternal)
=
500
mg/
kg/
day,
LOAEL
(
maternal
)
=
1000
mg/
kg/
day,
based
on
maternal
mortality.
NOAEL
(
developmental)
is
equal
or
greater
than
1000
mg/
kg/
day
(
limit
dose).
LOAEL
(
developmental)
greater
than
1000
mg/
kg/
day
(
MRID
45313807)

Mutagenicity
No
Concern
(
See
Table
3.4)
No
Concern
(
See
Table
3.4)
Page
24
of
118
Table
3.4.
MUTAGENICITY
STUDIES
WITH
ACETOCHLOR
WATER
DEGRADATES
Test
System
MRID
(
year)
Purity
Batch
No.
Result
Acetochlor
ethane
sulfonic
acid
(
ESA)

870.5100
Bacterial
Gene
Mutation
Assay(
plate
or
preincubation)
Salmonella
typhimurium,
Escherichia
coli
44632706
(
1997)
97.6%
R290131
Acceptable/
guideline
100­
5000
µ
g/
plate
­
/+
S9
plate
or
preincubation
Negative
up
to
the
limit
dose
(
5000
µ
g/
plate
­/+
S9)
plate
or
preincubation
870.5300
In
vitro
mammalian
cell
gene
mutation
L5178Y
mouse
lymphoma
cells
45313803
(
2000)
97.6%
R290131
Acceptable/
guideline
250­
3010
µ
g/
mL
(
equiv
to
10mM)
+/­
S9;
two
trials
Negative
up
cytotoxic
levels
(
3010
µ
g/
mL
­/+
S9).

870.5375
Cytogenetics
In
vitro
mammalian
cell
chromosomal
aberration
assay
human
lymphocytes
45313804
(
2000)
97.6%
R290131
Acceptable/
guideline
250­
3010
µ
g/
mL
(
equiv
to
10mM)
+/­
S9;
two
trials
Negative
up
to
the
limit
dose,
3010
µ
g/
mL
(
equiv
to
10mM)
+/­
S9
870.5395
Mammalian
Erythrocyte
Micronucleus
Test
CD­
1
Mice
45313802
(
2000)
97.6%
R290131
Acceptable/
guideline
0,
500,
1000,
2000
mg/
kg
oral
gavage
1X
Negative
up
to
the
limit
dose
(
2000
mg/
kg).

Acetochlor
oxanilic
acid
(
OXA)

870.5100
Bacterial
Gene
Mutation
Assay(
plate
or
preincubation)
Salmonella
typhimurium,
Escherichia
coli
44632705
(
1998)
97%
R290130
Acceptable/
guideline
100­
5000
µ
g/
plate
­
/+
S9
plate
or
preincubation
Negative
up
to
the
limit
dose
(
5000
µ
g/
plate
­/+
S9)
plate
or
preincubation
870.5300
In
vitro
mammalian
cell
gene
mutation
L5178Y
mouse
lymphoma
cells
45313809
(
2000)
93.15%
R290130
Acceptable/
guideline
250­
2650
µ
g/
mL
(
equiv
to
10mM)
+/­
S9;
two
trials
Negative
up
cytotoxic
levels
or
the
limit
dose
(
2650
µ
g/
mL).
Positive:
S
8in
MF
at
2000
&
2650
µ
g/
mL
+
S9
both
trials 
outside
of
historical
control
range.
Predominantly
small
colony
mutants
MUTAGENICITY
STUDIES
WITH
ACETOCHLOR
WATER
DEGRADATES
Test
System
MRID
(
year)
Purity
Batch
No.
Result
Acetochlor
oxanilic
acid
(
OXA)
Table
3.4.
MUTAGENICITY
STUDIES
WITH
ACETOCHLOR
WATER
DEGRADATES
Test
System
MRID
(
year)
Purity
Batch
No.
Result
Page
25
of
118
870.5375
Cytogenetics
In
vitro
mammalian
cell
chromosomal
aberration
assay
human
lymphocytes
45313810
(
2000)
93.15%
R290130
Acceptable/
guideline
250­
2650
µ
g/
mL
(
equiv
to
10mM)
+/­
S9;
two
trials
Negative
up
to
the
limit
dose
(
2650
µ
g/
mL
­/+
S9).

870.5395
Mammalian
Erythrocyte
Micronucleus
Test
CD­
1
Mice
45313808
(
2000)
93.15%
R290130
Acceptable/
guideline
0,
500,
1000,
2000
mg/
kg
oral
gavage
1X
Negative
up
to
a
the
limit
dose
(
2000
mg/
kg).

Compound
57
870.5375
Cytogenetics
In
vitro
mammalian
cell
chromosomal
aberration
assay
human
lymphocytes
43785702
(
1995)
99%
P3
Acceptable/
guideline
500­
2500
µ
g/
mL
(
Donor
1)
200­
2500
µ
g/
mL
(
Donor
2)
+/­
S9
Negative
up
to
cytotoxicity
(
2500
µ
g/
mL­
S9)
or
the
highest
tested
level
w
S9
(
2500
µ
g/
mL)
.

In
vivo/
in
vitro
unscheduled
DNA
synthesis
Alderley
Park
(
Alpk:
APfSD)
rats
43785701
(
1995)
99%
P3
Acceptable/
nonguideline
1250
or
2000
mg/
kg
oral
gavage
1X
Negative
up
to
a
the
limit
dose
(
2000
mg/
kg).

PJ
2
(
mixture
of
compound
57
and
its
3­
OH
isomer,
compound
55)

870.5100
Bacterial
Gene
Mutation
Assay(
plate
or
preincubation)
Salmonella
typhimurium,
Escherichia
coli
42713118
(
1991)
96%
ASW­
1351­
R
Acceptable/
guideline
100­
5000
µ
g/
plate
­
/+
S9
plate
or
preincubation
Negative
up
to
the
limit
dose
(
5000
µ
g/
plate
­/+
S9)
plate
or
preincubation
S
=
Significant
(
p<
0.01)
NS=
Nonsignificant
MF
=
Mutation
frequency
3.6
Summary
of
Residues
for
Tolerance
Expression
and
Risk
Assessment
Summarizing,
MARC
has
determined
that
the
tolerance
expression
for
residues
in/
on
corn
and
rotational
crop
commodities
should
include
only
acetochlor
and
its
metabolites
containing
the
EMA
or
HEMA
moiety,
expressed
in
acetochlor
equivalents
(
M.
Flood,
MARC
Memorandum,
9/
30/
93).
For
purposes
of
the
dietary
risk
assessment,
residues
in/
on
rotational
crops
should
also
include
metabolites
containing
the
HMEA
moiety,
expressed
in
acetochlor
equivalents.
The
HED
MARC
also
determined
that
parent
only
in
drinking
water
should
be
considered
in
the
dietary
risk
assessment
(
A.
Protzel,
MARC
Memorandum,
8/
31/
2004).
Table
3.5
is
a
summary
of
the
HED
MARC
decisions
concerning
the
residues
of
concern
in
plants,
rotational
crops,
and
drinking
water.
Page
26
of
118
3.6.1
Tabular
Summary
for
Residues
for
Tolerance
Expression
and
Risk
Assessment
Table
3.5.
Residues
for
Tolerance
Expression
and
Risk
Assessment.

Matrix
Residues
included
in
Risk
Assessment
Residues
included
in
Tolerance
Expression
Plants
­
field
corn
parent
and
metabolites
containing
the
EMA
or
HEMA
moiety
parent
and
metabolites
containing
the
EMA
or
HEMA
moiety
Rotational
Crops
­
sorghum,
soybean,
and
wheat
parent
and
metabolites
containing
the
EMA,
HEMA,
or
HMEA
moiety
parent
and
metabolites
containing
the
EMA
or
HEMA
moiety
Drinking
Water
parent
only
parent
only
3.6.2
Rationale
for
Inclusion
of
Metabolites.
Based
on
their
structures,
the
MARC
was
unable
to
conclude
that
the
metabolites
in
raw
agricultural
commodities
(
RACS)
containing
the
EMA,
HEMA
or
HMEA
moieties
(
See
Table
3.1)
will
not
be
significantly
less
toxic
than
the
parent
and
therefore
recommended
that
these
residues
be
included
in
the
risk
assessment,
as
summarized
in
Table
3.5.

3.6.3
Rationale
for
Exclusion
of
Degradates
The
HED
MARC
met
on
May
13,
2004
to
consider
whether
the
ESA
and
OXA
degradates
of
acetochlor
should
be
included
in
the
dietary
drinking
water
assessment,
based
on
the
available
toxicity
data
(
TXR
No.
0052813).
Based
on
consideration
of
the
data
(
summarized
in
Tables
3.2­
3.4)
and
structure­
activity
relationships,
the
MARC
concluded
that:
(
1)
the
ESA
and
OXA
degradates
of
acetochlor
should
not
be
included
in
the
water
risk
assessment
with
the
parent.
The
weight­
of­
the­
evidence
determination
was
based
on
the
following
rationales
for
carcinogenic
potential
and
non­
carcinogenic
toxicity:

Carcinogenicity:
In
contrast
to
acetochlor,
both
the
OXA
and
ESA
degradates
show
the
following
characteristics
that
would
make
them
unlikely
to
be
carcinogenic:

(
1)
are
highly
polar
compounds
showing
poor
to
limited
absorption;
the
majority
of
the
administered
dose
is
excreted
without
biotransformation;
(
2)
are
nonmutagenic;
(
3)
lack
reactive
chlorine;
(
4)
lack
the
capacity
to
form
a
quinoneimine
species
leading
to
nasal
tumor
formation;
(
5)
do
not
show
thyroid
and
liver
effects
indicating
potential
to
disrupt
thyroid­
pituitary
homeostasis
Non­
carcinogenicity
toxicity
assessment:
The
toxicity
data
on
the
OXA
and
ESA
degradates
indicated
that
they
are
of
lower
anticipated
toxicity
than
the
parent
acetochlor
based
on
the
following
data:
Page
27
of
118
(
1)
are
highly
polar
compounds
showing
poor
to
limited
absorption,
with
the
majority
excreted
untransformed;
(
2)
subchronic
toxicity
in
the
rat
is
lower
than
acetochlor
(
3)
developmental
toxicity
is
not
observed
in
the
rat.

Given
that
both
the
ESA
and
OXA
degradates
have
been
detected
in
water
samples
(
both
groundwater
and
surface
water)
­
in
many
cases
at
concentrations
higher
than
the
parent
acetochlor
­
worst­
case
non­
carcinogenic
margin­
of­
exposure
(
MOE)
calculations
were
done
for
the
two
water
degradates
to
better
support
the
MARC
conclusion.
The
values
were
found
to
be
not
of
HED
concern.
The
detailed
results
are
presented
in
Appendix
2.

4.0
Hazard
Characterization/
Assessment
4.1
Hazard
and
Dose­
Response
Characterization
4.1.1
Database
Summary
4.1.1.1
Studies
available
and
considered
Acute­
oral
neurotoxicity,
rat;
LD50
(
oral
and
dermal),
rat;
LC50
(
inhalation),
rat;
primary
dermal/
eye
irritation,
rabbit;
dermal
sensitization,
guinea
pig.
Subchronic­
oral
toxicity,
rat
(
2);
oral,
dog
(
2);
21­
day
dermal
toxicity,
rabbit
and
rat;
oral
neurotoxicity,
rat.
Chronic
and/
or
carcinogenicity­
oral
toxicity,
rat
(
3
combined
chronic
toxicity/
carcinogenicity);
oral
toxicity,
dog
(
2);
oral
carcinogenicity,
mouse
(
2).
Reproductive/
developmental­
oral
developmental
toxicity,
rat
(
2),
oral
developmental
toxicity,
rabbit
(
2);
oral
multigeneration
reproductive
toxicity,
rat
(
3).
Other­
general
metabolism,
rat
(
2);
genotoxicity
screening
studies,
all
categories;
dermal
penetration,
rat;
special
nonguideline
mechanistic
studies
provided
on
the
mechanism
of
nasal,
thyroid
and
liver
tumor
formation
in
the
rat;
pathology
working
group
(
PWG)
reevaluations
of
tumors.

4.1.2
Mode
of
Action,
Metabolism,
Toxicokinetic
Data
Acetochlor
is
a
chloroacetanilide
herbicide
related
to
alachlor,
butachlor,
propachlor
and
metolachlor.
These
structurally
similar
compounds
show
an
overlapping,
but
not
identical,
tumor
profile.
On
March
19,
1997,
this
group
of
compounds
was
presented
as
a
case
study
for
evaluation
of
a
common
mechanism
of
action
to
the
OPP
Science
Advisory
Panel
(
SAP)
as
part
of
the
presentation
on
methodology
for
evaluation
of
cumulative
toxicity
(
EPA,
1997,
2001).
The
Panel
determined
that
there
was
sufficient
evidence
to
support
a
common
mode
of
action
of
acetochlor,
alachlor
and
butachlor
for
nasal
olfactory
epitheilial
and
thyroid
follicular
cell
tumorigenesis.
The
SAP
also
recommended
that
only
the
nasal
tumors
and
not
thyroid
tumors
Page
28
of
118
should
be
included
in
the
cumulative
assessment.
Numerous
mechanistic
studies
on
acetochlor
have
been
submitted
in
support
of
the
proposed
mechanisms.
The
HED
MTARC/
CARC
reviewed
the
mechanistic
data
on
these
two
tumors
for
acetochlor
on
April
21­
22,
2004
and
concurred
that
it
supported
a
non­
genotoxic
mode
of
action
for
formation
of
the
nasal
olfactory
epithelial
and
thyroid
follicular
cell
tumors
(
HED
TXR#
0052727).

In
the
rat,
acetochlor
is
highly
metabolized
and
rapidly
excreted,
primarily
in
the
urine.
Increased
levels
of
radioactivity
are
excreted
in
the
feces
with
increased
dose.
Radioactivity
is
not
retained
in
tissues
to
a
significant
extent,
but
does
show
binding
to
red
blood
cells
and
to
nasal
olfactory
epithelium
and
is
found
in
at
higher
levels
in
highly
perfused
organs.
The
major
urinary
metabolite
of
acetochlor
is
a
mercapturic
acid
conjugate
of
N­
deethylated
acetochlor.
Biliary
excretion
is
also
significant
and
the
major
biliary
metabolite
is
a
glucuronide
conjugate.

Mode
of
action
for
nasal
olfactory
epithelial
cell
tumorigenesis:
The
formation
of
nasal
tumors
in
the
rat
is
considered
a
non­
genotoxic
event
that
occurs
secondary
to
binding
of
a
cytotoxic
benzoquinoneimine
metabolite.
This
metabolite
is
formed
in
situ
by
the
metabolizing
enzymes
of
the
nasal
olfactory
epithelial
cells
from
circulating
metabolites
of
acetochlor
that
are
delivered
to
the
nasal
olfactory
epithelial
cells.
The
benzoquinoneimine
metabolite,
a
highly
reactive
compound
that
binds
to
cellular
proteins,
may
also
cause
oxidative
stress
and
cell
death,
consistent
with
findings
of
lipofucsin
pigment
accumulation
in
the
nasal
olfactory
epithelial
cells.
Cytotoxicity
to
the
nasal
olfactory
epithelial
cells
results
in
replacement
of
the
cells
by
respiratory
metaplasia
of
undifferentiated
cells;
stimulation
of
cellular
proliferation
eventually
leads
to
tumor
formation.
Mechanistic
studies
submitted
to
characterize
nasal
tumorigenesis
in
the
rat
indicate
that
the
reactive
agent
(
the
benzoquinoneimine)
has
higher
rates
of
formation
in
the
nasal
tissue
of
rats
than
in
mice,
primates
or
humans.
Although
rats
are
considered
to
be
much
more
sensitive
to
formation
of
these
nasal
tumors,
the
potential
for
acetochlor
to
cause
nasal
tumors
in
humans
cannot
be
ruled
out
at
this
time,
based
on
apparent
potential
for
the
human
liver
to
produce
the
EMA
metabolite,
which
could
then
be
delivered
to
other
organs.

Mode
of
action
for
thyroid
follicular
cell
tumorigenesis:
Acetochlor
has
been
shown
to
cause
disruption
of
thyroid­
pituitary
homeostasis
by
increased
activity
of
hepatic
UDPGT,
leading
to
increased
clearance
of
thyroid
hormones
and
compensatory
increases
in
pituitary
release
of
thyroid
stimulating
hormone
(
TSH).
Although
some
of
the
experimental
parameters
that
are
used
to
support
this
mechanism
(
EPA,
1998)
were
not
evaluated
in
the
study
(
e.
g.,
evaluation
of
thyroid
follicular
cell
proliferation),
the
data
were
considered
sufficient
by
the
HED
CARC/
MTARC
when
considered
together
with
the
data
on
the
structural
analog
alachlor,
to
classify
the
thyroid
tumors
under
this
non­
genotoxic
mechanism.
These
tumors
were
not
considered
as
part
of
the
quantitative
assessment
for
the
carcinogenicity
of
acetochlor.

Effects
of
acetochlor
on
liver:
At
high
doses,
acetochlor
causes
acute
toxicity
to
the
liver.
Studies
evaluating
the
acute
effects
of
acetochlor
on
rat
liver
showed
that
hepatic
toxicity
was
associated
with
depletion
of
hepatocellular
glutathione
reserves
at
doses
at
which
a
slight
increase
in
UDS
are
observed.
The
data
provide
some
evidence
that
the
UDS
is
secondary
to
depleted
glutathione,
Page
29
of
118
rather
than
direct
genotoxicity.
Hepatocellular
proliferation
was
also
evaluated
in
mice
administered
acetochlor
in
the
diet
for
90
days.
At
higher
doses,
BrdU
incorporation
was
shown
to
increase
during
this
time,
providing
some
evidence
that
a
non­
genotoxic,
proliferative
mechanism
may
be
involved
in
formation
of
hepatocellular
tumors.
Significantly
increased
hepatocellular
tumors
were
only
observed
at
excessively
toxic
doses
in
both
the
mouse
and
the
rat.

Modes
of
action
for
other
types
of
toxicity
observed
with
acetochlor
have
not
been
characterized.

4.1.3
Sufficiency
of
Studies/
Data
The
toxicological
database
for
acetochlor
is
incomplete
at
this
time.
The
following
studies
are
required:
(
1)
A
developmental
neurotoxicity
(
DNT)
study
in
the
rat,
due
to
observations
in
several
oral
studies
indicating
effects
on
the
nervous
system
and
uncertainties
regarding
the
sensitivity
of
fetal
and
neonatal
animals
to
neurotoxic
effects.
The
effects
observed
in
the
available
studies
included
clinical
observations
indicating
neurotoxicity
in
several
studies
in
the
rat
and
the
dog,
and
in
the
dog,
frank
microscopic
pathology
of
the
brain
in
a
chronic
oral
study.
A
small
but
statistically
significant
decrease
in
brain
acetylcholinesterase
of
males
was
also
observed
in
one
subchronic
oral
study
in
the
rat
at
the
highest
dose
tested.
An
alternative
test
to
the
rat
DNT
which
addresses
the
sensitivity
observed
in
the
dog
may
also
be
considered.
(
2)
In
addition,
submission
of
the
positive
control
(
validation)
studies
for
the
rat
acute
and
subchronic
neurobehavioral
screening
studies
(
MRIDs
45357501,
45357502),
as
cited
in
the
neurobehavioral
study
reports,
are
requested
as
confirmatory
data
to
upgrade
the
studies
to
Acceptable/
guideline.

The
requirement
of
a
28­
day
inhalation
toxicity
study
is
deferred
until
the
next
assessment
of
acetochlor
where
occupational
exposures
are
evaluated.

Although
the
above
information
is
required
for
acetochlor,
the
database
is
nonetheless
considered
sufficient
to
provide
endpoints
and
a
dose­
response
evaluation
for
risk
assessment,
based
on
the
available
studies
in
the
rat,
rabbit,
dog
and
mouse.

4.1.4.
Toxicological
Effects
The
database
for
acute
toxicity
for
acetochlor
is
complete
and
is
summarized
below
in
Table
4.1a.
Acetochlor
is
classified
as
Toxicity
Category
III
for
acute
exposure
via
the
oral,
dermal
and
inhalation
routes
and
in
ocular
irritation
studies.
Although
one
primary
dermal
irritation
study
reported
low
levels
of
dermal
irritation,
severe
irritation
was
observed
in
a
second
study,
including
microscopic
changes
(
hair
follicle
hyperplasia,
and
in
some
animals,
acanthosis
and
inflammatory
cell
infiltration).
Acetochlor
has
been
shown
to
be
a
potent
dermal
sensitizer
in
two
studies.

The
subchronic,
chronic
and
other
guideline
studies
submitted
to
support
acetochlor
registration
are
summarized
below
in
Table
4.1b.
Page
30
of
118
Table
4.1a
Acute
Toxicity
Profile
­
Test
Substance
Guideline
No.
Study
Type
MRID(
s)
Results
Toxicity
Category
870.1100
Acute
oral,
rat
(
1)
41565104
(
1986)
Acceptable/
guideline
(
2)
00118944
(
1982)
Acceptable/
guideline
(
1)
LD50
=
4238
mg/
kg
(
males);
4025
mg/
kg
(
females);
4124
mg/
kg
(
combined)
(
2)
LD50
=
2389
mg/
kg
(
males;
1929
mg/
kg
(
females);
2148
mg/
kg
(
combined)
III
(
both
studies)

870.1200
Acute
dermal,
rabbit
(
1)
41565105
(
1986)
Acceptable/
guideline
(
2)
00118945
(
1982)
Unacceptable/
guidelin
e
(
upgradable
with
submission
of
dosing
procedure
(
surface
area
treated)
(
1)
LD50
>
2000
mg/
kg
(
combined
males
and
females)

(
2)
LD50
=
4166
(
combined
males
and
females).
Estimated
between
3536­
5000
mg/
kg
for
males
and
females.
III
(
both
studies)

870.1300
Acute
inhalation,
rat
(
1)
41565106
(
1989)
Acceptable/
guideline
(
2)
40994401(
1988)
Acceptable/
guideline
LC50
>
4.46
mg/
L
(
males)
LC50
=
3.99
mg/
L
(
females)
(
2)
LC50
>
3.0
mg/
L
(
both
males
and
females)
III
(
both
studies)

870.2400
Acute
eye
irritation,
rabbit
(
1)
41592003
(
1989)
Acceptable/
guideline
(
2)
00118947
(
1982)
Acceptable/
guideline
slightly
irritating
(
both
studies)
III
(
both
studies)

870.2500
Acute
dermal
irritation,
rabbit
(
1)
41565107
(
1989)
Acceptable/
guideline
(
2)
00118946
(
1982)
Acceptable/
guideline
(
1)
severe
(
including
microscopic
changes)
(
2)
mild
irritation
at
72
hrs
(
1)
II
(
2)
IV
870.2600
Skin
sensitization,
guinea
pig
(
1)
00131396
(
1983)
Acceptable/
guideline
(
2)
41565108
(
1989)
Acceptable/
guideline
Both
studies­
very
strong
dermal
sensitizer
N/
A
The
major
target
organs
of
acetochlor
appear
to
be
the
liver,
thyroid
(
secondary
to
liver),
nervous
system,
kidney,
testes,
erythrocyte
and
in
the
rat,
nasal
olfactory
epithelium.
Liver
enlargement
was
sometimes
observed
to
be
accompanied
by
increased
plasma
levels
of
GGT
or
other
liver
enzymes
and
microscopic
alterations.
Acute
liver
toxicity
studies
in
the
rat
demonstrated
depletion
of
Page
31
of
118
hepatocellular
glutathione
(
GSH)
reserves
and
cytotoxicity
at
higher
dose
levels.
Increases
in
thyroid
weight
and
thyroid
follicular
cell
tumors
in
chronic/
carcinogenicity
studies
in
the
rat
are
considered
secondary
to
induction
of
hepatic
UDPGT
and
subsequent
perturbations
to
thyroid
hormone
levels,
although
acetochlor
is
not
a
potent
inducer
of
this
enzyme.
Testicular
atrophy
was
observed
in
dogs
with
chronic
exposure.
Interstitial
nephritis
was
observed
in
some
studies.
The
proposed
mechanisms
for
nasal
epithelial
hyperplasia
and
subsequent
tumor
formation
are
discussed
above
in
Section
4.1.1.2.
Decreased
body
weight/
weight
gain
were
observed
in
most
studies
but
not
always
at
the
LOAEL.

Evidence
of
neurotoxicity
has
been
observed
in
several
studies.
In
general,
dogs
appear
to
be
somewhat
more
sensitive
than
rats
to
effects
on
the
nervous
system.
Clinical
signs
such
as
excessive
salivation
or
perianal
staining
were
observed
in
dog
subchronic
and
chronic
studies
and
in
the
rat
developmental
toxicity
studies.
Females
in
the
acute
rat
neurotoxicity
study
showed
decreased
motor
activity;
at
higher
dose
levels
but
clinical
signs
were
observed
in
both
sexes.
In
the
rat
subchronic
neurotoxicity
study,
a
transient
decrease
in
hindlimb
grip
strength
in
males
was
observed
at
week
2
but
not
at
later
times.
In
one
chronic
dog
study,
frank
neuropathology
(
degeneration
of
neurons
in
the
cerebellum)
accompanied
by
clinical
effects
such
as
ataxia,
abnormal
head
movements
and
other
findings,
were
observed.
A
small
number
of
females
in
one
rat
chronic
toxicity/
carcinogenicity
study
had
peripheral
neuropathy,
but
this
was
also
at
an
excessively
toxic
dose.
A
slight
but
statistically
significant
decrease
in
brain
acetylcholinesterase
was
observed
at
the
high
dose
in
a
subchronic
rat
study
and
small
but
statistically
significant
effects
on
brain
weights
have
been
observed
in
some
studies,
although
the
direction
of
the
weight
change
(
increase
or
decrease)
was
not
consistent
and
in
some
instances
was
associated
primarily
with
body
weight
changes.

Measurement
of
tissue
distribution
of
radioactivity
in
rat
metabolism
studies
shows
that
significant
amounts
are
found
in
whole
blood
bound
to
erythrocytes.
This
finding
may
explain
the
slight
anemia
observed
in
some
subchronic
and
chronic
dietary
studies
at
higher
dose
levels.
It
is
not
known
whether
the
toxicity
to
the
erythrocyte
is
related
to
glutathione
depletion,
as
observed
in
hepatocytes,
or
is
due
to
some
other
mode
of
toxicity.

There
is
no
evidence
that
acetochlor
is
teratogenic
or
that
offspring
are
more
susceptible
than
adults,
but
acetochlor
does
cause
developmental
toxicity
at
maternally
toxic
doses.
In
both
of
the
rat
developmental
toxicity
studies,
decreased
fetal
weights
are
observed.
Offspring
in
rat
multigeneration
reproductive
studies
show
reduced
pup
weight
on
lactation
day
21
at
doses
causing
maternal
toxicity.
One
rat
developmental
study
also
showed
increased
early
resorptions
and
postimplantation
loss;
the
second
study
tested
at
lower
doses.
One
rat
reproductive
toxicity
study
also
showed
slightly
reduced
live
litter
size
and
another
showed
decreased
implantations.
A
low
incidence
of
nasal
epithelial
hyperplasia
was
also
observed
in
the
adult
F1
offspring.
The
rabbit
is
less
sensitive
than
the
rat
and
no
developmental
effects
have
been
seen
at
maternally
toxic
levels.

Mutagenicity
studies
on
acetochlor
do
not
indicate
that
it
has
significant
genotoxic
potential
in
vivo.
Bacterial
gene
mutation
studies
are
negative
or
show
equivocal
increases,
but
the
positive
responses
were
only
observed
in
the
presence
of
significant
cytotoxicity.
A
weak
increase
in
sister
chromatic
Page
32
of
118
exchange
(
SCE)
induction
has
been
reported
but
SCE
is
not
known
to
be
linked
to
cancer
risk
at
this
time.
Although
acetochlor
is
clastogenic
in
in
vitro
clastogenicity
assays,
in
vivo
clastogenicity
assays
(
rat
or
mouse
bone
marrow
assays,
dominant
lethal
studies)
are
negative.
An
unscheduled
DNA
synthesis
study
in
rat
hepatocytes
also
showed
a
weak
positive
response,
but
this
appeared
to
be
related
to
liver
cytotoxicity
(
depletion
of
glutathione).
A
comet
assay
specifically
evaluating
nasal
olfactory
and
respiratory
tissues
of
rats
exposed
to
acetochlor
at
doses
causing
nasal
tumors
was
negative.

As
discussed
above
(
Section
4.1.1.2),
acetochlor
causes
an
increased
incidence
of
nasal
cell
tumors
in
the
olfactory
region
of
the
nasal
cavity
and
thyroid
follicular
cell
tumors
in
the
rat.
These
tumors
are
considered
to
show
a
threshold
for
induction
dependent
on
their
tumorigenic
mode
of
action.
A
dose­
related
increase
in
the
incidence
of
lung
tumors
in
male
and
female
mice
and
histiocytic
sarcomas
in
female
mice
was
also
observed.
Although
the
genotoxicity
data
do
not
indicate
a
strong
potential
for
acetochlor
to
act
as
a
genotoxic
carcinogen,
there
are
no
mechanistic
data
available
at
this
time
to
characterize
the
mechanism
of
formation
of
these
two
tumor
types.
A
statistically
significant
increase
in
hepatocellular
tumors
in
mice
and
rats
was
also
reported,
but
only
at
a
dose
level
that
resulted
in
excessive
toxicity
in
both
species.

Table
4.1b
Subchronic,
Chronic
and
Other
Toxicity
Profile
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
870.3100
90­
Day
oral
toxicity
(
rat)
00050933
(
1980)
Acceptable/
guideline
0,
800,
2000,
6000
ppm
(
diet)
0,
40,
100,
300
mg/
kg/
day
NOAEL
=
40
mg/
kg/
day
LOAEL
=
100
mg/
kg/
day
based
on
decreased
mean
body
weight/
weight
gain
in
males
and
females.

870.3100
90­
Day
oral
toxicity
(
rat)
41565115
(
1986)
Acceptable/
guideline
0,
20,
200,
2000
ppm
(
diet)
males
0,
1.6,
16.1,
161.1
mg/
kg/
day;
females
0,
1.9,
18.7,
191.9
mg/
kg/
day
NOAEL
=
16.1
mg/
kg/
day
males
(
18.7
mg/
kg/
day
females)
LOAEL
=
161.1
mg/
kg/
day
males
(
18.7
mg/
kg/
day
females)
based
on
decreased
body
weight/
weight
gain
in
males
and
females.

870.3150
119­
Day
oral
toxicity
(
dog)
00050928
(
1980)
Acceptable/
guideline
0,
25,
75,
200
(
capsule)
NOAEL
=
25
mg/
kg/
day
LOAEL
=
75
mg/
kg/
day
based
on
death
of
1
male
(
diarrhea,
emaciation
also
in
this
animal)
and
in
both
sexes,
decr.
body
weights
and
decr.
food
consumption,
liver
effects.
(
It
is
noted
that
in
this
study,
mid
and
high
dose
animals
were
acclimated
by
increasing
dose
weekly:
mid
dose
started
at
25
mg/
kg/
day
week
1,
50
mg/
kg/
day
week
2,
then
75
mg/
kg/
day.
High
dose
started
at
50
mg/
kg/
day,
incr.
weekly
by
50
mg/
kg/
day
then
200
mg/
kg/
day)
Table
4.1b
Subchronic,
Chronic
and
Other
Toxicity
Profile
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
Page
33
of
118
870.3150
90­
Day
oral
toxicity
(
dog)
41565116
(
1986)
Acceptable/
guideline
0,
2,
10,
60
mg/
kg/
day
(
capsule)
NOAEL
=
10
mg/
kg/
day
LOAEL
=
60
mg/
kg/
day
based
on
mucous
diarrhea,
decr.
body
wt,
slight
anemia,
incr.
alanine
aminotransferase,
incr.
relative
liver
weight,
decr.
blood
glucose.

870.3200
21­
Day
dermal
toxicity
(
rabbit)
00116637
(
1981)
Acceptable/
guideline
0,
100,
400,
1200
mg/
kg/
day
(
applied
5
days/
week
for
3
weeks)
systemic
NOAEL
=
400
mg/
kg/
day
systemic
LOAEL
=
1200
mg/
kg/
day
based
on
high
mortality
and
agonal
clinical
signs
of
toxicity.
Local
dermal
irritation
was
observed
at
all
dose
levels.

870.3200
21­
Day
dermal
toxicity
(
rat)
41565117
(
1989)
Acceptable/
guideline
0,
0.1
1.0,
10,
100
mg/
kg/
day
(
applied
5
days/
week
for
3
weeks)
systemic
NOAEL
=
100
mg/
kg/
day
(
HDT)
systemic
LOAEL
=
>
100
mg/
kg/
day
(
not
tested
at
higher
dose
levels
due
to
reported
excessive
dermal
irritation
in
preliminary
testing).
Local
dermal
irritation
reported
in
this
study
in
all
groups
including
controls
but
epithelial
hyperplasia
was
observed
at
100
mg/
kg/
day.

870.3465
90­
Day
inhalation
toxicity
none
submitted
(
not
required)
N/
A
870.3700a
Prenatal
developmental
in
rats
00050929
(
1980)
Acceptable/
guideline
0,
50,
200,
400
mg/
kg/
day
(
gavage)
Maternal
NOAEL
=
200
mg/
kg/
day
LOAEL
=
400
mg/
kg/
day
based
on
clinical
signs
of
toxicity
and
decreased
maternal
body
weight/
weight
gain.
Developmental
NOAEL
=
200
mg/
kg/
day
LOAEL
=
400
mg/
kg/
day
based
on
slightly
decreased
mean
fetal
weight.

870.3700b
Prenatal
developmental
in
rats
41592005
(
1989),
42054903
Acceptable/
guideline
0,
40,
150,
600
mg/
kg/
day
(
gavage)
Maternal
NOAEL
=
150
mg/
kg/
day
LOAEL
=
600
mg/
kg/
day
based
on
mortality,
clinical
signs
of
toxicity
and
decreased
maternal
body
weight
gain.
Developmental
NOAEL
=
150
mg/
kg/
day
LOAEL
=
600
mg/
kg/
day
based
on
increased
early
resorptions,
postimplantation
loss
and
decreased
fetal
weight.

870.3700b
Prenatal
developmental
in
rabbits
40134101(
1986)
Acceptable/
guideline
0,
30,
100,
300
mg/
kg/
day
(
gavage)
Maternal
NOAEL
=
300
mg/
kg/
day
LOAEL
>
300
mg/
kg/
day
(
HDT;
study
acceptable
based
on
results
of
a
range­
finding
study).
Developmental
NOAEL
=
300
mg/
kg/
day
LOAEL
>
300
mg/
kg/
day
.

870.3700b
Prenatal
developmental
in
rabbits
41592006
(
1989)
Acceptable/
guideline
0,
15,
50,
190
mg/
kg/
day
(
gavage)
Maternal
NOAEL
=
50
mg/
kg/
day
LOAEL
=
190
mg/
kg/
day
based
on
body
weight
loss.
Developmental
NOAEL
=
190
mg/
kg/
day
LOAEL
>
190
mg/
kg/
day
(
HDT).
Table
4.1b
Subchronic,
Chronic
and
Other
Toxicity
Profile
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
Page
34
of
118
870.3800
Reproduction
and
fertility
effects
rats
00131391(
1982)
Acceptable/
guideline
0,
500,
1500,
5000
ppm
(
diet)
F0
premating
0,
30.8,
60.4
or
316
mg/
kg/
day,
males;
0,
46.2,
130.4
or
442
mg/
kg/
day,
females;
F1
premating
0,
29.9,
87.8
or
333
mg/
kg/
day,
males;
0,
43.6,
129.8
or
441
mg/
kg/
day,
females.
Parental/
Systemic
NOAEL
=
30.8/
46.2
mg/
kg/
day
males/
females
LOAEL
=
60.4/
130.4
mg/
kg/
day
males/
females,
based
on
decreased
maternal
gestation
body
weight
gain
and
slightly
reduced
male
and
female
premating
body
weight
gain.
Offspring
NOAEL
=
30.8/
46.2
mg/
kg/
day
males/
females
LOAEL
=
60.4/
130.4
mg/
kg/
day
males/
females,
based
on
slightly
decreased
mean
pup
weights
in
F2b
pups
at
lactation
day
21.
Reproductive
NOAEL
=
316/
442
mg/
kg/
day
males/
females.
LOAEL
=
mg/
kg/
day
(
HDT).

870.3800
Reproduction
and
fertility
effects
rats
41565120
(
1989)
Acceptable/
guideline
0,
18,
175,
1750
ppm
(
diet)
Premating
F0
males
0,
1.27,
12.6
or
123.8
mg/
kg/
day;
F0
females
0,
1.63,
15.5
or
157.4
mg/
kg/
day
Premating
F1
males
0,
1.53,
15.2
or
152.1
mg/
kg/
day;
F1
females
0,
1.83,
18.3
or
192.4
mg/
kg/
day
Parental/
Systemic
NOAEL
=
12.6
mg/
kg/
day
males/
15.2
mg/
kg/
day
females
LOAEL
=
123.8
mg/
kg/
day
males/
157.4
mg/
kg/
day
females,
based
on
decreased
body
weight
gain
during
premating.
Offspring
NOAEL
=
12.6
mg/
kg/
day
males/
15.2
mg/
kg/
day
females.
LOAEL
=
123.8/
157.4
mg/
kg/
day
males/
females,
based
on
reduced
pup
weight
during
lactation.
Reproductive
NOAEL
=
123.8/
157.4
mg/
kg/
day
(
HDT).
LOAEL
>
123.8/
157.4
mg/
kg/
day
males/
females.

870.3800
Reproduction
and
fertility
effects
rats
45357503
(
2001)
Acceptable/
guideline
0,
200,
600,
1750
ppm
(
diet)
Premating
F1
males
0,
21.2,
65.6,
196.4
mg/
kg/
day;
Premating
F1
females
0,
22.4,
70.9,
215.9
mg/
kg/
day
Parental/
Systemic
NOAEL
=
males
21.2
mg/
kg/
day;
females
22.4
mg/
kg/
day
LOAEL
=
males
65.6
mg/
kg/
day;
females
70.9
mg/
kg/
day,
based
on
focal
hyperplasia
and
polypoid
adenomata
in
nasal
epithelium
of
adult
F1
offspring
at
study
termination.
Offspring
NOAEL
=
males
65.6
mg/
kg/
day;
females
70.9
mg/
kg/
day
LOAEL
=
males
196.4
mg/
kg/
day;
females
215.9
mg/
kg/
day
based
on
decreased
pup
weights
during
lactation
(
F1
and
F2),
decreased
F2
litter
size
at
birth,
focal
hyperplasia
and
polypoid
adenomata
in
nasal
epithelium
of
adult
F1
offspring
at
study
termination.
Reproductive
NOAEL
=
males
65.6
mg/
kg/
day;
females
70.9
mg/
kg/
day
LOAEL
=
males
196.4
mg/
kg/
day;
females
215.9
mg/
kg/
day
based
on
decreased
implantations.
Table
4.1b
Subchronic,
Chronic
and
Other
Toxicity
Profile
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
Page
35
of
118
870.4100a
Chronic
toxicity
(
rat)
See
870.4200,
below
870.4100b
Chronic
toxicity
(
dog)
00116631,
00164944
(
1981)
Acceptable/
guideline
0,
4,
12,
40
mg/
kg/
day
(
capsule)
NOAEL
=
12
mg/
kg/
day
LOAEL
=
40
mg/
kg/
day
based
on
decr.
body
wt.
(
females)
and
decr.
wt.
gain
(
males),
incr.
adrenal
wt.
(
females),
incr.
liver
weight
(
males
and
females),
decr.
testes
wt.,
testicular
atrophy.

870.4100b
Chronic
toxicity
(
dog)
41565118
(
1988),
Acceptable/
guideline
0,
2,
10,
50
mg/
kg/
day
(
capsule)

46100901
(
2003)
Unacceptable/
nonguidelin
e
(
reexamination
of
testicular
/
epididymal
tissue)
NOAEL
=
2
mg/
kg/
day
LOAEL
=
10
mg/
kg/
day
based
on
incr.
salivation,
incr.
ornithine
carbamyltransferase
and
triglycerides,
decr.
blood
glucose;
incr.
incidence
of
interstitial
nephritis,
testicular
degeneration/
hypospermia
and
liver
glycogen
depletion.
[
Neurotoxic
effects
seen
at
50
mg/
kg/
d
­
salivation,
ataxia,
histopathological
changes
in
the
brain]

Reexamination
of
testicular/
epididymal
tissue
(
MRID
46100901)
was
not
performed
according
to
Agency
pathology
working
group/
peer
review
policy
and
the
findings
do
not
change
the
original
dog
study
(
MRID
41565118)
conclusions.

870.4200
Carcinogenicity
(
rat)
00131088,
40484801
(
1983)
0,
500,
1500
or
5000
ppm
in
diet
males:
0,
22,
69
or
250
mg/
kg/
day,
115
weeks
females:
0,
30,
93
or
343
mg/
kg/
day
for
103
weeks
(
females;
discontinued
earlier
due
to
high
mortality).
NOAEL
<
22
mg/
kg/
day
LOAEL
=
22
mg/
kg/
day
based
on
decreased
body
weight/
weight
gain
(
males)
and
increased
abs/
rel
thyroid
weight
in
females.
HDT
(
250
males,
343
females)
considered
excessive
based
on
high
mortality
and
markedly
reduced
body
weight/
weight
gain,
both
sexes.
evidence
of
carcinogenicity)­
at
69/
93
mg/
kg/
day
and
higher­
increased
incidence
of
nasal
epithelial
adenomas
(
males).
At
250/
343
mg/
kg/
day
(
excessively
toxic
dose
based
on
high
mortality
and
markedly
decreased
body
weight/
weight
gain
(
both
sexes)­
increased
incidence
of
nasal
epithelial
carcinomas
and
thyroid
follicular
cell
adenomas
(
males)
and
hepatocellular
tumors
(
both
sexes).
Table
4.1b
Subchronic,
Chronic
and
Other
Toxicity
Profile
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
Page
36
of
118
870.4200
Carcinogenicity
(
rat)
40077601
(
1986)
Acceptable/
guideline
0,
40,
200
or
1000
ppm
in
diet
0,
2,
10
or
50
mg/
kg/
day
in
diet
(
estimated
for
both
sexes
using
standard
conversion
factor
of
0.05)
NOAEL
=
10
mg/
kg/
day
LOAEL
=
50
mg/
kg/
day
based
on
decreased
body
weight/
weight
gain
(
both
sexes,
slight
in
females),
increased
bilirubin
in
females
and
in
males,
increased
GGT,
cholesterol,
thyroid
c­
cell
hyperplasia,
papillary
hyperplasia
of
the
nasal
epithelium,
hepatocellular
alterations
and
necrosis.
evidence
of
carcinogenicity­
at
50
mg/
kg/
day,
increased
incidence
of
nasal
epithelial
papillary
adenoma
in
males
and
females
and
thyroid
follicular
cell
adenoma/
cystadenoma
in
females.
PWG
reevaluation
of
liver
did
not
show
increase
with
treatment.

870.4200
Carcinogenicity
(
rat)
41592004
(
1988)
Acceptable/
guideline
0,
18,
175
or
1750
ppm
in
diet
males
0,
0.67,
6.37
or
66.9
mg/
kg/
day;
females
0,
0.88,
8.53
or
92.1
mg/
kg/
day
NOAEL
=
6.37
mg/
kg/
day
LOAEL
=
66.9
mg/
kg/
day
based
on
decreased
body
weight/
weight
gain,
increased
GGT
and
cholesterol
(
both
sexes;
marginal
in
females),
nasal
epithelial
hyperplasia,
degeneration
of
retinal
outer
layer,
renal
pelvic
epithelial
hyperplasia,
stromal
fatty
infiltration
of
the
pancreas.
evidence
of
carcinogenicity­
increased
incidence
of
nasal
epithelial
adenoma/
carcinoma
and
thyroid
follicular
cell
adenomas
in
males
and
females.
Benign
chondroma
of
femur
and
basal
cell
tumor
of
the
stomach
were
reevaluated
and
reclassified
by
the
PWG
and
are
not
considered
treatment­
related
tumors.

870.4300
Carcinogenicity
(
mouse)
00131089
(
1983)
Acceptable/
guideline
0,
500,
1500
or
5000
ppm
in
diet
0,
75,
225,
750
mg/
kg/
day
(
estimated
for
both
sexes
using
standard
conversion
factor
of
0.15)
NOAEL
=
75
mg/
kg/
day
LOAEL
=
225
mg/
kg/
day
based
on
reduced
survival
(
females),
slightly
decreased
body
weight
during
part
of
study
(
males),
anemia
(
females),
increased
abs/
re/
thyroid
weight
(
females)
and
renal
interstitial
nephritis
(
males).
evidence
of
carcinogenicity­
incidence
of
lung
tumors
showed
a
dose­
related
increase.
A
PWG
reevaluation
of
liver
showed
increases
only
at
the
HDT
(
excessive
dose);
ovarian
and
kidney
tumors
were
not
considered
treatment­
related.

870.4300
Carcinogenicity
(
mouse)
41565119
(
1989)
Acceptable/
guideline
0,
10,
100
or
1000
ppm
in
diet
Males
0,
1.1,
11,
116
mg/
kg/
day;
females
0,
1.4,
13,
135
mg/
kg/
day
NOAEL
=
1.1
mg/
kg/
day
males;
135
mg/
kg/
day
females
LOAEL
=
11
mg/
kg/
day
in
males,
based
on
increased
incidence
of
brochiolar
hyperplasia
and
possibly
renal
tubular
hyperplasia;
>
135
mg/
kg/
day
in
females.
evidence
of
carcinogenicity­
increased
incidence
of
lung
adenomas
(
females)
and
adenoma/
carcinoma
(
males)
at
116/
135
mg/
kg/
day.
Table
4.1b
Subchronic,
Chronic
and
Other
Toxicity
Profile
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
Page
37
of
118
Gene
Mutation
870.5100
Bacterial
reverse
mutation
Salmonella
typhimurium
00050930
(
1978)
Acceptable/
guideline
0.001­
1
µ
l/
plate
­
/+
S9
Negative
up
to
the
highest
dose
tested
(
1
µ
l/
plate
­
/+
S9);
higher
concentrations
($
10
µ
l/
plate
­
/+
S9)
were
cytotoxic
Gene
Mutation
870.5100
Bacterial
reverse
mutation
Salmonella
typhimurium
41565121
(
1989)
Acceptable/
guideline
1.6­
5000
µ
g/
plate
­
/+
S9
Equivocal
positive
in
TA
1538
at
2500
and
1000
µ
g/
plate
+
S9;
reproducible
at
1000
µ
g/
plate
but
<
2­
fold,
not
doserelated
and
not
seen
in
TA98
Gene
Mutation
870.5100
Bacterial
reverse
mutation
Salmonella
typhimurium
(
strain
T1538
only)
44863202
(
1989)
Acceptable/
nonguideline
100­
5000
µ
g/
plate
­
/+
S9
(
Arochlor
1254
or
Phenobarbital
/$­
naphthoflavone
induced
rat
livers)
Negative
in
TA1538
using
3
different
batches
of
acetochlor
(
89.8­
99.6%)
in
two
separate
tests
Gene
Mutation
870.5300
Mammalian
cell
gene
mutation
Chinese
hamster
ovary
(
CHO)
cells
00131395
(
1983)
Acceptable/
guideline
25­
150
µ
g/
mL
­
S9
25­
125
µ
g/
mL
+
10%
S9
Positive
$
2­
fold
in
mutation
frequency
(
MF)
at
125
or
150
µ
g/
mL
­
S9
&
125
µ
g/
mL
+
S9
accompanied
by
cytotoxicity
(
61%
or
93%
decrease
in
cell
survival
­/+
S9)

Gene
Mutation
870.5300
Mammalian
cell
gene
mutation
CHO
cells
42713106
(
1989)
Acceptable/
guideline
50­
200
µ
g/
mL
­
S9
50­
300
µ
g/
mL
+
1,
2,
5
or
10%
S9
Negative
up
to
cytotoxic
levels
($
200
µ
g/
mL
­/+
10%
S9)

Cytogenetics
870.5300
Mammalian
cell
gene
mutation
Mouse
lymphoma
L5178Y
cells
00131394
(
1982)
Acceptable/
guideline
20­
400
µ
L/
mL
­
S9
5­
250
µ
L/
mL
+
S9
Positive
30­
50
µ
L/
mL
+
S9
2.2­
5.2
fold
increase
accompanied
by
cytotoxicity
(<
10%
survival
at
$
50
µ
L/
mL
+
S9)
Table
4.1b
Subchronic,
Chronic
and
Other
Toxicity
Profile
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
Page
38
of
118
870.5375
Cytogenetics
In
vitro
mammalian
cell
chromosomal
aberration
assay
human
lymphocytes
(
whole
blood
vs
separated
blood)
44863204
(
1998)
Acceptable/
guideline
(
1)
0,
10,
75
150
µ
g/
mL
­
/+
S9
(
2)
0,
100
µ
g/
mL
­
S9
(
whole
blood)
0,
75
µ
g/
mL
­
S9
(
separated
blood)
(
1)
Whole
Blood:
Positive
at
75
and
150
µ
g/
mL
­
S9
and
150
µ
g/
mL
+
S9
accompanied
by
slight
reduction
in
mitotic
indices
at
150
µ
g/
mL
(
31%
­
S9;
13
%
+
S9decrease).
Types
of
aberrations:
breaks,
fragments
and
minutes.

(
2)
Whole
Blood:
Positive
9­
fold
increase
in
aberrations
at
100
µ
g/
mL
Separated
Blood:
Positive
26­
fold
increase
in
aberrations
at
75
µ
g/
mL
870.5375
Cytogenetics
In
vitro
mammalian
cell
chromosomal
aberration
assay
human
lymphocytes
41565122
(
1989)
Acceptabe/
guideline
0,
10,
50,
100
µ
g/
mL
+/­
S9
Positive
at
50
and
100
µ
g/
mL
+
S9
accompanied
by
marked
reduction
in
mitotic
indices
at
100
µ
g/
mL
($
59%
decrease).
Types
of
aberrations:
breaks,
fragment
and
minutes.

870.5385
Mammalian
Bone
Marrow
Chromosomal
Aberration
Test
Rat
00131392
(
1983)
Acceptable/
guideline
0,
40,
150,
500
mg/
kg
IP
injection
Negative
up
to
overt
toxicity
(
significant
decrease
in
body
weight
gain)

870.5395
Mammalian
Erythrocyte
Micronucleus
Test
CD­
1
Mice
00164941
(
1986)
Acceptable/
guideline
0,
200,
660,
2000
mg/
kg
oral
gavage
Negative
up
to
overt
toxicity
(
mortality)
&
cytotoxicity
(
significant
decrease
in
PCE:
NCE
ratio
at
2000
mg/
kg,
both
sexes
combined)

870.5395
Mammalian
Erythrocyte
Micronucleus
Test
CD­
1
Mice
41565123
(
1989)
Acceptable/
guideline
0,
898
or
1436
mg/
kg
%

0,
1075
or
1719
mg/
kg&
Negative
up
to
a
cytotoxic
dose
(
significant
decrease
in
PCE:
NCE
ratio)
seen
at
both
doses
in
%&

870.5450
Cytogenetics
Dominant
Lethal
Rat
44069502
(
1996)
Unacceptable/
guideline
0,
200,
1000,
1500
ppm
for
10
weeks
Negative
for
dominant
lethal
mutations
but
dosage
was
insufficient
870.5450
Cytogenetics
Dominant
Lethal
Rat
41963309/
44093703
(
1991/
1996)
Acceptable/
guideline
0,
200,
1000,
2000
mg/
kg
oral
gavage
Negative;
earlier
report
of
positive
results
now
considered
to
be
due
to
reproductive
(
infertility)
toxicity
Table
4.1b
Subchronic,
Chronic
and
Other
Toxicity
Profile
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
Page
39
of
118
870.5450
Cytogenetics
Dominant
Lethal
Mouse
44093701(
1996)
Unacceptable/
guideline
0,
200,
1000,
3500
ppm
for
8
weeks
Negative
for
dominant
lethal
mutations
but
dosage
was
insufficient
870.5900
Other
Genotoxicity
In
vitro
sister
chromatid
exchange
assay
Human
Lymphocytes
Hill
et
al.
(
1997)
Acceptable/
guideline
10
µ
M
(
2.7
µ
g/
mL)
Weak
evidence
of
positive
response
(
1.5­
fold
increase)
in
one
of
two
donor
cells
870.5550
Other
Genotoxicity
In
vitro
UDS
in
Primary
Rat
Hepatocytes
00131393
(
1983)
Acceptable/
guideline
0.032­
320
µ
g/
well
Negative
up
to
cytotoxic
concentrations
($
10.6
µ
g/
well)

870.5550
Other
Genotoxicity
In
vitro
UDS
in
Primary
Rat
Hepatocytes
41565124
(
1989)
Acceptable/
guideline
0,
500,
1000,
2000
mg/
kg
oral
gavage
Weak
positive
response
accompanied
by
major
hepatic
pathology
(
necrosis,
70%
decreased
GSH,
60­
fold
increase
in
aspartate
transaminase
)

870.6200
Other
Genotoxicity
In
vivo
Comet
Assay
in
Rat
Olfactory
and
respiratory
cells
44863208
(
1999)
Acceptable/
nonguideline
1750
ppm
(
175
mg/
kg/
day)
7
days
Negative
at
a
tumorigenic
dose
in
vivo
870.6200a
Acute
neurotoxicity
screening
battery
MRID
45357501
(
2001)
Unacceptable
(
guideline)­
upgradable
0,
150,
500,
1500
mg/
kg
NOAEL
=
150
mg/
kg
(
females);
500
mg/
kg
(
males)
LOAEL
=
500
mg/
kg
based
on
decreased
motor
activity
in
females
(
1500
mg/
kg
in
males
based
on
clinical
signs
in
the
FOB
and
decreased
body
weight/
weight
gain).

Positive
control
(
validation)
studies
cited
in
study
required
to
confirm
endpoints.

870.6200b
Subchronic
neurotoxicity
screening
battery
MRID
45357502
(
2001)
Unacceptable
(
guideline)­
upgradable.
0,
200,
600,
1750
ppm
(%
0,
15.4,
47.6,
139.0
mg/
kg/
day;
&
0,
18.3,
55.9,
166.5
mg/
kg/
day)
NOAEL
=
47.6
mg/
kg/
day
LOAEL
=
139.0
mg/
kg/
day
based
on
decreased
body
weight/
weight
gain
in
males
and
females,
possible
transiently
decreased
hindlimb
grip
strength
in
males
at
week
2.

Positive
control
(
validation)
studies
cited
in
study
required
to
confirm
endpoints.
Table
4.1b
Subchronic,
Chronic
and
Other
Toxicity
Profile
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
Page
40
of
118
870.6300
Developmental
neurotoxicity
Not
available
N/
A
870.7485
Metabolism
and
pharmacokinetics
(
rat)
00130839
(
1983)
Acceptable/
guideline
Oral
10
mg/
kg,
400
mg/
kg
(
14C­
acetochlor)
Rapidly
eliminated
(>
70%
of
administered
dose
by
day
2),
elimination
biphasic
(
rapid
phase
½
­
life
5.4­
10.4
hrs,
slow
phase
128.6­
286.4
hrs
for
10
mg/
kg
dose).
Tissues
did
not
retain
high
levels
of
radioactivity
except
for
RBC,
which
retained
about
2.5%
of
dose
at
study
termination.
Acetochlor
was
completely
metabolized,
via
N­
dealkylation
and
glucuronide
conjugation,
primarily
to
mercapturic
acid
derivatives,
with
other
sulfur­
containing
derivatives
identified.

870.7485
Metabolism
and
pharmacokinetics
(
rat)
41565125,
­
26,
­
27,
41592007,
­
08
(
1987,
1989,
1990)
Acceptable/
guideline
Oral
10
mg/
kg,
200
mg/
kg
and
10
mg/
kg/
day
x
14
days
(
14C­
acetochlor)
Well­
absorbed
and
rapidly
eliminated
(
92­
96%
of
dose
by
day
5,
½
life
of
elimination
20­
30
hrs),
primarily
excreted
in
urine
(
about
60%
by
24
hrs)
but
significant
fecal
excretion
observed,
especially
males
and
at
high
dose,
with
biliary
excretion
observed.
Elimination
biphasic.
Retention
in
tissue/
carcass
negligible,
primarily
in
blood
(
binding
to
RBC)
and
well­
perfused
organs
(
heart,
spleen,
kidney,
lungs,
liver).
Acetochlor
was
completely
metabolized
(
15
compounds
separated
in
urine,
4
in
bile,
5
in
feces),
with
glutathione,
mercapturic
acid
or
glucuronide
conjugation
of
n­
dealkylated
acetochlor
a
major
route
of
metabolism;
sulphoxymethyl
and
cysteine
conjugates
also
identified
in
feces.
In
urine,
major
metabolite
was
mercapturic
acid
conjugate
of
N­
deethylated
acetochlor;
in
bile,
major
metabolite
was
the
glucuronide
conjugate.
Major
fecal
metabolite
not
characterized.

870.7600
Dermal
in
vivo
penetration
(
rat)
41778303
(
1990)
Acceptable/
guideline
Acetochlor
was
dermally
absorbed
in
rats
in
a
dose
and
timerelated
manner.
Maximum
%
of
dose
absorbed
during
a
10
hr
exposure
duration
(
used
for
unintentional
occupational
exposure)
was
19­
23%
using
an
application
of
1/
70
or
1/
1000
dilution
of
formula
concentrate
(
equivalent
to
11.772
or
0.763
mg/
g,
respectively).
Page
41
of
118
In
addition
to
the
above
studies
that
were
submitted
to
fulfill
guideline
requirements
for
acetochlor,
numerous
special
and
mechanistic
studies
have
been
submitted
to
address
the
mechanism
of
nasal
and
thyroid
tumorigenesis
(
see
Section
4.1.1.2,
above).
These
studies
have
been
reviewed
and
a
toxicology
profile
is
presented
below
in
Table
4.1c:

Table
4.1c
Special
(
Nonguideline)
Mechanistic
Study
Toxicity
Profile
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
Studies
on
Nasal
Tumorigenesis
Comparative
metabolism
(
rat/
mouse)
44496203
(
1998)
Acceptable/
nonguideline
(
1)
200
mg/
kg
single
gavage
dose
or
(
2)
1750
ppm
in
diet
for
6
months,
then
200
mg/
kg
single
dose
or
(
30
0,
10,
200,
1000
or
2000
mg/
kg
single
gavage
dose
(
14C­
acetochlor)
Differences
in
metabolism
between
rats
and
mice
were
seen.
Initial
reactions
both
species
were
oxidative
O­
deethylation
of
the
N­
ethoxymethyl
sidechain
and
glucuronidation
of
the
methylol
group.
In
rats­
glucuronide
conjugate
excreted
in
the
bile,
followed
by
hepatic
removal
of
methylol
group
and
glutathione
conjugation,
yielding
mercapturic
acid
derivative
of
the
glutathione
conjugate
(
major
urinary
metabolite
in
rats).
Sulfoxides
and
sulfone
derivatives
also
identified.
In
mice­
major
urinary
metabolite
was
a
chloramideenterohepatic
circulation
not
observed
and
glutathione
conjugation
not
a
major
route
of
metabolism.

Nasal
cell
proliferation
(
rat)
44496207
(
1996)
Acceptable/
nonguideline
0,
200,
1750
or
5000
ppm
in
diet
for
160
days
Cell
proliferation
in
nasal
turbinate
olfactory
respiratory
epithelium,
but
not
respiratory
epithelium,
was
significantly
increased
at
1750
and
5000
ppm
as
measured
by
tritiated
thymidine
incorporation
into
DNA
at
each
dose
level
at
60
days
(
5000
ppm
only),
90
or
160
days
of
treatment.
Bromodeoxyuridine
incorporation
also
showed
significant
increases
after
160
days
at
1750
and
5000
ppm,
but
not
at
200
ppm.
No
increase
was
seen
in
respiratory
epithelium.
Cell
proliferation
increased
1.5­
2.0­
fold
at
5000
ppm
and
1.3­
1.5­
fold
at
1750
ppm.

Nasal
cell
proliferation
(
mouse)
44496209
(
1996)
Acceptable/
nonguideline
0,
1000
or
5000
ppm
in
diet
for
60
and
90
days.
Acetochlor
did
not
cause
increased
nasal
olfactory
or
respiratory
epithelial
cell
proliferation
in
mice
as
evaluated
by
bromodeoxyuridine
nuclear
incorporation.
Table
4.1c
Special
(
Nonguideline)
Mechanistic
Study
Toxicity
Profile
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
Page
42
of
118
Quinoneimine­
protein
binding,
autoradiography
(
rat)
44496210
(
1998)
Unacceptable/
nonguideline
(
upgradable)
1710
or
5170
ppm
acetochlor
in
diet
containing
14C­
acetochlor
for
14
days.
In
rat
nasal
turbinate
tissue,
a
dose­
dependent
formation
of
3­
ethyl,
5­
methyl­
benzoquinoneimine­
cysteine
(
EMIQ­
cysteine)
adducts
was
observed
(
119
and
206
pmole/
mg
protein
at
1710
and
5170
ppm,
respectively)
(
determined
by
acid
hydrolysis
and
HPLC).
Whole
body
autoradiography
showed
localization
of
radioactivity
in
gut,
stomach
contents,
urinary
bladder,
highly
perfused
organs
and
in
the
nasal
turbinates,
adrenal
and
preputial
glands.
Microautoradiography
of
decalcified
noses
showed
localization
in
Bowman's
glands
at
1720
and
5170
ppm
and
RBC
at
5170
ppm,
with
equivocal
localization
in
the
neuron
layer
of
the
olfactory
surface
epithelium.

Quinoneimine­
protein
binding
autoradiography
(
mouse)
44496211
(
1998)
Unacceptable/
nonguideline
(
upgradable)
1800
or
4750
ppm
acetochlor
in
diet
containing
14C­
acetochlor)
for
14
days.
EMIQ­
cysteine
adduct
formation
not
observed
in
mice
as
assessed
by
acid
hydrolysis
and
HPLC.

Quinoneimine­
protein
binding
autoradiography
acetochlor
secondary
sulfide
(
rat)
44496212
(
1998)
Unacceptable/
nonguideline
(
upgradable)
7
mg/
kg/
day
14C­
acetochlor
for
either
5
consecutive
days
or
single
dose,
sacrificed
either
one
or
5
days
after
final
dose.
EMIQ­
cysteine
adducts
were
observed
in
nasal
turbinate
tissue
as
assessed
by
acid
hydrolysis
and
HPLC.
Autoradiography
showed
localization
in
nasal
turbinates
and
microautoradiography
of
decalcified
noses
showed
binding
in
the
Bowman's
glands.

Quinoneimine­
protein
binding
autoradiography
(
Rhesus
monkey)
44496213
(
1998)
Acceptable/
nonguideline
126
mg/
kg
14C­
acetochlor
for
14
days
EMIQ­
cysteine
adducts
were
not
detected
in
nasal
turbinate
tissues
as
assessed
by
acid
hydrolysis
and
HPLC.

Nasal
tumor
mapping
(
rat)
44496214
(
1997)
Acceptable/
nonguideline
nasal
passages
examined
from
rats
in
chronic/
carcinogenicity
dietary
studies
on
acetochlor
(
1750
ppm)
and
butachlor
(
3000
ppm)
and
a
one­
year
gastric
initiation­
promotion
study
on
alachlor
(
126
mg/
kg).
Hyperplastic
and
preneoplastic/
neoplastic
lesions
for
all
compounds
were
located
primarily
in
the
ethmoid
turbinates,
regions
normally
lined
by
olfactory
mucosa,
with
many
near
the
olfactory­
respiratory
junctions.
Olfactory
to
respiratory
metaplasia
was
a
significant
feature
of
neoplastic
progression.
Females
given
acetochlor
also
showed
basal
cell
hyperplasia
in
the
region
underlying
Bowman's
glands
in
dorsal
and
medial
airways.
Table
4.1c
Special
(
Nonguideline)
Mechanistic
Study
Toxicity
Profile
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
Page
43
of
118
In
vitro
metabolism
(
rat/
mouse/
one
human
sample)
44530001
(
1998)
Acceptable/
nonguideline
14C­
acetochlor
sulfoxide
(
0.025
mM,
15.5
kBq)
incubated
w/
microsomes
from
rat
liver,
nasal
olfactory
and
nasal
respiratory
epithelia;
mouse
nasal
olfactory
and
liver
cells;
and
human
nasal
epithelia
(
mixed
olfactory/
respiratory)
Acetochlor
sulfoxide
was
rapidly
hydroxylated
in
rat
and
mouse
olfactory
microsomal
fractions,
but
not
respiratory
or
liver
fractions.
Major
metabolites
were
(
1)
side
chain
oxidation
product
of
acetochlor
sulphone
and
(
2)
parahydroxy
metabolite
of
acetochlor
sulfoxide.
Hydroxylation
of
acetochlor
sulfoxide
was
not
detected
in
the
sample
of
human
nasal
tissue.

In
vitro
metabolism
(
rat/
mouse/
squirrel
monkey)
44530002
(
1998)
46081803
(
2003)
Unacceptable/
nonguideline
(
upgradable)
14C­
acetochlor
(
30
mM,
0.05
mBq)
Study
evaluated
rates
of
steps
in
metabolism
of
acetochlor
to
p­
hydroxy­
2­
ethyl­
6­
methylaniline
(
pOH­
EMA),
a
precursor
to
quinoneimine
formation,
in
cellular
fractions
from
rat
and
mouse
liver,
nasal
olfactory
epithelia
and
nasal
respiratory
epithelia;
and
from
monkey
combined
nasal
olfactory/
respiratory
epithelia.
In
mice
and
rat
tissues,
the
rate
of
acetochlor­
GSH
conjugation
of
acetochlor
was
comparable,
but
slightly
higher
in
rat
olfactory
tissue
than
mouse
olfactory
tissue.
Rate
of
secondary
sulfide
hydrolysis
to
EMA
was
significantly
lower
in
olfactory
and
respiratory
tissues
of
mice
vs.
rats;
p­
hydroxylation
of
EMA
was
comparable
in
nasal
tissues
of
rats
and
mice
but
lower
in
rat
liver
than
mouse
liver.
Overall
conversion
of
acetochlor
to
pOH­
EMA
was
slower
in
mice
than
rats,
lowering
potential
to
form
reactive
intermediates.
Rates
of
all
reactions
were
much
lower
in
monkey
nasal
tissue
than
rat
nasal
or
liver
tissue,
suggesting
lower
potential
to
form
reactive
intermediates.

Protein
adduct
formation
(
rat)
46009402
(
2001)
in
vivo
protein
binding,
10
mg/
kg
14C­
acetochlor
sulfoxide;
in
vitro
binding,
0.4
mM
14C­
acetochlor
sulfoxide,
407­
458
Kbq
to
cellular
fractions
of
nasal
and
liver
tissue
Unacceptable/
nonguideline
(
upgradable)
(
1)
HPLC
analysis
comparing
radioactivity
of
acid
hydrolysates
from
olfactory
vs
respiratory
mucosa
showed
significantly
higher
levels
of
radioactivity
in
the
olfactory
mucosa;
(
2)
SDS­
PAGE
of
bound
proteins
from
incubation
of
olfactory
epithelial
microsomal
fractions
showed
similar
patterns
for
carbonyl
and
phenyl­
labeled
acetochlor
sulfoxide,
indicating
that
the
sulfoxide
moiety
was
retained
in
much
of
the
bound
radioactivity;
(
3)
Histoautoradiography
of
the
olfactory
and
respiratory
regions
of
the
rat
nasal
cavity
at
8
and
24
hrs
postdosing
showed
the
highest
levels
of
bound
radioactivity
over
Bowman's
glands
in
the
olfactory
mucosa,
with
none
in
the
respiratory
region.
The
areas
of
binding
coincide
with
the
cellular
location
of
xenobiotic
metabolizing
enzymes
in
the
nasal
passages.
Table
4.1c
Special
(
Nonguideline)
Mechanistic
Study
Toxicity
Profile
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
Page
44
of
118
In
vitro
metabolism
(
rat/
mouse/
squirrel
monkey/
human)
46009401
(
2000)
46081802
(
2003)
Unacceptable/
nonguideline
(
upgradable)
Rate
of
hydroxylation
of
acetochlor
sulfoxide
to
p­
OHacetochlor
sulfoxide
evaluated.
Highest
levels
of
activity
observed
in
the
rat
and
mouse
nasal
olfactory
tissues,
no
detectable
activity
seen
in
monkey
or
human
samples.
Enzyme
characterization
studies
indicated
that
the
reaction
is
catalyzed
by
a
cytochrome
similar
to
the
CYP2A
family,
but
not
coumarin
hydroxylase
itself.

Studies
on
thyroid
tumorigenesis
Characterization
of
thyroid
toxicity
and
liver
effects­
time
course
(
rats)
44496208
(
1996)
Acceptable/
nonguideline
0,
1750
or
5000
ppm
(
0,
100.6
or
280.9
mg/
kg/
day)
in
diet
for
14,
28
or
56
days;
0,
200,
1750
or
5000
ppm
(
0,
10.4,
91.9
or
270.3
mg/
kg/
day)
in
diet
for
160
days.
Effects
on
liver
and
thyroid
weights,
thyroid
hormones
and
liver
UDPGT
activity
were
observed
at
1750
and
5000
ppm,
consistent
w/
perturbation
of
thyroid­
pituitary
homeostasis
via
UDPGT­
mediated
clearance
of
T4.
Increased
hepatic
UDPGT
activity
(
by
day
14),
increased
TSH
(
by
day
14
at
5000
ppm
and
day
56
at
1750
ppm)
and
T4
(
day
14
only)
and
decreased
T3
(
day
14
only)
were
observed.
Liver
and
thyroid
weights
were
increased
(
days
14­
90;
liver
also
at
day
160).

Studies
on
acute
liver
toxicity
(
supplemental
data
for
UDS
studies)
and
liver
cell
proliferation
Acute
liver
toxicity
(
rats)
44863205
(
1993)
Unacceptable/
nonguideline
(
upgradable
with
test
material
purity
information)
(
1)
2000
mg/
kg
via
gavage
in
corn
oil
(
evaluation
of
UDS);
(
2)
0,
500,
1000
or
2000
mg/
kg
via
gavage
in
corn
oil
(
evaluation
of
liver
tissue
non­
protein
sulphydryl
groups)
Dose­
dependent
depletion
of
hepatocellular
glutathione
leading
to
mild
to
marked
necrosis
at
$
500
mg/
kg
was
observed,
with
slight
stimulation
of
UDS
at
2000
mg/
kg.
Increased
serum
AST
and
ALT
were
observed
at
2000
mg/
kg.
UDS
therefore
observed
at
conditions
of
excessive
hepatocellular
toxicity
and
reduced
hepatocellular
glutathione
levels.

Acute
liver
toxicity
(
rats)
44863207
(
1994)
Unacceptable/
nonguideline
(
upgradable
with
submission
of
test
material
purity)
0,
500,
1000
or
2000
mg/
kg
via
gavage
in
corn
oil
Dose­
dependent
depletion
of
hepatocellular
glutathione
observed
at
$
500
mg/
kg,
peaking
6­
12
hrs
post­
dosing
(
17
to
63%
of
control
levels
between
3­
12
hrs).
Necrosis
and
serum
liver
enzymes
returned
to
normal
levels
thereafter
and
normal
levels
of
glutathione
were
observed
by
48
hr.

Hepatocellular
proliferation
(
mice)
44863601
(
1999)
Acceptable/
nonguideline
0,
1000
or
5000
ppm
in
diet
for
90
days
(
males
only).
Equivalent
to
0,
166.6
or
887.9
mg/
kg/
day).
Incorporation
of
BrdU
in
mice
treated
with
acetochlor
was
approximately
doubled
(
0.15,
0.35,
0.38
at
0,
1000
and
5000
ppm,
respectively).
Page
45
of
118
4.1.5
Dose­
Response
Appropriate
endpoints
were
identified
for
all
potential
exposure
scenarios
for
acetochlor.
Studies
considered
in
the
development
of
this
risk
assessment
showed
developmental
effects
on
,
weight
gain
decrements
in
offspring,
evidence
of
neurotoxicity
and
microscopic
effects
in
several
tissues.
Although
weight
gain
decrements
in
young
adult/
adult
animals
were
consistently
observed
in
studies
on
acetochlor,
they
tended
to
occur
at
higher
dose
levels
than
these
other,
more
sensitive
findings.

The
acute
oral
RfD
for
the
general
population
including
females
age
13­
49
was
derived
from
the
acute
neurotoxicity
study
in
the
rat,
based
on
decreased
motor
activity
in
females
at
the
time
of
peak
effect.
The
endpoint
selected
is
considered
to
be
protective
of
pregnant
or
nursing
females
because
the
NOAEL
selected
(
150
mg/
kg)
is
same
as
the
developmental
toxicity
NOAEL
in
the
rat,
which
was
based
on
an
increase
in
fetal
resorptions/
postimplantation
loss,
an
effect
that
is
potentially
caused
by
a
single
exposure.
The
chronic
RfD
was
derived
from
a
chronic
oral
toxicity
study
in
the
dog,
which
provided
the
most
sensitive
endpoint
available
and
was
based
on
clinical
signs
(
excessive
salivation)
and
microscopic
findings
in
the
liver,
testes
and
kidney.
Incidental
oral
endpoints
were
not
selected
because
there
are
presently
no
residential
uses
for
acetochlor.

For
dermal
risk
assessment,
a
21­
day
dermal
exposure
study
in
the
rabbit
provided
the
endpoint
for
short­
term
exposure.
The
route
of
exposure
and
study
duration
were
appropriate:
although
significant
mortality
was
observed
in
this
study,
it
occurred
at
a
dose
exceeding
the
limit
dose
and
significantly
higher
than
the
NOAEL.
The
endpoint
is
considered
protective
of
pregnant
or
nursing
females
who
may
be
occupationally
exposed
(
the
dermal
endpoint
is
lower
than
the
developmental
endpoint
from
the
oral
developmental
toxicity
study
when
the
latter
is
adjusted
for
20%
dermal
absorption).

For
intermediate­
term
dermal
exposure,
the
findings
of
two
subchronic
toxicity
studies
in
the
dog
were
considered
together
to
provide
the
highest
NOAEL
and
lowest
LOAEL
on
which
to
base
the
quantitative
hazard
estimate.
It
is
noted
that
the
offspring
NOAELs/
LOAELs
from
reproductive
toxicity
studies
on
acetochlor
provide
additional
support
for
the
endpoint
selected.
Long­
term
exposure
was
assessed
using
the
NOAEL
from
the
dog
chronic
study
as
discussed
above.
These
oral
endpoints
were
adjusted
for
anticipated
dermal
absorption
of
20%,
as
determined
in
a
rat
dermal
penetration
study.

Since
there
are
no
inhalation
studies
for
acetochlor,
oral
studies
were
selected
for
inhalation
risk
assessment.
The
developmental
NOAEL
from
the
developmental
toxicity
study
in
the
rat
was
selected
to
provide
an
appropriate
endpoint
that
would
be
protective
for
pregnant
females
who
may
be
occupationally
exposed.
The
intermediate
and
long­
term
inhalation
exposure
scenarios
used
the
same
studies
as
the
dermal
exposure
scenarios
of
the
same
length
(
see
above).

For
all
exposure
scenarios,
uncertainty
factors
of
10x
for
interspecies
and
10x
for
intraspecies
variation
(
total
UF
of
100x)
were
used.
In
addition,
a
database
uncertainty
factor
of
10x
(
total
UF
=
1000)
was
used
for
the
acute
dietary
assessment
to
account
for
the
lack
of
a
developmental
Page
46
of
118
neurotoxicity
study
in
the
rat.

Acetochlor
is
classified
as
"
likely
to
be
carcinogenic
to
humans,"
showing
dose­
related
increases
in
lung
tumors
in
male
and
female
mice,
histiocytic
sarcoma
in
female
mice,
nasal
epithelial
tumors
in
male
and
female
rats
and
thyroid
tumors
in
male
and
female
rats.
A
Q
1
*
of
3.27
x
10­
2
was
calculated,
based
on
increased
lung
tumor
incidence
in
male
mice
(
HED
TXR#
0052743).
Nasal
epithelial
cell
tumors
in
the
rat
were
considered
to
have
a
non­
linear
dose­
response,
based
on
the
proposed
mode
of
action
for
induction
of
these
tumors
(
see
Section
4.1.1.2).

4.1.6
FQPA
The
database
is
considered
adequate
for
selection
of
study
endpoints
and
determination
of
a
doseresponse
to
characterize
the
potential
prenatal
or
postnatal
toxicity
of
acetochlor
to
infants
and
children.
No
increase
in
susceptibility
was
seen
in
developmental
toxicity
studies
in
rat
and
rabbit
or
in
three
multigeneration
reproductive
toxicity
studies
in
the
rat.
Toxicity
to
offspring
was
observed
at
dose
levels
the
same
or
greater
than
those
causing
maternal
or
parental
toxicity.
A
developmental
neurotoxicity
study
is
required
because
evidence
of
neurotoxicity,
was
observed
in
studies
in
the
dog
and
the
rat
including
frank
neuropathology
in
a
chronic
study
in
the
dog.
The
uncertainty
associated
with
the
lack
of
this
data
is
accounted
for
by
use
of
a
database
uncertainty
factor
(
UF
DB
)
of
10,
where
appropriate.
Since
there
are
no
residual
uncertainties
that
indicate
the
need
for
a
special
safety
factor,
the
factor
has
been
reduced
to
1X.

4.2
FQPA
Hazard
Considerations
4.2.1
Adequacy
of
the
Toxicity
Data
Base
The
database
for
acetochlor
is
considered
incomplete
at
this
time.
A
developmental
neurotoxicity
study
is
required
for
acetochlor
based
on
neurological
observations,
primarily
in
the
dog
(
see
below),
or
an
alternative
test
which
addresses
the
sensitivity
of
the
dog
to
neurological
effects.
In
addition,
submission
of
the
positive
control
studies
for
validation
of
the
laboratory
methodology
used
in
the
acute
and
subchronic
rat
oral
neurotoxicity
screening
studies
is
required
as
confirmatory
data
and
to
upgrade
these
studies
to
Acceptable/
guideline.
However,
the
endpoints
identified
in
the
neurotoxicity
studies
are
considered
adequate
for
use
in
this
risk
assessment.
The
need
for
a
28­
day
inhalation
study
has
not
been
evaluated
at
this
time.

4.2.2
Evidence
of
Neurotoxicity
Evidence
of
neurotoxicity
from
exposure
to
acetochlor
was
observed
in
several
studies.
Salivation
and
other
clinical
signs
(
anogenital
staining,
diarrhea)
were
reported
in
some
studies
in
both
the
rat
(
two
developmental
toxicity
studies)
and
the
dog
(
subchronic
and
chronic
oral).
A
marginal
decrease
in
brain
cholinesterase
was
observed
at
the
high
dose
in
one
subchronic
rat
study.
The
dog
appears
to
be
more
sensitive
than
the
rat
or
mouse
to
effects
on
the
nervous
system,
in
that
salivation
occurred
at
lower
dose
levels
and
frank
neuropathology
of
the
brain
was
observed
in
one
study.
In
a
Page
47
of
118
one­
year
oral
(
capsule)
toxicity
study
in
the
dog,
pronounced
neurological
signs
(
ataxia,
abnormal
head
movements,
tremor,
depressed
righting,
hopping
and
flexor
reflexes,
exaggerated
tonic
neck
reflex
and
stiffness
and
rigidity
of
the
hindlimbs)
were
observed
at
the
high
dose
and
were
associated
with
degenerative
lesions
of
the
cerebellum.
An
acute
and
a
subchronic
oral
neurotoxicity
screening
study
in
the
rat
were
submitted
for
acetochlor.
In
the
acute
study
at
the
time
of
peak
effect,
decreased
total
motor
activity
at
mid
and
high
dose
was
observed
in
females,
but
not
males;
at
the
highest
dose,
both
males
and
females
showed
clinical
signs
of
toxicity
in
the
FOB
(
perioral
staining,
piloerection,
hunched
posture).
Single
animals
showed
signs
such
as
chromodacryorrhea,
upward
curvature
of
the
spine
and
hypothermia.
In
the
subchronic
study,
decreased
body
weight/
weight
gain
in
both
sexes
at
the
high
dose
was
observed.
A
decrease
in
hindlimb
grip
strength
in
males
at
2
weeks,
but
not
at
later
times,
was
observed
and
considered
a
possible
effect
of
treatment.
The
neurotoxicity
studies
did
not
evaluate
cholinesterase
levels.

Acute
Neurotoxicity
Screening
Study
in
Rats
In
an
acute
neurotoxicity
study
(
MRID
45357501),
groups
of
fasted,
42
day
old
Alpk:
AP
f
SD
(
Wistar­
derived)
rats
(
10/
sex/
dose)
were
given
a
single
oral
dose
of
acetochlor
(
94.7%
a.
i.,
batch/
lot
#
P11)
at
doses
of
0,
150,
500
or
1500
mg/
kg
bw
and
observed
for
14
days.
Neurobehavioral
assessment
(
functional
observational
battery
and
motor
activity
testing)
was
performed
at
pre­
test
and
study
Days
1
(
time
of
peak
effect),
8
and
15.
Cholinesterase
activity
was
not
determined.
At
study
termination,
5
animals/
sex/
group
were
euthanized
and
perfused
in
situ
for
neuropathological
examination.
Of
the
perfused
animals,
5
rats/
sex
from
the
control
and
high
dose
groups
were
subjected
to
histopathological
evaluation
of
brain
and
peripheral
nervous
system
tissues.

At
1500
mg/
kg
bw,
body
weights
adjusted
for
initial
weight
were
significantly
lower
than
the
control
group
on
Day
8
for
males
and
on
Days
1
(
peak
effect),
8
and
15
for
females.
Body
weight
gains
were
significantly
lower
for
the
Day
 
7
to
8
time
period
for
males
(
77%
of
controls)
and
during
throughout
the
study
for
females
(
65­
76%
of
controls).
Food
consumption
by
the
high­
dose
males
and
females
was
significantly
reduced
during
the
first
week
of
the
study
compared
with
the
controls.
During
the
FOB,
findings
were
limited
to
the
time
of
peak
effect
at
the
high­
dose
level.
These
consisted
of
hunched
posture
observed
in
5­
6
animals/
sex,
piloerection
on
7­
10/
sex,
and
staining
around
the
mouth
seen
in
3­
4/
sex.
The
severity
was
considered
slight
in
the
males
and
from
slight
to
moderate
in
females.
Other
findings
at
1500
mg/
kg
bw
were
decreased
activity
in
one
female,
chromodacryorrhea
in
one
female,
hypothermia
in
one
female,
labored
breathing
in
one
male,
sides
pinched
in
in
one
male,
and
upward
curvature
of
the
spine
in
one
female.
No
effects
of
treatment
were
noted
on
landing
foot
splay
measurement,
time
to
tail­
flick,
or
grip
strengths.
No
effects
of
treatment
were
noted
for
motor
activity
in
males.
Total
activity
counts
for
high­
dose
females
on
Day
1
were
significantly
decreased
compared
to
controls
at
500
and
1500
mg/
kg
(
401.7
and
251.7,
respectively,
vs.
571.4
for
controls;
equivalent
to
reductions
of
30%
and
56%)
and
also
were
decreased
by
43.8%
of
the
pre­
test
value.
A
statistically
significant
increase
in
motor
activity
of
28%
was
also
observed
in
high
dose
females
on
Day
8.
There
were
no
treatment­
related
effects
on
brain
weights
or
gross
and
histologic
pathology
or
neuropathology.
The
LOAEL
in
females
was
500
mg/
kg
bw,
based
on
dose­
related
decreases
in
motor
activity
on
Day
1
and
the
NOAEL
was
Page
48
of
118
150
mg/
kg
bw.
In
males,
the
LOAEL
was
1500
mg/
kg
bw,
based
on
decreased
body
weights
and
body
weight
gain
(
males
and
females),
reduced
food
consumption
(
males
and
females),
increased
incidence
of
clinical
signs
during
the
FOB
(
males
and
females)
at
the
time
of
peak
effect,
with
a
NOAEL
of
500
mg/
kg
bw.

This
neurotoxicity
study
is
classified
as
Unacceptable/
Guideline
(
upgradable)
pending
submission
of
information
on
positive
control
studies
conducted
at
the
performing
laboratory
and
does
not
satisfy
the
guideline
requirement
for
an
acute
neurotoxicity
study
in
rats
(
870.6200;
OECD
424).
If
such
data
have
already
been
submitted
to
the
agency,
the
registrant
or
performing
laboratory
should
provide
reference
to
the
data
and
when
the
study(
ies)
were
conducted.
In
addition,
methods
and
equipment
used
for
the
quantitative
measures
during
the
FOB
were
not
described.
This
information
should
also
be
provided.

4.2.3
Developmental
Toxicity
Studies
Developmental
Toxicity
in
Rats
(
Two
Studies
Available)

(
1)
In
an
oral
developmental
toxicity
study
(
MRID
00050929),
25
mated
female
Crl:
CD
(
SD)
BR
VAF/
Plus
rats
were
administered
acetochlor
(
tech.
91.4%
a.
i.,
lot
XHK­
119)
by
gavage
in
corn
oil
vehicle
(
dosing
volume
of
10
mL/
kg
bw)
as
single
daily
doses
of
0
(
corn
oil
only),
50,
200
or
400
mg/
kg/
day
from
Gestation
Days
6
through
19,
inclusive,
with
sacrifice
and
cesarean
evaluations
on
Day
20.

Maternal
toxicity:
At
400
mg/
kg/
day,
excessive
salivation
(
post­
dosing
in
3
females
on
one
occasion)
and
increased
frequency
of
urogenital
staining
(
13
rats,
vs.
5,
9
and
6
in
control,
low
and
mid
dose
groups,
respectively)
were
observed.
Mean
body
weight
gain
during
treatment
(
Days
6­
20)
was
decreased
(­
30%
less
than
controls)
and
gestational
weight
gain
(
Days
0­
20)
adjusted
for
gravid
uterine
weight
was
approximately
­
50%
less
than
controls
(
adjusted
gains
from
controls
to
high
dose,
respectively,
were
43,
56,
46
and
20
g).
There
were
no
treatment­
related
effects
on
survival
or
cesarean
parameters.
Food
consumption
was
not
evaluated
in
this
study.
The
maternal
toxicity
LOAEL
is
400
mg/
kg/
day,
based
on
clinical
signs
of
toxicity
and
reduced
body
weight
gain
during
treatment.
The
NOAEL
is
200
mg/
kg/
day.

Developmental
toxicity:
At
400
mg/
kg/
day,
a
slight
but
not
statistically
significant
reduction
in
mean
fetal
weight
was
observed.
No
other
cesarean
parameters
were
affected
and
there
were
no
treatment­
related
increases
in
fetal
variations
or
malformations.
The
developmental
toxicity
LOAEL
is
400
mg/
kg/
day,
based
on
slightly
(
not
statistically
significant)
reduced
mean
fetal
weight.
The
developmental
toxicity
NOAEL
is
200
mg/
kg/
day.

This
oral
developmental
toxicity
study
in
the
rat
is
classified
Acceptable
(
guideline)
and
satisfies
the
guideline
requirement
for
a
developmental
toxicity
study
(
OPPTS
870.3700;
OECD
414)
in
the
rat.
[
Note:
the
original
DER
did
not
present
data
from
the
study
and
the
only
copy
available
of
the
original
study
report
had
cesarean
tables
that
were
illegible;
the
percent
decrease
in
fetal
weight
at
Page
49
of
118
400
mg/
kg/
day
is
therefore
not
available
for
this
supplemental
review.
However,
the
reported
findings
are
consistent
with
the
findings
in
a
later
acceptable
developmental
toxicity
study
(
MRID
41592005;
see
supplemental
DER
in
this
TXR)
and
therefore
a
new
copy
of
this
study
report
is
not
required
at
this
time.]

(
2)
In
an
oral
developmental
toxicity
study
(
MRIDs
41592005,
42054902
and
42054903),
25
mated
female
Crl:
CD
(
SD)
BR
VAF/
Plus
rats
were
administered
acetochlor
(
tech.
90.5%
a.
i.,
batch/
lot
#
2)
by
gavage
in
corn
oil
vehicle
(
dosing
volume
of
10
mL/
kg
bw)
as
single
daily
doses
of
0,
40,
150
or
600
mg/
kg/
day
from
Gestation
Days
6
through
15,
inclusive.

Maternal
toxicity:
At
600
mg/
kg/
day,
two
females
died
(
on
GD
13
and
15),
apparently
due
to
treatment.
Clinical
signs
of
increased
salivation
post­
dosing
and
urogenital
staining
were
reported.
Mean
body
weight
gain
was
reduced
during
the
dosing
period
(­
47%
below
controls;
mean
corrected
body
weight
gain
from
Days
6
to
20
was
­
38%
below
controls).
A
significant
reduction
in
food
consumption
on
Days
6­
7
and
8­
9
(­
20%
and
­
16%
less
than
controls,
respectively)
was
observed
only
between
Days
6­
9
of
dosing;
thereafter,
consumption
was
comparable
among
all
groups.
The
maternal
toxicity
LOAEL
is
600
mg/
kg/
day,
based
on
mortality,
clinical
signs
of
toxicity
and
reduced
body
weight
gain
during
treatment.
The
NOAEL
is
150
mg/
kg/
day.

Developmental
toxicity:
At
600
mg/
kg/
day,
the
following
effects
showed
statistically
significant
differences
from
controls
and
were
considered
treatment­
related:
increased
early
resorptions/
dam
(
0.8
vs.
0.2,
controls)
and
total
resorptions/
dam
(
1.0
vs.
0.3,
controls);
increased
postimplantation
loss
(
7.6%
vs.
3.5%,
controls)
and
reduced
mean
fetal
weight
(­
7.1%
less
than
controls).
There
were
no
treatment­
related
increases
in
fetal
variations
or
malformations.
The
developmental
toxicity
LOAEL
is
600
mg/
kg/
day,
based
on
increased
fetal
early
resorptions
and
postimplantation
loss
and
reduced
mean
fetal
weight.
The
developmental
toxicity
NOAEL
is
150
mg/
kg/
day..

This
oral
developmental
toxicity
study
in
the
rat
is
classified
Acceptable
(
guideline)
and
satisfies
the
guideline
requirement
for
a
developmental
toxicity
study
(
OPPTS
870.3700;
OECD
414)
in
the
rat.

Developmental
Toxicity
in
the
Rabbit
(
Two
Studies
Available)

(
1)
In
a
developmental
toxicity
study
(
MRID
40134101),
MON
097
(
acetochlor
tech.,
94.2%
a.
i.,
lot
#
XLF­
349)
was
administered
to
20
artificially
inseminated
female
New
Zealand
White
rabbits/
dose
by
gavage
(
in
a
dosing
volume
of
0.5
mL/
kg
bw
corn
oil)
at
dose
levels
of
0,
15,
50
or
190
mg/
kg
bw/
day
from
days
7
through
19
of
gestation,
inclusive.

Maternal
toxicity:
At
190
mg/
kg/
day,
maternal
body
weight
loss
during
the
treatment
period
was
observed
(
mean
­
146
g,
compared
to
gain
of
+
81
g,
+
112g
and
+
93
g
for
control,
low
and
mid
dose
groups,
respectively,
from
Days
7­
19
of
gestation).
Loss
of
weight
during
treatment
was
reported
in
14/
19
high
dose
females
compared
to
4­
5/
18­
19
in
the
other
groups.
A
rebound
in
body
weight
gain
was
observed
postdosing
(
control
to
high
dose
mean
gain
from
days
19
through
29
was
129,
30,
134
Page
50
of
118
and
231
g,
respectively).
There
were
no
treatment­
related
effects
on
survival,
clinical
signs
of
toxicity
or
cesarean
parameters.
The
maternal
toxicity
LOAEL
is
190
mg/
kg
bw/
day,
based
on
weight
loss
during
treatment.
The
maternal
toxicity
NOAEL
is
50
mg/
kg
bw/
day.

Developmental
toxicity:
There
were
no
treatment­
related
effects
on
litter
cesarean
parameters,
nor
on
the
incidence
of
fetal
variations
or
malformations.
The
developmental
toxicity
NOAEL
is
190
mg/
kg
bw/
day.
A
developmental
toxicity
LOAEL
was
not
established
in
this
study
(>
190
mg/
kg
bw/
day).

The
developmental
toxicity
study
in
the
rabbit
is
classified
Acceptable
(
guideline)
and
satisfies
the
guideline
requirement
for
a
developmental
toxicity
study
(
OPPTS
870.3700;
OECD
414)
in
the
rabbit
(
nonrodent).

(
2)
In
an
oral
developmental
toxicity
study
(
MRIDs
41592006,
42054901
and
42077101),
acetochlor
(
technical,
90.5%
a.
i.,
lot
#
P2)
was
administered
to
16
female
New
Zealand
White
rabbits/
dose
by
gavage
in
corn
oil
vehicle
(
dosing
volume
of
1
mL/
kg)
at
dose
levels
of
0,
30,
100
or
300
mg/
kg
bw/
day
from
days
6
through
18
of
gestation.

Maternal
toxicity:
There
were
no
effects
of
treatment
observed
on
maternal
survival,
clinical
signs
of
toxicity,
body
weight
or
weight
gain,
food
consumption
or
cesarean
parameters.
Although
no
toxicity
was
observed
in
this
study,
the
results
of
the
range­
finding
study
(
MRID
42077101)
indicated
that
toxicity
(
body
weight
decrement)
was
observed
between
200­
400
mg/
kg
bw/
day
and
therefore
that
a
LOAEL
was
approached
in
the
main
study;
dose
selection
was
therefore
determined
to
be
appropriate.
The
maternal
toxicity
NOAEL
is
300
mg/
kg
bw/
day
(
highest
dose
tested).
A
maternal
LOAEL
was
not
established
in
this
study
but
was
likely
approached,
based
on
the
results
of
the
range­
finding
study.

Developmental
toxicity:
There
were
no
effects
of
treatment
observed
on
cesarean
parameters
and
no
effect
on
the
incidence
of
fetal
variations
or
malformations.
The
developmental
NOAEL
is
300
mg/
kg
bw/
day
(
highest
dose
tested).
A
developmental
LOAEL
was
not
established
in
this
study.

The
developmental
toxicity
study
in
the
rabbit
is
classified
Acceptable/
guideline
and
satisfies
the
guideline
requirement
for
a
developmental
toxicity
study
(
OPPTS
870.3700;
OECD
414)
in
the
rabbit.
Although
a
maternal
toxicity
LOAEL
was
not
achieved,
dosing
is
considered
adequate
based
on
the
results
of
the
range­
finding
study
(
see
above).
In
addition,
a
second
acceptable
developmental
toxicity
study
in
the
rabbit
is
available
(
MRID
40134101)
which
showed
weight
loss
during
treatment
at
190
mg/
kg
bw/
day.
Page
51
of
118
4.2.4
Reproductive
Toxicity
Study
Three
two­
generation
reproductive
toxicity
studies
in
the
rat
have
been
submitted
for
acetochlor.

(
1)
In
a
two­
generation
reproduction
study
(
MRID
00131391),
MON
097
(
acetochlor
tech.,
94.2%
a.
i.,
lot
#
1992024)
was
continuously
administered
to
24
female
and
12
male
Charles
River
albino
rats/
dose
in
the
diet
at
dose
levels
of
0,
500,
1500
or
5000
ppm
(
equivalent
to
average
daily
intakes
during
premating
in
F0
animals
of
0,
30.8,
60.4
or
316
mg/
kg
bw/
day,
males
and
0,
46.2,
130.4
or
442
mg/
kg
bw/
day,
females
and
in
F1
animals
of
0,
29.9,
87.8
or
333
mg/
kg/
day,
males
and
43.6,
129.8
or
441
mg/
kg/
day,
females).
Mating
was
initiated
after
at
least
100
days
of
treatment
for
the
F0
parental
animals
and
at
least
120
days
of
treatment
for
the
F1
parental
animals.
Matings
were
performed
twice
for
each
generation.
Five
F1b
and
F2b
pups/
sex/
dose
and
ten
F1
parents/
sex/
dose
were
also
selected
for
evaluation
of
testes,
ovary,
pituitary,
thyroid,
spleen
and
liver
weights
and
histopathology.

Parental
toxicity:
At
1500
ppm,
mean
parental
premating
body
weights
were
slightly
reduced
compared
to
controls.
At
the
end
of
the
premating
periods
(
about
Study
Week
14),
F0
parental
male
and
female
weights
were
reduced
by
­
6.8%
(
p<
0.01)
and
­
4.3%
(
NS)
compared
to
controls,
respectively,
with
gains
decreased
by
­
9
to
­
10%.
F1
parental
male
and
female
weights
were
reduced
by
­
7.2%
(
NS)
and
­
8.3%
(
p<
0.01)
by
the
end
of
premating
(
about
Study
Week
51),
with
gains
reduced
by
6.4%
in
males
and
9.4%
in
females.
Mean
maternal
gestational
body
weights
were
reduced
among
all
maternal
parental
groups
except
for
the
F2a
dams
(
average
decrease
during
gestation
was
about
­
13%
less
than
controls).
Adjusted
maternal
body
weights
were
not
provided
in
this
study.
At
5000
ppm,
mean
parental
body
weights
were
reduced
compared
to
controls
for
all
groups.
The
mean
weights
of
F0
males
and
females
were
significantly
lower
by
the
end
of
premating
at
Week
14
(­
11%
and
­
20%,
respectively;
weight
gain
­
16%
and
­
20%
less,
respectively),
as
well
as
at
Week
34
(­
10%
and
­
25%,
respectively;
weight
gains
­
14%
and
­
41%
less,
respectively).
F1
males
and
females
had
significantly
lower
body
weights
at
the
start
of
premating
(
Week
33,
males
­
39%
and
females
­
34%),
but
weights
during
the
study
continued
to
be
lower
than
controls:
by
the
end
of
premating
(
about
Week
51,
males
were
reduced
by
­
23%
in
males
(
gain
­
20%)
and
­
26%
in
females
(
gain
­
43%).
At
week
74
(
end
of
study),
body
weights
of
males
were
­
19%
below
controls
(
gain
­
13%)
and
female
weights
were
­
33%
below
controls
(
gain
­
51%).
Mean
maternal
gestational
body
weights
were
lower
for
all
parental
mating
groups
(
an
average
of
­
34%
below
controls).
Slight
reductions
(<
10%)
in
food
consumption
were
also
reported.
Some
increases
in
absolute/
relative
organ
weights
were
observed
in
F1
parents
(
e.
g.,
thyroid,
liver,
kidney).
The
incidence
of
chronic
nephritis
was
increased
in
F1
females
(
8/
10
vs.
0/
10
examined).
F0
animals
were
not
evaluated
for
organ
weights
except
testes
in
males,
which
showed
no
effects.
There
were
no
treatment­
related
effects
on
survival
or
clinical
signs
of
toxicity.
The
parental
systemic
LOAEL
is
1500
ppm
(
60.4
mg/
kg
bw/
day
in
males,
130.4
mg/
kg
bw/
day
in
females),
based
on
reduced
body
weight/
weight
gain
during
premating
in
both
generations.
The
parental
systemic
NOAEL
is
500
ppm
(
30.8
mg/
kg
bw/
day
in
males,
46.2
mg/
kg
bw/
day
in
females).

Offspring
toxicity:
At
1500
ppm,
mean
pup
body
weights
on
Lactation
Day
21
showed
a
slight
Page
52
of
118
decrease
in
the
F2a
and
F2b
offspring
(­
7
to
­
13%
below
controls,
statistically
significant
only
for
F2b
males).
At
5000
ppm,
mean
pup
body
weights
on
Lactation
Day
21
in
all
F1
and
F2
pup
groups
were
reduced
(
about
­
42%
less
than
controls)
and
mean
litter
size
tended
to
be
smaller
(
grand
mean
for
all
generations:
at
high
dose
9.9
vs.
12.3,
13.0
and
11.8
at
control,
low
and
mid
dose;
statistical
significance
only
achieved
for
the
F1b
generation).
Although
statistically
significantly
increased
abs/
rel
thyroid
weights
were
reported
at
low
and
mid
dose,
they
were
not
considered
to
be
a
clear
treatment­
related
finding
based
on
lack
of
a
dose­
response
and
lack
of
a
corresponding
increase
in
liver
weights.
No
effects
on
pup
survival,
birth
weight,
gross
abnormalities
or
other
cesarean
offspring
parameter
were
observed.
The
offspring
LOAEL
is
1500
ppm
(
60.4
mg/
kg
bw/
day,
males;
130.4
mg/
kg
bw/
day),
based
on
slightly
reduced
pup
body
weight
during
lactation
in
F2
offspring.
The
offspring
NOAEL
is
500
ppm
(
30.8
mg/
kg
bw/
day,
males;
46.2
mg/
kg
bw/
day).

Reproductive
toxicity:
There
was
no
evidence
of
reproductive
toxicity
observed
at
any
dose
tested
in
this
study.
The
reproductive
NOAEL
is
5000
ppm
(
324.5
mg/
kg
bw/
day
in
males,
441.5
mg/
kg
bw/
day
in
females).
A
reproductive
toxicity
LOAEL
was
not
determined
in
this
study.

This
study
is
classified
Acceptable/
guideline
and
satisfies
the
guideline
requirement
for
a
2­
generation
reproductive
study
(
OPPTS
870.3800);
OECD
416
in
the
rat.

(
2)
In
a
two­
generation
reproduction
study
(
MRID
41565120),
SC­
5676
(
acetochlor
tech.,
90.8%
a.
i.,
batch/
lot
#
1
and
3)
was
administered
to
25
Sprague­
Dawley
CD
rats/
sex/
dose
in
the
diet
at
dose
levels
of
0,
18,
175
or
1750
ppm
(
equivalent
to
average
daily
premating
intakes
for
the
F0
generation
of
0,
1.27,
12.6
or
123.8
mg/
kg/
day,
F0
males
and
0,
1.63,
15.5
or
157.4
mg/
kg/
day,
F0
females;
0,
0,
1.53,
15.2
or
152.1
mg/
kg
bw/
day,
F1
males
and
1.83,
18.3
or
192.4
mg/
kg
bw/
day,
F1
females).
Matings
were
performed
twice
for
each
generation.

Parental
toxicity:
At
1750
ppm,
mean
body
weights
were
significantly
lower
by
the
end
of
premating
in
all
parental
animals
(
F0
males
and
females
­
5%
and
­
6%
below
controls,
respectively,
at
Week
8;
F1
males
and
females
­
11%
and
­
12%
below
controls,
respectively,
at
the
end
of
Week
13).
Premating
mean
body
weight
gain
of
parental
animals
was
also
lower
than
controls
(­
10%
and
­
18%,
F0
males
and
females,
respectively,
and
­
12%
and
­
14%,
F1
males
and
females,
respectively),
and
slight
reductions
(<
10%)
in
food
consumption
were
reported.
Some
increases
in
absolute/
relative
organ
weights
were
observed
(
e.
g.,
liver,
kidney)
but
were
not
accompanied
by
microscopic
findings.
There
were
no
treatment­
related
effects
on
survival,
clinical
signs
of
toxicity
or
gross/
microscopic
pathology
(
microscopic
examination
included
evaluation
of
nasal
turbinates).
The
parental
systemic
LOAEL
is
1750
ppm
(
123.8
mg/
kg
bw/
day
in
males,
157.4
mg/
kg
bw/
day
in
females),
based
on
reduced
body
weight/
weight
gain
during
premating
in
both
generations.
The
parental
systemic
NOAEL
is
175
ppm
(
12.6
mg/
kg
bw/
day
in
males,
15.5
mg/
kg
bw/
day
in
females).

Offspring
toxicity:
At
1750
ppm,
mean
pup
body
weights
were
reduced
on
lactation
Day
21
(
17%
Page
53
of
118
and
9%
in
F1a
and
F1b
pups,
respectively;
23%
and
16%
in
F2a
and
F2b
pups,
respectively;
p<
0.01
except
F1b
pups
NS).
No
effects
on
pup
survival,
birth
weight,
gross
abnormalities
or
other
offspring
parameters
were
observed.
The
offspring
LOAEL
is
1750
ppm
(
123.8
mg/
kg
bw/
day,
males;
157.4
mg/
kg
bw/
day,
females),
based
on
reduced
pup
body
weight
during
lactation.
The
offspring
NOAEL
is
175
ppm
(
12.6
mg/
kg
bw/
day,
males;
15.5
mg/
kg
bw/
day,
females.

Reproductive
toxicity:
There
was
no
evidence
of
reproductive
toxicity
observed
at
any
dose
tested
in
this
study.
The
reproductive
NOAEL
is
1750
ppm
(
123.8
mg/
kg
bw/
day
in
males,
157.4
mg/
kg
bw/
day
in
females).
A
reproductive
toxicity
LOAEL
was
not
determined
in
this
study.

This
study
is
classified
Acceptable/
guideline
and
satisfies
the
guideline
requirement
for
a
2­
generation
reproductive
study
(
OPPTS
870.3800);
OECD
416
in
the
rat.

(
3)
In
a
2­
generation
reproduction
toxicity
study,
acetochlor
was
administered
continuously
in
the
diet
to
CD
(
SD)
IGS
BR
(
Sprague­
Dawley)
rats
(
26/
sex/
dose)
at
nominal
dose
levels
of
0,
200,
600,
or
1750
ppm
(
equivalent
to
0,
21.2,
65.6,
and
196.4
mg/
kg/
day
in
F1
males
and
0,
22.4,
70.9,
and
215.9
mg/
kg/
day
in
F1
females).
F0
animals
were
given
test
article
diet
formulations
for
10
weeks
prior
to
mating
to
produce
the
F1
litters.
On
postnatal
day
(
PND)
29,
F1
animals
(
26/
sex/
dose)
were
selected
to
become
the
F1
parents
of
the
F2
generation
and
were
given
the
same
concentration
test
formulation
as
their
dams.
F1
animals
were
given
test
formulations
for
10
weeks
prior
to
mating
to
produce
the
F2
litters.
Dietary
administration
of
the
test
material
to
all
animals
was
continuous
throughout
the
study.
The
analytical
data
indicated
that
the
mixing
procedure
was
adequate
and
that
variability
was
within
acceptable
ranges.

Parental
toxicity
and
tumorigenicity:
No
treatment­
related
clinical
observations
were
observed
in
this
study.
Survival
of
parental
animals
was
unaffected
by
treatment
at
any
dose
level.
Mean
premating
body
weight,
body
weight
gain,
and
food
consumption
were
consistently
and
statistically
significantly
reduced
in
both
F0
and
F1
animals
at
the
high
dose
level
(
1750
ppm).
In
addition,
mean
body
weight
and
body
weight
gain
were
reduced
in
F0
and
F1
dams
during
early
gestation
and
lactation
at
the
high­
dose
level,
often
coinciding
with
decreased
food
consumption.
No
effects
of
treatment
were
observed
at
600
and
200
ppm.
At
1750
ppm,
relative
kidney,
liver,
and
thyroid
weights
were
significantly
increased
for
F0
and
F1
parental
males
and
females,
and
relative
ovarian
weights
were
decreased
for
F0
and
F1
females
as
compared
to
controls.
Increased
relative
liver
and
thyroid
weights
were
also
observed
at
600
ppm.
However,
there
were
no
gross
or
histopathological
changes
in
these
tissues
that
appeared
to
be
associated
with
treatment.

Histopathological
evaluation
revealed
treatment­
related
incidences
of
benign
prolferative
lesions
(
focal
epithelial
hyperplasia
and
polypoid
adenomata)
in
the
epithelial
lining
of
the
ethmoid
region
of
the
nasal
cavity
in
F0
and
F1
adult
animals
receiving
1750
ppm
acetochlor
and
in
F1
animals
at
the
600
ppm
level.
Although
no
clear
evidence
of
malignant
change
was
apparent,
the
animals
were
just
over
4
months
of
age
and
had
been
exposed
to
acetochlor
for
approximately
18
weeks
(
F0)
or
25
weeks
(
F1)
when
these
lesions
were
observed.
Minimally
increased
brown
pigment
(
lipofuscin)
was
observed
in
the
olfactory
mucosa,
mainly
in
the
lamina
propria
and
occasionally
in
the
basal
Page
54
of
118
epithelium
in
most
animals
receiving
600
and
1750
ppm
in
both
F0
and
F1
generations
and
also
in
F1
females
at
the
200
ppm
dose
level;
however,
this
finding
was
not
considered
to
be
of
toxicological
significance.
The
parental
LOAEL
is
600
ppm
(
65.6
mg/
kg/
day
in
F1
males;
70.9
mg/
kg/
day
in
F1
females),
based
on
focal
hyperplasia
and
polypoid
adenomata
in
the
nasal
epithelium
of
adult
F1
offspring
at
study
termination.
The
parental
NOAEL
is
200
ppm
(
21.2
mg/
kg/
day
in
F1
males;
22.4
mg/
kg/
day
in
F1
females).

Offspring
toxicity:
A
significant
treatment­
related
decrease
in
the
number
of
implantations
was
observed
at
1750
ppm
in
both
the
F0
and
F1
generations.
In
addition,
the
mean
number
of
live
pups
on
postnatal
day
1
decreased
in
a
dose
related
manner
in
both
the
F1
and
F2
litters.
Mean
live
F1
pups
per
litter
was
significantly
decreased
at
1750
ppm,
and
the
mean
number
of
live­
plus­
dead
pups
per
litter
was
statistically
significantly
lower
in
F1
and
F2
litters
at
1750
ppm
and
also
in
F2
litters
at
600
ppm.
These
findings
are
considered
possible
evidence
of
fetal
loss.
Postnatal
survival
was
not
affected
by
treatment.
Initial
mean
body
weights
of
F1
pups
of
both
sexes
were
significantly
decreased
in
both
the
600
and
1750
ppm
groups.
At
the
1750
ppm
level,
significantly
decreased
mean
F1
pup
body
weights
were
also
observed
in
late
lactation
and
overall
body
weight
gain
was
significantly
reduced
as
compared
to
controls.
In
F2
litters,
male
and
female
pup
body
weights
were
reduced
in
both
1750
and
600
ppm
dose
levels
from
mid­
to
late­
lactation,
and
overall
F2
pup
weight
gain
was
reduced.
A
decrease
in
anogenital
distance
in
F2
males
on
PND
1,
and
a
3­
day
treatment­
related
delay
in
the
day
of
vaginal
opening
in
F1
females
at
the
high
dose
level
appeared
to
be
associated
with
delayed
growth.
Decreases
in
absolute
mean
brain
weights
of
F1
males
and
F2
males
and
females
were
noted
at
1750
ppm.
On
a
relative
to
body
weight
basis,
ratios
were
statistically
increased
for
the
brain
in
F2
pups
at
the
600
ppm
dose
as
well.
Mean
absolute
spleen
weights
were
also
decreased
in
F1
males
and
in
both
sexes
of
the
F2
pups
at
both
the
mid
and
high
dose
levels.
They
were
also
reduced
on
a
relative
basis
in
600
ppm
F2
females.
Mean
absolute
thymus
weights
were
also
decreased
in
F2
pups
at
the
high
dose
level,
but
not
relative
to
body
weight.
No
macroscopic
changes
were
reported.
The
offspring
LOAEL
is
600
ppm
(
65.6
mg/
kg/
day
in
F1
males;
70.9
mg/
kg/
day
in
F1
females),
based
on
decreased
F2
litter
size
at
birth,
decreased
F1
and
F2
pup
body
weights
during
lactation,
and
decreased
absolute
and
relative
spleen
weights
in
F2
weanlings;
and
on
the
presence
of
focal
hyperplasia
and
polypoid
adenomata
in
the
nasal
epithelium
of
adult
F1
offspring
at
study
termination.
The
offspring
NOAEL
is
200
ppm
(
21.2
mg/
kg/
day
in
F1
males;
22.4
mg/
kg/
day
in
F1
females).

Reproductive
toxicity:
The
number
of
implantations
decreased
in
a
dose
related
manner
in
both
the
F0
and
F1
generations,
the
differences
reaching
statistical
significance
at
the
high
dose
level
in
both
generations.
In
addition,
the
mean
number
of
live
pups
on
postnatal
day
1
decreased
in
a
dose
related
manner
in
both
the
F0
and
F1
litters.
Due
to
the
lack
of
corpora
lutea
count
data,
the
origin
of
the
decreased
implantation
counts
could
not
be
determined;
therefore,
this
was
conservatively
interpreted
as
a
possible
effect
on
reproduction.
The
LOAEL
for
reproductive
toxicity
is
1750
ppm
(
196.4
mg/
kg/
day
in
F1
males;
215.9
mg/
kg/
day
in
F1
females),
based
on
decreased
number
of
implantations.
The
reproductive
toxicity
NOAEL
is
600
ppm
(
65.6
mg/
kg/
day
in
F1
males;
70.9
mg/
kg/
day
in
F1
females).
Page
55
of
118
This
study
is
Acceptable/
Guideline
(
870.3800)
and
satisfies
the
requirements
for
a
two­
generation
reproduction
and
fertility
effects
study
in
rats.
Several
deficiencies
have
been
identified,
but
do
not
compromise
the
interpretation
of
the
study.
These
include:
the
lack
of
reproductive
and
viability
indices
and
the
absence
of
historical
control
pathology
incidence
data.
These
data
should
be
submitted
as
confirmatory.

4.2.5
Additional
Information
from
Literature
Sources
No
additional
information
pertinent
to
FQPA
considerations
was
identified.

4.2.6
Pre­
and/
or
Postnatal
Toxicity
4.2.6.1
Determination
of
Susceptibility
The
available
developmental
toxicity
studies
in
two
species
do
not
show
evidence
of
increased
susceptibility
of
the
offspring.
No
evidence
of
increased
susceptibility
was
observed
in
three
twogeneration
reproductive
toxicity
studies
in
the
rat.
Toxicity
to
offspring
was
observed
at
or
above
maternally
toxic
dose
levels.

4.2.6.2
Degree
of
Concern
Analysis
and
Residual
Uncertainties
for
Pre
and/
or
Post­
natal
Susceptibility
Concern
for
increased
susceptibility
is
low
since
toxicity
to
offspring
was
observed
only
at
maternally
toxic
doses
in
developmental
toxicity
studies
in
the
rat
and
rabbit
and
three
multigeneration
reproductive
toxicity
studies
in
the
rat.
Clear
NOAELs
for
offspring
and
adults
were
observed
in
all
of
the
studies.

4.3
Recommendation
for
a
Developmental
Neurotoxicity
Study
4.3.1
Evidence
that
supports
requiring
a
Developmental
Neurotoxicity
study
Acetochlor
has
shown
neurotoxic
potential
in
several
studies
in
more
than
one
species
(
see
summary
above
in
Section
4.2.2).
Pre­
and/
or
post­
natal
sensitivity
for
neurotoxic
effects
of
acetochlor
is
not
known.
The
HED
HIARC
(
HED
TXR#
013858,
meeting
of
May
27,
1999)
recommended
that
a
developmental
neurotoxicity
study
be
submitted,
based
on
these
neurotoxicity
findings.
Since
that
time,
the
rat
acute
and
subchronic
neurotoxicity
studies
have
been
submitted.
Results
of
the
acute
neurotoxicity
study
show
a
LOAEL
of
500
mg/
kg
(
single
gavage
dose)
based
on
decreased
motor
activity
in
females
(
NOAEL
of
150
mg/
kg)
and
clinical
signs
of
toxicity
including
hunched
posture,
piloerection
and
staining
around
the
mouth;
in
single
animals,
decreased
activity,
chromodacryorrhea,
hypothermia,
labored
breathing,
sides
pinched
in
and
upward
curvature
of
the
spine
were
reported.
In
the
subchronic
rat
neurotoxicity
study,
transiently
decreased
hindlimb
grip
strength
(
only
at
week
2)
was
observed
in
males,
but
not
females,
also
at
the
highest
dose
tested
of
139
mg/
kg/
day.
The
two
developmental
toxicity
studies
in
rats
­
both
dosing
pregnant
rats
via
Page
56
of
118
gavage
­
showed
clinical
signs
at
400
mg/
kg/
d
and
600
mg/
kg/
d
(
with
death
observed
at
the
higher
dose).

4.3.2
Evidence
that
supports
not
requiring
a
Developmental
Neurotoxicity
study
No
evidence
of
increased
fetal
or
offspring
susceptibility
to
acetochlor
was
observed
in
four
developmental
toxicity
studies
(
two
rat
and
two
rabbit),
nor
in
three
two­
generation
reproductive
toxicity
studies
in
the
rat.
No
evidence
of
neuropathology
or
overt
neurobehavioral
effects
to
offspring
was
observed
in
these
studies.
Although
a
transient
decrease
in
hindlimb
grip
strength
was
observed
in
males
at
week
2,
there
was
no
evidence
of
persistent
neurobehavioral
effects
in
the
subchronic
neurotoxicity
study
up
to
the
highest
tested
dose
(
139/
166.5
mg/
kg/
d
via
the
diet).

4.3.2.1
Rationale
for
the
UFDB
(
when
a
DNT
is
recommended)

It
is
possible
that
the
results
of
the
DNT
study
could
impact
the
current
selected
regulatory
dose
for
acute
oral
exposure,
since
the
NOAEL
used
for
that
risk
assessment
endpoint
(
150
mg/
kg/
day)
is
greater
than
the
NOAELs
in
the
reproductive
toxicity
study
(
21
mg/
kg/
day)
on
acetochlor.
A
DNT
study
will
likely
be
conducted
at
dose
levels
similar
to
those
of
the
two­
generation
reproductive
toxicity
study.
A
10X
database
uncertainty
factor
(
UF
DB
)
is
proposed
for
acetochlor
to
account
for
the
lack
of
a
DNT.

4.4
Hazard
Identification
and
Toxicity
Endpoint
Selection
Table
4.4
summarizes
the
endpoints
chosen
for
use
in
this
risk
assessment.

4.4.1
Acute
Reference
Dose
(
aRfD)
­
General
Population
Including
Females
Age
13­
49
Study
Selected:
Acute
oral
neurotoxicity
screening
in
the
rat
MRID
No.
45357501
Executive
Summary:
See
Neurotoxicity
Section
of
this
document
(
4.2.2)

Dose
and
Endpoint
for
Establishing
aRfD:
150
mg/
kg,
based
on
decreased
motor
activity
in
females
at
500
mg/
kg
on
the
day
of
dosing.

Uncertainty
Factor
(
UF):
1000x
(
10x
for
interspecies
variation,
10x
for
intraspecies
variation
and
10x
UF
DB
for
lack
of
developmental
neurotoxicity
study)

Comments
about
Study/
Endpoint/
Uncertainty
Factor:
The
effect
observed
at
the
selected
endpoint
(
decreased
motor
activity
in
females
on
the
day
of
dosing)
occurred
following
a
single
dose.
This
endpoint
is
considered
protective
of
females
age
13­
49
because
there
are
no
lower
relevant
endpoints
that
may
potentially
result
from
a
single
exposure.
Page
57
of
118
Acute
RfD
for
General
Population
=
150
mg/
kg
(
NOAEL)
=
0.15
mg/
kg
1000
(
UF)

4.4.2
Chronic
Reference
Dose
(
cRfD)

Study
Selected:
Chronic
(
1­
year)
oral
toxicity
in
the
dog
MRID
No.
41565118
Executive
Summary:
In
a
chronic
toxicity
study
(
MRID
41565118),
SC­
5676
(
acetochlor
tech.,
90.5%
a.
i.,
batch/
lot
#
1
and
3)
was
administered
to
5
beagle
dogs/
sex/
dose
in
gelatin
capsules
at
dose
levels
of
0
(
empty
capsules
only),
2,
10
or
50
mg/
kg
bw/
day)
for
52
weeks.
In
addition
to
the
standard
parameters
evaluated
in
a
chronic
oral
toxicity
study
in
the
dog,
plasma
and
erythrocyte
cholinesterase
activities
(
at
12,
24
and
50
weeks)
and
brain
cholinesterase
activity
(
termination)
were
evaluated.
A
neurological
evaluation
(
tests
examining
cranial
nerve
function,
segmental
reflexes,
postural
reactions
and
general
observations)
was
also
performed
at
Week
47
to
assess
treatmentrelated
signs
of
toxicity.

At
10
mg/
kg/
day,
male
dogs
showed
an
increased
incidence
of
salivation
following
dosing
throughout
the
study
(
primarily
animal
#
1374).
Males
also
showed
increased
incidence
of
renal
interstitial
nephritis
(
incidence
in
control
to
high
dose
0/
5,
0/
5,
2/
5
and
5/
5,
respectively)
and
renal
chronic
vasculitis
(
control
to
high
dose
0/
5,
0/
5,
3/
5,
4/
5),
tubular
degeneration
of
the
testes
(
control
to
high
dose
0/
5,
0/
5,
4/
5
and
5/
5,
respectively),
hypospermia
of
the
epididymides
(
control
to
high
dose
0/
5,
1/
5,
2/
5
and
5/
5,
respectively)
and
reduced
glycogen
in
the
liver
(
control
to
high
dose
0/
5,
1/
5,
2/
5
and
4/
5,
respectively).
At
50
mg/
kg/
day,
the
incidence
of
salivation
was
markedly
increased
in
females
(
beginning
in
week
13)
as
well
as
males
and
neurologic
symptoms
including
head
shaking/
nodding
and
ataxia
(
also
hunched
posture,
abnormal
gait,
tremor)
were
reported
in
both
sexes
towards
the
later
weeks
of
the
study:
severity
of
neurological
symptoms
resulted
in
unscheduled
sacrifice
of
females
1325
in
Week
39,
1347
in
Week
46,
1329
in
Week
48
and
1311
in
Week
51
and
males
1366
and
1368
in
Week
46.
Mean
body
weight
gain
was
reduced
(
significantly
during
weeks
13­
26,
where
weight
losses
of
­
0.1
kg
in
males
and
­
1.2
kg
in
females
were
observed;
early
sacrifice
of
many
animals
during
the
last
weeks
of
the
study
left
only
a
few
animals
for
body
weight
evaluation
at
termination).
Water
consumption
was
increased.
Changes
in
clinical
chemistry
values
included
increased
ALT,
GGT
(
males)
OCT
(
males),
cholesterol
(
males)
and
triglycerides,
along
with
increased
urea,
creatinine
and
decreased
glucose.
In
females,
statistically
significant
increases
in
plasma
AChE
at
week
24
(+
26%)
and
BChE
at
week
24
(+
24%)
and
50
(+
33%)
were
observed.
At
weeks
23
and
49,
significantly
increased
urinary
volume
in
males
and
reduced
specific
gravity
in
both
sexes
were
observed.
Organ
weight
changes
included
increased
relative
brain
weight
in
females,
decreased
testicular
weights
in
males
(
abs
and
rel)
and
possibly
increased
absolute
adrenal
weights
in
females,
increased
relative
liver
weights
in
both
sexes
and
thyroid
weights
in
males.
Kidneys
showed
grossly
visible
abnormal
shape
and
multiple
pale
areas
in
males
and
females.
In
the
kidney
of
most
or
all
animals
of
both
sexes,
cortical
fibrosis
and/
or
scarred
areas,
collecting
duct
hyperplasia,
dilatation
of
Bowman's
space,
cortical
atrophy,
transitional
cell
hyperplasia
and
Page
58
of
118
lipofuchsin
pigment
in
cortical
tubules
(
one
female
also
showed
papillary
necrosis
and
focal
necrosis)
were
reported
in
the
microscopic
evaluation.
Brain
histopathology
(
degeneration
of
the
granular
layer,
4/
5
males
and
3/
5
females;
depletion
of
Purkinje
cells,
4/
5
males
and
2/
5
females;
demyelination
and
degeneration
of
granule
cell
axons,
1/
5
males)
was
observed,
along
with
maturation
arrest
within
the
testes
(
5/
5
males),
pigment
in
hepatocytes
(
1/
5
each,
male
and
female).
There
were
no
treatment­
related
effects
observed
on
brain
cholinesterase
activity
or
on
ophthalmologic
or
hematological
parameters.
The
LOAEL
is
10
mg/
kg/
day,
based
on
testicular,
hepatic
and
renal
histopathology
and
increased
salivation
in
males.
The
NOAEL
is
2
mg/
kg/
day.

This
chronic
study
in
the
dog
is
classified
as
Acceptable/
guideline
and
satisfies
the
guideline
requirement
for
a
chronic
oral
study
[
OPPTS
870.4100,
OECD
452]
in
the
dog.

Dose
and
Endpoint
for
Establishing
a
cRfD:
2.0
mg/
kg/
day,
based
on
excessive
salivation
and
histopathology
of
the
testes,
kidney
and
liver
at
10
mg/
kg/
day.

Uncertainty
Factor
(
UF):
100x
(
10x
for
interspecies
variation
and
10x
for
intraspecies
variation)

Comments
about
Study/
Endpoint/
Uncertainty
Factor:
A
10x
UF
DB
was
not
used
in
calculation
of
the
UF
for
this
endpoint
because
the
results
of
the
developmental
neurotoxicity
study
are
not
expected
to
affect
this
risk
assessment.

Chronic
RfD
=
2.0
mg/
kg
(
NOAEL)
=
0.02
mg/
kg
100
(
UF)

4.4.3
Incidental
Oral
Exposure
(
Short
and
Intermediate
Term)

Acetochlor
has
not
been
approved
for
residential
uses;
therefore,
selection
of
a
toxicity
endpoint
is
not
necessary
for
this
exposure
scenario
at
this
time.

4.4.4
Dermal
Absorption
A
dermal
absorption
factor
of
20%
was
estimated
from
an
in
vivo
rat
dermal
absorption
study
(
MRID
41778303),
based
on
absorption
observed
following
a
10­
hr
dermal
exposure
to
acetochlor
(
see
HIARC
Document,
TXR
#
00135858).

4.4.5
Dermal
Exposure
(
Short,
Intermediate
and
Long
Term)

4.4.5.1
Dermal
Exposure:
Short­
Term
(
1­
30
Days)

Study
Selected:
21­
day
dermal
toxicity
in
the
rabbit
Page
59
of
118
MRID
No.
00116637
Executive
Summary:
In
a
21
day
dermal
toxicity
study
(
MRID
00116637),
acetochlor
as
MON
­
097
(
94.5%;
Lot
No.
NBP­
1737874)
was
applied
to
the
abraded
and
intact
shaved
skin
of
groups
of
10
New
Zealand
white
rabbits/
sex/
dose
at
dose
levels
of
0,100,
400
or
1200
mg/
kg
bw/
day,
6
hours/
day
for
5
days/
week
during
a
21­
day
period.

At
1200
mg/
kg/
day,
excessive
mortality
(
8/
10
males
and
7/
10
females)
was
observed
(
first
death
occurred
on
Day
7,
last
on
Day
19).
Clinical
signs
of
toxicity
were
first
observed
on
Day
5
and
included
nasal
and
ocular
discharge,
nasal
congestion;
this
group
also
exhibited
possible
treatmentrelated
signs
of
anorexia,
respiratory
congestion,
labored
breathing,
ataxia,
hypoactivity,
rigid
body,
tonic
convulsions,
decreased
limb
tone,
impaired
righting
reflex,
emaciation
and
hypothermia.
No
deaths
were
seen
at
lower
levels
and
there
were
no
adverse
effects
on
body
weight,
hematology,
clinical
chemistry
or
organ
weight
but
it
is
noted
that
there
were
insufficient
surviving
high
dose
animals
to
evaluate
effects
at
termination.
Histopathology
revealed
skin
lesions
at
the
application
sites
in
all
treatment
groups.
Irritation
consisted
of
erythema
and
edema;
desquamation
was
observed
both
macroscopically
and
microscopically
in
all
dosed
groups.
At
day
21,
the
intensity
of
dermal
irritation
was
higher
in
the
mid­
dose
group
than
in
the
low
dose
group.
The
LOAEL
(
for
systemic
effects)
is
1200
mg/
kg/
day,
based
on
mortality
and
clinical
signs
of
toxicity.
The
NOAEL
is
400
mg/
kg/
day.
The
LOAEL
(
for
local
dermal
effects)
is
100
mg/
kg/
day,
based
on
skin
lesions.
The
NOAEL
is
not
established.

This
21­
day
dermal
toxicity
study
in
the
rabbits
is
acceptable/
guideline;
it
satisfies
the
guideline
requirement
for
a
21­
day
dermal
toxicity
study
(
OPPTS
870.3200;
OECD
410)
in
the
rabbit.

Dose
and
Endpoint
for
Risk
Assessment:
400
mg/
kg/
day,
based
on
mortality
and
clinical
signs
at
1200
mg/
kg/
day.

Comments
about
Study/
Endpoint:
The
route
and
duration
of
exposure
is
appropriate
for
this
exposure
scenario.
Although
mortality
is
an
endpoint,
it
was
seen
at
a
dose
level
which
is
higher
than
the
limit
dose.

4.4.5.2
Dermal
Exposure:
Intermediate­
Term
(
1­
6
Months)

Study
Selected:
Subchronic
oral
toxicity
in
the
dog
(
two
studies
considered
together)

MRID
Nos.
00050928
and
41565116
Executive
Summaries:
(
1)
In
a
119­
day
oral
toxicity
study
(
MRID
00050928),
CP
55097
(
acetochlor
tech.,
91.3%
a.
i.,
lot
#
XHK­
119)
was
administered
to
6
beagle
dogs/
sex/
dose
in
gelatin
capsules
at
dose
levels
of
0
(
capsule
only),
25,
75
or
200
mg/
kg
bw/
day.
Due
to
vomiting
observed
in
a
pilot
study,
mid­
and
high­
dose
animals
received
gradually
increasing
dosages
as
follows
to
acclimate
the
dogs
to
the
test
material:
mid­
dose,
25
mg/
kg/
day
for
the
first
week,
50
mg/
kg/
day
for
Page
60
of
118
the
second
week,
then
75
mg/
kg/
day
for
the
duration
of
the
study
and
(
2)
high
dose,
50
mg/
kg/
day
for
the
first
week,
100
mg/
kg/
day
for
the
second
week,
150
mg/
kg/
day
for
the
third
week
and
200
mg/
kg/
day
for
the
duration
of
the
study.

At
25
mg/
kg/
day,
increased
liver
weights
in
females
(
abs.
+
22%,
NS
and
rel
+
27%,
p<
0.05)
and
SGPT
(
about
2­
fold
above
controls)
were
observed
but
were
not
considered
sufficient
to
establish
a
LOAEL
due
to
lack
of
corresponding
pathology
or
other
liver
enzyme
effects.
Although
mean
body
weights
of
males
were
somewhat
lower
than
controls
during
the
study,
this
was
due
to
lower
initial
body
weights
and
gains
were
comparable.
At
75
mg/
kg/
day,
one
male
(#
1281)
died
at
week
11,
with
diarrhea
occurring
during
week
and
inactivity
in
the
last
weeks
prior
to
death.
Mean
body
weights
were
lower
for
much
of
the
study
and
at
termination
were
+
13%
and
+
15%
lower
than
controls
for
males
and
females,
respectively;
weight
gain
at
termination
was
reduced
by
­
42%
in
males
and
­
50%
in
females.
Food
consumption
tended
to
be
lower
at
all
weeks
in
males
(
usually
4
to
8%
below
controls),
but
not
significantly.
Increased
SGPT
was
observed
in
males
and
females
at
some
time
points.
Relative
liver
weights
were
increased
(+
32%
in
males
and
+
22%,
females,
p<
0.05).
Atrophy
of
the
liver
in
one
male
and
infiltration
of
the
kidney
in
one
male
were
observed.
At
200
mg/
kg/
day,
5
males
and
6
females
died
or
were
sacrificed
in
extremis,
beginning
at
week
5,
with
no
females
surviving
by
Week
12
and
only
one
male
surviving
from
week
8
through
17;
severity
of
clinical
signs
(
bloody
diarrhea,
vomiting)
increased,
increased
relative
liver
weight
(
males
+
13%
and
females
+
17%).
Food
consumption
in
males
and
females
was
significantly
reduced
at
several
time
points
(
later
times
not
analyzed
due
to
mortality/
unscheduled
sacrifice).
Mean
body
weights
showed
statistically
significant
reductions
in
surviving
males
by
Week
4
through
7
(
about
­
30%
below
controls
at
week
7),
with
weight
loss
observed
during
that
time
and
surviving
females
showed
statistically
significantly
reduced
mean
body
weights
from
weeks
3
through
10
(­
25
to
­
47%
below
controls).
Some
dogs
showed
proteinuria
and
hematuria,
primarily
at
Month
2
(
evaluations
not
performed
later
due
to
mortality).
Microscopic
findings
included
hypercellularity
of
the
bone
marrow
in
3
males
and
2
females,
atrophy
of
the
liver
in
one
male
and
one
female,
infiltration
of
the
kidneys
in
2
males
and
4
females
and
thymic
atrophy
in
4
males
and
3
females.
There
were
no
biologically
significant
effects
on
hematology
parameters
or
gross
pathology
(
although
statistically
significantly
decreased
Hgb
and
Hct
were
seen
in
females
at
25
mg/
kg/
day,
no
dose­
response
was
observed
and
these
decreases
were
not
considered
treatment­
related).
The
LOAEL
is
75
mg/
kg/
day,
based
on
decreased
body
weight/
weight
gain,
mortality
and
slight
effects
on
the
liver
and
kidney.
The
NOAEL
is
25
mg/
kg/
day.

This
119­
day
oral
toxicity
study
in
the
dog
is
classified
as
Acceptable/
guideline
and
satisfies
the
guideline
requirement
for
a
subchronic
oral
toxicity
study
(
OPPTS
870.3150;
OECD
409)
in
the
dog.

(
2)
In
a
90­
day
oral
toxicity
study
(
MRID
41565116),
SC­
5675
(
acetochlor
tech.,
91%
a.
i.,
batch/
lot
#
1
and
3)
was
administered
to
4
beagle
dogs/
sex/
dose
in
gelatin
capsules
at
dose
levels
of
0,
2.0,
10
or
60
mg/
kg
bw/
day.
In
addition
to
the
standard
parameters
evaluated
in
a
guideline
subchronic
oral
study,
plasma,
erythrocyte
and
brain
cholinesterase
were
evaluated.
Page
61
of
118
At
60
mg/
kg/
day,
increased
incidence
of
mucous
diarrhea
was
reported
for
both
sexes,
beginning
during
week
1,
and
3
high
dose
females
and
1
male
tended
to
have
more
liquid
feces
than
other
animals.
Females
had
an
increased
incidence
of
salivation
during
the
last
5
weeks
of
the
study,
occasional
emesis
and
in
2
females,
vocalization
during
defecation
was
reported
from
weeks
8
through10.
A
statistically
significantly
decrease
in
mean
body
weight
gain
was
observed
in
males
(­
32%
less
than
controls)
and
females
(­
40%);
in
females
food
consumption
was
reduced
at
weeks
12
and
13
(­
15
and
­
24%
below
controls,
respectively).
Also
observed
were
mild
anemia
in
females
(
Hct
­
13%,
Hb
­
9%,
RBC
­
14%),
increased
alanine
aminotransferase
(
more
than
2­
fold
greater
in
males
and
females),
slightly
reduced
blood
glucose
(
males
and
females
­
13%
at
week
12)
and
slightly
increased
relative
liver
weight
(
males
+
13%
and
females
+
17%).
There
were
no
treatment­
related
effects
observed
at
#
10
mg/
kg/
day.
No
mortality,
abnormalities
of
the
urinalysis
or
ophthalmologic
parameters,
nor
alterations
in
the
gross
or
microscopic
pathological
evaluation
were
observed
at
any
dose
level.
Plasma,
erythrocyte
and
brain
cholinesterase
were
not
affected
by
treatment.
The
LOAEL
is
60
mg/
kg/
day,
based
on
clinical
signs
of
toxicity,
decreased
body
weight
gain,
mild
anemia,
slightly
increased
relative
liver
weight
and
increased
serum
alanine
aminotransferase.
The
NOAEL
is
10
mg/
kg/
day.

This
90­
day
oral
toxicity
study
in
the
dog
is
classified
as
Acceptable/
guideline
and
satisfies
the
guideline
requirement
for
a
90­
day
oral
toxicity
study
(
OPPTS
870.3150;
OECD
409)
in
the
dog.
Although
the
test
material
purity
was
unspecified
in
this
study
report,
information
on
the
purity
was
obtained
from
other
studies
on
SC­
5676
from
this
laboratory
in
which
batch
#
1
and
3
were
used.
A
gradual
change
in
the
test
material
coloration
of
the
sample
for
daily
use
(
not
bulk
storage
sample)
was
reported,
but
the
NOAEL/
LOAEL
for
this
study
are
within
a
consistent
range
of
other
acceptable
subchronic
and
chronic
oral
dog
studies.
When
considered
together
with
the
information
from
these
other
available
studies
on
the
oral
toxicity
studies
on
the
dog,
this
study
is
considered
acceptable
for
purposes
of
risk
assessment
and
no
additional
data
or
subchronic
studies
in
the
dog
are
required
at
this
time.

Dose
and
Endpoint
for
Risk
Assessment:
25
mg/
kg/
day,
based
on
clinical
signs
of
toxicity,
decreased
body
weight
gain,
mild
anemia,
slightly
increased
relative
liver
weight
and
increased
serum
alanine
aminotransferase
at
60
mg/
kg/
day;
data
from
two
dog
subchronic
studies
were
used..

Comments
about
Study/
Endpoint:
Oral
studies
were
selected
because
a
dermal
study
of
the
appropriate
duration
was
not
available.
The
two
subchronic
dog
studies
were
considered
together
to
provide
the
highest
NOAEL
and
the
lowest
LOAEL
(
Study
1
­
NOAEL
25/
LOAEL
75
and
Study
2
­
NOAEL
10/
LOAEL
60).
The
selection
of
this
endpoint
is
further
supported
by
the
NOAELs
and
LOAELs
for
multigeneration
reproductive
toxicity
studies
in
rats
(
summarized
in
Table
4.1b;
also
see
Section
4.2.4
on
reproductive
toxicity
for
executive
summaries).
Since
an
oral
NOAEL
was
selected,
the
20%
dermal
absorption
factor
should
be
used
in
risk
assessment.
Page
62
of
118
4.4.5.3
Dermal
Exposure:
Long­
Term
(>
6
Months)

Study
Selected:
Chronic
(
1­
year)
oral
toxicity
in
the
dog
MRID
No.
41565118
Executive
Summary:
See
Chronic
RfD
Section,
above
(
4.4.3)

Dose
and
Endpoint
for
Risk
Assessment:
2.0
mg/
kg/
day,
based
on
excessive
salivation
and
histopathology
of
the
testes,
kidney
and
liver
at
10
mg/
kg/
day.

Comments
about
Study/
Endpoint:
An
oral
study
was
selected
because
a
dermal
study
of
the
appropriate
duration
was
not
available.
Since
an
oral
NOAEL
was
selected,
the
20%
dermal
absorption
factor
should
be
used
in
risk
assessment.

4.4.6
Inhalation
Exposure
(
Short,
Intermediate
and
Long
Term)

4.4.6.1
Inhalation
Exposure:
Short­
Term
(
1­
30
Days)

Study
Selected:
Developmental
toxicity
in
the
rat
(
oral)

MRID
Nos.
41592005,
42054903
Executive
Summary:
See
Developmental
Toxicity
Section
of
this
document
(
4.2.3)

Dose
and
Endpoint
for
Risk
Assessment:
Developmental
NOAEL
=
150
mg/
kg/
day,
based
on
increased
fetal
early
resorptions
and
postimplantation
loss,
reduced
mean
fetal
weight
at
600
mg/
kg/
day.

Comments
about
Study/
Endpoint:
An
oral
study
was
selected
because
there
was
no
inhalation
study
of
appropriate
duration.
The
effects
observed
at
the
selected
endpoint
(
early
resorptions,
postimplantation
loss)
are
presumed
to
occur
after
a
single
dose.
For
route­
to­
route
extrapolation,
absorption
via
the
inhalation
route
is
assumed
to
be
equivalent
to
oral
absorption.

4.4.6.2
Inhalation
Exposure:
Intermediate­
Term
(
1­
6
Months)

Study
Selected:
Subchronic
oral
toxicity
in
the
dog
(
two
studies
considered
together)

MRID
Nos.
00050928
and
41565116
Executive
Summaries:
See
Dermal
Exposure:
Intermediate­
Term,
above
(
Section
4.4.5.2)

Dose
and
Endpoint
for
Risk
Assessment:
25
mg/
kg/
day,
based
on
clinical
signs
of
toxicity,
decreased
Page
63
of
118
body
weight
gain,
mild
anemia,
slightly
increased
relative
liver
weight
and
increased
serum
alanine
aminotransferase
at
60
mg/
kg/
day;
data
from
two
dog
subchronic
studies
were
used.

Comments
about
Study/
Endpoint/
Uncertainty
Factor:
Oral
studies
were
selected
because
there
was
no
inhalation
study
of
appropriate
duration.
The
two
subchronic
dog
studies
were
considered
together
to
provide
the
highest
NOAEL
and
the
lowest
LOAEL
on
which
to
base
the
quantitative
hazard
estimate
(
Study
1
­
NOAEL
25/
LOAEL
75
and
Study
2
­
NOAEL
10/
LOAEL
60).
The
selection
of
this
endpoint
is
further
supported
by
the
NOAELs
and
LOAELs
for
multigeneration
reproductive
toxicity
studies
in
rats
(
summarized
in
Table
4.1b;
also
see
Section
4.2.4
on
reproductive
toxicity
for
executive
summaries).
For
route­
to­
route
extrapolation,
absorption
via
the
inhalation
route
is
assumed
to
be
equivalent
to
oral
absorption.

4.4.6.3
Inhalation
Exposure:
Long­
Term
(>
6
Months)

Study
Selected:
Chronic
(
1­
year)
oral
toxicity
in
the
dog
MRID
No.
41565118
Executive
Summary:
See
Chronic
RfD
Section,
above
(
4.4.3)

Dose
and
Endpoint
for
Risk
Assessment:
2.0
mg/
kg/
day,
based
on
excessive
salivation
and
histopathology
of
the
testes,
kidney
and
liver
at
10.0
mg/
kg/
day.

Comments
about
Study/
Endpoint:
An
oral
study
was
selected
because
there
was
no
inhalation
study
of
appropriate
duration.
For
route­
to­
route
extrapolation,
absorption
via
the
inhalation
route
is
assumed
to
be
equivalent
to
oral
absorption.

4.4.7
Margins
of
Exposure
The
target
Margins
of
Exposure
(
MOEs)
for
residential
and
occupational
exposure
and
risk
assessment
are
as
follows:
Page
64
of
118
Route
of
Exposure
Duration
of
Exposure
Short­
Term
(
1­
30
Days)
Intermediate­
Term
(
1­
6
Months)
Long­
Term
(>
6
Months)

Occupational
Exposure
Dermal
100
100
100
Inhalation
100
100
100
Residential
Exposure
Incidental
Oral
NR
NR
NR
Dermal
NR
NR
NR
Inhalation
NR
NR
NR
NR­
not
required.
There
are
currently
no
registered
residential
uses
for
acetochlor.

All
MOEs
above
are
based
on
the
factors
of
10x
for
interspecies
variation
and
10x
for
intraspecies
variation.
The
(
hazard­
based)
special
FQPA
safety
factor
is
1X.

4.4.8
Recommendation
for
Aggregate
Exposure
Risk
Assessments
Since
there
are
no
residential
uses
and
therefore
no
expectation
of
exposure
to
humans
through
routes
and
pathways
other
than
the
oral,
food
plus
drinking
water,
there
is
no
further
aggregate
risk
assessment
than
the
dietary
food
plus
water
for
this
tolerance
reassessment.

4.4.9
Classification
of
Carcinogenic
Potential
4.4.9.1
Combined
Chronic
Toxicity/
Carcinogenicity
Studies
in
the
Rat
(
1)
In
an
oral
combined
chronic
toxicity/
carcinogenicity
study
(
MRID
41592004),
SC­
5676
(
acetochlor,
91.0%
a.
i.,
batch
#
s
1
and
3)
was
administered
to
50
Sprague­
Dawley
CD
rats/
sex/
dose
in
the
diet
at
dose
levels
of
0,
18,
175
or
1750
ppm
(
equivalent
to
average
daily
intakes
of
0,
0.67,
6.37
or
66.9
mg/
kg
bw/
day
for
males
and
0,
0.88,
8.53
or
92.1
mg/
kg
bw/
day
for
females)
for
104
consecutive
weeks.
In
addition,
10
CD
rats/
sex/
for
the
18
and
175
ppm
groups
and
20
CD
rats/
sex
for
the
0
and
1750
ppm
groups
were
administered
the
test
material
for
52
weeks
and
sacrificed
for
an
interim
one­
year
evaluation.

At
1750
ppm
(
HDT),
decreased
mean
body
weight/
weight
gain
(
at
week
104,
­
12%/­
14%
less
than
controls,
males
and
­
27%/­
24%,
females;
at
week
13,
significant
decreases
of
­
12%
in
males
and
­
14%
in
females
were
also
reported),
decreased
mean
food
consumption
(
overall
study
­
13%,
males
and
­
8%,
females),
decreased
food
efficiency
(
males
9.1,
9.5,
9.5
and
10.4
g
food/
g
body
weight
gain;
females
21,7,
19.3,
18.4
and
27.5
g
food/
g
body
weight
gain),
increased
incidence
of
ocular
Page
65
of
118
lesions
at
the
ophthalmologic
examinations
at
76
and
101
weeks
(
in
females,
hyperreflection
and
in
males,
foci
or
plaques
in
the
vitreous
or
on
the
posterior
capsule
of
the
lens)
were
reported.
Statistically
significant
increases
in
GGT
in
males
at
24,
50,
78
and
102
weeks
(+
50%
to
+
100%
above
controls)
and
cholesterol
in
males
at
102
weeks
(+
66%)
were
observed,
with
only
marginal
changes
in
GGT
and
cholesterol
seen
in
females
at
some
time
points.
Statistically
significantly
increased
microscopic
lesions
at
1750
ppm
included
nasal
epithelial
hyperplasia
(
50%,
males
and
57%,
females,
compared
to
0%,
all
other
groups),
renal
pelvic
epithelial
hyperplasia
(
from
control
to
high
dose,
12%,
14%,
20%
and
44%
in
males
and
8%,
14%,
18%
and
28%
in
females)
and
degeneration
of
the
outer
nuclear
layer
of
the
retina
(
4%,
2%,
4%
and
14%,
males
and
26%,
14%,
28%
and
48%;
significant
only
in
high
dose
females).
Stromal
fatty
infiltration
of
the
pancreas
was
also
increased
but
not
significantly
(
males
18%,
22%,
16%
and
30%;
females
30%,
38%,
40%
and
47%).
At
the
52­
week
interim
sacrifice,
nasal
epithelial
hyperplasia
was
reported
in
55%
of
males
(
11/
20)
and
76%
of
females
(
13/
16)
only
at
1750
ppm.
Increased
relative
brain
(
females,
+
21%),
liver,
heart
and
kidney
weights
at
52
weeks
were
reported
but
may
have
been
related
to
decreased
body
weights
and
were
not
associated
with
gross
or
microscopic
findings.
At
104
weeks
in
females,
slightly
decreased
brain
weight
of
­
3%
and
increased
relative
brain
weight
of
+
33%
were
reported.
No
compound
related,
biologically
significant
effects
on
mortality,
clinical
signs,
food
consumption,
hematology
parameters,
urinalysis
parameters
or
gross
pathology
were
noted.
The
LOAEL
for
systemic
toxicity
is
1750
ppm
(
66.9
mg/
kg
bw/
day),
based
on
decreased
body
weight
and
weight
gain,
clinical
chemistry
alterations
and
microscopic
findings
in
the
retina,
nasal
epithelium,
kidney
and
possibly
pancreas.
The
NOAEL
for
systemic
toxicity
is
175
ppm
(
6.37
mg/
kg
bw/
day).

Tumor
incidence
for
this
study
was
reevaluated
by
the
HED
CARC
(
HED
TXR
#
0052727,
8/
5/
04,
fourth
cancer
evaluation
of
acetochlor)
due
to
submission
of
tissue
reevaluations
for
several
tumor
types
by
a
pathology
working
group
peer
review
(
MRIDs
44496205,
45367404).
The
CARC
determined
that
tumor
incidences
in
this
study
were
as
follows:
(
1)
liver:
in
males,
the
incidence
of
hepatocellular
adenomas
was
0%,
0%,
0%
and
4%
(
positive
trend
only).
The
incidence
of
carcinomas
was
5%,
7%,
5%
and
2%.
Combined
incidence
was
5%,
7%,
5%
and
6%.
In
females,
the
incidence
of
adenomas
was
0%,
2%,
0%
and
4%
and
no
carcinomas
were
observed
The
CARC
concluded
that
the
tumors
were
unrelated
to
treatment
due
to
the
low
incidence
in
both
sexes;
(
2)
thyroid
follicular
cell:
in
males,
adenoma
incidence
was
4%,
2%,
4%
and
10%
(
positive
trend
only).
The
incidence
of
carcinoma
was
2%,
6%,
0%
and
6%.
Combined
tumor
incidence
was
6%,
8%,
4%
and
16%.
In
females,
adenoma
incidence
was
1%,
2%,
5%
and
10%
(
positive
trend
observed).
The
incidence
of
carcinoma
was
0%,
0%,
0%
and
2%
(
positive
trend
only)
and
combined
tumors
incidence
was
1%,
1%,
5%
and
11%
(
pairwise
p<
0.01
with
positive
trend
observed).
The
CARC
determined
that
the
increase
was
treatment­
related
in
both
sexes
and
that
the
tumors
were
due
to
perturbation
of
thyroid­
pituitary
homeostasis
that
was
secondary
to
increased
clearance
of
thyroid
hormones
by
hepatic
UDPGT
activity.
The
tumors
were
not
included
in
the
cancer
quantification;
(
3)
nasal
olfactory
epithelia:
the
incidence
of
nasal
epithelial
adenoma
at
1750
ppm
(
main
study
groups)
was
50%
in
males
and
57%
in
females,
compared
to
0%
in
controls
and
lower
dose
groups
(
p#
0.01,
both
sexes
with
positive
trend).
Nasal
epithelial
carcinoma
was
reported
in
3%
of
males
and
2%
of
females
at
1750
ppm
but
not
in
controls
or
lower
dose
levels
(
tumors
and
epithelial
Page
66
of
118
hyperplasia
often
were
found
in
the
same
animal).
At
the
52­
week
interim
sacrifice,
25%
of
males
and
50%
of
females
at
1750
ppm
had
adenoma
of
the
nasal
epithelium.
The
CARC
concluded
that
the
increased
nasal
tumors
were
related
to
treatment
and
that
mechanistic
data
were
adequate
to
support
a
mode
of
action
of
tumor
formation
in
the
rat;
(
4)
bone
and
stomach:
benign
chondroma
of
the
femur
in
1/
50
males
and
benign
basal
cell
tumor
of
the
stomach
in
1/
50
males
and
1/
49
females
were
reported
only
at
1750
ppm
in
the
original
study
report.
However,
in
a
Peer
Review
Working
Group
histopathology
reevaluation
(
MRID
45367404),
the
femur
and
stomach
tumors
were
reclassified
as
nonneoplastic
lesions
(
cartilage
hyperplasia,
femur
and
well­
differentiated
squamous
cell
carcinoma,
stomach)
and
not
considered
treatment­
related
tumors.
The
CARC
concurred
with
this
reclassification.
Dosing
was
considered
adequate
based
on
body
weight
effects,
clinical
chemistry
alterations
and
nonneoplastic
lesions
in
both
sexes.

This
chronic
toxicity/
carcinogenicity
study
in
the
rat
is
classified
Acceptable/
guideline
and
satisfies
the
guideline
requirement
for
a
combined
chronic
toxicity/
carcinogenicity
study
(
OPPTS
870.4300);
OECD
453)
in
the
rat.

(
2)
In
an
oral
combined
chronic
toxicity/
carcinogenicity
study
(
MRID
40077601),
MON
097
(
acetochlor
tech.,
96.1%
a.
i.,
lot
#
Dayton
RDNT
08001)
was
administered
to
60
Sprague­
Dawley
rats/
sex/
dose
in
the
diet
at
dose
levels
of
0,
40,
200
or
1000
ppm
(
equivalent
to
estimated
average
daily
intakes
of
0,
2.0,
10.0
or
50.0
mg/
kg
bw/
day;
calculated
using
a
standard
conversion
factor
of
0.05
for
conversion
of
ppm
to
mg/
kg
bw/
day
in
adult
rats)
for
24
consecutive
months.
In
addition,
groups
of
10
rats/
sex/
dose
were
administered
the
test
material
for
12
months
and
sacrificed
for
a
one­
year
interim
evaluation.

At
1000
ppm
(
HDT),
decreased
mean
body
weight/
weight
gain
primarily
during
the
second
year
of
the
study
(
in
males
at
24
months,
­
8.5%/­
12.1%
less
than
controls,
statistically
significant
decreases
observed
between
days
455
to
678;
and
in
females
­
3.2%/­
4.8%
less
than
controls,
not
statistically
significant,
although
decreases
up
to
­
7%/­
10%
were
observed
in
the
last
weeks),
decreased
food
efficiency,
statistically
significant
increases
in
serum
GGT
in
males
at
18
and
24
months
(>
300%
above
controls),
cholesterol
in
males
at
24
months
(+
67%
above
controls)
and
increased
total
bilirubin
in
females
at
24
months
(+
363%
above
controls)
were
observed.
Slightly,
statistically
significantly
increased
relative
liver
weight
(+
18.3%
above
controls;
absolute
weight
increased
+
9.9%,
NS)
and
relative
testes
weight
(+
11.9%;
abs
weight
+
5.7%,
NS)
were
reported
at
12
and
24
months
in
males
and
non­
significantly
increased
kidney
weights
at
24
months
(+
10.9%
abs/
15.3%
rel),
but
kidney
and
testes
did
not
show
microscopic
effects.
A
statistically
significant
increase
in
thyroid
c
cell
hyperplasia
was
seen
in
terminal
sacrifice
males
(
0%,
12.5%,
4.5%
and
34.8%),
with
a
smaller,
non­
significant
increase
in
all
males
on
study
(
4.3%,
7.1%,
5.7%
and
11.4%).
Nasal
mucosal
findings
similar
to
those
seen
in
other
rat
studies
showed
slight,
non­
significant
increases
in
males
at
1000
ppm
that
were
possibly
threshold
increases,
but
did
not
show
a
clear
dose­
relationship
to
treatment
(
e.
g.,
papillary
hyperplasia
1.4%,
1.4%,
5.7%
and
7.1%;
inflammation
of
the
nasal
mucosa
18.6%,
25.7%,
14.3%
and
27.1%).
Some
microscopic
findings
in
the
livers
(
e.
g.,
hepatocellular
alterations,
control
to
high
dose
24.3%,
20.0%,
18.6%
and
35.7%,
and
hepatocyte
necrosis,
5.7%,
5.7%,
7.1%
and
10%)
showed
marginal
increases
in
males
at
1000
ppm
(
not
Page
67
of
118
statistically
significant).
Plasma
cell
hyperplasia
of
the
lymph
node
was
possibly
increased
in
high
dose
males
(
5.7%,
5.7%,
8.6%
and
15.7%).
No
compound
related,
biologically
significant
effects
on
mortality,
clinical
signs,
food
consumption,
ophthalmological
findings,
gross
pathological
findings
or
parameters
of
hematology
and
urinalysis
were
noted.
The
LOAEL
is
1000
ppm
(
50.0
mg/
kg
bw/
day),
based
on
decreased
body
weight
and
weight
gain
(
both
sexes,
marginal
in
females),
clinical
chemistry
alterations
and
possibly
a
slight
increase
in
microscopic
findings
in
the
nasal
epithelium
and
liver.
The
NOAEL
is
200
ppm
(
10.0
mg/
kg
bw/
day).

The
relationship
of
tumors
to
treatment
was
evaluated
by
the
HED
CARC/
MTARC
(
fourth
cancer
evaluation
of
acetochlor,
HED
TXR#
0052727,
8/
5/
04),
which
included
review
of
a
PWG
reevaluation
of
liver
tumors
(
MRID
44496205).
The
CARC
determined
that
the
tumor
incidences
in
this
study
were
as
follows:
(
1)
liver:
the
incidence
of
adenomas
in
males
was
0%,
0%,
0%
and
4%
(
positive
trend
only).
The
incidence
of
carcinomas
was
5%,
7%,
5%
and
2%
and
the
combined
incidence
was
5%,
7%,
5%
and
6%.
In
females,
the
incidence
of
adenomas
was
0%,
2%,
0%
and
4%.
The
CARC
concluded
that
liver
tumors
did
not
show
a
treatment­
related
increase
in
this
study;
(
2)
nasal
olfactory
epithelium:
in
males
the
incidence
of
papillary
adenomas
was
1.7%,
0%,
0%
and
20.3%
(
pairwise
p<
0.01
at
1000
ppm
with
positive
trend
observed).
In
females
the
incidence
was
0%,
0%,
0%
and
28%
(
pairwise
p<
0.01
at
1000
ppm
with
positive
trend
observed).
At
interim
sacrifice
groups,
1/
10
high
dose
(
1000
ppm)
female
had
a
papillary
adenoma
of
the
mucosa
of
the
nasal
turbinates
(
included
in
the
above
incidence).
The
CARC
determined
that
the
tumors
were
treatment­
related;
(
3)
thyroid
follicular
cell:
the
incidence
of
thyroid
follicular
cell
adenoma
in
females
was
2.6%,
4.5%,
5.6%
and
8.7%.
The
incidence
of
carcinoma
was
2.8%.
Combined
tumor
incidence
was
2.6%,
4.5%,
5.6%
and
10.9%
(
positive
trend
only).
Males
did
not
show
an
increase.
The
CARC
concluded
that
the
tumors
showed
a
treatment­
related
increase
at
1000
ppm
and
were
secondary
to
liver
effects
(
perturbation
of
pituitary­
thyroid
homeostasis
by
increased
hepatic
UDPGT).
Dosing
was
considered
adequate
based
on
decreased
body
weight/
weight
gain,
clinical
chemistry
alterations
and
nonneoplastic
lesions
in
males
and
females.

This
chronic
toxicity/
carcinogenicity
study
in
the
rat
is
classified
as
Acceptable/
guideline
and
satisfies
the
guideline
requirement
for
a
chronic
toxicity/
carcinogenicity
study
(
OPPTS
870.4300;
OECD
453)
in
the
rat.

(
3)
In
an
oral
combined
chronic
toxicity/
carcinogenicity
study
(
MRID
00131099,
reevaluation
of
nasal
pathology
in
MRID
40484801),
MON
097
(
acetochlor
tech.,
94.5%
a.
i.,
lot
#
NBP­
1737874)
was
administered
to
60
Sprague­
Dawley
CD
rats/
sex/
dose
in
the
diet
at
dose
levels
of
0,
500,
1500
or
5000
ppm
(
equivalent
to
average
daily
intakes
of
0,
22,
69
or
250
mg/
kg
bw/
day
for
males
and
0,
30,
93
or
343
mg/
kg
bw/
day
for
females)
for
115
consecutive
weeks
(
males)
and
103
consecutive
weeks
(
females;
discontinued
earlier
due
to
high
mortality).
Groups
of
10
additional
CD
rats/
sex/
dose
were
administered
the
test
material
for
52
weeks
at
the
same
dose
levels
and
sacrificed
at
one
year
for
an
interim
evaluation.

At
500
ppm
(
LDT),
decreased
mean
body
weight/
weight
gain
in
males
during
the
last
3
months
of
the
study
(
at
week
115,
­
14%/­
17.5%
less
than
controls)
and
increased
absolute/
relative
mean
Page
68
of
118
thyroid
weights
in
females
(+
33%
above
controls,
p<
0.05;
increasing
to
+
33%
absolute/+
100%
at
5000
ppm)
were
observed.
Mean
relative
(
but
not
absolute)
brain
weight
was
statistically
significantly
increased
(+
14.9%)
in
males.
At
1500
ppm,
sporadic
statistically
significantly
decreased
mean
body
weight/
weight
gain
in
females
between
weeks
31­
103
(
e.
g.,
­
9.6%/­
14%
below
controls
at
week
79)
and
slightly
increased
mean
relative
thyroid
weight
in
males
(+
22%
above
controls)
were
observed.
Mean
absolute
brain
weights
were
reduced
in
both
sexes
(
males
­
3.66%;
females
­
4.6%,
p<
0.05)
but
relative
weight
in
males
was
increased
(+
20%;
unchanged
in
females).
At
5000
ppm,
toxicity
was
excessive.
Decreased
survival
in
females
(
at
24
months
41.7%,
31.7%,
43.3%
and
18.3%,
control
to
high
dose)
was
observed,
resulting
in
termination
of
all
females
by
Week
103.
Male
survival
at
27
months
was
31.7%,
33.3%,
45.0%
and
25.0%.
Sharply
decreased
mean
body
weight/
weight
gain
in
both
sexes
($­
30%
below
controls
in
the
second
year
of
the
study),
occasional
statistically
significantly
decreased
food
consumption,
significantly
decreased
hematocrit
(
up
to
­
15.5%
less
than
controls)
and
hemoglobin
(
up
to
­
18%
less
than
controls)
in
females
at
6,
12
and
18
months
were
also
observed.
Thyroid
relative
weight
was
significantly
increased
by
+
50%
in
males;
absolute
weight
was
increased
40%
but
was
not
significant
and
relative
liver
weights
were
significantly
increased
in
both
sexes.
Brain
absolute
weights
were
reduced
(­
5.4%
males,
­
10%,
females)
but
relative
weights
were
increased
(+
50%,
males
and
+
32%,
females).
Microscopic
lesions
significantly
increased
at
5000
ppm
(
p#
0.05)
included
nasal
mucosal
inflammation
in
males
(
control
to
high
dose,
4.3%,
12.9%,
10.1%
and
23.2%),
polyarteritis
of
the
testes
(
10%,
15.7%,
17.1%
and
24.3%)
and
gastric
fibrosis
in
females
(
5.7%,
7.1%,
10%
and
17.1%).
The
incidence
of
nasal
inflammatory
epithelial
hyperplasia
in
males
was
1.4%,
0%,
2.9%
and
4.3%
(
not
significant)
and
in
females
was
1.4%,
0%,
2.9%
and
0%.
Incidence
of
inflammation
of
nasal
mucosa
in
females
was
2.9%,
11.4%,
8.7%
and
11.6%
(
not
significant).
Peripheral
nerve
neuropathy
was
reported
in
4
females
(
not
significant).
No
compound
related,
biologically
significant
effects
on
clinical
signs
of
toxicity,
ophthalmologic
findings,
clinical
chemistry
or
urinalysis
parameters
were
reported.
The
LOAEL
is
#
500
ppm
(
22
mg/
kg
bw/
day),
based
on
slightly
decreased
body
weight/
weight
gain
in
males
and
increased
abs/
rel
thyroid
weights
in
females.
A
NOAEL
was
not
established
(<
500
ppm
or
22
mg/
kg/
day).

Tumor
incidence
for
this
study
was
reevaluated
by
the
HED
CARC
(
HED
TXR
#
0052727,
8/
5/
04,
fourth
cancer
evaluation
of
acetochlor)
due
to
submission
of
tissue
reevaluations
of
liver
tumors
in
this
study
by
a
pathology
working
group
peer
review
(
MRIDs
44496205).
The
CARC
determined
that
tumor
incidences
in
this
study
were
as
follows:
(
1)
liver:
In
males,
the
incidence
of
hepatocellular
adenoma
was
3%,
2%,
2%
and
11%
(
positive
trend
only).
The
incidence
of
carcinomas
was
2%,
5%,
5%
and
11%
(
positive
trend
only).
Combined
tumor
incidence
was
5%,
7%,
7%
and
20%
(
pairwise
p<
0.05
at
5000
ppm
with
positive
trend
observed.
In
females
the
incidence
of
adenoma
was
0%,
0%,
2%
and
7%
(
pairwise
p<
0.05
at
5000
ppm
with
positive
trend
observed).
The
incidence
of
carcinomas
was
0%,
0%,
0%
and
13%
(
positive
trend
only).
The
incidence
of
combined
tumors
was
0%,
0%,
2%
and
12%
(
pairwise
p<
0.01
at
5000
ppm
with
positive
trend
observed).
The
CARC
concluded
that
although
these
tumors
showed
a
treatmentrelated
increase
at
5000
ppm
they
were
observed
only
at
a
dose
that
caused
excessive
toxicity
and
should
not
be
included
in
the
weight­
of­
evidence
determination
for
acetochlor;
(
2)
thyroid
follicular
cell:
in
males,
the
incidence
of
adenoma
was
0%,
0%,
4.3%
and
7.1%
(
p<
0.05
at
5000
ppm).
The
Page
69
of
118
incidence
of
adenoma
in
females
was
2.9%,
0%,
0%
and
4.3%,
with
no
carcinomas
observed.
The
CARC
determined
that
thyroid
tumors
in
both
sexes
were
treatment­
related
and
secondary
to
perturbation
of
thyroid­
pituitary
homeostasis
by
increased
UDPGT
activity,
but
that
toxicity
at
5000
ppm
was
excessive;
(
3)
nasal
olfactory
epithelia:
In
a
reevaluation
of
nasal
tissues
from
this
study,
an
increased
incidence
of
nasal
papillary
adenomas
(
posterior
nasal
cavity)
in
males
at
0%,
1.4%,
8.7%
(
p#
0.05)
and
26.1%
(
p#
0.01)
was
observed
and
at
5000
ppm
only,
there
were
2/
69
papillary
adenocarcinomas
of
the
nasal
turbinates
(
not
significant).
Females
had
only
2/
70
and
1/
69
papillary
adenomas
of
the
nasal
turbinates
at
1500
and
5000
ppm,
respectively
(
not
significant).
The
CARC
considered
the
nasal
tumors
treatment­
related
but
toxicity
at
5000
ppm
was
excessive.
Mechanistic
data
was
considered
sufficient
to
support
a
proposed
mode
of
action
for
nasal
tumors.
Dosing
was
considered
adequate
at
500
and
1500
ppm
for
males
and
females
based
on
body
weight
effects,
clinical
chemistry
alterations
and
nonneoplastic
lesions,
but
toxicity
at
5000
ppm
was
excessive.

This
chronic
toxicity/
carcinogenicity
study
in
the
rat
is
classified
as
Acceptable/
guideline
and
satisfies
the
guideline
requirement
for
a
chronic
toxicity/
carcinogenicity
study
(
OPPTS
870.4300;
OECD
453)
in
the
rat.

4.4.9.2
Carcinogenicity
Studies
in
the
Mouse
(
1)
In
an
oral
carcinogenicity
study
(
MRID
41565119),
SC­
5676
(
acetochlor
tech.,
90.5%
a.
i.,
batch
nos.
1
and
3)
was
administered
to
50
CD­
1
mice/
sex/
dose
in
the
diet
for
78
weeks
at
dose
levels
of
0,
10,
100
or
1000
ppm
(
equivalent
to
an
average
daily
intake
of
0,
1.1,
11
or
116
mg/
kg
bw/
day,
males
and
0,
1.4,
13
or
135
mg/
kg
bw/
day,
females).
Additional
groups
of
10
CD­
1
mice/
sex/
dose
were
administered
the
test
material
at
the
above
dose
levels
for
52
weeks
for
interim
sacrifice
at
one
year.

At
10
ppm
and
above,
males
showed
statistically
significant
increases
in
absolute
kidney
weights
(
low
to
high
dose
+
8.2%,
+
12.9%
and
+
29.4%
above
controls)
associated
with
increased
incidence
of
renal
tubular
basophilia
(
from
control
to
high
dose,
5%,
33%,
28%
and
44%
affected,
respectively);
however,
these
findings
at
10
or
100
ppm
were
not
considered
clearly
adverse.
At
100
ppm
in
males,
the
incidence
of
bronchiolar
hyperplasia
was
significantly
(
p<
0.05)
increased
(
control
to
high
dose
13%,
10%,
39%
and
38%)
and
relative
kidney
weights
were
significantly
increased
at
100
ppm
(+
15.8%)
and
1000
ppm
(+
36.6%)
and
a
single
male
had
renal
tubular
epithelial
hyperplasia
(
0%
at
control
and
low
dose).
At
1000
ppm
in
males,
statistically
significantly
increased
incidence
of
nephropathy
(
cortical
mineralization,
hyaline
casts,
interstitial
fibrosis,
tubular
epithelial
hyperplasia;
all
increased
by
more
at
least
two­
fold
relative
to
controls
and
lower
dose
groups)
were
reported.
At
1000
ppm
in
females,
a
statistically
significant
increase
in
the
incidence
of
anterior
polar
vacuoles
in
the
ocular
lens
was
observed
at
76
weeks,
with
a
slight,
non­
significant
doserelated
increase
observed
at
lower
dose
levels
(
from
control
to
high
dose,
percent
incidence
was
19%,
24%,
32%
and
54%,
respectively)
but
were
not
associated
with
increased
ocular
opacities.
A
statistically
significant
decrease
(­
3.8%
below
controls)
in
absolute
brain
weight
was
observed
(
relative
weight
­
3.4%,
not
significant),
with
no
associated
histopathology.
Slight
but
statistically
significant
decreases
in
some
RBC
parameters
were
observed
in
males
at
50
and/
or
76
weeks
and
Page
70
of
118
females
at
50
weeks,
but
were
of
small
magnitude
(<
10%).
Males
in
the
interim
sacrifice
1000
ppm
group
had
nephropathy
(
44%
vs.
0%,
controls);
a
slight
increase
was
observed
in
females
(
20%
vs.
10%
controls)
but
this
finding
was
not
observed
in
females
at
terminal
sacrifice.
There
were
no
treatment­
related
clinical
signs
and
no
biologically
significant
effects
on
survival,
food
consumption,
body
weight
or
weight
gain.
The
systemic
toxicity
LOAEL
in
males
is
100
ppm
(
11
mg/
kg
bw/
day),
based
on
an
increased
incidence
of
bronchiolar
hyperplasia
and
possibly
renal
tubule
epithelial
hyperplasia.
The
systemic
toxicity
NOAEL
in
males
is
10
ppm
(
1.1
mg/
kg/
day).
The
systemic
toxicity
LOAEL
in
females
was
not
achieved
(>
1000
ppm
or
135
mg/
kg
bw/
day).

Tumor
incidence
for
this
study
was
reevaluated
by
the
HED
CARC
(
HED
TXR
#
0052727,
8/
5/
04)
due
to
submission
of
tissue
reevaluations
for
several
tumor
types
by
a
pathology
working
group
peer
review
(
MRIDs
44496204,
­
05,
­
06).
The
CARC
determined
that
tumor
incidences
in
this
study
were
as
follows:
(
1)
lung
tumors:
the
incidence
of
pulmonary
adenomas
(
alveologenic)
was
15%,
8%,
19%
and
30%
(
pairwise
at
high
dose
p<
0.05;
positive
trend
also
observed)
in
males
and
7%,
8%,
10%
and
15%
in
females.
The
incidence
of
carcinomas
was
5%,
5%,
5%
and
7%
in
males
and
2%,
0%,
3%
and
3%
in
females.
The
combined
tumor
incidence
was
18%,
13%,
22%
and
33%
(
pairwise
at
high
dose
p<
0.05
with
positive
trend
also
observed)
in
males
and
9%,
8%,
14%
and
18%
(
positive
trend
only)
in
females.
In
the
interim
sacrifice
groups,
one
high
dose
female
and
one
mid
dose
male
had
pulmonary
adenomas.
Based
on
these
findings
and
available
historical
control
data,
the
CARC
determined
that
the
increased
incidence
of
adenoma
in
males
and
combined
lung
tumors
in
both
sexes
was
treatment­
related.
(
2)
liver
tumors:
the
incidence
of
liver
carcinomas
in
males
showed
a
positive
trend
(
0%,
5%,
7%,
8%).
The
incidences
of
liver
adenoma
(
14%,
21%,
12%
and
16%)
and
combined
tumors
(
14%,
26%,
20%
and
24%)
showed
no
significant
change.
Females
did
not
show
an
increase
in
these
tumors.
Based
on
these
findings
and
available
historical
control
data,
the
CARC
concluded
that
the
liver
tumor
incidence
was
within
historical
range
and
did
not
show
a
treatment­
related
effect.
(
3)
uterus­
histiocytic
sarcoma:
the
incidence
of
histiocytic
sarcoma
in
females
was
3%,
2%,
0%
and
8%
(
positive
trend
only).
The
CARC
concluded
that
when
considered
with
the
23­
month
mouse
study,
a
positive
dose­
response
was
observed
and
that
the
increase
at
1000
ppm
was
treatment­
related.
Although
kidney
effects
in
males
and
ocular
effects
in
females
were
reported
in
this
study,
neither
males
nor
females
showed
effects
considered
sufficient
to
demonstrate
achievement
of
an
MTD.
However,
dosing
was
considered
adequate
in
males
based
on
the
finding
of
significantly
decreased
body
weight
gain
(­
9%
less
than
controls)
at
1200
ppm
in
a
sixweek
range­
finding
study.
In
females,
body
weight
effects
were
not
achieved
in
the
range­
finding
study
but
additional
testing
was
not
considered
necessary
based
on
the
significantly
increased
incidence
of
pulmonary
adenoma
observed
in
both
males
and
females
at
1000
ppm.
In
addition,
the
MTD
was
achieved
for
both
males
and
females
in
a
separate
mouse
carcinogenicity
study
(
MRID
00131089;
see
review
in
HED
TXR#
004586
and
Supplemental
DER,
TXR
#
0050658).
Additional
mouse
oncogenicity
testing
is
therefore
not
required
at
this
time.

This
carcinogenicity
study
in
the
mouse
is
classified
as
Acceptable/
Guideline
and
satisfies
the
guideline
requirement
for
a
carcinogenicity
study
in
the
mouse
[
OPPTS
870.4200;
OECD
451].
Page
71
of
118
(
2)
In
an
oral
carcinogenicity
study
(
MRID
00131089),
MON­
097
(
acetochlor
tech.,
94.5%
a.
i.,
lot
#
NBP
1737874)
was
administered
to
50
Swiss­
bred
CD­
1
albino
mice/
sex/
dose
in
the
diet
for
23
months
at
dose
levels
of
0,
500,
1500
or
5000
ppm
(
equivalent
to
an
estimated
average
daily
intake
of
0,
75,
225
or
750
mg/
kg
bw/
day;
calculated
using
a
dietary
ppm­
to­
mg/
kg/
day
conversion
factor
of
0.15
for
mice).
Additional
groups
of
10
mice/
sex/
dose
were
administered
the
same
diets
for
12
months
and
sacrificed
for
a
one­
year
interim
evaluation.

At
500
ppm
and
above,
statistically
significantly
increased
absolute/
relative
kidney
weights
were
observed
in
males
at
the
interim
and
terminal
sacrifices
(
at
23
months,
abs/
rel
wt
was
increased
+
39.5%/+
39.1%,
+
42.1%/+
45.3%
and
+
14.5%/+
38.9%
above
controls,
low
to
high
dose).
Statistically
significantly
increased
mean
abs/
rel
liver
weights
were
observed
at
all
dose
levels
in
males
at
interim
and
terminal
sacrifice
(
at
23
months,
+
29.5%/+
28.5,
+
23.5%/+
23.7
and
+
55.6%/+
91.4%
above
controls,
low
to
high
dose,
respectively),
with
females
showing
significant
increases
only
at
the
interim
sacrifice
time
(
abs/
rel
wt
+
11.5%/+
13.9%,
+
24.6%/+
23.5%
and
+
17.8%/+
45.3%).
(
In
the
absence
of
correlated
microscopic/
clinical
chemistry
findings,
liver
and
kidney
organ
weight
changes
at
low
and
mid
dose
were
not
used
to
establish
a
LOAEL;
increased
liver
weights
at
terminal
sacrifice
in
the
high
dose
group
may
have
reflected,
in
part,
the
presence
of
tumors).
At
1500
ppm
in
males,
slight
effects
on
mean
body
weights
(­
4.7%
and
­
6.5%
below
controls
at
53
and
79
weeks,
p<
0.05
but
not
significant
at
termination)
and
slightly
increased
incidence
of
interstitial
nephritis
(
from
control
to
high
dose,
50%,
58.3%,
70%
and
83.3%)
were
observed.
In
females,
survival
was
reduced
during
the
last
months
of
the
study
(
62%,
50%,
34%
and
26%
at
termination)
and
abs/
rel
thyroid
plus
parathyroid
weights
were
increased
(+
29%/+
39%
and
at
5000
ppm
+
43%/
68%).
At
5000
ppm
(
HDT),
survival
was
also
significantly
reduced
in
males,
beginning
at
about
1
year
(
at
termination,
control
to
high
dose
60%,
50%,
50%
and
26%,
respectively),
mean
body
weights
were
significantly
reduced
in
both
males
and
females
throughout
the
study
(
up
to
about
20%
by
study
termination),
and
females
showed
significant
decreases
in
RBC
count
(­
21%
below
controls),
Hgb
(­
22.5%)
and
Hct
(­
23%);
relative
thyroid
weight
in
males
was
increased
by
+
31%;
and
at
23
months,
the
incidence
of
interstitial
nephritis
was
also
statistically
significantly
increased
in
females
(
control
to
high
dose
51.6%,
55%,
51.6%
and
76.3%,
females).
A
significantly
increased
incidence
of
retinal
degeneration
was
seen
in
females
(
control
to
high
dose
2/
60,
3/
60,
1/
60
and
8/
59).
There
were
no
treatment­
related
effects
observed
on
clinical
signs
of
toxicity,
food
consumption/
feed
efficiency,
nor
in
clinical
chemistry
or
urinalysis
parameters.
The
systemic
toxicity
LOAEL
is
1500
ppm
(
225
mg/
kg/
day),
based
on
slightly
reduced
mean
decreased
body
weight
and
increased
incidence
of
interstitial
nephritis
in
males
and
increased
mortality
and
abs/
rel
thyroid
plus
parathyroid
weights
in
females.
The
systemic
toxicity
NOAEL
is
500
ppm
(
75
mg/
kg/
day).

Tumor
incidence
for
this
study
was
reevaluated
by
the
HED
CARC
(
HED
TXR
#
0052727,
8/
5/
04)
due
to
submission
of
tissue
reevaluations
for
several
tumor
types
by
a
pathology
working
group
peer
review
(
MRIDs
44496204,
­
05,
­
06
and
45367403).
The
CARC
determined
that
tumor
incidences
in
this
study
were
as
follows:
(
1)
liver
­
in
males,
the
incidence
of
hepatocellular
adenomas
was
16%,
18%,
22%
and
48%
(
pairwise
p<
0.01
at
5000
ppm
with
positive
trend
also
observed).
The
incidence
of
carcinoma
was
9%,
11%,
9%
and
23%
(
p<
0.05
at
5000
ppm,
positive
trend
observed)
Page
72
of
118
and
combined
tumors
was
24%,
26%,
31%
and
65%
(
pairwise
p<
0.01
at
5000
ppm
with
positive
trend
observed).
In
females,
the
incidence
of
adenomas
was
5%,
0%,
3%
and
21%
(
pairwise
p<
0.05
at
5000
ppm
with
positive
trend),
of
carcinomas
was
0%,
0%,
0%
and
9%
(
trend
only)
and
combined
tumors
was
5%,
0%<
3%
and
29%
(
pairwise
p<
0.01
at
5000
ppm
with
positive
trend
observed).
The
CARC
concluded
that
an
increase
in
liver
tumors
was
only
observed
at
the
excessive
dose
of
5000
ppm
and
should
not
be
included
in
the
cancer
weight­
of­
evidence
determination
for
acetochlor;
(
2)
lung
­
in
females,
the
incidence
of
adenoma
was
2%,
17%,
22%
and
23%
(
pairwise
p<
0.05
at
500
ppm
and
p<
0.01
at
1400
and
5000
ppm
with
positive
trend
also
observed).
The
incidence
of
carcinomas
was
0%,
9%,
2%
and
18%
(
pairwise
p<
0.05
at
500
ppm
and
p<
0.01
at
5000
ppm
with
positive
trend
also
observed).
Combined
lung
tumor
incidence
was
2%,
23%,
25%
and
33%
(
pairwise
p<
0.01,
all
doses
with
positive
trend
also
observed).
Males
did
not
show
an
increase.
The
CARC
concluded
that
the
lung
tumors
in
females
were
treatment­
related
at
500
and
1500
ppm
(
5000
ppm
was
excessive
dose),
based
on
incidence
exceeding
available
historical
control
data;
(
3)
uterus
­
histiocytic
sarcoma
­
the
incidence
in
females
was
0%,
7%,
15%
and
15%
(
pairwise
p<
0.05
at
low
and
high
dose
and
p<
0.01
at
mid
dose).
The
CARC
concluded
that
the
tumors
were
related
to
treatment
and
should
be
included
in
the
cancer
classification
of
acetochlor,
based
on
significant
increases
at
500
and
1500
ppm
(
5000
ppm
excessive
dose);
(
4)
kidney
­
the
incidence
of
renal
adenoma
was
0%,
0%,
0%
and
14%
(
positive
trend
only)
in
males
and
0%,
0%,
0%
and
7%
in
females.
The
CARC
concluded
that
these
tumors
were
not
related
to
treatment
based
on
low
incidence
and
occurrence
only
at
an
excessively
toxic
dose
of
5000
ppm;
(
5)
ovaries
­
benign
tumors
(
adenoma,
granulosa
cell
tumor
and
luteoma)
were
determined
not
to
be
related
to
treatment
based
on
low
incidence
of
each
type.
It
was
determined
that
it
was
not
appropriate
to
combine
the
incidence
of
these
types
of
tumors.
Dosing
was
considered
adequate,
based
on
slightly
reduced
survival
in
females
and
slightly
reduced
body
weights
and
increased
interstitial
nephritis
in
males
at
1500
ppm;
toxicity
at
5000
ppm
was
considered
excessive
in
both
sexes
based
on
pronounced
effects
(
sharply
reduced
survival,
anemia,
reduced
body
weight
in
both
sexes
and
renal
toxicity).

This
carcinogenicity
study
in
the
mice
is
classified
as
Acceptable/
guideline
and
satisfies
the
guideline
requirement
for
a
carcinogenicity
study
[
OPPTS
870.4200;
OECD
451]
in
mice.

4.4.9.3
Cancer
Classification
The
carcinogenicity
of
acetochlor
was
evaluated
by
the
HED
CARC/
MTARC
in
a
joint
meeting
(
April
21­
22,
2004).
Three
carcinogenicity
studies
in
the
rat
and
two
in
the
mouse
were
submitted
for
acetochlor.
In
addition,
numerous
mechanistic
studies
were
submitted
to
evaluate
the
mechnism
of
nasal,
thyroid
and
liver
tumorigenesis.
Acetochlor
is
classified
as
"
Likely
to
be
Carcinogenic
to
Humans"
based
on
treatment­
related
increases
in
lung
tumors
in
male
and
female
mice,
histiocytic
sarcoma
in
female
mice
and
nasal
epithelial
and
thyroid
follicular
cell
tumors
in
male
and
female
rats.
Mechanistic
data
supports
non­
mutagenic
(
threshold)
mechanisms
of
carcinogenicity
for
the
rat
nasal
and
thyroid
tumors
(
see
Section
4.1.1.2).
Genotoxicity
data
do
not
indicate
that
acetochlor
has
high
genotoxic
potential
in
vivo.
Weak
positive
findings
in
some
studies
(
UDS,
dominant
lethal)
appeared
to
be
related
to
cytotoxicity
secondary
to
depleted
cellular
glutathione
reserves.
Although
the
available
genotoxicity
data
do
not
provide
strong
support
for
a
mutagenic
mechanism
of
Page
73
of
118
carcinogenicity,
the
Committee
recommended
that
in
the
absence
of
supporting
mechanistic
data
for
the
formation
of
lung
tumors
and
histiocytic
sarcomas
in
mice,
a
default
linear
low­
dose
extrapolation
should
be
used
to
estimate
cancer
risk
for
those
tumors.
Calculation
of
a
Q1
*
of
3.27
x
10­
2
(
mg/
kg/
day)
­
1
was
based
on
lung
tumor
incidence
in
male
mice.
Nasal
and
thyroid
tumors
in
rats
were
not
included
as
part
of
the
quantitation
of
tumor
risk.

Table
4.4.
Summary
of
Toxicological
Doses
and
Endpoints
for
Acetochlor
for
Use
in
Human
Risk
Assessments
Exposure
Scenario
Dose
Used
in
Risk
Assessment,
UF
Special
FQPA
SF*
and
Level
of
Concern
for
Risk
Assessment
Study
and
Toxicological
Effects
Acute
Dietary
(
general
population
including
females
age
13­
49)
NOAEL
=
150
mg/
kg/
day
UF
=
1000
Acute
RfD
=
0.15
mg/
kg/
day
FQPA
SF
=
1X
aPAD
=
acute
RfD
(
0.15)
FQPA
SF
(
1)

=
0.15
mg/
kg/
day
Acute
oral
neurotoxicity
in
rats
LOAEL
=
500
mg/
kg/
day,
based
on
decreased
motor
activity
in
females.

Chronic
Dietary
(
all
populations)
NOAEL
=
2.0
mg/
kg/
day
UF
=
100
Chronic
RfD
=
0.02
mg/
kg/
day
FQPA
SF
=
1X
aPAD
=
chronic
RfD
(
0.02)
FQPA
SF
(
1)

=
0.02
mg/
kg/
day
Chronic
oral
toxicity
in
beagle
dogs
LOAEL
=
10
mg/
kg/
day,
based
on
increased
salivation
and
histopathology
in
the
testes,
kidney
and
liver.

Incidental
Oral
Short­
Term
(
1
­
30
days)
Not
determined
(
there
are
no
registered
residential
uses
for
acetochlor)

Incidental
Oral
Intermediate­
Term
(
1
­
6
months)
Not
determined
(
there
are
no
registered
residential
uses
for
acetochlor)

Dermal
Short­
Term
(
1
­
30
days)
NOAEL
=
400
mg/
kg/
day
Residential
LOC
for
MOE
=
Not
applicable
Occupational
LOC
for
MOE
=
100
21­
day
dermal
toxicity
study
in
rabbits
LOAEL
=
1200
mg/
kg/
day,
based
on
mortality
and
clinical
signs
of
toxicity.

Dermal
Intermediate­
Term
(
1
­
6
months)
NOAEL
=
25
mg/
kg/
day
(
dermal
absorption
rate
20%)

NOAELadj
=
125
mg/
kg/
day
Residential
LOC
for
MOE
=
Not
applicable
Occupational
LOC
for
MOE
=
100
Subchronic
oral
toxicity
in
beagle
dogs
(
two
studies
considered
together)
LOAEL
=
60
mg/
kg/
day,
based
on
decreased
body
weight/
weight
gain,
slight
anemia,
slight
liver
effects.
Table
4.4.
Summary
of
Toxicological
Doses
and
Endpoints
for
Acetochlor
for
Use
in
Human
Risk
Assessments
Exposure
Scenario
Dose
Used
in
Risk
Assessment,
UF
Special
FQPA
SF*
and
Level
of
Concern
for
Risk
Assessment
Study
and
Toxicological
Effects
Page
74
of
118
Dermal
Long­
Term
(>
6
months)
NOAEL
=
2.0
mg/
kg/
day
(
dermal
absorption
rate
20%)

NOAELadj
=
10
mg/
kg/
day
Residential
LOC
for
MOE
=
Not
applicable
Occupational
LOC
for
MOE
=
100
Chronic
oral
toxicity
in
beagle
dogs
LOAEL
=
10
mg/
kg/
day,
based
on
increased
salivation
and
histopathology
in
the
testes,
kidney
and
liver.

Inhalation
Short­
Term
(
1
­
30
days)
NOAEL
=
150
mg/
kg/
day
(
Assume
inhalation
absorption
=
oral
absorption)
Residential
LOC
for
MOE
=
Not
applicable
Occupational
LOC
for
MOE
=
100
Developmental
toxicity
study
in
rats
(
oral)
Developmental
LOAEL
=
600
mg/
kg/
day,
based
on
decreased
fetal
weight;
increased
resorptions
and
postimplantation
loss.

Inhalation
Intermediate­
Term
(
1
­
6
months)
NOAEL
=
25
mg/
kg/
day
(
Assume
inhalation
absorption
=
oral
absorption)
Residential
LOC
for
MOE
=
Not
applicable
Occupational
LOC
for
MOE
=
100
Subchronic
oral
toxicity
in
beagle
dogs
(
two
studies
considered
together)
LOAEL
=
60
mg/
kg/
day,
based
on
decreased
body
weight/
weight
gain,
slight
anemia,
slight
liver
effects.

Inhalation
Long­
Term
(>
6
months)
NOAEL
=
2.0
mg/
kg/
day
(
Assume
inhalation
absorption
=
oral
absorption)
Residential
LOC
for
MOE
=
Not
applicable
Occupational
LOC
for
MOE
=
100
Chronic
oral
toxicity
in
beagle
dogs
LOAEL
=
10
mg/
kg/
day,
based
on
increased
salivation
and
histopathology
in
the
testes,
kidney
and
liver.

Cancer
(
oral,
dermal,
inhalation)
Classification:
Likely
to
be
carcinogenic
to
humans,
based
on
increased
incidence
of
lung
tumors
in
male
and
female
mice,
histiocytic
sarcoma
in
female
mice
and
nasal
epithelial
tumors
and
thyroid
follicular
cell
adenomas
in
male
and
female
rats.
Q1
*
=
3.27
x
10­
2,
based
on
lung
tumor
incidence
in
male
mice.

UF
=
uncertainty
factor,
FQPA
SF
=
Special
FQPA
safety
factor,
NOAEL
=
no
observed
adverse
effect
level,
LOAEL
=
lowest
observed
adverse
effect
level,
PAD
=
population
adjusted
dose
(
a
=
acute,
c
=
chronic)
RfD
=
reference
dose,
MOE
=
margin
of
exposure,
LOC
=
level
of
concern,
NA
=
Not
Applicable
*
Refer
to
Section
4.5
Page
75
of
118
4.5
Special
FQPA
Safety
Factor
Based
upon
the
hazard
data
presented
above,
it
is
recommended
that
the
special
FQPA
SF
be
reduced
to
1x
because
there
are
no/
low
concerns
and
no
residual
uncertainties
with
regard
to
pre­
and/
or
postnatal
toxicity.

4.6
Endocrine
disruption
EPA
is
required
under
the
FFDCA,
as
amended
by
FQPA,
to
develop
a
screening
program
to
determine
whether
certain
substances
(
including
all
pesticide
active
and
other
ingredients)
"
may
have
an
effect
in
humans
that
is
similar
to
an
effect
produced
by
a
naturally
occurring
estrogen,
or
other
such
endocrine
effects
as
the
Administrator
may
designate."
Following
recommendations
of
its
Endocrine
Disruptor
and
Testing
Advisory
Committee
(
EDSTAC),
EPA
determined
that
there
was
a
scientific
basis
for
including,
as
part
of
the
program,
the
androgen
and
thyroid
hormone
systems,
in
addition
to
the
estrogen
hormone
system.
EPA
also
adopted
EDSTAC's
recommendation
that
the
Program
include
evaluations
of
potential
effects
in
wildlife.
For
pesticide
chemicals,
EPA
will
use
FIFRA
and,
to
the
extent
that
effects
in
wildlife
may
help
determine
whether
a
substance
may
have
an
effect
in
humans,
FFDCA
authority
to
require
the
wildlife
evaluations.
As
the
science
develops
and
resources
allow,
screening
of
additional
hormone
systems
may
be
added
to
the
Endocrine
Disruptor
Screening
Program
(
EDSP).

Studies
in
the
rat
evaluating
thyroid
and
liver
effects
following
dietary
administration
of
acetochlor
at
various
dose
levels
indicate
that
acetochlor
may
disrupt
thyroid­
pituitary
homeostasis
via
increased
hepatic
UDPGH­
mediated
increased
clearance
of
the
thyroid
hormone
thyroxine
(
T4).
Slightly
increased
incidence
of
thyroid
follicular
cell
tumors
have
been
observed
in
rat
two­
year
bioassay
studies
at
higher
dose
levels.
Structure­
activity
relationship
data
on
the
related
chloroacetanilide
herbicides
alachlor
and
butachlor
support
this
conclusion.
The
available
data
do
not
indicate
that
acetochlor
disrupts
androgen
or
estrogen
hormone
systems.

When
additional
appropriate
screening
and/
or
testing
protocols
being
considered
under
the
Agency's
EDSP
have
been
developed,
acetochlor
may
be
subjected
to
further
screening
and/
or
testing
to
better
characterize
effects
related
to
endocrine
disruption.
Page
76
of
118
5.0
Public
Health
Data
5.1
Incident
Reports
In
addition
to
the
Scientific
Literature,
the
following
data
bases
have
been
consulted
for
the
poisoning
incident
data
on
the
active
ingredient
Acetochlor
("
Review
of
Acetochlor
Incident
Reports",
Memorandum
from
J.
Blondell,
HED)
to
A.
Protzel
(
HED)
dated
July
5,
2005,
DP
Barcode
D318498):

1)
OPP
Incident
Data
System
(
IDS)
2)
Poison
Control
Centers
3)
California
Department
of
Pesticide
Regulation
4)
National
Pesticide
Information
Center
(
NPIC)
5)
National
Institute
of
Occupational
Safety
and
Health's
Sentinel
Event
Notification
System
for
Occupational
Risks
(
NIOSH
SENSOR)

The
few
reports
of
acetochlor
exposure
mostly
involve
minor
effects
to
the
eyes
and
skin.
No
recommendations
are
made
based
on
the
limited
information
available.

5.2
Other
1.
Ag
Health
Data
Acetochlor
was
not
among
the
chemicals
named
in
the
Agricultural
Health
Study
(
AHS)
Phase
1
questionnaire.
There
is
not
a
final
AHS
publication
specifically
on
acetachlor.

In
a
chemical
closely
related
to
acetochlor,
the
Alachlor
chemical­
specific
AHS
publication
(
Lee
WJ
et
al.
2004
Am
J
Epid;
159),
found
"
a
significant
increasing
trend
for
incidence
or
all
lymphohematopoietic
cancer
associated
with
lifetime­
exposure
days
(
p
for
trend
=
0.02)
and
intensity­
weighted
exposure
days
(
p
for
trend
=
0.03).
The
authors
caution
that
the
number
of
cases
is
small.
"
Additional
follow­
up
of
this
cohort
will
shed
further
light
on
the
risks
for
these
and
other
cancers
as
the
number
of
cancer
cases
increases
over
time."

2.
NHANES
Data.
Acetochlor
was
not
among
the
chemicals
examined
in
NHANES
III
(
1988­
94)
human
biomonitoring
assessment.
The
metabolite
acetochlor
mercapturate
was
among
the
chemicals
measured
in
the
NHANE99+
(
1999­
2000
and
2001­
2002).

6.0
Exposure
Characterization/
Assessment
6.1
Dietary
Exposure/
Risk
Pathway
6.1.1
Residue
Profile
Acetochlor,
2­
chloro­
N­(
ethoxymethyl)­
N­(
2­
ethyl­
6­
methylphenyl)
acetamide,
is
a
chloroacetanilide
herbicide
used
for
preemergence
control
of
weeds
in
corn.
In
the
United
States,
acetochlor
is
Page
77
of
118
conditionally
registered
for
use
on
field
corn
to
the
Acetochlor
Registration
Partnership
(
ARP),
which
is
comprised
of
Dow
AgroSciences,
LLC
(
Dow)
and
Monsanto
Company
(
Monsanto).
In
addition
to
the
ARP
members,
Drexel
Chemical
Company
(
Drexel),
Syngenta
Crop
Protection,
Inc.
(
Syngenta)
and
Tenkoz,
Inc.
(
Tenkoz)
also
have
end­
use
products
containing
acetochlor.
Acetochlor
is
formulated
as
a
variety
of
emulsifiable
concentrate
(
EC),
soluble
concentrate
(
SC),
microencapsulated
(
Mcap),
or
granular
(
G)
formulations
that
can
be
applied
to
field
corn
as
a
preplant,
preemergence,
or
early
postemergence
application
using
only
ground
equipment.

For
the
use
on
field
corn,
the
nature
of
the
residues
in
plants
is
adequately
understood
based
on
adequate
corn
metabolism
studies
and
the
confined
rotational
crop
study.
The
HED
Metabolism
Committee
(
M.
Flood,
9/
30/
1993)
determined
that
the
residues
of
concern
in
corn
include
parent
and
the
its
ethyl
methyl
aniline
(
EMA)
and
hydroxyethyl
methyl
aniline
(
HEMA)
producing
metabolites.
For
purposes
of
the
dietary
risk
assessment,
residues
in
rotational
crops
also
include
metabolites
containing
the
hydroxymethyl
ethyl
aniline
(
HMEA)
moiety,
expressed
in
acetochlor
equivalents.

The
qualitative
nature
of
acetochlor
residues
in
livestock
is
also
adequately
understood,
although
the
studies
using
direct
dosing
with
14C­
acetochlor
are
not
fully
acceptable.
Adequate
studies
are
available
examining
the
metabolism
of
various
classes
of
plant
metabolites
(
EMA,
HEMA,
and
Metabolite
57)
in
both
ruminants
and
poultry.
Based
on
these
studies,
the
Agency
concluded
that
acetochlor
residues
in
ruminants
and
poultry
include
EMA­
and
HEMA­
type
metabolites
and
Metabolite
57.

Tolerances
are
established
for
the
combined
residues
of
acetochlor
and
its
metabolites
convertible
to
EMA
or
HEMA,
to
be
analyzed
as
acetochlor,
and
expressed
as
acetochlor
equivalents
[
40
CFR
§
180.470].
Tolerances
range
from
0.05
to
1.5
ppm
in/
on
field
corn
(
forage,
grain,
and
stover)
resulting
from
the
direct
use
of
acetochlor
and
from
0.02
to
1.0
ppm
in
commodities
from
rotational
crops
of
sorghum,
soybean,
or
wheat.
There
are
no
tolerances
for
residues
in
livestock
commodities.

Adequate
methods
are
available
for
enforcing
tolerances
and
collecting
data
on
acetochlor
residues
in/
on
plant
and
livestock
commodities.
The
high
performance
liquid
chromatography
with
oxidative
coulometric
electrochemical
detection
enforcement
methods
are
listed
as
Method
I
for
plants
commodities
and
Method
A
for
livestock
commodities
in
PAM
Vol.
II.
The
validated
limit
of
quantitation
(
LOQ)
for
the
method
is
0.02
ppm
for
each
analyte.

Considering
the
data
from
the
available
livestock
metabolism
and
feeding
studies
and
the
calculated
maximum
theoretical
dietary
burdens
(
MTDBs)
of
3.0­
3.8
ppm
for
cattle
and
0.04
ppm
for
poultry
and
swine,
the
Agency
concluded
that
there
is
no
reasonable
expectation
of
quantifiable
residues
of
acetochlor
or
its
metabolites
occurring
in
livestock
commodities.
Therefore,
tolerances
for
livestock
commodities
are
not
required
at
the
present
time.

Adequate
field
trial
data
are
available
to
support
the
use
of
acetochlor
on
field
corn
as
a
preplant,
preemergence,
or
early
post­
emergence
application.
An
adequate
number
of
tests
were
conducted
in
Page
78
of
118
the
appropriate
geographical
regions
using
representative
formulations
applied
at
the
maximum
labeled
use
rate
of
3.0
lb
ai/
A.
These
studies
are
also
supported
by
adequate
storage
stability
data.
The
maximum
combined
residues
of
acetochlor
and
its
EMA­
and
HEMA­
type
metabolites,
expressed
in
acetochlor
equivalents,
resulting
from
use
of
acetochlor
at
the
maximum
application
rate
were
<
0.05
ppm
in
grain,
2.52
ppm
in
forage,
and
1.08
ppm
in
fodder.
The
available
corn
grain
processing
studies
indicate
that
acetochlor,
its
EMA­
and
HEMA­
type
metabolites,
and
Metabolite
57
do
not
concentrate
in
processed
corn
grain
fractions.

Adequate
confined
rotational
crop
studies
and
adequate
field
rotational
crops
studies
are
available
supporting
the
label­
specified
restrictions
allowing
rotation
to
only
corn,
soybeans,
sorghum,
wheat
and
tobacco.
The
available
residue
data
support
the
current
tolerances
on
rotational
sorghum,
soybean,
and
wheat
commodities
and
indicate
that
residues
do
not
concentrate
in
processed
fractions
derived
from
these
rotational
crops.

6.1.2
Acute
and
Chronic
Dietary
Exposure
and
Risk
Acute,
chronic,
and
cancer
dietary
(
food
and
water)
exposure
assessments
were
conducted
using
the
Dietary
Exposure
Evaluation
Model
software
with
the
Food
Commodity
Intake
Database
(
DEEMFCID
 
,
Version
2.03),
which
uses
food
consumption
data
from
the
USDA's
Continuing
Surveys
of
Food
Intakes
by
Individuals
(
CSFII)
from
1994­
1996
and
1998.
The
acute,
chronic,
and
cancer
dietary
risk
assessments
were
conducted
for
all
supported
acetochlor
food
uses
and
were
performed
to
support
the
tolerance
reassessment
eligibility
decision.
See:
Acetochlor.
Acute,
Chronic,
and
Cancer
Dietary
Exposure
Assessments
for
the
Tolerance
Reassessment
Eligibility
Decision
(
TRED).
PC
Code:
121601,
DP
Barcode:
D297061.
Samuel
Ary
.
June
30,
2005
Acute
Dietary
Exposure
Results
and
Characterization
of
Input
Data
The
acute
dietary
exposure
assessment
incorporated
tolerance
level
residues
for
all
crops
and
percent
crop
treated
data
provided
by
the
Acetochlor
Registration
Partnership
(
ARP)
in
MRID
45322101.
Processing
data
were
available
for
all
commodities
and
incorporated
into
the
assessment.
The
assessment
also
included
the
highest
water
concentration
generated
from
the
ARP
acetochlor
water
monitoring
program.
Acute
dietary
risk
estimates
are
provided
for
the
general
U.
S.
population
and
various
population
subgroups,
with
the
major
emphasis
placed
on
the
exposure
estimates
for
infants
and
children.
This
assessment
concludes
that
for
all
supported
registered
commodities,
the
acute
dietary
risk
estimates
do
not
exceed
HED's
level
of
concern
(
less
than
100%
of
the
aPAD)
at
the
99.9th
exposure
percentile
for
the
U.
S.
population
at
2%
of
the
aPAD
and
all
population
subgroups,
with
the
highest
exposed
population
subgroup
being
infants
less
than
1
year
old
at
6%
of
the
aPAD.

Chronic
Dietary
Exposure
Results
and
Characterization
of
Input
Data
Page
79
of
118
The
chronic
dietary
exposure
assessment
incorporated
tolerance
level
residues
for
all
crops
and
percent
crop
treated
data
provided
by
the
ARP
in
MRID
45322101.
Processing
data
were
available
for
all
commodities
and
incorporated
into
the
assessment.
The
assessment
also
included
the
highest
time­
weighted
annualized
mean
(
TWAM)
water
concentration
generated
from
the
ARP
acetochlor
water
monitoring
program.
Chronic
dietary
risk
estimates
are
provided
for
the
general
U.
S.
population
and
various
population
subgroups,
with
the
major
emphasis
placed
on
the
exposure
estimates
for
infants
and
children.
This
assessment
concludes
that
for
all
supported
registered
commodities,
the
chronic
dietary
risk
estimates
do
not
exceed
HED's
level
of
concern
(
less
than
100%
of
the
cPAD)
for
the
U.
S.
population
and
all
population
subgroups
(
all
were
less
than
1%
of
the
cPAD).

Cancer
Dietary
Exposure
Results
and
Characterization
of
Input
Data
The
cancer
dietary
exposure
assessment
incorporated
tolerance
level
residues
for
all
crops
and
percent
crop
treated
data
provided
by
the
ARP
in
MRID
45322101.
Processing
data
were
available
for
all
commodities
and
incorporated
into
the
assessment.
The
assessment
also
included
the
highest
overall
multi­
year
time
weighted
annualized
mean
water
concentration
generated
from
the
ARP
acetochlor
water
monitoring
program.
The
estimated
exposure
of
the
general
U.
S.
population
to
acetochlor
is
0.000026
mg/
kg/
day.
Applying
the
Q
1
*
of
3.27
x
10­
2
(
mg/
kg/
day)­
1
to
the
exposure
value
results
in
a
cancer
risk
estimate
of
8.40
x
10­
7.
Therefore,
the
cancer
dietary
risk
estimate
does
not
exceed
HED's
level
of
concern
of
1.0
x
10­
6.

Table
6.
1
Summary
of
Dietary
(
food
+
water)
Exposure
and
Risk
for
Acetochlor
Population
Subgroup
Acute
Dietary
(
99.9th
Percentile)
Chronic
Dietary
Cancer
Dietary
Exposure
(
mg/
kg/
day)
%
aPAD
Dietary
Exposure
(
mg/
kg/
day)
%
cPAD
Dietary
Exposure
(
mg/
kg/
day)
Risk
General
U.
S.
Population
0.003613
2
0.000050
<
1
0.000026
8.40
x
10­
7
All
Infants
(<
1
year
old)
0.009168
6
0.000129
<
1
N/
A
N/
A
Children
1­
2
years
old
0.003635
2
0.000086
<
1
Children
3­
5
years
old
0.003611
2
0.000087
<
1
Children
6­
12
years
old
0.002187
1
0.000063
<
1
Youth
13­
19
years
old
0.002350
2
0.000048
<
1
Adults
20­
49
years
old
0.002682
2
0.000044
<
1
Adults
50+
years
old
0.001861
1
0.000039
<
1
Table
6.
1
Summary
of
Dietary
(
food
+
water)
Exposure
and
Risk
for
Acetochlor
Population
Subgroup
Acute
Dietary
(
99.9th
Percentile)
Chronic
Dietary
Cancer
Dietary
Exposure
(
mg/
kg/
day)
%
aPAD
Dietary
Exposure
(
mg/
kg/
day)
%
cPAD
Dietary
Exposure
(
mg/
kg/
day)
Risk
Page
80
of
118
Females
13­
49
years
old
0.002543
2
0.000044
<
1
The
bolded
values
represent
the
highest
exposed
populations
for
each
of
the
risk
assessments.

6.2
Water
Exposure/
Risk
Pathway
The
drinking
water
values
used
in
the
dietary
risk
assessment
were
generated
by
the
ARP
acetochlor
water
monitoring
program.
The
Environmental
Fate
and
Effects
Division
(
EFED)
analyzed
and
reported
the
data
in
the
following
memorandum:
"
Drinking
Water
Exposure
Assessment
for
Acetochlor"
(
M.
Barrett,
EFED
Memorandum,
1/
3/
2005).
Water
residues
were
incorporated
in
the
DEEM­
FCID
 
into
the
food
categories
"
water,
direct,
all
sources"
and
"
water,
indirect,
all
sources".
Characterization
of
the
water
monitoring
program
and
complete
details
of
the
uncertainties
associated
with
the
program
may
be
found
in
the
EFED
memorandum.
A
highlight
of
the
uncertainties
associated
with
the
water
monitoring
program
are
listed
below.

°
The
surface
drinking
water
supply
(
SDWS)
and
state
ground
water
(
SGW)
monitoring
programs
were
designed
to
focus
on
areas
of
high
acetochlor
use.
The
monitoring
does
not
cover
the
entire
geographic
distribution
of
acetochlor
use.
A
lower
rate
of
utilization
of
surface
water
sources
by
drinking
water
facilities
and
lower
overall
numbers
of
CWS'
utilizing
surface
water
in
these
high
acetochlor
use
regions
appears
to
be
a
factor
in
the
paucity
of
sites
in
these
regions
that
were
eventually
selected
for
monitoring
in
the
SDWS.
Nonetheless,
the
lack
of
monitoring
in
some
of
the
high
acetochlor
use
areas
is
especially
problematic
for
the
SDWS
where
the
lack
of
sampling
of
raw
(
pre­
facility
treatment)
water
at
most
locations
makes
it
difficult
to
isolate
the
effects
of
site­
specific
usage
and
vulnerability
factors
and
water
treatment
processes
on
the
observed
residue
levels.

°
Acute
exposure
in
this
risk
assessment
is
defined
as
the
overall
maximum
observed
concentration
at
a
site.
The
actual
peak
concentration,
however,
may
have
occurred
between
sampling
times.
This
study
design,
like
the
vast
majority
of
surveys
of
surface
waters
for
pesticide
concentrations,
is
less
well
suited
for
estimating
acute
exposures
than
chronic
exposures,
especially
in
smaller
and
more
rapidly
flowing
streams
and
rivers.
However,
the
bias
tends
to
be
to
underestimate,
rather
than
overestimate
to
acute
exposure
levels
(
because
peak
exposure
durations
may
be
much
shorter
than
the
sampling
intervals).
It
was
determined
that
exposure
to
acetochlor
parent
was
significantly
higher
in
the
surface
water
monitoring
sites
than
the
ground
water
monitoring
sites.
The
concentration
used
in
the
acute
dietary
Page
81
of
118
assessment
was
from
a
surface
water
monitoring
site
(
214­
GI­
IL)
that
produced
the
highest
concentration
of
0.01821
ppm
(
M.
Barrett,
EFED
Memorandum,
pg.
41,
1/
3/
2005).
The
concentration
used
in
the
chronic
dietary
assessment
was
from
a
surface
water
monitoring
site
(
214­
GI­
IL)
that
produced
the
highest
TWAM
concentration
for
a
single
year
(
M.
Barrett,
EFED
Memorandum,
pg.
13,
1/
3/
2005).
The
concentration
used
in
the
cancer
dietary
assessment
was
calculated
from
site
214­
GI­
IL,
which
produced
the
highest
overall
multi­
year
(
seven
year)
time
weighted
annualized
mean
concentration
of
0.000287
ppm.
Table
6.2
lists
the
top
ten
sites
that
produced
the
highest
average
TWAM
values.
It
is
noted,
that
site
214­
GI­
IL
produced
the
highest
single
concentration,
the
highest
TWAM
value
for
a
single
year,
and
the
highest
TWAM
value
that
was
averaged
over
the
number
of
years
the
data
was
collected
from
the
site.

Table
6.2
Highest
Calculated
Average
TWAMs
Using
Data
Provided
by
the
ARP.
The
Highest
TWAM
Values
for
a
Single
Year
along
with
the
Highest
Single
Concentration
are
also
Presented.

CWS
Name
Type
Average
TWAM
Value
(
ppm)
No.
of
Years
Highest
TWAM
Value
for
a
Single
Year
(
ppm)
Highest
Single
Concentration
(
ppm)

214­
GI­
IL
Finished
0.0002871
7
0.001432
(
1996)
0.01823
(
5/
15/
1996)

330­
LO­
IN
Finished
0.000236
3
0.000418
(
1997)
0.00735
(
5/
27/
1997)

340­
NV­
IN
Finished
0.000208
2
0.000375
(
1996)
0.00431
(
5/
28/
1996)

168­
PA­
IL
Raw
0.000192
7
0.000591
(
1998)
0.00719
(
5/
28/
1998)

455­
MO­
OH
Finished
0.000179
7
0.000584
(
1997)
0.0111
(
5/
27/
1997)

451­
ML­
OH
Finished
0.000159
7
0.000281
(
1997)
0.00356
(
5/
21/
2001)

408­
DE­
OH
Finished
0.000154
5
0.000309
(
1997)
0.00382
(
5/
5/
1997)

157­
MA­
IL
Finished
0.000154
7
0.000461
(
1996)
0.00793
(
5/
1/
1996)

345­
RI­
IN
Raw
0.000144
3
0.000306
(
1997)
0.00227
(
6/
4/
1997)

518­
US­
OH
Finished
0.000137
7
0.000378
(
1996)
0.00220
(
5/
20/
1996)

1.
This
value,
0.000287
ppm,
was
used
in
the
cancer
dietary
exposure
assessment.
2.
This
value,
0.00143
ppm,
was
used
in
the
chronic
dietary
exposure
assessment
3.
This
value,
0.01821
ppm,
was
used
in
the
acute
dietary
exposure
assessment.

6.3
Residential
(
Non­
Occupational)
Exposure/
Risk
Pathway
Currently
there
are
no
registered
residential
uses
for
acetochlor,
thus
there
is
no
exposure
via
this
pathway.

7.0
Aggregate
Risk
Assessments
and
Risk
Characterization
In
accordance
with
the
FQPA,
HED
must
consider
and
aggregate
(
add)
pesticide
exposures
and
Page
82
of
118
risks
from
three
major
sources:
food,
drinking
water,
and
residential
exposures
(
oral,
dermal,
and
inhalation
exposures).
In
an
aggregate
assessment,
exposures
from
relevant
sources
are
added
together
and
compared
to
quantitative
estimates
of
hazard
(
e.
g.,
a
NOAEL
or
PAD),
or
the
risks
themselves
can
be
aggregated.
When
aggregating
exposures
and
risks
from
various
sources,
HED
considers
both
the
route
and
duration
of
exposure.

In
general,
exposures
from
various
sources
(
routes)
are
aggregated
only
when
the
toxic
effects,
determined
by
the
endpoint
selected
for
that
route,
are
the
same.
In
the
present
risk
assessment
no
residential
exposures
need
to
be
considered,
since
there
are
no
registered
residential
uses
for
acetochlor.
Thus
the
aggregate
risks
assessments
include
the
contribution
of
risk
from
dietary
(
food
+
drinking
water)
sources
only.
The
results
and
specifics
of
these
assessments
are
presented
in
Sections
6.1.2
and
6.2
reported
in
Table
6.1.
Only
the
results
of
the
assessments
are
reported
in
Sections
7.1
­
7.3
7.1
Acute
Aggregate
Risk
This
assessment
concludes
that
for
all
supported
registered
commodities,
the
acute
dietary
risk
estimates
do
not
exceed
HED's
level
of
concern
(
less
than
100%
of
the
aPAD)
at
the
99.9th
exposure
percentile
for
the
U.
S.
population
at
2%
of
the
aPAD
and
all
population
subgroups,
with
the
highest
exposed
population
subgroup
being
infants
less
than
1
year
old
at
6%
of
the
aPAD.

7.2
Short­
Term
Aggregate
Risk
This
scenario
is
not
expected,
since
there
are
no
residential
uses.

7.3
Long­
Term
Aggregate
Risk
This
assessment
concludes
that
for
all
supported
registered
commodities,
the
chronic
dietary
(
food
+
water)
risk
estimates
do
not
exceed
HED's
level
of
concern
(
less
than
100%
of
the
cPAD)
for
the
U.
S.
population
and
all
population
subgroups
(
all
were
less
than
1%
of
the
cPAD).

7.5
Cancer
Risk
The
cancer
dietary
exposure
assessment
incorporated
tolerance
level
residues
for
all
crops
and
percent
crop
treated
data
provided
by
the
ARP
in
MRID
45322101.
Processing
data
were
available
for
all
commodities
and
incorporated
into
the
assessment.
The
assessment
also
included
the
overall
multi­
year
time
weighted
annualized
mean
water
concentration
generated
from
the
ARP
acetochlor
water
monitoring
program.
The
estimated
exposure
of
the
general
U.
S.
population
to
acetochlor
is
0.000026
mg/
kg/
day.
Applying
the
Q
1
*
of
3.27
x
10­
2
(
mg/
kg/
day)­
1
to
the
exposure
value
results
in
a
cancer
risk
estimate
of
8.40
x
10­
7.
Therefore,
the
cancer
dietary
risk
estimate
does
not
exceed
HED's
level
of
concern
of
1.0
x
10­
6.
Page
83
of
118
8.0
Cumulative
Risk
Characterization/
Assessment
Acetochlor
is
part
of
a
Common
Mechanism
Group
with
the
related
chloroacetanilides
butachlor
and
alachlor.
See:
Implementation
of
the
Determination
of
a
Common
Mechanism
of
Toxicity
for
N­
Methyl
Carbamate
Pesticides
and
for
Certain
Chloroacetanilide
Pesticides.
Memorandum
from
M.
M.
Mulkey,
Director,
EPA/
OPP,
dated
July
12,
2001.
A
cumulative
risk
assessment
is
currently
underway
for
acetochlor
and
alachlor.
Butachlor
is
excluded
because
it
is
not
registered
in
the
US.

9.0
Occupational
Exposure/
Risk
Pathway
This
assessment
supports
the
Tolerance
Reassessment
Eligibility
Decision
(
TRED)
document
for
acetochlor
and
addresses
exposures
resulting
from
dietary
(
food
+
drinking
water)
intakes
only.
Non­
occupational
(
residential/
recreational)
exposures
do
not
need
to
be
addressed
in
this
document
because
acetochlor
is
not
registered
for
residential/
recreational
uses.
Occupational
exposures/
risks
will
not
be
addressed
in
this
assessment.

10.0
Data
Needs,
Regulatory
Recommendations,
and/
or
Label
Requirements
10.1
Toxicology
1.
A
Developmental
Neurotoxicity
study
is
required.
2.
Validation
studies
(
positive
controls)
should
be
submitted
for
the
rat
neurotoxicity
studies.

10.2
Residue
Chemistry
1.
It
has
been
determined
that
a
permanent
tolerance
of
2.0
ppm
be
set
for
wheat
hay
based
on
the
maximum
residues
of
0.457
ppm
in
wheat
forage
corrected
for
moisture
content.

2.
As
the
tolerances
on
field
corn
commodities
are
for
the
direct
application
to
a
primary
crop,
these
general
tolerances
on
corn
should
be
reassigned
to
40
CFR
§
180.470(
a).
Likewise,
tolerances
on
sorghum,
soybeans,
and
wheat
commodities
are
for
inadvertent
residues
on
rotational
crops;
therefore,
these
tolerances
should
be
reassigned
to
40
CFR
§
180.470(
d).

3.
The
available
field
trial
data
indicate
that
the
current
tolerances
on
corn
grain
and
stover
are
adequate,
but
the
tolerance
on
corn
forage
should
be
increased
to
3.0
ppm
based
on
data
from
the
early
post­
emergence
use.

4.
Labels
allowing
direct
application
to
pop
corn
should
be
amended
to
prevent
such
application
until
the
registrant
formally
petitions
for
the
use.
Page
84
of
118
References:
RESIDUE
CHEMISTRY
Study
Citations
00064797
Wilson,
G.
R.;
Baszis,
S.
R.;
Steinmetz,
J.
R.;
et
al.
(
1980)
Residues
of
Acetochlor
in
Soybean
and
Corn
Grain
following
Preemergent
Treatment
with
Acetochlor
Alone
or
in
Tank­
mix
Combinations
with
Atrazine,
Linuron
and
Metribuzin:
Report
No.
MSL­
1242.
Final
rept.
(
Unpublished
study
received
Dec
12,
1980
under
524­
EX­
56;
submitted
by
Monsanto
Co.,
Washington,
D.
C.;
CDL:
099813­
A).
00085062
Malik,
J.
M.
(
1981)
Acetochlor
Crop
Metabolism
in
Soybeans
and
Corn:
Special
Report
MSL­
1873.
(
Unpublished
study
received
Oct
27,
1981
under
524­
EX­
56;
submitted
by
Monsanto
Co.,
Washington,
D.
C.;
CDL:
070434­
A).

00106078
Monsanto
Co.
(
1982)
?
Residues
of
Acetochlor
in
Soybeans
and
Other
Crops|.
(
Compilation;
unpublished
study
received
Jul
14,
1982
under
2G2726;
CDL:
070984­
A).

00116632
Wilson,
G.;
Dubelman,
S.
(
1982)
Residue
Determination
of
Acetochlor
Metabolites
in
Hog
Tissue:
Report
No.
MSL­
2286.
Final
rept.
(
Unpublished
study
received
Oct
21,
1982
under
524­
EX­
56;
submitted
by
Monsanto
Co.,
Washington,
DC;
CDL:
248621­
A;
248622).

00116633
Wilson,
G.;
Dubelman,
S.
(
1982)
Residue
Determination
of
Acetochlor
Metabolites
in
Milk
and
Beef
Tissues:
Report
No.
MSL­
2285.
Final
rept.
(
Unpublished
study
received
Oct
21,
1982
under
524­
EX­
56;
prepared
in
corporation
with
Hazleton
Raltech,
Inc.,
submitted
by
Monsanto
Co.,
Washington,
DC;
CDL:
248623­
A;
248624).

00116634
Wilson,
G.;
Dubelman,
S.
(
1982)
Residue
Determination
of
Acetochlor
Metabolites
in
Eggs
and
Chicken
Tissues:
Report
No.
MSL­
2287.
Final
rept.
(
Unpublished
study
received
Oct
21,
1982
under
524­
EX­
56;
prepared
in
cooperation
with
Hazleton
Raltech,
Inc.,
submitted
by
Monsanto
Co.,
Washington,
DC;
CDL:
248625­
A;
248626).

00118950
Monsanto
Co.
(
1982)
?
Acetochlor:
Residues
in
Goats|.
(
Compilation;
unpublished
study
received
Nov
18,
1982
under
524­
EX­
56;
CDL:
071246­
A).

40365601
Oppenhuizen,
M.;
Wilson,
G.
(
1987)
Residues
of
Acetochlor
from
Two
Metabolite
Classes
in
Corn
Forage,
Corn
Grain
and
Corn
Fodder:
Laboratory
Project
No.
MSL­
6843:
R.
D.
No.
817.
Unpublished
study
prepared
by
Monsanto
Agricultural
Co.
294
p.

40365602
Letendre,
L.;
Hooblen,
M.;
Wratten,
S.
(
1987)
Metabolism
of
Synthetic
Plant
Metabolites
of
Acetochlor
in
the
Laying
Hens:
Laboratory
Project
No.
MSL­
6941:
R.
D.
No.
818.
Unpublished
study
pre­
pared
by
Monsanto
Agricultural
Co.
171
p.

40383401
Mueth,
M.
(
1987)
Acetochlor
Residues
from
Two
Metabolite
Classes
in
Defeated
Corn
Page
85
of
118
Meal:
Laboratory
Project
No.
MSL­
6835:
R.
D.
No.
824.
Unpublished
study
prepared
by
Monsanto
Agricultural
Co.
171
p.

40383402
Wilson,
G.
(
1987)
An
Acetochlor
Analytical
Method
Interference
Study:
Laboratory
Project
No.
MSL­
6900:
R.
D.
No.
825.
Unpublished
study
prepared
by
Monsanto
Agricultural
Co.
188
p.

40879201
Oppenhuizen,
M.
(
1988)
Additional
Chromatograms
Requested
by
the
Agency
in
Support
of
Monsanto
Report
No.
MSL
6843,
"
Residues
of
Acetochlor
from
Two
Metabolite
Classes
in
Corn
Forage,
Corn
Grain
and
Corn
Fodder",
Volume­­
Corn
Grain:
RD
895.
Unpublished
study
prepared
by
Monsanto
Agricultural
Co.
212
p.

40879202
Oppenhuizen,
M.
(
1988)
Additional
Chromatograms
Requested
by
the
Agency
in
Support
of
Monsanto
Report
No.
MSL­
6843,
"
Residues
of
Acetochlor
from
Two
Metabolite
Classes
in
Corn
Forage,
Corn
Grain
and
Corn
Fodder",
Volume
II­­
Corn
Forage:
RD
895.
Unpublished
study
prepared
by
Monsanto
Agricultural
Co.
207
p.

40879203
Oppenhuizen,
M.
(
1988)
Additional
Chromatograms
Requested
by
the
Agency
in
Support
of
Monsanto
Report
No.
MSL­
6843,
"
Residues
of
Acetochlor
from
Two
Metabolite
Classes
in
Corn
Forage,
Corn
Grain
and
Corn
Fodder",
Volume
III­­
Corn
Fodder:
RD
895.
Unpublished
study
prepared
by
Monsanto
Agricultural
Co.
186
p.

40879204
Mueth,
M.
(
1988)
Additional
Chromatograms
Requested
by
the
Agency
in
Support
of
Monsanto
Report
No.
MSL­
6835,
"
Acetochlor
Residues
from
Two
Metabolite
Classes
in
Defeated
Corn
Meal":
RD
895.
Un­
published
study
prepared
by
Monsanto
Agricultural
Co.
170
p.

40965101
Oppenhuizen,
M.
(
1989)
Regulatory
Enforcement
Method
for
the
Determination
of
Acetochlor
Residues
in
Raw
Agricultural
Commodities:
Laboratory
Project
No.
MSL­
8453:
R.
D.
No.
908.
Unpublished
study
prepared
by
Monsanto
Agricultural
Co.
in
cooperation
with
Craven
Laboratories,
Inc.
51
p.

40965102
Meuth,
M.
(
1989)
Regulatory
Enforcement
Method
for
the
Determination
of
Acetochlor
Residues
in
Beef
Tissues
and
Milk:
Laboratory
Project
No.
MSL­
8567:
R.
D.
No.
908.
Unpublished
study
prepared
by
Monsanto
Agricultural
Co.
36
p.

41304201
Lauer,
R.;
Mayonado,
N.
(
1989)
Acetochlor
Residues
from
Two
Metabolite
Classes
in
Corn,
Dry­
milled
and
Wet­
milled
Processed
Corn
Fractions:
Lab
Project
Number:
MSL­
8512:
965.
Unpublished
study
prepared
by
Monsanto
Agricultural
Co.
301
p.

41304202
Oppenhuizen,
M.
(
1989)
Storage
Stability
of
Two
Classes
of
Acetochlor
Metabolites
in
Corn
Grain,
Forage
and
Fodder:
Lab
Project
Number:
MSL­
9043:
965.
Unpublished
study
prepared
by
Monsanto
Agricultural
Co.
128
p.
Page
86
of
118
41304203
Arras,
D.
(
1989)
Regulatory
Enforcement
Method
for
the
Determination
of
Acetochlor
Residues
in
Milk,
Beef
Tissues
and
Raw
Agricultural
Commodities:
Lab
Project
Number:
MSL­
9572:
965.
Unpublished
study
prepared
by
Monsanto
Agricultural
Co.
32
p.

41565156
Corden,
M.;
Skidmore,
M.
(
1990)
Acetochlor:
Metabolism
in
Maize:
Lab
Project
Number:
88JH439.
Unpublished
study
prepared
by
ICI
Agrochemicals.
127
p.

41565157
Hawkins,
D.;
Kirkpatrick,
D.;
Dean,
G.;
et
al.
(
1989)
Biokinetics
and
Metabolism
of
[
14C]­
Acetochlor
in
the
Goat:
Lab
Project
Number:
HRC/
STR
25/
89412.
Unpublished
study
prepared
by
Huntingdon
Research
Centre
Ltd.
78
p.

41565158
Hawkins,
D.;
Kirkpatrick,
D.;
Dean,
G.;
et
al.
(
1990)
Biokinetics
and
Metabolism
of
(
14C)­
Acetochlor
in
the
Laying
Hen:
Lab
Project
Number:
HRC/
STR
26/
90147.
Unpublished
study
prepared
by
Huntingdon
Research
Centre
Ltd.
54
p.

41565159
Hand,
L.;
Skidmore,
M.
(
1990)
Acetochlor:
Metabolism
and
Bio­
transformation
in
Hens:
Lab
Project
Number:
RJ0854B.
Unpublished
study
prepared
by
ICI
Agrochemicals.
87
p.

41565160
Zilka,
S.;
Simmons,
N.
(
1990)
Acetochlor:
Residue
Analytical
Method
Report
for
the
Determination
of
2­
Chloro­
N­(
Ethoxymethyl)­
N­
2­
Ethyl­
6­
Methylphenyl)
Acetamide
in
Field
Corn:
Grain,
Cob,
Fodder,
Forage
&
Silage,
Processed
Corn
and
other
Crops:
Lab
Project
Number:
RJ
0819B.
Unpublished
study
prepared
by
ICI
Agrochemicals.
30
p.

41565161
Crook,
S.;
Simmons,
N.
(
1990)
Acetochlor:
Residue
Analytical
Method
Report
for
the
Determination:
Lab
Project
Number:
5676­
88­
MR­
01.
Unpublished
study
prepared
by
ICI
Agrochemicals.
26
p.

41565162
Simmons,
N.;
O'Brien,
M.
(
1989)
Acetochlor
and
R25788:
Residues
in
Processed
Corn
Fractions
from
Trials
Carried
Out
in
the
USA
during
1988:
Lab
Project
Number:
5676­
88­
PR­
01.
Unpublished
study
prepared
by
ICI
Agrochemicals.
45
p.

41565163
Pay,
J.;
Gaunt,
N.;
Simmons,
N.
(
1990)
Acetochlor:
Residues
in
Field
Corn
from
Trials
Carried
Out
in
the
USA
during
1988:
Lab
Project
Number:
5676­
88­
MR­
01.
Unpublished
study
prepared
by
ICI
Agrochemicals.
116
p.

41592014
Crook,
S.;
Zilka,
S.;
Simmons,
N.
(
1990)
Acetochlor:
Residues
of
2­
Ethyl­
6­
methylaniline
(
E.
M.
A)
Metabolites
in
Field
Corn
from
Trials
Carried
Out
in
the
USA
during
1988:
Lab
Project
Number:
5676­
88­
MR­
01.
Unpublished
study
prepared
by
ICI
Agrochemicals.
116
p.

41633501
Arras,
D.
(
1990)
Regulatory
Enforcement
Method
for
the
Determination
of
Acetochlor
Residues
in
Milk,
Beef
Tissues,
and
Raw
Agricultural
Commodities:
Lab
Project
Number:
MSL­
10380:
1008.
Un­
published
study
prepared
by
Monsanto
Agricultural
Co.,
and
Hazleton
Page
87
of
118
Laboratories
America,
Inc.
148
p.

41633601
Cheng,
T.
(
1990)
Nature/
Magnitude
of
the
Residue
in
Lactating
Goats
Preliminary
and
Definitive
Phases:
Lab
Project
Number:
HLA
6103­
116:
1009.
Unpublished
study
prepared
by
Hazleton
Laboratories
America,
Inc.
221
p.

41961201
Corden,
M.;
Skidmore,
M.
(
1990)
Acetochlor:
Metabolism
in
Maize:
Amendment/
Addendum:
Lab
Project
Number:
88JH439.
Unpublished
study
prepared
by
ICI
Agrochemicals,
Jeallott's
Hill
Research
Station.
41
p.

41961202
Crook,
S.;
Simmons,
N.
(
1990)
Acetochlor:
Residue
Analytical
Method
Report
for
the
Determination
of
2­
Ethyl­
6­
Methylaniline
(
E.
M.
A)
in
Field
Corn,
Grain,
Fodder
and
Forage­­
Addendum:
Lab
Project
Number:
RJ0840B.
Unpublished
study
prepared
by
ICI
Agrochemicals,
Jealott's
Hill
Research
Station.
9
p.

41961203
Zilka,
S.;
Simmons,
N.
(
1991)
Acetochlor:
Residue
Analytical
Method
Report
for
the
Determination
of
2­
Chloro­
N­(
Ethoxymethyl)­
N­
(
2­
Methyl­
6­
Methylphenyl)
Acetamide
in
Field
Corn:
Grain,
Cob,
Fodder,
Forage
&
Silage,
Processed
Corn
and
other
Crops­­
Addendum:
Lab
Project
Number:
RJ0819B.
Unpublished
study
prepared
by
Agrochemicals,
Jealott's
Hill
Research
Station.
9
p.

41961204
Zilka,
S.;
Simmons,
N.
(
1990)
Acetochlor:
Residue
Analytical
Method
Report
for
the
Determination
of
2­
Chloro­
N­(
Ethoxymethyl)­
N­
(
2­
Ethyl­
6­
Methylphenyl)
Acetamide
in
Field
Corn:
Grain,
Cob,
Fodder,
Forage
&
Silage,
Processed
Corn
and
Other
Crops­­
Amendment:
Lab
Project
Number:
RJ0819B.
Unpublished
study
prepared
by
Agrochemicals,
Jealott's
Hill
Research
Station.
7
p.

41961205
Simmons,
N.;
O'Brien,
M.
(
1989)
Acetochlor
and
R25788:
Residue
in
Processed
Corn
Fractions
from
Trials
Carried
Out
in
the
USA
During
1988:
Addendum:
Lab
Project
Number:
5676­
88­
PR­
01:
RJ0786B.
Unpublished
study
prepared
by
ICI
Agrochemicals,
Jealott's
Hill
Research
Station.
10
p.

41963322
Corden,
M.;
Mathis,
S.;
Skidmore,
M.
(
1991)
Acetochlor:
Metabolism
in
Maize:
Final
Report:
Lab
Project
Number:
88JH439.
Unpublished
study
prepared
by
ICI
Agrochemicals.
137
p.

41963323
Crook,
S.;
Downey,
C.;
Skidmore,
M.
(
1991)
Acetochlor:
Accumulation
and
Biotransformation
of
Carbon­
14
Acetochlor
Plant
Metabolites
in
Ruminants:
Lab
Project
Number:
90JH345.
Unpublished
study
prepared
by
ICI
Agrochemicals.
189
p.

41963324
Crook,
S.;
Khundker,
S.;
Skidmore,
M.
(
1991)
Acetochlor:
Accumulation
and
Biotransformation
of
[
14C]
Metabolites
in
Poultry:
Lab
Project
Number:
91JH142.
Unpublished
study
prepared
by
ICI
Agrochemicals.
131
p.
Page
88
of
118
41963325
Crook,
S.;
Simmons,
N.
(
1991)
Acetochlor:
Residue
Analytical
Method
Report
for
the
Determination
of
2­
Ethyl­
6­
Methylaniline
(
E.
M.
A.)
and
2­(
1­
Hydroxyethyl)­
6­
Methylalanine
(
H.
E.
M.
A)
in
Field
Corn;
Grain;
Fodder;
Forage
and
Process
Fractions.
Unpublished
study
prepared
by
ICI
Agrochemicals.
33
p.

41963326
Zilka,
S.;
Simmons,
N.
(
1991)
Acetochlor:
Tolerance
Enforcement
Method
Report
for
the
Determination
of
2­
Chloro­
N­(
Ethoxymethyl)­
N­(
2­
Ethyl­
6­
Methylphenyl)
Acetamide
in
Field
Corn:
Grain,
Cob,
Fodder,
Forage
and
Processed
Corn:
Lab
Project
Number:
5676­
88­
MR­
01.
Unpublished
study
prepared
by
ICI
Agrochemicals.
68
p.

41963327
Gillard,
D.
(
1991)
Analysis
of
Acetochlor
by
Multiresidue
Methods
FDA
Pesticide
Analytical
Manuel
Volume
I:
Lab
Project
Number:
A030.
007D:
0021­
CL­
ML­
01.
Unpublished
study
prepared
by
Huntingdon
Analytical
Services.
118
p.

41963328
Crook,
S.;
Wilson,
B.;
Simmons,
N.
(
1991)
Acetochlor:
Residues
of
2­(
1­
Hydroxyethyl)­
6­
Methylaniline
(
H.
E.
M.
A)
Metabolites
in
Field
Corn
From
Trials
Carried
Out
in
the
U.
S.
A.
During
1988:
Lab
Project
Number:
5676­
88­
MR­
01.
Unpublished
study
prepared
by
ICI
Agrochemicals.
129
p.

42549903
Powell,
S.;
Skidmore,
M.
(
1991)
Acetochlor:
Quantification
and
Characterisation
of
Radioactive
Residues
in
Tissues,
Milk
and
Excreta
of
Goats
after
Oral
Dosing
with
[
14C]­
Acetochlor:
Lab
Project
Number:
90JH195:
RJ1019B.
Unpublished
study
prepared
by
ICI
Agrochemicals.
185
p.

42549904
Downey,
C.;
Skidmore,
M.
(
1992)
ICIA5676/
57:
Metabolism
in
Hens
following
Dosing
at
10
ppm
in
the
Diet:
Lab
Project
Number:
91JH253:
RJ1179B.
Unpublished
study
prepared
by
ICI
Agrochemicals.
111
p.

42549905
Corden,
M.;
Renwick,
R.;
Mathis,
S.;
et.
al
(
1992)
ICIA5676/
57:
Metabolism
in
Lactating
Cow
following
Oral
Dosing
at
25
ppm
in
the
Diet:
Lab
Project
Number:
91JH220:
RJ1228B.
Unpublished
study
prepared
by
ICI
Agrochemicals.
79
p.

42549908
Mannion,
R.;
Steinmetz,
J.
(
1992)
Storage
Stability
of
Acetochlor
Metabolites
in
Soybean,
Wheat,
and
Sorghum
Raw
Agricultural
Commodities:
Lab
Project
Number:
MSL­
12139.
Unpublished
study
prepared
by
Monsanto
Company.
162
p.

42549909
Wilson,
B.;
Simmons,
N.
(
1992)
Acetochlor:
Storage
Stability
of
Residue
in
Deep
Frozen
Processed
Corn
Fractions:
Lab
Project
Number:
89JH352:
RJ1096B.
Unpublished
study
prepared
by
ICI
Agrochemicals.
60
p.

42549910
Simmons,
N.;
Crook,
S.
(
1991)
Acetochlor:
Storage
Stability
of
the
EMA
Acetochlor
Metabolite
Class
in
Deep
Frozen
Field
Corn
Fractions:
Interim
Report:
Lab
Project
Number:
91JH307:
RJ1060B.
Unpublished
study
prepared
by
ICI
Agrochemicals.
24
p.
Page
89
of
118
42549911
Simmons,
N.;
Crook,
S.
(
1991)
Acetochlor:
Storage
Stability
of
the
HEMA
Acetochlor
Metabolite
Class
in
Deep
Frozen
Field
Corn
Fractions:
Lab
Project
Number:
5676­
88­
MR­
01:
RJ1067B.
Unpublished
study
prepared
by
ICI
Agrochemicals.
23
p.

42549914
Kerregan,
R.;
Lau,
P.
(
1992)
Acetochlor
Metabolite
Residues
in
Processed
Fractions
from
Soybeans
as
a
Rotation
Crop:
Lab
Project
Number:
MSL­
12091:
SARS­
89­
NC­
92TP:
SARS­
89­
NE­
92P.
Unpublished
study
prepared
by
Monsanto
Company.
309
p.

42549919
O'Neal,
S.;
Johnson,
T.
(
1992)
A
Confined
Rotational
Crop
Study
with
[
14C]­
Acetochlor
using
Radishes
(
Raphanus
sativus),
Lettuce
(
Lactuca
sativa)
and
Wheat
(
Triticum
aestivum):
Lab
Project
Number:
MSL­
12105:
474.
Unpublished
study
prepared
by
PTRL
East,
Inc.,
Pharmacology
&
Toxicology
Research
Lab,
and
Plant
Sciences,
Inc.
377
p.

42591501
Sidhu,
R.
(
1992)
Acetochlor
Metabolite
Residues
in
Rotational
Crops
Following
Preemergent
Application
of
Acetochlor
to
Corn:
Lab
Project
Number:
MSL­
11963
(
MONSANTO):
39084
(
ABC
LABS):
40104
(
ABC
LABS).
Unpublished
study
prepared
by
Monsanto
Co.,
ABC
Laboratories,
and
Stewart
Agricultural
Research
Services,
Inc.
2845
p.

42713111
Lauer,
R.
(
1991)
Interference
Determination
of
Metolachlor
in
Corn
Forage,
Fodder
and
Grain
Following
Preemergent
Treatment
with
Acetochlor:
Lab
Project
Number:
MSL­
10452:
1033.
Unpublished
study
prepared
by
Monsanto
Agricultural
Company
and
ChemAlysis.
153
p.

42713112
Nash,
R.
(
1991)
Multiresidue
Methodology
Testing
of
CP
95200,
CP
92429,
CP
97290,
CP
108669,
CP
106070,
and
CP
106077
(
Acetochlor
Metabolites):
Lab
Project
Number:
11520:
115­
008:
1033.
Unpublished
study
prepared
by
EPL
Bio­
Analytical
Services,
Inc.
170
p.

42713113
Ralph,
C.;
Veal,
P.;
French,
D.
(
1992)
Acetochlor:
Residues
of
N­(
6­
Ethyl­
3­
Hydroxy­
2­
Methylphenyl)
Oxamic
Acid
in
Filed
Corn
from
Trials
Carried
Out
in
the
USA
During
1991:
Lab
Project
Number:
ACET­
91­
MR­
01:
RJ1337B.
Unpublished
study
prepared
by
ICI
Agrochemicals.
40
p.

42713114
Johnson,
T.;
French,
D.;
Bathke,
P.;
et
al.
(
1992)
Acetochlor:
Residues
in
Field
Corn
from
Trials
Carried
Out
in
the
USA
During
1991:
Lab
Project
Number:
ACET­
91­
MR­
01:
RJ1321B.
Unpublished
study
prepared
by
ICI
Agrochemicals.
78
p.

42713115
Veal,
P.;
French,
D.
(
1992)
Acetochlor:
Residues
of
2­
Ethyl­
6­
Methylaniline
(
EMA)
and
2­(
1­
Hydroxyethyl)­
6­
Methylaniline
(
HEMA)
in
Field
Corn
from
Trials
Carried
Out
in
the
USA
During
1991:
Lab
Project
Number:
ACET­
91­
MR­
01:
RJ1235B.
Unpublished
study
prepared
by
ICI
Agrochemicals.
241
p.

42713116
Crook,
S.
(
1992)
Acetochlor:
Analytical
Method
for
the
Determination
of
N­(
6­
Ethil­
3­
Hydroxy­
2­
Methylphenyl)­
Oxamic
Acid
in
Crops
and
Processed
Corn
Fractions:
Lab
Project
Number:
92JH078:
RJ1257B.
Unpublished
study
prepared
by
ICI
Agrochemicals.
25
p.
Page
90
of
118
42713117
Crook,
S.
(
1992)
Acetochlor:
Storage
Stability
of
the
N­(
6­
Ethil­
3­
Hydroxy­
2­
Methylphenyl)
Oxamic
Acid
Metabolite
in
Deep
Frozen
Field
Corn,
Grain,
Forage
and
Fodder:
Interim
Results:
Lab
Project
Number:
91JH223:
RJ1352B.
Unpublished
study
prepared
by
ICI
Agrochemicals.
25
p.

42831607
Lau,
P.
(
1992)
Residues
of
Acetochlor
from
two
Metabolite
Classes
in
Field
Corn
Following
Preemergent
Application
of
MON
8422:
Lab
Project
Number:
MSL­
11794:
HWI
6103­
129:
0642­
90­
1.
Unpublished
study
prepared
by
Monsanto
Co.,
Hazleton
Wisconsin,
Inc.
and
Stewart
Agricultural
Research
Services,
Inc.
611
p.

42908601
Veal,
P.;
Bathke,
P.;
French,
D.
(
1993)
ACETOCHLOR:
Residues
of
N­(
6­
ethyl­
3­
hydroxy­
2­
methylphenyl)
Oxamic
Acid
in
Processed
Corn
Fractions
from
a
Trial
Carried
Out
in
the
USA
During
1991:
(
Interim
Report):
Lab
Project
Number:
ACET­
91­
PR­
01:
RJ1460B.
Unpublished
study
prepared
by
ICI
Agrochemicals.
49
p.

43266501
Veal,
P.;
French,
D.;
Johnson,
T.
et
al.
(
1994)
Acetochlor
and
(
inert
ingredient)
Residue
Levels
in
Field
Corn
Following
Treatment
with
two
New
Formulations:
Lab
Project
Number:
ACET­
93­
MR­
01:
RJ1591B.
Unpublished
study
prepared
by
Zeneca
Agrochemicals,
Jealott's
Hill
Research
Station.
128
p.

43470001
Arras,
D.
(
1994)
Regulatory
Enforcement
Method
for
the
Determination
of
Acetochlor
Residues
in
Milk,
Beef
Tissues,
and
Raw
Agricultural
Commodities:
Reformatted
Method:
Lab
Project
Number:
RES­
074­
93.
Unpublished
study
prepared
by
Monsanto
Environmental
Science
Dept.
34
p.

43616401
French,
D.;
Crook,
S.;
Veal,
P.;
et
al.
(
1994)
Acetochlor
and
(
inert
ingredient):
Magnitude
of
Residues
in
Field
Corn
Following
Post­
Emergence
Application
(
USA
1993):
Lab
Project
Number:
RJ
1735B:
ACET­
93­
MR­
03:
94­
IL­
93­
410.
Unpublished
study
prepared
by
Zeneca
Agrochemicals.
178
p.

43616402
Allan,
J.
(
1994)
Acetochlor
Metabolite
Residues
in
Field
Corn
Commodities
Following
Early
Post­
emergent
Applications
of
Acetochlor:
Lab
Project
Number:
MSL­
13414:
41383:
93­
27­
R­
2.
Unpublished
study
prepared
by
Monsanto
Co.;
ABC
Labs.;
and
Stewart
Agricultural
Research
Services,
Inc.
319
p.
Page
91
of
118
Agency
Memoranda
Citations
Table
9.
Agency
Memoranda
Citations.

Date
DP
Barcode
CB
No.
From
To
MRID
Nos.
Subject
6/
2/
81
None
None
J.
Worthington
R.
Taylor
Not
listed
PP#
1G2454.
Acetochlor
on
Corn
and
Soybeans.

Evaluation
of
the
Analytical
Methods
and
Residue
Data.

1/
18/
82
None
None
J.
Worthington
R.
Taylor
and
Toxicology
Branch
Not
listed
PP#
1G2454.
Acetochlor
on
Corn
and
Soybeans.

Comments
on
the
amendment
of
10/
23/
81.

10/
28/
82
None
None
S.
Malak
R.
Taylor
Not
listed
PP#
2G2726.
Acetochlor
on
Corn,
Soybeans,
and
Peanuts.
Evaluation
of
Analytical
Method
and
Residue
Data.

6/
6/
83
None
None
S.
Malak
R.
Taylor
and
Toxicology
Branch
Not
listed
PP#
3G2797
and
PP#
2G2726.
Acetochlor
in
Milk,
Eggs,

and
Tissues
of
Livestock.
Evaluation
of
Analytical
Method
and
Residue
Data
including
Amendment
of
December
2,
1982
submitted
in
connection
with
PP#
2G2726.

7/
20/
84
None
R.
Cook
PP#
3F2966.
Memo
was
not
available
for
review.

8/
3/
88
None
3894­

3899,

3902
F.
Griffith
R.
Taylor
and
C.
Trichilo
40554801­
40554804,

40365601,
40365602
PP#
3F2966
and
PP#
6G3345
­
Acetochlor
in
Corn,
Corn
Products,
Meat,
Milk,
Poultry,
and
Eggs.
Evaluation
of
Amendments.

4/
11/
89
None
M.
Flood
PP#
3F2966.
Memo
was
not
available
for
review.

8/
7/
90
None
6262,

6263
L.
Cheng
R.
Taylor
and
Toxicology
Branch
41304201­
41304203,

41013201­
41013206,

40994402
PP#
1G2454
&
524­
EUP­
56.
Acetochlor
on
Field
Corn.

Evaluation
on
Analytical
Methods
and
Residue
Data.

1/
3/
91
None
7035,

7131
L.
Cheng
J.
Miller,
and
Toxicology
Branch
41565150,
41565151,

41565155­
41565163,

41592014
PP#
0G3888
&
10182­
EUP­
LU.
Acetochlor
on
Field
Corn.
Evaluation
of
Analytical
Methods
and
Residue
Data.
Table
9.
Agency
Memoranda
Citations.

Date
DP
Barcode
CB
No.
From
To
MRID
Nos.
Subject
Page
92
of
118
4/
29/
91
D156740
7118­
7121
N.
Dodd
R.
Taylor,
and
Toxicology
Branch
41633500,
41633501,

41633601
PP#
3F2966/
1G2454.
Acetochlor
no
Corn,
Corn
Products,
Meat,
Milk,
Poultry,
and
Eggs.
Amendment
dated
9/
20/
90.

10/
28/
91
D167686,

D167690
8423,

8454
L.
Cheng
J.
Miller,
and
J.
Mayes
41961201­
41961205
PP#
0G3888
&
10182­
EUP­
LU.
Acetochlor
on
Field
Corn.
Response
to
1/
3/
91
Review.
Waiver
Request
on
Feeding
Studies.

7/
12/
93
D187729,
D187731,
D187733,
D190315,
D190317,
D190320,

D190322
11330­

11332,
11747­

11750
M.
Flood
R.
Taylor,

V.
Walters,

A.
Kocialski,
and
S.
Willett
41963322­
41963328,

42549903­
42549905,

42549909,
42549912,

42713111­
42713117
PP#
3F2966/
PP#
1F4011,
Acetochlor
Registration
Partnership.
Acetochlor
EC
Herbicide
for
Use
on
Field
Corn.

8/
23/
93
D189047,
D187729,
D187731,

D187733
11330­

11332,
11540,

11541
M.
Flood
R
Taylor
and
V.

Walters
42549908,
42549914,

42549919,
42591501
PP#
3F2966/
PP#
1F4011.
Acetochlor
Registration
Partnership.
Acetochlor
EC
Herbicide
for
Use
on
Field
Corn.
Confined
Rotational
Crop
Study.
Field
Rotational
Crop
Studies.

9/
30/
93
None
None
M.
Flood
Metabolism
Committee,
HED
None
The
Metabolism
Committee
Meeting
Held
on
September
15,
1993.
Plant
and
Animal
Metabolism
of
Acetochlor.

11/
24/
93
D194327­

D194329,
D195035,
D195036,

D196269
12417­

12419,
12539,

12540
M.
Flood
R.
Taylor,

V.
Walters,

A.
Kocialski,
and
S.
Willett
42908601
PP#
3F2966/
PP#
1F4011.
Acetochlor
Registration
Partnership.
Acetochlor
EC
Herbicide
for
Use
on
Field
Corn.
Response
to
CBTS
Memo
Dated
7/
12/
93.

1/
11/
94
D197597,
D197599,
D197601­

D197605
12974­

12980
M.
Flood
R.
Taylor,

V.
Walters,

A.
Kocialski,
and
S.
Willett
None
PP#
3F4232
 
Acetochlor,
Rotational
Crop
Tolerances.

Amendment
Dated
12/
13/
93
from
Acetochlor
Registration
Partnership
(
ARP).
Table
9.
Agency
Memoranda
Citations.

Date
DP
Barcode
CB
No.
From
To
MRID
Nos.
Subject
Page
93
of
118
8/
1/
94
D196581
12774
M.
Flood
R
Taylor
and
V.

Walters
42831607
Acetochlor
 
Microencapsulated
Formulation.

Evaluation
of
Residue
Data.
ID#.
00524­
UTR
MON­

8421.

2/
6/
95
D210066
14851
M.
Flood
R
Taylor
and
V.

Walters
43470001
Acetochlor.
ID#:
066478­
00002.
Reformatted
Analytical
Method.

4/
14/
95
D204673
13896
S.
Willet
R
Taylor
and
V.

Walters
43266501
ID
No.
10182­
GOR.
ICIA
6576
3.2
CS
Herbicide
(
a.
i.

acetochlor
w/
the
safener
dichlormid).
New
Formulation
of
Use
on
Field
Corn
and
Popcorn.

6/
25/
96
D214735,

D214738
None
G.
Herndon,

W.
Dykstra,

and
C.
Lewis
V.
Walters
and
R.
Taylor
43616401
PP#
5F4505.
Section
3
Registration
and
Permanent
Tolerance
Petition
to
Expand
the
Use
of
Acetochlor
End­

Use
Products
to
Include
Postemergence
Application
to
Corn.

10/
25/
96
D229611
None
S.
Willett
D.
McCall
None
PP
No.
5F4505.
Acetochlor
(
Chemical
No.
121601)
on
Corn.
Revised
Label
and
Section
F
in
Response
to
6/
25/
96
RCAB/
PIRAT
Review.
Page
94
of
118
HAZARD
CHARACTERIZATION
00050928
Ahmed,
F.
E.,
Tegeris,
A.
S.,
Underwood,
P.
C.
et
al.
(
1980)
CP
55097:
119­
Day
Study
in
the
Dog.
Pharmacopathics
Research
Laboratories,
Inc.,
Laurel,
MD.
Lab
Report
No.
7920
(
Sponsor's
Report
No.
79­
114),
October
10,
1980.
Unpublished
report.

00050929
Rodwell,
D.
E.
and
McMeekin,
S.
O.
(
1980)
Teratology
Study
in
Rats
IR­
79­
009.
International
Research
and
Development
Corp.,
Mattawan,
MI.
Laboratory
Report
No.
IRDC
401­
066.
October
15,
1980.
Unpublished
report.

00050930
Ross,
W.
D.
and
Kulik,
F.
A.
(
1978)
Salmonella
Mutagenicity
Assay
of
CP­
55097,
DA­
78­
186:
Monsanto
Co.
Study
Report
No.
MRC­
DA­
838.
Unpublished
report.

00050933
Ahmed,
F.
E.,
Seely,
J.
C.,
Tegeris,
A.
S.
et
al.
(
1980)
CP
55097:
91­
Day
Feeding
Study
in
the
Rat.
Pharmacopathics
Research
Laboratories,
Inc.,
Laurel,
MD.
Report
No.
7914.
October
10,
1980.
Unpublished
report.

00116631
Ahmed,
F.
E.
(
1981)
A
One­
Year
Feeding
Study
in
Dogs
with
MON
097.
Pharmacopathics
Research
Laboratories,
Laurel,
MD.
Study
No.
8006
(
Sponsor
Report
No.
PR­
80­
008),
October
14,
1981.
Unpublished
report.

00116637
Johnson,
D.
E.
(
1981)
21­
Day
Dermal
Toxicity
Study
in
Rabbits.
International
Research
and
Development
Corp.,
Mattawan,
MI.
Study
no.
IR­
80­
356,
December
11,
1981.
Unpublished
report.

00118944
Branch,
D.,
Stout,
L.
and
Folk,
R.
(
1982)
Primary
Skin
Irritation
of
MON
097
to
Rabbits.
Environmental
Health
Laboratory,
St.
Louis,
MO,
Study
EHL
820031.
October
18,
1982.
Unpublished
report.

00118945
Branch,
D.
K.,
Stout,
L.
D.
and
Folk,
R.
M.
(
1982)
Acute
Dermal
Toxicity
of
MON
097
to
Rabbits.
Environmental
Health
Laboratory,
St.
Louis,
MO.
Study
No.
820032.
Unpublished
report.

00118946
Branch,
D.
K.,
Stout,
L.
D.
and
Folk,
R.
M.
(
1982)
Primary
Skin
Irritation
of
MON
097
to
Rabbits.
Environmental
Health
Laboratory,
St.
Louis,
MO.
Study
No.
820033,
October
18,
1982.
Unpublished
report.

00118947
Branch,
D.
K.,
Stout,
L.
D.
and
Folk,
R.
M.
(
1982)
Primary
Eye
Irritation
of
MON
097
to
Rabbits.
Environmental
Health
Laboratory,
St.
Louis,
MO.
Study
No.
820034,
October
18,
1982.
Unpublished
report.
Page
95
of
118
00130839
Carr,
K.,
Elliott,
R.,
Halasinski,
K.
et
al.
(
1983)
The
Metabolism
of
Acetochlor
in
the
Laboratory
Rat.
Hazleton
Raltech
Inc.,
Laboratory
Report
No.
MSL­
2824,
June
1,
1983.
Unpublished
report.

00131088
Ahmed,
F.
E.
and
Seely,
J.
C.
(
1983)
Acetochlor:
Chronic
Feeding
Toxicity
and
Oncogenicity
Study
in
the
Rat.
Pharmacopathics
Research
Laboratories,
Inc.,
Laurel,
MD.
Study
No.
PR­
80­
006.
May
20,
1983.
Unpublished
report.

00131089
Ahmed,
F.
E.,
Tegeris,
A.
S.
and
Seely,
J.
C.
(
1983)
MON
097:
24­
Month
Oncogenicity
Study
in
the
Mouse.
Pharmacopathics
Research
Laboratories,
Inc.,
Laurel,
MD.
Report
No.
PR­
80­
007.
May
4,
1983.
Unpublished
report.

00131391
Schardein,
J.
Marroquin,
F
and
Thorstenson,
J.
(
1982)
Two
Generation
Reproduction
Study
in
Rats:
MON
097.
International
Research
and
Development
Corp.,
Mattawan,
MI.
Study
No.
IR­
80­
053,
December
16,
1982.
Unpublished
report.

00131392
Farrow,
M.
G.
and
Cortina,
T.
(
1983)
In
Vivo
Bone
Marrow
Chromosome
Study
in
Rats
with
Acetochlor
(
MON
097).
Hazleton
Laboratories,
Study
No.
HL83­
006
(
Hazleton
Project
No.
241­
143),
May
24,
1983.
Unpublished
report.

00131393
Naismith,
R.
W.
and
Mathews,
R.
(
1983)
Rat
Hepatocyte
Primary
Culture/
DNA
Repair
Test.
Pharmakon
Research
International,
Inc.,
Waverly,
PA.
Monsanto
Study
No.
PK
82­
151
(
Pharmakon
Project
No.
PH
311­
MO­
001­
82),
February
18,
1983.
Unpublished
report.

00131394
Mitchell,
A.
D.,
Rudd,
C.
and
Coleman,
R.
(
1983)
An
Evaluation
of
Mutagenic
Potential
of
MON
097
Employing
the
L5178Y
Tk
+/­
Mouse
Lymphoma
Assay.
SRI
International,
Menlo
Park,
CA.
Study
No.
SR
81­
150
(
Project
No.
LSC­
2575),
August
1,
1982.
Unpublished
report.

00131395
Li,
A.
P.,
Rice,
T.,
Folk,
R.
et
al.
(
1983)
CHO/
HGPRT
Gene
Mutation
Assay
with
Mon
097.
Monsanto
Environmental
Health
Laboratory.
Study
No.
ML­
82­
281;
Project
No.
EHL
830013,
June
9,
1983.
Unpublished
report.

00131396
Auletta,
C.,
Daly,
I.,
Loder,
C.
et
al.
(
1983)
A
Dermal
Sensitization
Study
in
Guinea
Pigs,
Test
Material:
MON
097.
Bio/
dynamics
Inc.,
Division
of
Biology
and
Safety
Evaluation,
E.
Millstone,
NJ.
Laboratory
Project
No.
4028­
82
(
Monsanto
Ref.
No.
BD­
82­
204).
April
13,
1983.
Unpublished
report.

00164941
Groya,
F.
L.,
Cavagnaro,
J.
and
Cortina,
T.
(
1986)
In
Vivo
Micronucleus
Assay
in
Mice
with
Acetochlor.
Hazleton
Biotechnologies
Corp,
Vienna,
VA.
Laboratory
Study
Report
No.
HL­
84­
405
(
Project
No.
241­
207),
June
2,
1986.
Unpublished
report.
Page
96
of
118
00164944
Pharmacopathics
Research
Laboratories
(
1986)
One­
year
Feeding
Study
in
Dogs
with
Acetochlor:
Historical
Control
Data
Provided
by
the
Animal
Supplier,
Hazleton
Research
Animals:
Historical
Control
Data
Provided
by
the
Testing
Laboratory,
Pharmacopathics
Research
Laboratories.
Unpublished
report.

40077601
Naylor,
M.
W.
and
Ribelin,
W.
E.
(
1986)
Chronic
Feeding
Study
of
MON
097
in
Albino
Rats.
Monsanto
Environmental
Health
Laboratory,
St.
Louis,
MO.
Laboratory
Project
ID
EHL­
83107
(
Report
No.
MSL­
6119).
September
25,
1986.
Unpublished
report.

40134101
Adam,
Gabriela
(
1986)
A
Teratology
Study
in
Rabbits
with
MON
097
(
Acetochlor).
WIL
Research
Laboratories,
Inc.,
Ashland,
OH.
Study
No.
WI­
86­
4,
Project
No.
50009
(
Monsanto
Study
No.
R.
D.
713).
September
5,
1986.
Unpublished
report.

40484801
Ribelin,
W.
E.
(
1987)
Histopathology
Findings
in
Noses
of
Rats
Administered
MON
097
in
a
Lifetime
Feeding
Study.
Tegeris
Laboratories,
Laurel,
MD
and
Monsanto
Environmental
Health
Laboratory,
St.
Louis,
MO.
Laboratory
Project
No.
ML­
86­
44/
EHL
86027.
November
4,
1987.
Unpublished
report.

40994401
Bechtel,
C.
L.
(
1988)
Acute
Inhalation
Study
of
MON
097.
Monsanto
Company
Environmental
Health
Laboratory,
St.
Louis,
MO.
Laboratory
Project
No.
MSL­
8317,
Study
No.
88097,
Project
No.
ML­
88­
107,
October
7,
1988.
Unpublished
report.

41565104
Cummins,
H.
A.
(
1986)
SC­
5676
Technical:
Acute
Oral
Toxicity
Study
in
the
Rat.
Life
Sciences
Research
Ltd.,
Suffolk,
England.
Study
No.
86/
SUCO13/
039,
February
24,
1986.
Unpublished
report.

41565105
Cummins,
H.
A.
(
1986)
SC­
5676
Technical:
Acute
Dermal
Toxicity
Study
in
Rats.
Life
Science
Research
Ltd.,
Suffolk,
England.
Study
No.
86/
SUCO14/
30,
February
24,
1986.
Unpublished
report.

41565106
Brammer,
A.
(
1989)
Acetochlor:
4­
Hour
Acute
Inhalation
Toxicity
Study
in
the
Rat.
ICI
Central
Toxicology
Laboratory,
Cheshire,
UK.
Study
No.
HRO864
(
Report
No.
CTL/
P/
2544),
June
30,
1989.
Unpublished
report.

41565107
Barlow,
A.
and
Ishmael,
J.
E.
(
1989)
Acetochlor:
Skin
Irritation
to
the
Rabbit.
ICI
Central
Toxicology
Laboratory,
Cheshire,
UK.
Study
no.
EB3655,
September
14,
1989.
Unpublished
report.

41565108
Botham,
P.
A.
and
Ishmael,
J.
E.
(
1989)
Acetochlor:
Skin
Sensitization
to
the
Guinea
Pig.
ICI
Central
Toxicology
Laboratory,
Cheshire,
UK.
Study
No.
GG4647
and
GG4553,
July
19,
1989.
Unpublished
report.
Page
97
of
118
41565115
Broadmeadow,
A.
(
1986)
SC­
5676:
Toxicity
Study
by
Dietary
Administration
to
CD
Rats
for
13
Weeks.
Life
Science
Research
Ltd.,
Suffolk,
England.
Study
No.
86/
SUC011/
0051.
June
23,
1986.
Unpublished
report.

41565116
Broadmeadow,
A.
(
1986)
SC­
5676:
Toxicity
Study
by
Oral
(
Capsule)
Administration
to
Beagle
Dogs
for
13
Weeks.
Life
Science
Research
Center,
Ltd.,
Suffolk,
England.
Study
No.,
LSR
86/
SUC010/
0059,
June
23,
1986.
Unpublished
report.

41565117
Leah,
A.
(
1989)
Acetochlor:
21­
Day
Dermal
Toxicity
to
the
Rat.
ICI
Central
Toxicology
Laboratory,
Cheshire,
UK.
Study
no.
LRO531,
September
15,
1989.
Unpublished
report.

41565118
Broadmeadow,
A.
(
1988)
SC­
5676:
Toxicity
Study
by
Oral
(
Capsule)
Administration
to
Beagle
Dogs
for
52
Weeks.
Life
Science
Research,
Ltd.,
Suffolk,
England.
Study
No.:
LSR
Report
88/
SUC018/
0136;
December
2,
1988.
Unpublished
report.

41565119
Amyes,
S.
J.
(
1989)
SC­
5676:
78
Week
Feeding
Study
in
CD­
1
Mice.
Life
Science
Research
Ltd.,
Suffolk,
England.
Study
No.
87/
SUC0012/
0702.
June
9,
1989.
Unpublished
report.

41565120
Willoughby,
C.
R.
(
1989)
SC­
5676:
Effects
Upon
Reproductive
Performance
of
Rats
Treated
Continuously
Throughout
Two
Successive
Generations.
Life
Sciences
Research
Ltd.,
Suffolk,
England.
Study
No.
89/
0414.
August
16,
1989.
Unpublished
report.

41565121
Callander,
R.
D.
and
Priestley,
K.
P.
(
1989)
Acetochlor:
An
Evaluation
in
the
Salmonella
Mutation
Assay.
ICI
Central
Toxicology
Laboratory,
Cheshire,
UK.
Study
Nos.
YV2370/
VV2423,
July
19,
1989.
Unpublished
report.

41565122
Howard,
C.
A.
(
1989)
An
Evaluation
in
the
In­
Vitro
Cytogenetic
Assay
with
Acetochlor
in
Human
Lymphocytes.
ICI
Central
Toxicology
Laboratory,
Cheshire,
UK.
Study
No.
SV0366,
July
20,
1989.
Unpublished
report.

41565123
Randall,
V.
(
1989)
Acetochlor:
An
Evaluation
in
the
Mouse
Micronucleus
Test.
ICI
Central
Toxicology
Laboratory,
Cheshire,
UK.
Study
No.
SM0339,
July
31,
1989.
Unpublished
report.

41565124
Trueman,
R.
W.
(
1989)
Acetochlor:
Assessment
for
the
Induction
of
Unscheduled
DNA
Synthesis
in
Rat
Hepatocytes
In
Vivo.
ICI
Central
Toxicology
Laboratory,
Cheshire,
UK.
Study
No.
SR0357,
August
8,
1989.
Unpublished
report.

41565125
Hawkins,
D.
R.,
Kirkpatrick,
D.
and
Dean,
G.
(
1987)
The
Biokinetics
of
14­
C
Acetochlor
after
Oral
Administration
to
Rats
at
a
Nominal
Level
of
10
mg/
kg.
Page
98
of
118
Huntingdon
Research
Centre
Ltd.,
Huntingdon,
Cambridgeshire,
UK.
Laboratory
Project
No.
HRC/
STR
18/
88502.
February,
1987.
Unpublished
report.

41565126
Hawkins,
D.
R.,
Kirkpatrick,
D.
and
Dean,
G.
(
1989)
The
Metabolism
of
14­
C
Acetochlor
in
the
Rat
after
Oral
Administration.
Huntingdon
Research
Centre
Ltd.,
Huntingdon,
Cambridgeshire,
UK.
Laboratory
Project
No.
HRC/
STR
89603.
March,
1990.
Unpublished
report.

41565127
Jones,
B.
K.
(
1990)
Acetochlor:
Biotransformation
Study
in
the
Rat.
ICI
Research
Centre,
Laboratory
Project
No.
CTL/
P/
2809.
March,
1990.
Unpublished
report.

41592003
Pemberton,
M.
A.
and
Ishmael,
J.
E.
(
1989)
Acetochlor:
Eye
Irritation
to
the
Rabbit.
ICI
Central
Toxicology
Laboratory,
Cheshire,
England.
Study
No.
FB4198
(
Report
No.
CTL/
P/
2639).
September
29,
1989.
Unpublished
report.

41592004
Virgo,
D.
M.
and
Broadmeadow,
A.
(
1988)
SC­
5676:
Combined
Oncogenicity
and
Toxicity
Study
in
Dietary
Administration
to
CD
Rats
for
104
Weeks.
Life
Science
Research
Ltd.,
Suffolk,
England.
Study
No.
88/
SUC017/
0348.
March
18,
1988.
Unpublished
report.

41592005
Brooker,
A.
J.,
Stubbs,
A.
and
John,
D.
M.
(
1989)
Acetochlor:
Teratogenicity
Study
in
the
Rat.
Huntingdon
Research
Centre
Ltd.,
Cambridgeshire,
England.
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204/
89369
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Sponsor
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1989.
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41592006
Brooker,
A.
J.,
Stubbs,
A
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John,
D.
M.
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1989)
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Huntingdon
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England.
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205/
89432
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1989.
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41592007
Hawkins,
D.
R.,
Kirkpatrick,
D.
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Dean,
G.
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1987)
The
Biokinetics
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14­
C
Acetochlor
after
Oral
Administration
to
Rats
at
a
Nominal
Level
of
200
mg/
kg.
Huntingdon
Research
Centre
Ltd.,
Huntingdon,
Cambridgeshire,
UK.
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STR
18/
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41592008
Hawkins,
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R.,
Kirkpatrick,
D.
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Dean,
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1987)
The
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Excretion
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Radioactivity
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Oral
Administration
of
14­
C
Acetochlor
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Rats
at
10
mg/
kg
to
Rats
Pre­
treated
with
Non­
Radiolabelled
Acetochlor.
Huntingdon
Research
Centre
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Huntingdon,
Cambridgeshire,
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STR
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Lythegoe,
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K.
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1990)
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Vivo
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ICI
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ICI
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42054901
Brooker,
A.
J.,
Stubbs,
A
and
John,
D.
M.
(
1991)
Acetochlor:
Teratogenicity
Study
in
the
Rabbit.
Huntingdon
Research
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Ltd.,
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205/
89432A
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26,
1991.
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report.

42054903
Brooker,
A.
J.,
Stubbs,
A.
and
John,
D.
M.
(
1991)
Acetochlor:
Teratogenicity
Study
in
the
Rat,
Report
Supplement
1.
Huntingdon
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Centre
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ISN204/
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42713106
Lie,
A.
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Myers,
C.
(
1989)
CHO/
HGPRT
Gene
Mutation
Assay
with
MON
097:
Monsanto
Environmental
Health
Laboratory.
Lab
Project
Number:
ML­
88­
314:
EHL
88183,
September
6,
1989.
Unpublished
report.

44069502
Milburn,
G.
M.(
1996)
Acetochlor:
Dominant
Lethal
Study
in
the
Rat
by
Dietary
Administration.
Zeneca
Central
Toxicology
Laboratory,
Cheshire,
UK.
Laboratory
Project
Number:
CTL/
P/
4780:
RR0688,
July
19,
1996.
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report.

44093701
Milburn,
G.
M.
(
1996)
Acetochlor:
Dominant
Lethal
Study
in
the
Mouse
by
Dietary
Administration.
Zeneca
Central
Toxicology
Laboratory,
Cheshire
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UK),
Report
No.
CTL
/
P/
4781
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Study
No.
RM0693),
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16,
1996.
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report.

44093703
Ashby,
J.,
Tinwell,
H.,
Lefevre,
P.
A.,
Williams,
J.,
Kier,
L.
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Clapp,
M.
J.
L.
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1996)
Evaluation
of
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Mutagenicity
of
Acetochlor
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Male
Rat
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Zeneca
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Laboratory,
Cheshire
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44496202
Green,
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The
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12,
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44496203
Green,
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1998)
The
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44496204
Hardisty,
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Pathology
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Female
Mice
from
Two
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Term
Studies
with
Acetochlor.
Experimental
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NC.
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ID
CTL/
C/
3196,
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11,
1997.
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report.
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Hardisty,
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1997)
Pathology
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Group
Peer
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in
the
Liver
of
Rats
and
Mice
from
Five
Long­
Term
Studies
with
Acetochlor.
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C/
3197,
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11,
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44496206
Hardisty,
J.
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1997)
Pathology
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the
Lung
of
Male
and
Female
Mice
from
Two
Long­
Term
Studies
with
Acetochlor.
Experimental
Pathology
Laboratories,
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Triangle
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NC.
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C/
3198,
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11,
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44496207
Hotz,
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J.
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Wilson,
A.
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unit
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Louis,
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1996.
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44496208
Hotz,
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A.
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E.
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1996)
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Acetochlor
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in
Male
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Louis,
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44496209
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G.
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(
1996)
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Study
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Effects
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Acetochlor
on
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Louis,
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44496210
Lau,
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1998)
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St.
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171),
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1998.
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44496211
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S.
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A.
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1998)
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Louis,
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Monsanto
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96­
109,
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1998.
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44496212
Lau,
H.
H.
S.,
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L.
J.,
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J.,
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1998)
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44496213
Lau,
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Characterization
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Life
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Coulston
Foundation,
Alamogordo,
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101
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44496214
Morgan,
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Tumor
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Tissue
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Evans
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Dawley
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44530001
Green,
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The
In
Vitro
Metabolism
of
the
Sulphoxide
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Acetochlor
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Zeneca
Central
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Cheshire,
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R/
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44530002
Green,
T.
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1998)
The
In
Vitro
Metabolism
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Acetochlor
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Rat,
Mouse
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Primate
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Nasal
Tissues.
Zeneca
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R/
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1998.
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44863201
Callander,
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Gaunt,
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Schofield,
S.
E.
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1992)
Acetochlor
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Zeneca
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Cheshire,
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R/
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1992.
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44863202
Callander,
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D.
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Schofield,
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Acetochlor:
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44863204
Mackay,
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Acetochlor
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Evaluation
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Vitro
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Laboratory,
Cheshire,
UK.
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SV0655,
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SV0734
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R/
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1999.
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report.

44863205
Ashby,
J.
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Lefevre,
P.
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1993)
Acute
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the
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Zeneca
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Cheshire,
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CTL/
R/
1177.
October
18,
1993.
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report.

44863207
Ashby,
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P.
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1994)
Acute
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the
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Zeneca
Central
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Cheshire,
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R/
1184,
February
16,
1994.
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Ashby,
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Clapp,
M.
J.
L.,
Tinwell,
H.
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Lefevre,
P.
A.
(
1999)
Use
of
the
Comet
Assay
to
Assess
Genetic
Toxicity
in
the
Nasal
Olfactory
Cells
of
Rats
Exposed
to
Acetochlor
in
Diet.
Zeneca
Central
Toxicology
Laboratory,
Cheshire,
UK.
Study
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XR4981
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R/
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1999.
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report.

44863209
Hodge,
M.
C.
E.
(
1991)
Acetochlor:
Male
Reproductive
Tract
Pathology
Study
in
the
Rat.
Central
Toxicology
Laboratory,
Cheshire,
UK.
Laboratory
Report
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T/
2759.
July
29,
1991.
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report.

44863601
Hotz,
K.
J.
and
Wilson,
A.
G.
E.
(
1999)
Effect
of
Dietary
Administration
of
Acetochlor
on
Cell
Proliferation
in
the
Liver
of
Male
CD­
1
®
Mice.
Monsanto
Life
Sciences
Co.,
Monsanto
Safety
Evaluation
­
Newstead
(
MSE­
N),
St.
Louis,
MO.
Laboratory
Report
Number
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15897
(
Study
No.
ML­
99­
017).
March
26,
1999.
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report.

45357501
Kilgour,
J.
D.
(
2001)
Acetochlor:
Acute
Neurotoxicity
Study
in
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Central
Toxicology
Laboratory,
Cheshire,
UK.
Study
Number:
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AR6884.
February
8,
2001.
Unpublished
report.

45357502
Kilgour,
J.
D.
(
2001)
Acetochlor:
Subchronic
Neurotoxicity
Study
in
Rats.
Zeneca
Central
Toxicology
Laboratory,
Cheshire,
UK.
Study
No.
CTL/
PR1176.
February
8,
2001.
Unpublished
report.

45357503
Milburn,
G.
M.
(
2001)
Acetochlor:
Multigeneration
Reproduction
Toxicity
Study
in
Rats.
Zeneca
Central
Toxicology
Laboratory,
Cheshire,
UK.
Study
No.
RR0818,
Report
No.
CTL/
RR0818,
ARP
Submission
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852­
544,
February
16,
2001.
Unpublished
report.

45367403
Hardisty,
J.
F.
(
2001)
Pathology
Working
Group
Peer
Review
of
Proliferative
Lesions
in
the
Kidney
of
Female
Mice
from
a
24­
Month
Oncogenicity
Study
in
the
Mouse
with
Acetochlor,
Final
PWG
Report.
Experimental
Pathology
Laboratories,
Inc.,
Research
Triangle
Park,
NC.
EPL
Project
ID
No.
EP­
2000­
227,
January
3,
2001.
Unpublished
report.

45367404
Hardisty,
J.
F.
(
2001)
Pathology
Working
Group
Peer
Review
of
Neoplastic
Lesions
in
the
Femur
and
Non­
Glandular
Stomach
of
Male
and
Female
Rats
from
a
Combined
Oncogenicity
and
Toxicity
Study
in
Dietary
Administration
to
CD
Rats
for
104
Weeks
with
Acetochlor.
Experimental
Pathology
Laboratories,
Inc.,
Research
Triangle
Park,
NC.
EPL
Project
ID
No.
550­
003.
January
3,
2001.
Unpublished
report.

46009401
Green,
T.
(
2000)
The
In
Vitro
Metabolism
of
the
Sulphoxide
Metabolite
of
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103
of
118
Acetochlor
in
Rat,
Mouse,
Primate
and
Human
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Nasal
Tissues.
Zeneca
Central
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Laboratory,
Cheshire,
UK.
Report
No.
CTL/
R/
1480.
August
23,
2000.
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report.

46009402
Green,
T.
(
2001)
C­
14
Acetochlor
sulphoxide:
Binding
and
Localisation
of
Radioactivity
in
Rat
Nasal
Tissues.
Zeneca
Central
Toxicology
Laboratory,
Cheshire,
UK.
CTL
Study
No.
011889,
Document
No.
CTL/
011889/
RES/
REPT.
December
12,
2001.
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report.

46081802
Dybowski,
J.
A.
(
2003)
Supplement
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In
Vitro
Metabolism
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Acetochlor
in
Rat,
Mouse,
Primate
and
Human
Liver
and
Nasal
Tissues.
Regulatory
Laboratories,
Indianapolis
Lab,
Dow
Agrosciences,
Indianapolis,
IN.
Laboratory
Study
ID
GHC
5683,
September
24,
2003.
Unpublished
report.

46081803
Dybowski,
J.
A.
(
2003)
Response
to
US
EPA
Data
Evaluation:
In
Vitro
Metabolism
of
Acetochlor
in
Rat,
Mouse
and
Primate
Liver
and
Nasal
Tissues,
CTL/
R/
1319.
Regulatory
Laboratories­
Indianapolis
Lab,
Dow
Agrosciences
LLC,
Indianapolis,
IN.
Laboratory
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ID
GHD
5698,
September
24,
2003.
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report.

46100901
Creasy,
D.
M.
(
2003)
Acetochlor:
Histopathological
Reevaluation
of
Dog
Testes
and
Epididymides
from
a
One
Year
Dog
Study
(
CTL/
C/
2194).
Huntingdon
Life
Sciences,
East
Millstone,
NJ.
Project/
Study
No.
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5697,
October
9,
2003.
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report.

ACETOCHLOR
METABOLITE
TOXICOLOGY
STUDIES
SUBMITTED
TO
THE
AGENCY
(
LISTED
BY
MRID
NUMBER)

42713118
Callander,
R.
D.
(
1991)
PJ2
Acetochlor
Metabolite:
An
Evaluation
of
Mutagenic
Potential
Using
S.
typhimurium
and
E.
coli.
ICI
Central
Toxicology
Laboratory,
Cheshire,
UK,
Study
No.
YV
2989
(
Report
No.
CTL/
P/
3358),
July
2,
1991.
Unpublished
report.

43785701
Barber,
G.
and
Mackay,
J.
M.
(
1995)
Compound
57:
Assessment
for
the
Induction
of
Unscheduled
DNA
Synthesis
in
Rat
Hepatocytes
In
Vivo.
Zeneca
Central
Toxicology
Laboratory,
Cheshire,
UK,
Study
No.
SR0747,
July
13,
1995.
Unpublished
report.

43785702
Fox,
V.
(
1995)
Compound
57:
An
Evaluation
in
the
In
Vitro
Cytogenetic
Assay
in
Human
Lymphocytes.
Zeneca
Central
Toxicology
Laboratory,
Cheshire,
UK,
Study
No.
SV0751,
July
24,
1995.
Unpublished
report.

43908101
Holson,
J.
F.
(
1995)
A
Developmental
Toxicity
Study
of
MON
5775
[
Alachlor
ESA]
in
Rats.
Wil
Research
Laboratories,
Inc.,
Ashland,
OH.
Laboratory
report
No.
1335
Page
104
of
118
(
Monsanto
Report
No,
WI­
95­
068;
Wil
Project
No.
WIL­
50237).
December
13,
1995.
Unpublished
report.

44632703
Lees,
D.
(
1997)
Oxanilic
Acid
(
R290130):
Acute
Oral
Toxicity
to
the
Rat.
Zeneca
Central
Toxicology
Laboratory,
Cheshire,
UK,
Laboratory
Study
No.
AR
6415
(
Report
No.
CTL/
P/
5648),
September
25,
1997.
Unpublished
report.

44632704
Lees,
D.
(
1997)
Sulphonic
Acid
(
R290131):
Acute
Oral
Toxicity
to
the
Rat.
Zeneca
Central
Toxicology
Laboratory,
Cheshire,
UK,
Laboratory
Study
No.
AR
6414
(
Report
No.
CTL/
P/
5644).
Unpublished
report.

44632705
Callander,
R.
D.,
Schofield,
S.
E.
and
Elliott,
B.
M.
(
1997)
Oxanilic
Acid
(
R290130):
An
Evaluation
of
Mutagenic
Potential
Using
S.
typhimurium
and
E.
coli.
Zeneca
Central
Toxicology
Laboratory,
Study
No.
YV3984
(
Report
No.
CTL/
P/
5542),
August
4,
1997.
Unpublished
report.

44632706
Callander,
R.
D.,
Schofield,
S.
E.
and
Elliott,
B.
M.
(
1997)
Sulphonic
Acid
(
R290131):
An
Evaluation
of
Mutagenic
Potential
Using
S.
typhimurium
and
E.
coli.
Zeneca
Central
Toxicology
Laboratory,
Cheshire,
UK.
Laboratory
Study
No.
YV3985
(
Report
No.
CTL/
P/
5568).
Unpublished
report.

45300503
Lees,
D.
(
2000)
R290131:
28
Day
Dietary
Toxicity
Study
in
Rats
(
Dose
Range
Finder
for
a
90
Day
Study).
Zeneca
Central
Toxicology
Laboratory,
Cheshire,
UK.
Laboratory
Document
No.
CTL/
KR1350/
REG/
REPT,
January
10,
2000.
Unpublished
report.

45300504
Albin,
L.
A.
and
Kraus,
L.
J.
(
2000)
Absorption,
Distribution,
Metabolism
and
Elimination
of
Acetochlor
Ethane
Sulfonate
in
Sprague­
Dawley
Rats
Following
Oral
Administration.
Monsanto
Company
Metabolism
and
Safety
Evaluation­
Newstead
(
MSE­
N)
and
Environmental
Science
Technology
Center
(
ESTC),
St.
Louis,
MO.
Laboratory
Study
No.
ML­
99­
042
(
MSE­
N
Project
No
99018,
MSE­
N
Report
No.
MSL­
16948;
ESTC
Report
No.
MSL­
16439),
November
3,
2000.
Unpublished
report.

45300506
Williams,
J.
(
2000)
R290130:
28
Day
Dietary
Toxicity
Study
in
Rats
(
Dose
Range
Finder
for
a
90
Day
Study).
Zeneca
Central
Toxicology
Laboratory,
Cheshire,
UK.
Laboratory
Document
No.
CTL/
KR1352/
REG/
REPT,
May
9,
2000.
Unpublished
report.

45300507
Albin,
L.
A.
and
Kraus,
L.
J.
(
2000)
Absorption,
Distribution,
Metabolism
and
Elimination
of
Acetochlor
Oxanilic
Acid
in
Sprague­
Dawley
Rats
Following
Oral
Administration.
Monsanto
Company
Metabolism
and
Safety
Evaluation­
Newstead
(
MSE­
N)
and
Environmental
Science
Technology
Center
(
ESTC),
St.
Louis,
MO.
Page
105
of
118
Monsanto
Study
No.
ML­
99­
079
(
MSE­
N
Project
No.
99019,
MSE­
N
Report
No.
MSL­
16947,
ESTC
Report
No.
MSL­
16707),
November
3,
2000.
Unpublished
report.

45313801
Lees,
D.
(
2000)
R290131:
90
Day
Dietary
Toxicity
Study
in
Rats.
Zeneca
Central
Toxicology
Laboratory,
Cheshire,
UK.
Laboratory
Document
No.
CTL/
PR1147/
REG/
REPT,
May
19,
2000.
Unpublished
report.

45313802
Fox,
V.
(
2000)
R209131:
Mouse
Bone
Marrow
Micronucleus
Test.
Zeneca
Central
Toxicology
Laboratory,
Cheshire,
UK.
Laboratory
Study
No.
SM0977
(
Report
No.
CTL/
SM0977),
January
31,
2000.
Unpublished
report.

45313803
Clay,
P.
(
2000)
R290131:
LK5178Y
TK+/­
Mouse
Lymphoma
Mutation
Assay.
Zeneca
Central
Toxicology
Laboratory,
Cheshire,
UK.
Laboratory
Study
No.
VV0232
(
Report
No.
CTL/
VV0232),
October
3,
2000.
Unpublished
report.

45313804
Fox,
V.
(
2000)
R290131:
In
Vitro
Cytogenetic
Assay
in
Human
Lymphocytes.
Zeneca
Central
Toxicology
Laboratory,
Cheshire,
UK.
Laboratory
Study
No.
SV1036
(
Report
No.
CTL/
SV1036/
REG/
REPT,
November
24,
2000.
Unpublished
report.

45313805
Williams,
J.
(
2000)
R290130:
90
Day
Dietary
Toxicity
Study
in
Rats.
Zeneca
Central
Toxicology
Laboratory,
Cheshire,
UK.
Laboratory
Document
No.
CTL/
PR1148/
REG/
REPT,
June
27,
2000.
Unpublished
report.

45313807
Holdon,
J.
F.
(
2000)
A
Prenatal
Developmental
Toxicity
Study
of
MON
52755
in
Rats.
Wil
Research
Laboratories,
Inc.,
Ashland,
OH.
Laboratory
Project
No.
WIL­
50259,
May
1,
2000.
Unpublished
report.

45313808
Fox,
V.
(
2000)
R290130:
Mouse
Bone
Marrow
Micronucleus
Test.
Zeneca
Central
Toxicology
Laboratory,
Cheshire,
UK.
Laboratory
Study
No.
SM0978
(
Report
No.
CTL/
SM0978),
January
31,
2000.
Unpublished
report.

45313809
Clay,
P.
(
2000)
R290130:
L5178Y
TK+/­
Mouse
Lymphoma
Mutation
Assay.
Central
Toxicology
Laboratory,
Cheshire,
UK.
Laboratory
Study
No.
VV0231
(
Report
No.
CTL/
VV0231),
October
6,
2000.
Unpublished
report.

45313810
Fox,
V.
(
2000)
R290130:
In
Vitro
Cytogenetic
Assay
in
Human
Lymphocytes.
Central
Toxicology
Laboratory,
Cheshire,
UK.
Laboratory
Study
No.
SV1035
(
Report
No.
CTL.
SV1035),
November
22,
2000.
Unpublished
report.

HED
TXR
DOCUMENTS
(
LISTED
BY
TXR
NUMBER)
Page
106
of
118
0013858
Acetochlor­
Report
of
the
Hazard
Identification
Assessment
Review
Committee.
Memorandum
from
Stephen
Dapson
to
George
Herndon
through
Pauline
Wagner
and
Jess
Rowland
dated
November
9,
1999.

0013874
Acetochlor­
Report
of
the
FQPA
Safety
Factor
Committee.
Memorandum
from
Brenda
Tarplee
to
Ed
Zager
through
George
Herndon
dated
December
3,
1999.

0052813
Acetochlor.
Report
of
the
Metabolism
Assessment
Review
Committee.
Memorandum
from
Alberto
Protzel
to
Yan
Donovan
through
Christine
Olinger
dated
August
31,
2004.

0052727
Acetochlor:
Report
of
the
Cancer
Assessment
Review
Committee
(
CARC)
(
Fourth
Evaluation).
Memorandum
from
Jessica
Kidwell
to
Linnea
Hansen,
Nancy
McCarroll,
Brian
Dementi,
Alberto
Protzel
and
Christina
Scheltema
dated
August
5,
2004.

0052743
Acetochlor
Quantitative
Risk
Assessment
(
Q)
Based
on
CD­
1
Mouse
Dietary
Studies
with
3/
4'
s
Interspecies
Scaling
Factor.
Memorandum
from
Lori
Brunsman
to
Linnea
Hansen
through
Jess
Rowland
dated
July
29,
2004.

OTHER
CITATIONS
(
PUBLISHED
REPORTS)

Hill,
AB,
Jefferies,
PR,
Quistad,
GB
and
Casida,
JE
(
1997).
Dialkylquinoneimine
metabolites
of
chloroacetanilide
herbicides
induce
sister
chromatid
exchanges
in
cultured
human
lymphocytes.
Mutat
Res.
395:
159­
171.

EPA
(
1997)
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.

EPA
(
1998)
Assessment
of
Thyroid
Follicular
Cell
Tumors.
Risk
Assessment
Forum,
Environmental
Protection
Agency,
Washington,
D.
C.

EPA
(
2001)
The
Grouping
of
a
Series
of
Chloroacetanilide
Pesticides
Based
on
a
Common
Mechanism
of
Toxicity,
Office
of
Pesticide
Programs,
USEPA
(
June
7,
2001).
Appendices
1.0
TOXICOLOGY
DATA
REQUIREMENTS
The
requirements
(
40
CFR
158.340)
for
food
use
for
acetochlor
are
in
Table
1.
Use
of
the
new
guideline
numbers
does
not
imply
that
the
new
(
1998)
guideline
protocols
were
used.
Page
107
of
118
Test
Technical
Required
Satisfied
870.1100
Acute
Oral
Toxicity
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.1200
Acute
Dermal
Toxicity
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.1300
Acute
Inhalation
Toxicity
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.2400
Primary
Eye
Irritation
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.2500
Primary
Dermal
Irritation
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.2600
Dermal
Sensitization
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
870.3100
Oral
Subchronic
(
rodent)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.3150
Oral
Subchronic
(
nonrodent)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.3200
21­
Day
Dermal
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.3250
90­
Day
Dermal
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.3465
90­
Day
Inhalation
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
yes
yes
yes
no
no
yes
yes
yes
no
no
870.3700a
Developmental
Toxicity
(
rodent)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.3700b
Developmental
Toxicity
(
nonrodent)
.
.
.
.
.
.
.
.
.
.
.
.
870.3800
Reproduction
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
yes
yes
yes
yes
yes
yes
870.4100a
Chronic
Toxicity
(
rodent)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.4100b
Chronic
Toxicity
(
nonrodent)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.4200a
Oncogenicity
(
rat)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.4200b
Oncogenicity
(
mouse)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.4300
Chronic/
Oncogenicity
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
yes
a
yes
yes
a
yes
yes
yes
yes
yes
yes
yes
870.5100
Mutagenicity 
Gene
Mutation
­
bacterial
.
.
.
.
.
.
.
.
870.5300
Mutagenicity 
Gene
Mutation
­
mammalian
.
.
.
.
.
.
870.5xxx
Mutagenicity 
Structural
Chromosomal
Aberrations
870.5xxx
Mutagenicity 
Other
Genotoxic
Effects
.
.
.
.
.
.
.
.
.
.
yes
yes
yes
yes
yes
yes
yes
yes
870.6100a
Acute
Delayed
Neurotox.
(
hen)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.6100b
90­
Day
Neurotoxicity
(
hen)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.6200a
Acute
Neurotox.
Screening
Battery
(
rat)
.
.
.
.
.
.
.
.
.
870.6200b
90
Day
Neuro.
Screening
Battery
(
rat)
.
.
.
.
.
.
.
.
.
.
.
870.6300
Develop.
Neuro
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
no
no
yes
yes
yes
­
­
nob
nob
no
870.7485
General
Metabolism
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.7600
Dermal
Penetration
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
yes
yes
yes
yes
Special
Studies
for
Ocular
Effects
Acute
Oral
(
rat)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
Subchronic
Oral
(
rat)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
Six­
month
Oral
(
dog)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
no
no
a
Guideline
870.4300
satisfies
guideline
870.4100a
and
870.4200a.
b
Submitted
study
is
upgradable
to
acceptable/
guideline
upon
submission
of
positive
control/
validation
studies.
Page
108
of
118
Appendix
2:
MOE
Assessment
of
Acetochlor
Water
Degradates.

I.
Introduction
The
HED
MARC
met
on
May
13,
2004
to
consider
whether
the
ESA
and
OXA
degradates
of
acetochlor
should
be
included
in
the
dietary
drinking
water
assessment
(
TXR
No.
0052813).
Based
on
comparison
of
the
available
toxicity
data
for
acetochlor
and
the
ESA
and
OXA
degradates.
(
summarized
in
Tables
3.2­
3.4
of
the
ACETOCHLOR
HED
Chapter
of
the
TRED)
and
structure­
activity
relationships,
the
MARC
concluded
that:
the
ESA
and
OXA
degradates
of
acetochlor
should
not
be
included
in
the
water
risk
assessment
with
the
parent.

The
Registrant
has
collected
extensive
surface
and
ground
water
monitoring
data
for
acetochlor
and
its
two
degradates,
as
required
by
the
Agency
under
the
conditional
reregistration
of
acetochlor.
The
monitoring
studies
found
that
both
the
ESA
and
OXA
degradates
have
been
detected
in
water
samples
(
both
groundwater
and
surface
water).
As
shown
later
in
this
Appendix,
although
concentrations
in
surface
waters
are
in
the
same
order
of
magnitude
for
acetochlor
and
its
degradates,
groundwater
concentrations
of
the
degradates
are
significantly
higher
than
those
of
the
parent.

Given
the
potential
for
relatively
high
levels
of
degradates
in
drinking
water,
worst­
case
marginof
exposure
(
MOE)
calculations
were
done
for
the
water
risk
for
the
two
water
degradates
to
better
support
the
MARC
conclusion.
The
results
were
found
to
be
not
of
concern
to
HED.
The
detailed
results
are
presented
in
this
Appendix.

II.
EndPoint
Selection
for
Risk
Assessment
a.
Studies
Available
and
Considered.
The
Registrant
has
submitted
a
series
of
studies
to
address
toxicity
and
mechanism
of
action
of
acetochlor
ESA
and
acetochlor
OXA.
These
studies
are
summarized
in
the
HED
MARC
memo
(
TXR
No.
0052813)
and
in
Tables
3.2­
3.4
of
the
ACETOCHLOR
HED
Chapter
of
the
TRED.
A
brief
summary
is
presented
below
as
Table
1
of
this
Appendix.

b.
Toxicity
Endpoint
Selection
for
MOE
Estimates.
Comparison
of
the
toxicities
of
the
ESA
and
OXA
degradates
with
the
toxicity
of
the
parent
acetochlor
[
See
Tables
3.2
and
3.3
of
the
ACETOCHLOR
HED
Chapter
of
the
TRED]
indicated
that
the
degradates
had
distinct,
different,
toxicological
profiles
from
the
parent.
Thus,
endpoints
for
the
risk
assessment
of
the
ESA
and
OXA
degradates
were
searched
within
their
respective
databases.

The
Endpoints
for
Chronic
Dietary
Evaluation
were
selected
from
the
respective
90­
day
feeding
studies
in
rats
for
Acetochlor
ESA
(
MRID
45313801)
and
Acetochlor
OXA
(
MRID
45313805).
NOAEL
and
LOAEL
data
for
these
studies
are
summarized
below
in
Table
2.
Because
these
studies
are
subchronic,
90­
day,
studies,
an
uncertainty
factor
(
UF)
of
10
was
Page
109
of
118
used
to
correct
for
the
extrapolation
involved
in
using
a
subchronic
study
to
evaluate
a
chronic
risk.
This
UF
of
10
is
a
conservative
estimate;
a
UF
of
3
has
also
been
found
to
be
acceptable
in
extrapolations
from
subchronic
to
chronic
for
other
chemicals.
The
NOAELs
corrected
with
this
factor
appear
also
in
Table
2
("
Corrected
NOAEL").

No
Endpoint
for
selection
for
Cancer
Evaluation
was
attempted
because
the
HED/
MARC
concluded
[
Meeting
of
May
13,
2004
(
TXR
0052813)]
that
Acetochlor
ESA
and
Acetochlor
OXA
are
not
likely
to
be
carcinogenic
[
See
Section
3.6.3
of
the
HED
Chapter
of
the
Acetochlor
TRED
or
the
HED/
MARC
memorandum
TXR
No.
0052813
for
the
rationale].

No
suitable
endpoints
were
found
for
Acute
Dietary
Evaluation,
attributable
to
a
single
exposure
to
the
chemical.
However,
a
very
conservative
estimate
of
acute
dietary
risk
has
been
attempted,
using
the
NOAELs
for
the
90­
day
feeding
studies
in
rats
for
Acetochlor
ESA
(
MRID
45313801)
and
Acetochlor
OXA
(
MRID
45313805).
The
NOAELs
appear
in
Table
2
("
NOAEL").
Page
110
of
118
Table
1.
Summary
of
toxicity
of
Acetochlor
ESA
and
Acetochlor
OXA
Test
Acetochlor
ESA
Acetochlor
OXA
Acute
oral
LD50
LD50(
M&
F)
>
2000
mg/
kg
(
no
mortality
at
limit
dose)
(
MRID
44632704)
LD50(
M&
F)
>
2000
mg/
kg
(
MRID
44632703)

Metabolism
Rats:
Poorly
absorbed
by
the
oral
route
(
about
10­
12%
of
the
dose).
Limited
biotransformation
(
75­
79%)
excreted
untransformed.
Does
not
bind
to
nasal
turbinates
like
acetochlor.
(
MRID
45300504)
Rats:
About
33.9­
38.6%
of
the
dose
absorbed
by
the
oral
route
(
as
seen
in
urine)
Limited
biotransformation:
(
81.4­
84.9%
excreted
untransformed.
Two
unidentified
metabolites
(
5
&
2%
of
dose,
resp.
).
Does
not
bind
to
nasal
turbinates
like
acetochlor.
No
data
for
mouse.
(
MRID
45300507)

4­
Week
feeding
range
finding
(
OXA)/
mechani
stic
thyroid
toxicity
.
(
Rats)
NOAEL
=
370.3
/
374.6
mg/
kg/
day
[
M/
F]
LOAEL
=
766.6/
762.3
mg/
kg/
day
[
M/
F],
based
on
decreased
body
weights
and
body
weight
gain
and
increased
TSH
and
free
T3
in
males.
At
1578.7
mg/
kg/
day
(
HDT)
there
was
a
statistically
significant
increase
in
T4­
UDPGT
(
microsomal
enzyme)
(
MRID
45300503)
NOAEL
=
372.6
/
367.2
mg/
kg/
day
[
M/
F]
LOAEL
=
768.5
/
737.3
mg/
kg/
day
[
M/
F],
based
on
decr.
TSH
&
T3
and
incr.
absolute
&
relative
thyroid
weights
in
males
and
decr.
TSH
&
T3
in
females.
(
MRID
45300506)

90­
Day
feeding
(
Rats)
NOAEL
=
225.4
/
259.1
mg/
kg/
day
[
M/
F]
LOAEL
=
919.4
/
1073.2
mg/
kg/
day
[
M/
F],
based
on
reduced
body
weights,
body
weight
gains
and
food
utilization
in
both
sexes.
Decreased
cell
proliferation
in
nasal
passages
was
seen
at
the
LOAEL,
but
not
statistically
significantly
diff.
with
controls
because
of
variability.
(
MRID
45313801)
NOAEL
=
230.2
/
268.0
mg/
kg/
day
[
M/
F]
LOAEL
=
955.2/
1082.7
mg/
kg/
day
[
M/
F],
based
on
reduced
body
weights,
body
weight
gains
and
food
utilization
in
both
sexes.
Thyroid
weight
increases
were
not
seen
in
this
study.
T4­
UDPGT
activity
was
slightly,
but
not
significantly,
increased
in
high­
dose
males
and
was
statistically
significantly
decreased
in
high­
dose
females
(
MRID
45313805)

Developmental
toxicity
No
data
for
Acetochlor
ESA.
Data
are
for
Alachlor
ESA.
Rats:
NOAEL
(
maternal
&
developmental):
greater
than
or
equal
to
900
(
HDT)
mg/
kg/
day
LOAEL
(
maternal
&
developmental):
greater
than
900
mg/
kg/
day
(
MRID
43908101)
Rats:
NOAEL
(
maternal)
=
500
mg/
kg/
day,
LOAEL
(
maternal
)
=
1000
mg/
kg/
day,
based
on
maternal
mortality.
NOAEL
(
developmental)
is
equal
or
greater
than
1000
mg/
kg/
day
(
limit
dose).
LOAEL
(
developmental)
greater
than
1000
mg/
kg/
day
(
MRID
45313807)

Mutagenicity
No
Concern
No
Concern
Page
111
of
118
Table
2.
Summary
of
NOAELS
for
MOE
calculations
for
the
ESA
and
OXA
degradates.

Acetochlor
Degradate
Study
NOAEL
(
mg/
kg/
day)
UF
for
Subchronic
to
Chronic
Corrected
NOAEL1
(
mg/
kg/
day)

ESA
Rat,
13­
Week
(
MRID
45313801)
225.4
10
23.0
OXA
Rat,
13­
Week
(
MRID
45313805)
230.2
10
23.0
1Corrected
for
extrapolation
of
subcronic
toxicity
study
to
chronic
toxicity.

III.
Exposure
Characterization
The
ARP
conducted
an
extensive
monitoring
program
for
acetochlor
and
its
ESA
and
OXA
degradates
in
water
As
summarized
in
Section
6.2
of
this
HED
Chapter
and
in
"
Drinking
Water
Exposure
Assessment
for
Acetochlor"
(
M.
Barrett,
EFED
Memorandum,
1/
3/
2005),
the
ARP
conducted
three
types
of
monitoring
studies:
Surface
Water
(
SDWS),
Prospective
Ground
Water
(
PWG)
and
States
Ground
Water
(
SWG).
The
SWG
studies
monitored
sites
of
high
acetochlor
use.
Important
caveats
for
the
monitoring
data
are
described
in
more
detail
in
Section
6.2
of
the
HED
Chapter
and
in
the
EFED
Memorandum
cited
above.

It
is
the
purpose
of
this
appendix
to
evaluate
the
risk
(
as
MOE)
from
acute
and
chronic
dietary
exposure
to
acetochlor
ESA
and
OXA
in
the
drinking
water,
using
a
worst­
case
scenario
for
exposure.

Selection
of
Concentrations
Comparative
results
from
all
three
types
of
studies
are
summarized
in
Figure
3a
for
acetochlor
parent
and
its
degradates.

i)
Chronic
Values:
Examination
of
table
3a
(
chronic
data)
indicates
that:

!
Surface
water
values
of
concentration
for
acetochlor
and
its
degradates
are
well
within
the
same
order
of
magnitude.

!
Ground
water
values
for
concentration
of
acetochlor
ESA
or
acetochlor
OXA
(
specially
from
the
ground
water
SGW
studies),
are
significantly
higher
those
observed
for
the
parent
acetochlor.

Thus
for
a
worse
case
scenario
chronic
calculation,
maximum
TWAM
ground
water
SGW
values
of
12.658
ppb
for
ESA
and
5.86
ppb
for
OXA
from
Table
3a,
are
selected.

ii)
Acute
Values:
Examination
of
Table
3b
(
Acute
data)
indicates
maximum
values
of
20.0
ppb
Page
112
of
118
Table
3a.
Summary
of
Time­
Weighed­
Annualized­
Means
(
TWAM)
in
surface
and
ground
water
from
the
ARP
monitoring
program
for
acetochlor,
acetochlor
ESA
and
acetochlor
OXA.
Values
are
maximum
TWAM
values
(
in
ppb),
95
th
percentiles
(
in
ppb)
and
medians
(
in
ppb)
observed
for
all
sites.

Study
Acetochlor
Parent1
Acetochlor
ESA2
Acetochlor
OXA2
Maximum
TWAM
95th
Percentile
Median
Maximum
TWAM
95th
Percentile
Median
Maximum
TWAM
95th
Percentile
Median
Surface
Water
­
SDWS
raw
0.591
0.355
0.042
0.752
­
1.289
­

Surface
Water
­
SDWS
finished
1.428
0.347
0.032
1.008
­
1.697
­

Ground
Water
(
shallow)­

PGW
site
averages
<
0.03
<
0.03
<
0.03
3.53
NA
1.21
Lower
NA
Ground
Water
(
shallow)­

PGW
cluster
maximums
<
0.03
<
0.03
<
0.03
9.24
NA
NA
Lower
NA
NA
Ground
Water
­
SGW
0.520
0.039
<
0.03
12.658
1.819
<
0.200
5.860
0.224
<
0.100
1
Data
from
EFED's
Drinking
Water
Exposure
Assessment
for
Acetochlor.
Memo
from
M.
Barrett
dated
December
31,
2005,
DP
Barcode
D245339
2
Water
data
furnished
by
M.
Barrett
(
EFED)
on
July
21,
2005.

NA
=
Calculation
not
appropriate
because
of
the
small
number
of
study
sites
(
8)
and
the
lack
of
reproduction
of
long­
term
use
patterns
at
the
study
sites.
This
is
also
why
the
PWG
maximum
single
TWAM
at
each
site
should
be
used
for
all
chronic
endpoints
instead
of
multiyear
means.
Page
113
of
118
Table
3b.
Acute
Exposure
Data:
Summary
presentation
of
acute
concentrations
(
ppb)
for
the
residues
of
acetochlor
ESA
and
Acetochlor
OXA
in
surface
and
ground
water
1
Study
Acetochlor
ESA
Acetochlor
OXA
No.
Points
Maximum
Concentration
(
ppb)
95th
Percentile
(
ppb)
Median
(
ppb)
No.
Points
Maximum
Concentration
(
ppb)
95th
Percentile
(
ppb)
Median
(
ppb)

Surface
Water
­
SDWS
raw
(
ca.
175
sites)
1496
2.310
0.633
<
0.02
1496
3.320
0.898
0.118
Surface
Water
­
SDWS
finished
(
ca.
175
sites)
6774
3.3202
0.571
<
0.02
6774
6.340
0.761
<
0.1
Ground
Water
(
shallow)­

PGW
site
averages
by
date
(
8
sites)
670
4.736
1.488
<
0.02
NC
low
low
low
Ground
Water
(
shallow)­

PGW
single
cluster
basis)

(
8
sites)
NC
14.200
­
­
NC
1.400
low
low
Ground
Water
­
SGW
(
ca.
175
sites)
1983
20.000
1.790
<
0.02
1984
19.100
0.177
<
0.1
1
Water
data
furnished
by
M.
Barrett
(
EFED)
on
July
21,
2005.

2
For
comparison,
the
corresponding
value
for
acetochlor
parent
is
18.21
ppb
(
the
value
used
in
its
acute
risk
assessment)
Page
114
of
118
for
ESA
and
19.1
ppb
for
OXA
for
the
ground
water
SGW
studies.
These
values
are
higher
than
the
Surface
Water
(
SDWS)
and
shallow
ground
water
(
PGW)
studies
shown
in
the
Table
and
thus
are
suitable
for
this
worse
case
scenario.
These
values
were
selected
for
the
acute
MOE
calculation
done
in
this
appendix.

It
is
noted,
for
comparison,
the
acute
value
of
concentration
used
for
acetochlor
parent
risk
assessment
(
from
surface
water,
see
HED
Chapter)
was
18.21
ppb.

The
values
selected
for
the
MOE
calculations
in
this
Appendix
are
summarized
in
Table
4.

Table
4.
Concentrations
of
acetochlor
ESA
and
acetochlor
OXA
in
ground
water
State
Groundwater
Studies
(
SGW),
used
in
chronic
and
acute
MOE
calculations
for
the
degradates.
1,
2
Acetochlor
Degradate
Max.
TWAM
(
ppb)
Max.
Concentration
(
ppb)

ESA
12.658
20
OXA
5.86
19.1
1
Data
for
this
table
was
obtained
from
Tables
3a
(
Chronic
data:
Max.
TWAM)
and
3b
(
Acute
data:
Max.
Concentration)
of
this
Appendix.
2
Corresponding
values
used
for
the
drinking
water
evaluation
of
parent
acetochlor
were:
1.43
ppb
(
chronic
dietary
exposure)
and
18.21
ppb
(
acute
dietary
exposure);
see
HED
chapter
for
details.

IV.
Margin
of
Exposure
(
MOE)
calculations
MOE
calculations
were
done
with
the
DEEM­
FCID
package
for
the
Acute
and
Chronic
assessments.
Acute
and
Chronic
DEEM
runs
were
done
for
each
degradate.

a.
Chronic
Analysis.
Parameters
used
for
the
chronic
analysis
were:

!
Max.
TWAM
from
ground
water
from
the
SGW
study
(
Table
4).

!
Rat
13­
wk
NOAEL
corrected
with
UF
(
subchronic
to
chronic)
of
10
(
Table
2)

Table
5
contains
the
respective
MOE
values
for
chronic
exposure
of
various
population
subgroups.
For
each
degradate
the
table
contains
MOEs
for
the
"
U.
S.
population"
and
the
populations
with
the
"
lowest"
and
"
highest
"
MOEs
in
the
DEEM
output
for
the
particular
analysis.
It
is
clear
that
the
lowest
values
(
21,227
for
ESA
and
45,852
for
OXA)
are
very
high
and
are
consistent
with
little
chronic
water
toxic
risk
from
the
degradates.
Page
115
of
118
Table
5.
Chronic
Analysis:
Highest
and
Lowest
chronic
MOE
values
obtained
using
DEEMFCID
for
various
population
subgroups
exposed
to
acetochlor
ESA
or
acetochlor
OXA
in
water.

Acetochlor
Degradate
Population
subgroup
Exposure
(
mg/
kg/
day)
MOE
ESA1
U.
S.
Population
(
Total)
0.000267
86,207
Non­
nursing
infants
0.001084
21,227
(
lowest)

Females
13­
19
(
not
pregnant
or
nursing)
0.000188
122,512
(
highest)

OXA2
U.
S.
Population
(
Total)
0.000124
186,213
Non­
nursing
infants
0.000502
45,852
(
lowest)

Females
13­
19
(
not
pregnant
or
nursing)
0.000087
264,365
1
Parameters
used
for
the
chronic
DEEM­
FCID
runs
for
acetochlor
ESA
were:
(
a)
Water
concentration:
Max.
TWAM,
single
cluster
from
Table
4
for
ESA
=
12.658
ppb.
(
b)
NOAEL
:
13­
week
NOAEL
corrected
with
UF
of
10,
from
Table
2
for
ESA,
=
23
mg/
kg/
day.

2
Parameters
used
for
the
chronic
DEEM­
FCID
runs
for
acetochlor
OXA
were:
(
a)
Water
concentration:
Max.
TWAM,
single
cluster
from
Table
4
for
OXA=
5.86
ppb.
(
b)
NOAEL
:
13­
week
NOAEL
corrected
with
UF
of
10,
from
Table
2
for
OXA
=
23
mg/
kg/
day.

b.
Acute
Analysis
Parameters
used
for
the
acute
analysis
were:

!
Max.
concentration
from
shallow
ground
water
from
the
PWG
study
(
Table
4).

!
Rat
13­
wk
NOAEL
uncorrected
with
UF.
(
Table
2)

Table
6
contains
the
respective
99.9
th.
percentile
MOE
values
for
acute
exposure
of
various
population
subgroups.
For
each
degradate
the
table
contains
MOEs
for
the
"
U.
S.
population"
and
the
populations
with
the
"
lowest"
and
"
highest
"
MOEs
in
the
DEEM
output
for
the
particular
analysis.
It
is
clear
that
the
lowest
values
(
58,579
for
ESA
and
60,006
for
OXA)
are
very
high
and
are
consistent
with
little
acute
water
toxic
risk
from
the
degradates.
Page
116
of
118
Table
6.
Acute
Analysis:
Highest
and
Lowest
99.9th.
Percentile
putative
Acute
MOE
values
obtained
using
DEEM­
FCID
for
various
population
subgroups
exposed
to
acetochlor
ESA
or
acetochlor
OXA
in
water.

Acetochlor
Degradate
Population
subgroup
Exposure
(
mg/
kg/
day)
99.
9
th.
percentile
MOE
ESA1
U.
S.
Population
(
Total)
0.003926
57,305
Non­
nursing
infants
(<
1
yr.
old)
0.010125
22,222
(
lowest)

Females
13+
(
pregnant/
not
nursing)
0.001474
152,614
(
highest)

OXA2
U.
S.
Population
0.003750
61,339
Non­
nursing
infants
(<
1
yr.
old)
0.009669
23,786
(
lowest)

Females
13+
(
pregnant/
not
nursing)
0.001408
163,357
(
highest)

1
Parameters
used
for
the
acute
DEEM­
FCID
runs
for
acetochlor
ESA
were:
(
a)
Water
concentration:
Max.
Concentration
from
Table
4
for
ESA
=
20.0
ppb.
(
b)
NOAEL
:
13­
week
NOAEL,
UF
of
10
not
used
(
in
lieu
of
Acute
NOAEL,
as
worst
case
scenario)
from
Table
2
for
ESA,
=
225
mg/
kg/
day.

2
Parameters
used
for
the
acute
DEEM­
FCID
runs
for
acetochlor
OXA
were:
(
a)
Water
concentration:
Max.
Concentration
from
Table
4
for
OXA
=
19.1
ppb.
(
b)
NOAEL
:
13­
week
NOAEL,
UF
of
10
not
used
(
in
lieu
of
Acute
NOAEL,
as
worst
case
scenario)
from
Table
2
for
OXA
=
230
mg/
kg/
day.

V.
Conclusions.

1.
Worst­
case
margin­
of­
exposure
(
MOE)
calculations
were
done
to
assess
the
water
risk
for
the
two
water
degradates
(
ESA
and
OXA)
of
acetochlor.
The
results
were
found
to
be
not
of
concern
to
HED.
2.
The
results
support
the
conclusions
of
the
HED/
MARC
meeting
on
acetochlor
water
degradates
(
ESA
and
OXA)
of
May
13,
2004.
Page
117
of
118
Appendix
3:
Tolerance
Reassessment
Summary
for
Acetochlor.

The
current
tolerance
expression
for
acetochlor
residues
is
adequate.
The
HED
MARC
(
M.
Flood,
MARC
Memorandum,
9/
30/
93)
has
determined
that
the
tolerance
expression
for
residues
in/
on
corn
and
rotational
crop
commodities
should
include
only
acetochlor
and
its
metabolites
containing
the
EMA
or
HEMA
moiety,
expressed
in
acetochlor
equivalents.
For
purposes
of
the
dietary
risk
assessment,
residues
in/
on
rotational
crops
should
also
include
metabolites
containing
the
HMEA
moiety,
expressed
in
acetochlor
equivalents.
A
summary
of
acetochlor
tolerance
reassessments
is
presented
in
Table
1
of
this
appendix.

Tolerances
Listed
Under
40
CFR
§
180.470:

Adequate
residue
data
have
been
submitted
to
reassess
the
established
tolerances
for
corn
commodities.
The
available
field
trial
data
indicate
that
the
current
tolerances
on
corn
grain
and
stover
are
adequate,
but
the
tolerance
on
corn
forage
should
be
increased
to
3.0
ppm
based
on
data
from
the
early
postemergence
use.
Adequate
field
rotational
crop
trials
are
also
available
to
support
the
currently
established
tolerances
on
commodities
of
rotational
sorghum,
soybeans,
and
wheat.

As
the
tolerances
on
field
corn
commodities
are
for
the
direct
application
to
a
primary
crop,
these
general
tolerances
on
corn
should
be
reassigned
to
40
CFR
§
180.470(
a).
Likewise,
tolerances
on
sorghum,
soybeans,
and
wheat
commodities
are
for
inadvertent
residues
on
rotational
crops;
therefore,
these
tolerances
should
be
reassigned
to
40
CFR
§
180.470(
d).

Based
on
the
current
use
on
corn,
tolerances
for
livestock
commodities
are
not
required
at
the
present
time.

Tolerances
Needed
Under
40
CFR
§
180.470(
d):

The
available
rotational
crop
field
trial
data
on
wheat
forage
and
straw
indicate
that
residues
are
also
likely
to
occur
on
wheat
hay,
which
is
a
RAC
of
wheat.
A
tolerance
for
wheat
hay
can
be
set
using
the
residue
data
for
wheat
forage
and
adjusting
for
the
differences
in
dry
weight
between
the
two
commodities.
Based
on
maximum
residues
of
0.457
ppm
in/
on
wheat
forage
(
25%
dry
wt.),
maximum
expected
residues
in/
on
wheat
hay
(
88%
dry
wt.)
would
be
1.61
ppm.
Therefore,
a
tolerance
of
2.0
ppm
should
be
established
for
wheat
hay.
The
addition
of
this
tolerance
will
not
change
the
current
calculated
maximum
dietary
burden
for
livestock.
Page
118
of
118
Appendix
3:
Table
1.
Tolerance
Reassessment
Summary
for
Acetochlor.

Commodity
Current
Tolerance
(
ppm)
Range
of
Residues
(
ppm)
Tolerance
Reassessment
(
ppm)
Comment/[
Correct
Commodity
Definition]

Tolerances
Listed
Under
40
CFR
§
180.470:

Corn,
field,
forage
1.0
<
0.05­
2.52
3.0
Tolerances
on
corn
commodities
should
be
reassigned
to
§
180.470(
a)
as
these
tolerances
are
for
the
direct
use
on
corn.
Corn,
field,
grain
0.05
<
0.05
0.05
Corn,
field,
stover
1.5
<
0.05­
1.08
1.5
Sorghum,
forage
0.1
<
0.02­
0.093
0.1
Tolerances
on
sorghum,
soybean,
and
wheat
commodities
should
be
reassigned
to
§
180.470(
d)
as
these
are
tolerances
for
inadvertent
residues
in/
on
rotational
crops.

The
correct
commodity
definition
for
Sorghum,
grain
is
Sorghum,
grain,
grain
and
for
Soybean,
grain
is
Soybean,
seed.
Sorghum,
grain
0.02
<
0.02
0.02
Sorghum,
grain,
stover
0.1
<
0.02­
0.068
0.1
Soybean,
forage
0.7
<
0.2­
0.648
0.7
Soybean,
grain
0.02
<
0.02­
0.101
0.1
Soybean,
hay
1.0
<
0.024­
1.064
1.0
Wheat,
forage
0.5
<
0.02­
0.457
0.5
Wheat,
grain
0.02
<
0.02
0.02
Wheat,
straw
0.1
<
0.02­
0.104
0.1
Tolerances
Needed
under
40
CFR
180.470(
d):

Wheat,
hay
None
1.611
2.0
A
tolerance
should
be
set
at
2.0
ppm
based
on
maximum
residues
in
wheat
forage
corrected
for
moisture
content.

1.
Maximum
expected
residues
in
wheat
hay
(
88%
dry
wt.),
based
on
maximum
residues
of
0.457
ppm
in
wheat
forage
(
25%
dry
wt.).

Codex/
International
Harmonization
As
there
are
no
Codex
MRLs
for
residues
of
acetochlor,
there
are
no
questions
with
respect
to
Codex/
U.
S.
tolerance
compatibility.
No
Canadian
or
Mexican
MRLs
have
been
established
for
acetochlor.
