UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
OFFICE
OF
PREVENTION,
PESTICIDES
AND
TOXIC
SUBSTANCES
Date:
8/
26/
04
MEMORANDUM
SUBJECT:
Dimethipin:
HED
Chapter
of
the
Reregistration
Eligibility
Decision
Document
(
RED).
PC
Code:
118901,
Case
#:
3063,
DP
Barcode:
D299124.

Regulatory
Action:
Phase
1
Reregistration
Action
Risk
Assessment
Type:
Single
Chemical
Aggregate
FROM:
Susan
Stanton,
Environmental
Scientist
Reregistration
Branch
3
Health
Effects
Division
(
7509C)

AND
John
Liccione,
Toxicologist
Danette
Drew,
Chemist
Seyed
Tadayon,
Chemist
Reregistration
Branch
3
Health
Effects
Division
(
7509C)

THROUGH:
Catherine
Eiden,
Branch
Chief
Reregistration
Branch
3
Health
Effects
Division
(
7509C)

TO:
Amaris
K.
Johnson,
MPH;
Chemical
Review
Manager
Reregistration
Branch
I
SRRD
(
7508C)
ii
Table
of
Contents
Executive
Summary
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1
2.0
Ingredient
Profile
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5
2.1
Summary
of
Registered/
Proposed
Uses
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6
2.2
Structure
and
Nomenclature
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8
2.3
Physical
and
Chemical
Properties
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8
3.0
Metabolism
Assessment
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9
3.1
Comparative
Metabolic
Profile
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9
3.2
Nature
of
the
Residue
in
Foods
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9
3.2.1.
Description
of
Primary
Crop
Metabolism
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9
3.2.2
Description
of
Livestock
Metabolism
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10
3.2.3
Description
of
Rotational
Crop
Metabolism,
including
identification
of
major
metabolites
and
specific
routes
of
biotransformation
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11
3.3
Environmental
Degradation
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11
3.4
Tabular
Summary
of
Metabolites
and
Degradates
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12
3.5
Toxicity
Profile
of
Major
Metabolites
and
Degradates
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13
3.6
Summary
of
Residues
for
Tolerance
Expression
and
Risk
Assessment
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14
3.6.1
Tabular
Summary
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14
3.6.2
Rationale
for
Inclusion
of
Metabolites
and
Degradates
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14
4.0
Hazard
Characterization/
Assessment
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16
4.1
Hazard
Characterization
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16
4.2
FQPA
Hazard
Considerations
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23
4.2.1
Adequacy
of
the
Toxicity
Data
Base
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23
4.2.2
Evidence
of
Neurotoxicity
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24
4.2.3
Developmental
Toxicity
Studies
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24
4.2.4
Reproductive
Toxicity
Study
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26
4.2.5
Additional
Information
from
Literature
Sources
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27
4.2.6
Pre­
and/
or
Postnatal
Toxicity
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27
4.2.6.1
Determination
of
Susceptibility
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27
4.2.6.2
Degree
of
Concern
Analysis
and
Residual
Uncertainties
for
Pre
and/
or
Post­
natal
Susceptibility
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28
4.3
Recommendation
for
a
Developmental
Neurotoxicity
Study
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28
4.3.1
Evidence
that
supports
requiring
a
Developmental
Neurotoxicity
study
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28
4.3.2
Evidence
that
supports
not
requiring
a
Developmental
Neurotoxicity
study
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28
4.3.2.1
Rationale
for
the
UF
DB
(
when
a
DNT
is
recommended)
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28
4.4
Hazard
Identification
and
Toxicity
Endpoint
Selection
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28
4.4.1
Acute
Reference
Dose
(
aRfD)
­
Females
age
13­
49
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28
4.4.2
Acute
Reference
Dose
(
aRfD)
­
General
Population
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28
4.4.3
Chronic
Reference
Dose
(
cRfD)
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29
iii
4.4.4
Incidental
Oral
Exposure
(
Short
and
Intermediate
Term)
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30
4.4.5
Dermal
Absorption
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30
4.4.6
Dermal
Exposure
(
Short,
Intermediate
and
Long
Term)
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30
4.4.7
Inhalation
Exposure
(
Short,
Intermediate
and
Long
Term)
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30
4.4.8
Margins
of
Exposure
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31
4.4.9
Recommendation
for
Aggregate
Exposure
Risk
Assessments
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31
4.4.10
Classification
of
Carcinogenic
Potential
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32
4.5
Special
FQPA
Safety
Factor
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34
4.6
Endocrine
disruption
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35
5.0
Public
Health
Data
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35
5.1
Incident
Reports
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35
5.2
Other
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36
6.0
Exposure
Characterization/
Assessment
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36
6.1
Dietary
Exposure/
Risk
Pathway
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36
6.1.1
Residue
Profile
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36
6.1.2
Chronic
Dietary
Exposure
and
Risk
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37
6.2
Water
Exposure/
Risk
Pathway
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39
6.3
Residential
(
Non­
Occupational)
Exposure/
Risk
Pathway
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40
6.3.1
Home
Uses
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40
6.3.2
Recreational
Uses
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40
6.3.3
Other
(
Spray
Drift,
etc.)
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40
7.0
Aggregate
Risk
Assessments
and
Risk
Characterization
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40
7.1
Acute
Aggregate
Risk
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41
7.2
Short­
Term
Aggregate
Risk
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41
7.3
Intermediate­
Term
Aggregate
Risk
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41
7.4
Long­
Term
Aggregate
Risk
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41
7.5
Cancer
Risk
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43
8.0
Cumulative
Risk
Characterization/
Assessment
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43
9.0
Occupational
Exposure/
Risk
Pathway
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44
9.1
Short/
Intermediate/
Long­
Term
Handler
Risk
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44
9.2
Short/
Intermediate/
Long­
Term
Postapplication
Risk
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45
10.0
Data
Needs
and
Label
Requirements
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46
10.1
Toxicology
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46
10.2
Residue
Chemistry
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46
10.3
Occupational
and
Residential
Exposure
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47
References:
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47
Appendices
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48
1
Executive
Summary
The
Health
Effects
Division
(
HED)
of
EPA's
Office
of
Pesticide
Programs
has
evaluated
the
toxicity
and
exposure
data
bases
for
the
pesticide
active
ingredient
dimethipin
and
has
conducted
a
human
health
risk
assessment
in
support
of
the
Reregistration
Eligibility
Decision
(
RED)
for
this
active
ingredient.

Use
and
Usage
Information
Dimethipin
[
2,3­
dihydro­
5,6­
dimethyl­
1,4­
dithiin
1,1,4,4­
tetraoxide]
is
a
plant
growth
regulator
registered
for
use
as
a
preharvest
cotton
defoliant
and
herbicide,
which
may
be
applied
using
groundboom
sprayers
and
fixed­
wing
aircraft.
Dimethipin
inhibits
the
synthesis
of
plant
proteins
responsible
for
stomatal
control.
This
loss
of
stomatal
control
causes
leaves
to
rapidly
lose
water,
stressing
the
plant
and
leading
to
the
production
of
ethylene,
which
ultimately
results
in
leaf
abscission
and
defoliation
of
the
cotton
plant.
Dimethipin
may
also
be
tank­
mixed
with
registered
post­
emergence
herbicides
and
applied
as
a
directed
spray
from
early
post­
emergence
through
layby
to
control
young
weeds
such
as
sicklepod
and
morningglory
in
cotton.
In
addition,
dimethipin
may
be
used
under
a
Special
Local
Need
registration
in
Washington
state
as
a
defoliant
on
non­
bearing
apples
in
nurseries
prior
to
transplanting
in
the
field.
Applications
to
apples
are
made
with
hand­
held
spray
equipment.

Toxicology
The
available
toxicity
data
on
dimethipin
are
adequate
to
assess
the
chemical's
hazard
potential.
Dimethipin
has
moderate
(
category
II)
acute
toxicity
via
the
oral
and
inhalation
routes
of
exposure
and
low
(
category
III)
acute
toxicity
via
the
dermal
route.
It
is
not
an
eye
or
skin
irritant
or
a
dermal
sensitizer.
Sub­
chronic
studies
in
the
rat
and
mouse
showed
no
treatmentrelated
effects
on
mortality,
clinical
signs,
food
consumption,
hematology,
clinical
chemistry
or
pathology.
Decreased
body
weights
and
body
weight
gains
were
noted
in
female
rats
administered
dimethipin
in
the
diet
for
90
days.
Dimethipin
has
relatively
low
chronic
toxicity.
The
chronic
studies
for
dimethipin
indicate
that
reduced
body
weight
gain,
coupled
with
various
organ
effects,
are
the
major
toxic
effects
of
long­
term
exposure
to
this
chemical.
Observed
organ
effects
include
toxicity
in
the
kidney,
lungs,
duodenum
and
testes
of
male
rats
and
toxicity
in
the
liver,
kidney,
glandular
stomach,
heart
and
aortic
artery
of
female
rats.

There
is
no
quantitative
or
qualitative
evidence
of
increased
susceptibility
of
rat
or
rabbit
fetuses
after
in
utero
and/
or
postnatal
exposure
to
dimethipin
in
the
developmental
and
reproduction
studies.
Dose­
response
relationships
are
well­
characterized
and
clear
NOAELs/
LOAELs
have
been
identified
for
the
critical
effects.
Therefore,
the
special
FQPA
safety
factor
can
be
reduced
to
1X,
since
the
degree
of
concern
is
low
and
there
are
no
residual
uncertainties
for
pre­
and/
or
postnatal
toxicity.

No
neurobehavioral
alterations
or
evidence
of
neuropathological
effects
were
observed
in
the
available
studies.
Based
on
the
weight
of
evidence,
a
developmental
neurotoxicity
(
DNT)
study
is
not
required
for
dimethipin.
2
Dimethipin
has
been
classified
as
a
Group
C
(
possible
human)
carcinogen
by
the
Toxicology
Peer
Review
Committee,
based
on
evidence
of
lung
adenomas
and
carcinomas
in
male
CD­
1
mice.
There
is
no
evidence
of
carcinogenicity
in
the
rat.
Calculation
of
a
q
1
*
for
quantification
of
the
cancer
risk
is
not
recommended.
Dimethipin
is
not
considered
to
be
mutagenic,
based
on
the
results
of
a
battery
of
mutagenicity
studies,
including
a
mammalian
cytogenetic
assay,
two
mouse
micronucleus
studies,
an
unscheduled
DNA
synthesis
assay
in
rat
hepatocytes,
a
bacterial
gene
mutation
assay
and
a
sister
chromatid
exchange
assay
in
Chinese
hamster
ovary
CHO
cells.

Residue
Chemistry
The
available
residue
chemistry
data
are
adequate
to
assess
human
dietary
exposure
to
dimethipin
from
the
consumption
of
treated
cottonseed
commodities
and
associated
livestock
commodities.
Although
data
have
not
been
submitted
for
cotton
gin
byproducts
(
a
cattle
feed
item),
HED
assumed
residues
in
gin
byproducts
equivalent
to
50x
the
tolerance
for
cottonseed
in
calculating
the
dimethipin
dietary
burden
for
cattle.
The
50x
residue
for
gin
byproducts
is
considered
very
conservative,
and
the
resulting
dietary
exposure
estimates
for
livestock
are
considered
protective
of
the
public
health.

Additional
storage
stability
data
and
field
rotational
crop
studies
are
required
to
fully
assess
the
potential
for
exposure
to
dimethipin
from
consumption
of
rotated
crops.
The
available
limited
rotational
crop
studies
indicate
that
dimethipin
residues
may
occur
at
low
levels
in
certain
rotated
crops
at
the
established
plantback
interval
(
6
months).
Extensive
field
rotational
crop
studies
must
be
submitted
for
all
crops,
except
leafy
vegetables,
for
which
the
registrant
wishes
to
allow
a
6­
month
plantback
interval.
HED
did
not
include
rotational
crops
in
the
dietary
exposure
assessment
for
dimethipin.
However,
based
on
the
low
residues
seen
in
the
limited
rotational
crop
studies
(

LOQ
for
all
crops
except
carrot
tops),
the
conservative
assumptions
of
the
dietary
assessment
for
cotton
and
livestock
commodities
(
tolerances,
100%
crop
treated,
etc.)
and
the
low
estimated
dietary
risk
(<
1%
of
the
cPAD
for
all
population
subgroups),
HED
believes
the
dietary
exposure
assessment
for
dimethipin
is
protective
of
the
public
health.

The
nature
of
the
residue
in
plants
and
livestock
is
adequately
understood
based
on
metabolism
studies
with
cotton,
goats,
and
hens.
The
residue
of
concern
for
tolerance
enforcement
is
dimethipin
per
se
for
both
plant
and
livestock
commodities.
The
residue
of
concern
for
risk
assessment
is
dimethipin
per
se
for
plant
commodities
and
livestock
commodities
except
liver.
The
residues
of
concern
for
risk
assessment
for
the
liver
of
cattle,
goats,
hogs
and
sheep
are
dimethipin
plus
acetyl
dithiane
tetraoxide.

Tolerances
are
established
under
40
CFR
§
180.406
(
a)
for
residues
of
dimethipin
(
2,3­
dihydro­
5,6­
dimethyl­
1,4­
dithiin
1,1,4,4­
tetraoxide;
CAS
Reg.
No.
55290­
64­
7)
per
se
in/
on
cotton,
undelinted
seed
at
0.5
ppm,
cotton
hulls
at
0.7
ppm,
and
the
fat,
meat,
and
meat
byproducts
of
cattle,
goats,
hogs,
horses,
and
sheep,
each
at
0.02
ppm.
There
are
no
tolerances
established
for
dimethipin
residues
in
poultry
tissues
or
eggs
as
the
Agency
has
concluded
that
there
is
no
reasonable
expectation
of
finite
residues
(
40
CFR
§
180.6(
a)(
3))
of
dimethipin
in
poultry
commodities
based
on
the
current
registered
uses.
3
Tolerances
for
dimethipin
have
been
reassessed.
The
tolerance
level
for
undelinted
cotton
seed
should
remain
at
the
established
level
(
0.5
ppm).
The
established
tolerance
for
cotton
hulls
should
be
revoked
as
processing
studies
indicate
that
dimethipin
residues
do
not
concentrate
in
cotton
hulls.

Although
feeding
study
data,
reflecting
exaggerated
dosing
levels,
indicate
that
there
is
no
expectation
of
finite
residues
in
the
fat,
meat,
or
meat
byproducts
of
cattle,
goat,
horses,
hogs
or
sheep,
HED
recommends
that
the
tolerances
for
dimethipin
in
livestock
meat
and
meat
byproducts
be
retained
in
order
to
harmonize
with
the
established
Codex
MRLs.
The
U.
S.
tolerances
for
livestock
meat
and
meat
byproducts
and
Codex
MRLs
for
mammalian
meat
and
edible
offal
are
established
at
0.02
ppm,
which
is
at
or
about
the
limit
of
quantitation.

The
U.
S.
tolerances
for
dimethipin
in
the
fat
of
cattle,
goats,
horses,
hogs
and
sheep
should
be
revoked
as
there
is
no
expectation
of
finite
residues
in
these
commodities
and
there
are
no
Codex
MRLs
established.

There
is
no
U.
S.
tolerance
for
dimethipin
in
milk.
A
tolerance
for
milk
is
not
required
as
there
is
no
expectation
of
finite
residues
of
dimethipin
in
milk.

For
enforcement
of
tolerances
for
residues
of
dimethipin,
PAM
Vol.
II
lists
two
methods,
Method
I
for
cottonseed
and
Method
II
for
livestock
tissues
and
eggs.
The
stated
detection
limits
are
0.1
ppm
for
cottonseed
and
0.02
ppm
for
livestock
commodities.
The
registrant
has
submitted
a
revised
version
of
the
enforcement
method
for
cottonseed
to
include
instructions
for
the
analysis
of
cottonseed
processed
commodities,
the
use
of
toluene
instead
of
benzene
as
a
solvent,
and
a
GPC
cleanup
step.
The
revised
method
has
undergone
adequate
independent
laboratory
validation
and
should
replace
Method
I
for
enforcement
of
tolerances
for
residues
of
dimethipin
in/
on
cottonseed.

Environmental
Fate
The
available
environmental
fate
data
for
dimethipin
are
adequate
to
assess
the
residues
of
concern
in
drinking
water.
Since
no
major
transformation
products
were
identified
in
any
study,
the
residue
of
concern
consists
of
parent
dimethipin
only.

The
available
data
indicate
that
dimethipin
is
both
persistent
and
mobile
and
has
a
high
potential
to
leach
to
ground
water.
Since
there
are
no
monitoring
data
for
dimethipin,
human
exposure
to
dimethipin
in
drinking
water
was
assessed
based
on
conservative,
Tier
1
residue
estimates
for
surface
water
and
ground
water
generated
by
EFED
using
the
FIRST
and
SCI­
GROW
models,
respectively.
Monitoring
data
or
information
to
refine
the
model
inputs
would
be
required
to
conduct
a
more
refined
drinking
water
assessment.

Based
on
the
chemical
and
toxicological
properties
of
dimethipin
(
i.
e.,
low
volatility,
lack
of
dermal
toxicity)
and
the
absence
of
any
residential
uses,
environmental
exposure
to
dimethipin,
apart
from
exposure
through
drinking
water,
is
not
expected
to
be
significant.

Aggregate
Risk
4
A
long­
term
(
chronic)
aggregate
risk
assessment
was
conducted
for
dimethipin.
The
chronic
assessment
considered
exposures
from
food
and
water
only,
because
there
are
no
residential
uses
and
no
residential
exposures
anticipated
for
this
chemical.
An
acute
aggregate
risk
assessment
was
not
conducted,
since
an
endpoint
attributable
to
a
single
exposure
scenario
was
not
identified
for
dimethipin.

The
results
of
the
deterministic,
Tier
1chronic
dietary
assessment
indicate
that
exposure
to
dimethipin
from
food
alone
is
well
below
HED's
level
of
concern,
with
estimated
exposures
representing
<
1%
of
the
cPAD
for
the
U.
S.
population
and
all
population
subgroups,
including
infants
and
children.
Since
adequate
water
monitoring
data
are
not
available
to
estimate
levels
of
dimethipin
in
drinking
water,
HED
calculated
DWLOCs
and
compared
them
to
the
modeled
EDWCs
for
surface
and
ground
water
to
determine
whether
aggregate
chronic
risks
are
of
concern.
The
chronic
surface
and
ground
water
EDWCs
generated
by
FIRST
and
SCI­
GROW
are
below
HED's
calculated
DWLOCs
for
chronic
exposure
to
dimethipin
for
the
U.
S.
population
and
each
population
subgroup.
Based
on
these
considerations,
HED
is
reasonably
certain
that
the
chronic
aggregate
risk
associated
with
the
use
of
dimethipin
does
not
exceed
HED's
level
of
concern
for
the
overall
U.
S.
population
or
population
subgroups,
including
infants
and
children.

Occupational
Exposure
Occupational
handlers
may
be
exposed
through
the
following
routes
during
mixing,
loading
and
application
of
dimethipin
using
aerial,
groundboom
or
high
pressure
handwand
equipment
and
during
flagging
operations
for
spray
applications:


Dermal:
Although
dermal
exposure
is
expected,
short­
and
intermediate­
term
dermal
endpoints
were
not
identified
due
to
the
lack
of
dermal,
systemic,
and
developmental
toxicity
concerns.
A
long­
term
dermal
endpoint
was
not
identified;
nor
would
long­
term
dermal
occupational
exposure
be
expected.
Therefore
dermal
exposure
was
not
assessed.


Inhalation:
Even
though
the
volatility
of
this
chemical
is
very
low,
based
on
the
use
patterns
for
dimethipin,
both
short­
and
intermediate­
term
inhalation
exposure
may
occur.
Long­
term
inhalation
exposure
is
not
anticipated.

Since
no
chemical­
specific
handler
exposure
data
are
available
for
dimethipin,
short­
and
intermediate­
term
inhalation
exposure
were
assessed
using
data
from
the
Pesticide
Handlers
Exposure
Database
(
PHED)
Version
1.1.
PHED
data
were
used
with
other
HED
standard
values
for
areas
treated
per
day,
body
weight
and
the
level
of
personal
protective
equipment
(
PPE)
and
engineering
controls
to
assess
handler
exposures
to
dimethipin.
Using
these
assumptions,
the
calculated
occupational
handler
MOEs
for
all
exposure
scenarios
are
greater
than
HED's
target
of
100
and
are,
therefore,
not
of
concern.
Short­
term
inhalation
MOEs
range
from
1,500
(
mixing/
loading
liquids
for
aerial
application)
to
1,300,000
(
mixing/
loading
liquids
for
highpressure
handwand
application).
Intermediate­
term
inhalation
MOEs
range
from
880
(
mixing/
loading
liquid
for
aerial
application)
to
770,000
(
mixing/
loading
liquids
for
high­
pressure
handwand
application).
5
Summary
Dimethipin
is
a
relatively
low
toxicity
pesticide
whose
potential
routes
of
exposure
include
food
and
drinking
water.
Residential
exposure
to
dimethipin
is
not
expected,
since
there
are
no
residential
uses
of
this
pesticide.
Under
the
conditions
of
its
current
use
on
cotton
and
nonbearing
apples,
dimethipin
presents
little
health
risk
to
workers
handling
the
pesticide
or
to
the
general
population,
including
infants
and
children,
from
consumption
of
foods
or
drinking
water
containing
dimethipin
residues.

2.0
Ingredient
Profile
Dimethipin
[
2,3­
dihydro­
5,6­
dimethyl­
1,4­
dithiin
1,1,4,4­
tetraoxide]
is
a
plant
growth
regulator
registered
for
use
as
a
preharvest
cotton
defoliant
and
herbicide.
It
is
a
member
of
the
sulfone
chemical
class.
Dimethipin
products
are
registered
in
the
U.
S.
to
Crompton
Manufacturing
Company,
Inc.
(
parent
company
to
Uniroyal
Chemical
Company,
Inc.)
under
the
trade
name
HARVADE
®
.
Currently,
the
2,
3.2
and
4.9
lb./
gal.
flowable
concentrate
formulations
of
dimethipin
are
registered
for
use
on
cotton.
The
products
are
typically
applied
as
postemergence
broadcast
applications
7
to
14
days
prior
to
harvest
at
an
application
rate
of
up
to
0.38
lb.
a.
i./
acre
using
ground
or
aerial
equipment.
Dimethipin
may
also
be
tank­
mixed
with
registered
postemergence
herbicides
and
applied
as
a
directed
spray
from
early
post­
emergence
through
layby
to
control
young
weeds
such
as
sicklepod
and
morningglory
in
cotton.
Application
rates
for
postdirected
weed
control
range
from
0.23
to
0.56
lb.
a.
i./
acre.
In
addition,
dimethipin
may
be
used
under
a
Special
Local
Need
registration
in
Washington
state
as
a
defoliant
on
non­
bearing
apples
in
nurseries
prior
to
transplanting
in
the
field.
Applications
to
apples
are
made
with
hand­
held
spray
equipment
at
an
application
rate
of
0.07656
lb.
a.
i./
acre.
The
Restricted
Entry
Interval
(
REI)
for
workers
is
48
hours
for
all
uses.
6
2.1
Summary
of
Registered/
Proposed
Uses
Table
2.1
Summary
of
Directions
for
Use
of
Dimethipin
SITE
NAME
Product/
Site
Limitations
Application
Type
(
for
any
Reg.#
at
any
rate)
(
aggregate)

Application
Timing
(
for
any
Reg.#
at
any
rate)

Application
Equipment
(
for
any
Reg.#
at
any
rate)

(
aggregate)
Max.
Single
Appl.

Rate
to
a
Single
Site
(
AI
unless
noted
otherwise)
Inconvertible
Label
(
L)
Dosages
Also
Present
Max
Seasonal
Rate
(
L)
Dosages
Also
Present
Max.
#

Apps
Per
Crop
Cycle
(
cc)

and
Year
(
at
any
rate)
Min
Retmt
Intv
(
days)

(
at
any
rate)
PHI/
PGI/
PSI
Use
Limitations
(
at
any
rate)
(
May
not
apply
to
all
Reg.
#
s
within
group)

COTTON
(
UNSPECIFIED)
Do
not
apply
directly
to
water,
or
to
areas
where
surface
water
is
present
or
to
intertidal
areas
below
the
mean
high
water
mark.

Do
not
apply
through
any
type
of
irrigation
system.

Do
not
apply
when
drift
is
likely
to
occur.

Do
not
apply
when
wind
velocity
is
10
mph
or
greater.

Do
not
contaminate
water
by
cleaning
of
equipment
or
disposal
of
equipment
wash
waters.

Do
not
contaminate
water,
food,
or
feed
by
storage
or
disposal.

Rotational/
plant
back
crop
restriction.

Spray
After
boll­
opening
Aircraft/
Ground
.30625
lb
A
NS
NS
NS
NS
Geographic
allowable:
CA
Broadcast/
Low
volume
spray
(
concentrate)/
Spray
Foliar
Aircraft/
Ground
.3125
lb
A
NS
NS
NS
NS
Geographic
allowable:
AL
AR
FL
GA
KS
LA
MO
MS
NC
NM
OK
SC
TN
TX
VA
Geographic
disallowable:
OK
TX
Spray
Preharvest
Aircraft/
Ground
.3828
lb
A
.5625
lb/
yr
NS
NS
5
Geographic
allowable:
AL
AR
FL
GA
LA
MO
MS
NC
OK
SC
TN
TX
VA
Geographic
disallowable:
OK
TX
7
APPLE
Do
not
apply
directly
to
water,
or
to
areas
where
surface
water
is
present
or
to
intertidal
areas
below
the
mean
high
water
mark.

Do
not
apply
through
any
type
of
irrigation
system.

Do
not
apply
to
food
or
feed
crops
within
1
year
of
harvest.

Do
not
contaminate
water
by
cleaning
of
equipment
or
disposal
of
equipment
wash
waters.

Do
not
contaminate
water,
food,
or
feed
by
storage
or
disposal.

Rotational/
plant
back
crop
restriction.

Spray
Nonbearing
nurserystock
Sprayer
.07656
lb
A
NS
NS
NS
5
Product
Number(
s)
Contained
in
this
Report
:

000400­
00155
000400­
00398
000400­
00505
and
WA980008
8
S
S
CH
3
CH
3
O
O
O
O
2.2
Structure
and
Nomenclature
TABLE
2.2
Test
Compound
Nomenclature
Chemical
structure
2,3­
dihydro­
5,6­
dimethyl­
1,4­
dithiin
1,1,4,4­
tetraoxide
Common
name
dimethipin
Chemical
class
sulfone
IUPAC
name
2,3­
dihydro­
5,6­
dimethyl­
1,4­
dithiine
1,1,4,4­
tetraoxide
CAS
name
2,3­
dihydro­
5,6­
dimethyl­
1,4­
dithiin
1,1,4,4­
tetraoxide
CAS
registry
number
55290­
64­
7
Known
impurities
of
concern
None
End­
use
products
(
EPs):

400­
155
4.9
lb/
gal
FlC1
Harvade
®
­
5F
Harvest
Growth
Regulant
For
Cotton
400­
398
2
lb/
gal
FlC
Harvade
®
­
25F
Harvest
Growth
Regulant
For
Cotton
400­
505
3.2
lb/
gal
EC2
Leafless
®
Harvest
Growth
Regulant
for
Cotton
1
Including
SLN
WA980008.
2
This
product
also
contains
thidiazuron.

2.3
Physical
and
Chemical
Properties
Dimethipin
is
a
non­
volatile
liquid
with
a
relatively
low
octanol/
water
partition
coefficient
and
high
water
solubility.
Based
on
its
low
volatility,
human
exposure
via
the
inhalation
route
is
likely
to
be
low.
Its
octanol/
water
partition
coefficient
and
high
water
solubility
suggest
that
dimethipin
may
have
relatively
low
bioavailability
in
the
body
and
be
excreted
from
the
body
fairly
rapidly.

Table
2.3
Physicochemical
Properties
of
Dimethipin
Parameter
Value
Reference
Melting
point/
range
162­
167

C
Dimethipin
RED,
PC
Chapter
pH
4.52
at
30

C
(
1%
w:
v
solution
in
50%
aqueous
dioxane
due
to
insolubility
in
water)
Dimethipin
RED,
PC
Chapter
Density
1.5935
g/
cm3
at
23

C
Dimethipin
RED,
PC
Chapter
Water
solubility
0.46
g/
100
mL
at
25

C
Dimethipin
RED,
PC
Chapter
Solvent
solubility
At
25

C:
acetone
0.097
g/
mL
1­
octanol
79.356
mg/
100
mL
hexane
1.664
mg/
100
mL
methanol
0.05
g/
100
mL
xylene
0.57
g/
100
mL
chloroform
7.92
g/
100
mL
Dimethipin
RED,
PC
Chapter
Table
2.3
Physicochemical
Properties
of
Dimethipin
Parameter
Value
Reference
9
Vapor
pressure
<
3.81
x
10­
7
mm
Hg
at
24

C
Dimethipin
RED,
PC
Chapter
Dissociation
constant,
pKa
10.88
+/­
0.39
at
25

C
Dimethipin
RED,
PC
Chapter
Octanol/
water
partition
coefficient,
Log(
KOW)
0.66
at
24

C
Dimethipin
RED,
PC
Chapter
UV/
visible
absorption
spectrum
not
available
3.0
Metabolism
Assessment
3.1
Comparative
Metabolic
Profile
Rat
metabolism:
A
series
of
rat
metabolism
studies
indicated
that
dimethipin
is
absorbed
from
the
gastrointestinal
tract.
Following
a
single
low
oral
dose,
~
59­~
66%
of
the
administered
dose
was
absorbed
in
male
and
female
rats,
respectively.
With
single
or
multiple
high
doses,
absorption
decreased
significantly
(~
37%
for
male
and
59%
for
females),
suggesting
absorption
was
ratelimited
Highest
levels
of
radioactivity
after
administration
of
radiolabeled
dimethipin
were
detected
in
the
gastrointestinal
tract,
liver,
kidneys
and
red
blood
cells.
Following
treatment,
~
57%
of
a
single
low­
dose
in
males
and
~
63%
in
females
was
recovered
in
the
urine
48­
96
hours
after
treatment,
while
~
28%
of
the
dose
was
recovered
in
the
feces
of
these
rats.
Following
single
or
multiple
high
doses,
approximately
33%
of
the
dose
was
recovered
in
the
urine
of
male
rats
and
~
45%
in
the
urine
of
female
rats
48­
96
hours
after
dosing.

Of
that
amount
of
radiolabel
recovered
in
the
urine,
~
77%
was
composed
of
three
metabolites
­
R­
4,
R­
5,
and
R­
6.
These
were
identified
as
a
cysteinylglycine
conjugate
of
the
parent
compound,
as
an
N­
acetylcysteinyl
conjugate
derived
from
cysteinylglycine
conjugate,
and
a
reductive
product
of
dimethipin
(
1,1,4,4­
tetraoxide,
2,3­
dimethyldithiane).
Also
identified
in
the
urine
were
polar
metabolites
which
were
not
further
characterized.
No
studies
were
conducted
to
identify
metabolites
in
the
feces
or
bile,
or
determine
whether
radiolabel
was
eliminated
in
the
expired
air.

Reduced
dimethipin
was
also
identified
in
the
poultry
and
ruminant
metabolism
studies;
however,
it
was
not
found
in
the
plant
metabolism
or
confined
rotational
crop
studies.
The
dimethipin
conjugates
seen
in
the
rat
metabolism
study
were
not
identified
in
other
animal
or
plant
matrices.
However,
similar
amino
acid
conjugates
were
identified
in
both
plants
and
livestock.

3.2
Nature
of
the
Residue
in
Foods
3.2.1.
Description
of
Primary
Crop
Metabolism
Metabolism
was
studied
only
in
cotton
because
dimethipin
is
registered
only
for
food
use
on
cotton.
In
a
cotton
metabolism
study
(
MRID
43436901),
greenhouse­
grown
cotton
was
treated
with
[
2,3­
14C]
dimethipin
at
1.22
lb
ai/
A
and
3.06
lb
ai/
A
(
2.2x
and
5.4x
the
maximum
seasonal
rate)
two
weeks
prior
to
harvest.
Total
radioactive
residues
were
97.1
ppm
in
foliage
and
10
0.291
ppm
in
seeds
from
plants
treated
at
the
2.2x
rate,
and
341.3
ppm
in
foliage
and
1.42
ppm
in
seeds
from
plants
treated
at
the
5.4x
rate.
Matrices
from
the
2.2x
treated
plants
were
subjected
to
extraction
and
characterization/
identification.
Dimethipin
per
se
was
found
to
comprise
74%
of
foliage
radioactivity
and
80%
of
seed
radioactivity;
no
additional
metabolites
were
identified.

3.2.2
Description
of
Livestock
Metabolism
Poultry:
Following
oral
administration
of
[
2,3­
14C]
dimethipin
to
hens
for
5
days
at
2772
ppm
(
27,720x
the
maximum
theoretical
dietary
burden),
the
TRR
were
0.12­
12
ppm
in
egg
whites,
0.34­
16
ppm
in
egg
yolks,
2.4
ppm
in
fat,
10
ppm
in
thigh
muscle,
10
ppm
in
breast
muscle,
39
ppm
in
kidney
and
65
ppm
in
liver.
Dimethipin
per
se
was
not
detected
in
any
poultry
matrices;
however,
reduced
dimethipin
was
found
in
all
matrices
except
thigh
muscle
and
fat
at
0.98­
7.8%
TRR
(
0.21­
5.0
ppm).
In
all
matrices
except
liver,
the
predominant
metabolite
was
Glu­
Cys­
S­
Harv
[
S­(
2,3­
dimethyl­
1,1,4,4­
tetraoxo­
1,4­
dithian­
yl)­
L­
cysteinyl­
 ­
glutamic
acid]
at
19­
36%
TRR
(
0.48­
7.5
ppm);
this
metabolite
was
found
in
liver
at
7.4%
TRR
(
4.8
ppm).
The
most
significant
liver
metabolite
was
dimethipin
cysteine
conjugate
(
Harv­
S­
Cys)
at
21.5%
TRR
(
14
ppm);
this
metabolite
was
found
in
all
other
matrices
except
fat
at
0.1­
7.0%
TRR
(
0.01­
2.8
ppm).
The
major
metabolic
pathway
proposed
by
the
registrant
involved
the
formation
of
thioethers
of
dimethipin;
other
minor
pathways
involved
reduction
and
hydroxylation
of
dimethipin.

Ruminant:

Following
oral
administration
of
[
2,3­
14C]
dimethipin
to
lactating
goats
for
5
days
at
3.066,
1010.8
and
1290.0
ppm
(
0.5x,
177x
and
226x
the
maximum
theoretical
dietary
burden),
the
TRR
were
0.005­
0.006
ppm
in
milk,
0.27
ppm
in
liver,
0.15
ppm
in
kidney,
0.002
ppm
in
muscle
and
0.001
ppm
in
fat
from
the
goat
dosed
at
3.066
ppm;
0.68­
1.20
ppm
in
milk,
78.5
ppm
in
liver,
28.4
ppm
in
kidney,
0.64
ppm
in
muscle
and
0.32
ppm
in
fat
from
the
goat
dosed
at
1010.8
ppm;
and
3.13­
4.26
ppm
in
milk,
45.0
ppm
in
liver,
55.2
ppm
in
kidney,
2.04
ppm
in
muscle
and
0.99
ppm
in
fat
from
the
goat
dosed
at
1290.0
ppm.

Dimethipin
was
not
detected
in
milk
and
tissues
from
the
goat
dosed
at
3.066
ppm.
In
milk
from
this
goat,
dimethipin
cysteine
conjugate
(
34.8­
52.8%
TRR,
0.001­
0.002
ppm)
was
the
only
residue
identified.
In
kidney,
the
only
metabolite
identified
was
ethane
disulfonic
acid
(
75.6%
TRR,
0.11
ppm).
In
liver,
two
metabolites
were
identified:
ethane
disulfonic
acid
(
14.6%
TRR,
0.38
ppm)
and
acetyl
dithiane
tetraoxide
(
16.6%
TRR,
0.045
ppm).
No
attempts
were
made
to
characterize/
identify
radioactive
residues
in
fat
and
muscle
because
the
total
radioactive
residues
in
these
tissues
were
0.001
and
0.002
ppm,
respectively.

The
parent
dimethipin
was
also
not
detected
in
the
milk
and
tissues
of
the
goats
dosed
at
higher
levels.
Dimethipin
cysteine
conjugate
was
also
the
only
residue
identified
in
milk
(
25.2­
50.6%
TRR,
0.22­
0.55
ppm).
In
kidney,
ethane
disulfonic
acid
(
27.6%
TRR,
7.8
ppm)
and
acetyl
dithiane
tetraoxide
(
32.3%
TRR,
9.2
ppm)
were
identified.
In
muscle,
reduced
dimethipin
(
2,3­
dimethyl­
1,1,4,4­
tetraoxo­
1,4­
dithiane;
21.9%
TRR,
0.140
ppm)
was
identified.
In
liver,
ethane
disulfonic
acid
(
44.8%
TRR,
20.1
ppm)
was
identified.
Based
on
several
fractionation
and
11
extraction
procedures
employed
in
the
study,
the
registrant
believes
that
the
majority
of
radioactive
residues
in
kidney
and
liver
were
covalently
bound
to
proteins.

3.2.3
Description
of
Rotational
Crop
Metabolism,
including
identification
of
major
metabolites
and
specific
routes
of
biotransformation
In
the
submitted
confined
rotational
crop
study
[
14C]
Dimethipin
was
applied
to
the
soil
at
0.54
lb
ai/
A
(
1x
the
maximum
seasonal
rate),
and
rotational
crops
of
lettuce,
carrots,
and
barley
were
planted
30
and
183
days
after
application.
Samples
of
immature
and
mature
lettuce,
immature
and
mature
carrot
root
and
top,
and
barley
forage,
grain,
and
straw
were
collected.

Total
radioactive
residues
accumulated
above
0.01
ppm
in
all
harvested
rotational
crop
commodities
at
both
plantback
intervals.
At
the
30­
day
plantback
interval,
the
highest
residues
were
observed
in
barley
forage
(
2.52
ppm),
and
the
lowest
residues
were
observed
in
carrot
root
(
immature
and
mature;
0.10
ppm)
and
barley
grain
(
0.02
ppm).
At
the
183­
day
plantback
interval,
the
highest
residues
were
observed
in
carrot
tops
(
immature
and
mature;
0.508­
0.705
ppm),
and
the
lowest
residues
were
observed
in
immature
carrot
root
(
0.017
ppm)
and
barley
grain
(
0.018
ppm).
In
the
30­
day
plantback
interval
samples,
dimethipin
was
identified
in
immature
and
mature
lettuce
(
0.064­
0.091
ppm),
mature
carrot
tops
(
0.024
ppm),
immature
and
mature
carrot
root
(
0.016­
0.039
ppm),
barley
forage
(
0.025
ppm),
and
barley
straw
(
0.012
ppm).
In
the
183­
day
plantback
interval
samples,
dimethipin
was
identified
in
immature
carrot
tops
(
0.041
ppm),
but
was
not
detected
in
any
other
matrix.
Metabolite
H­
5
(
hydroxylated
dimethipin)
was
identified
at
low
levels
in
barley
straw
from
the
30­
day
plantback
interval.
Additional
characterization
data
demonstrated
that
unidentified
radioactivity
generally
consisted
of
several
components,
each
of
which
comprised

0.05
ppm.
Two
additional
metabolites,
H­
80
(
dimethipin
cysteine
conjugate)
and
a
mercaptolactic
acid
conjugate,
were
identified
in
the
extracts
of
30­
DAT
immature
lettuce,
at
2.10%
TRR
(
0.023
ppm)
and
13.68%
TRR
(
0.151
ppm),
respectively.

The
results
of
the
confined
rotational
crop
study
indicate
that
dimethipin
is
extensively
metabolized
in
rotational
crops.
The
registrant
proposed
that
dimethipin
is
metabolized
in
rotational
lettuce
and
carrots
through
glutathione
conjugation
followed
by
degradation
to
cysteine
conjugates.
Further
oxidation
at
the
amino
group
leads
to
the
formation
of
mercaptolactic
acid
conjugates.

3.3
Environmental
Degradation
Dimethipin
degrades
slowly
under
laboratory
and
field
conditions,
with
the
apparent
primary
route
of
dissipation
in
the
field
being
leaching
coupled
with
photodegradation
at
the
soil
surface
and
metabolic
degradation
throughout
the
soil
column.
In
buffered
aqueous
solutions,
dimethipin
was
stable
to
hydrolysis
with
half­
lives
>
2
years
at
pHs
3­
9
and
photodegraded
slowly
to
very
slowly
with
half­
lives
ranging
from
60
days
(
pH
5)
to
224
days
(
pH
7)
at
pH
5­
9.
In
sandy
loam
soil,
dimethipin
photodegraded
with
a
half­
life
of
75
days.
In
metabolism
studies,
dimethipin
degraded
under
aerobic
conditions
with
a
half­
life
of
408
days
and
under
anaerobic
aquatic
conditions
with
a
half­
life
of
277
days.
12
S
S
CH
3
CH
3
O
O
O
O
Octanol/
water
partitioning
(
Kow)
data
provided
by
the
registrant
indicate
a
low
potential
for
dimethipin
to
accumulate
in
fish
(
Kow
for
dimethipin
=
0.66).

Dimethipin
has
very
high
mobility
in
soils
ranging
from
sand
to
clay,
with
Freundlich
adsorption
coefficients
of

0.09.
In
field
studies
using
bare
ground
and
cropped
plots,
dimethipin
leached
to
a
depth
of
75­
90
cm.

Volatilization
is
not
expected
to
be
a
significant
since
the
reported
vapor
pressure
is
<
3.87
x
10­
7
mm
Hg
at
24

C.

No
major
transformation
products
were
identified
in
any
of
the
environmental
fate
studies.
2,3­
Dihydro­
5­
hydroxymethyl­
6­
methyl­
1,4­
dithiin­
1,1,4,4­
tetraoxide
(
H­
5)
was
present
as
a
minor
transformation
product
(
less
than
2%
of
the
applied
dimethipin)
in
the
aquaeous
photolysis
study
only.
The
saturated
carboxylic
acid
of
dimethipin
was
identified
in
the
anaerobic
aquatic
study
but
was
not
quantified.

3.4
Tabular
Summary
of
Metabolites
and
Degradates
Table
3.4
Tabular
Summary
of
Metabolites
and
Degradates
Name
Structure
Study
Identified
(%
TRR)

Dimethipin
Cotton
metabolism:
foliage
(
74%);
seed
(
80%)

Reduced
Dimethipin
Poultry
metabolism
(
0.98­
7.8%
in
all
matrices,
except
thigh
muscle)

Ruminant
metabolism
(
21.9%,
only
in
muscle
at
the
high
dose)

Rat
metabolism
(
urine)

Glu­
Cys­
S­
Harv:

S­(
2,3­
dimethyl­
1,1,4,4­
tetraoxo­
1,4­
dithian­
yl)­
L­
cysteinyl­

­
glutamic
acid
Poultry
metabolism
(
19­
36%
in
all
matrices)
Table
3.4
Tabular
Summary
of
Metabolites
and
Degradates
Name
Structure
Study
Identified
(%
TRR)

13
SO
3
H
HO
3
S
S
S
O
O
O
O
CH
3
O
S
S
CH
3
O
O
O
O
S
CH
3
N
H
2
COOH
S
S
CH
3
O
O
O
O
S
CH
3
O
H
COOH
HARV­
S­
Cys
(
dimethipin­
cysteine):

S­(
2,3­
dimethyl­
1,1,4,4­
tetraoxo­
1,4­
dithian­
2­
yl)­
L­
cysteine
Poultry
metabolism
(
0.1­
7.0%
in
all
matrices,
except
fat)

Ruminant
metabolism
(
25.2
­
52.8%
in
milk
only)

Confined
rotational
crop
study
(
2.1%
in
immature
lettuce
only
at
the
30­
day
PBI)

Ethane
disulfonic
acid
Ruminant
metabolism
(
14.6­
44.8%
in
liver;
27.6­
75.6%
in
kidney)

Acetyl
dithiane
tetraoxide
Ruminant
metabolism
(
16.6%
in
liver
at
low
dose;
40­
50%
in
liver
at
high
dose;
32.3%
in
kidney
at
high
dose
only)

H­
80
S­(
2,3­
dimethyl­
1,4­
dithian­
2­
yl)­
1,1,4,4­
tetraoxide
cysteine
Confined
rotational
crop
study
(
2.1%
in
immature
lettuce
only
at
the
30­
day
PBI)

Hydroxylated
dimethipin
(
H­
5)
N/
A
Confined
rotational
crop
study
(
0.009
ppm
in
barley
straw
only
at
the
30­
day
PBI).
Aqueous
photolysis
study
at
<
2%
of
the
applied.

Dimethipin
mercaptolactic
acid
conjugate
Confined
rotational
crop
study
(
13.68%
in
immature
lettuce
only
at
the
30­
day
PBI)

Cysteinylglycine
conjugate
N/
A
Rat
metabolism
(
urine)

N­
acetylcysteinyl
conjugate
N/
A
Rat
metabolism
(
urine)

3.5
Toxicity
Profile
of
Major
Metabolites
and
Degradates
Toxicity
data
are
not
available
on
the
metabolites
and
degradates
of
dimethipin.
In
the
absence
of
toxicity
data
or
information
on
the
precise
mechanism
of
action
of
the
parent
compound,
major
metabolites/
degradates
that
retain
the
intact
six­
membered
ring
structure
are
assumed
to
be
of
potential
concern
from
a
toxicity
perspective
(
personal
communication,
Leonard
Keifer,
OPPT,
3/
9/
04).
Of
the
metabolites
having
this
structure,
only
the
acetyl
dithiane
tetraoxide
metabolite
seen
in
the
ruminant
study
was
found
at
levels
indicating
a
potential
for
human
exposure
through
the
diet.
The
remaining
metabolites
having
this
structure
were
excluded
from
consideration
in
the
14
risk
assessment,
based
on
their
presence
in
only
one
matrix
or
at
low
levels.
Ethane
disulfonic
acid,
a
major
metabolite
found
in
the
liver
and
kidney
of
ruminants,
is
a
short­
chain,
polar
compound
that
is
likely
to
be
excreted
rapidly
in
the
urine.
Based
on
its
polarity
and
lack
of
structural
similarity
to
the
parent
(
i.
e.,
not
a
ring
compound),
it
is
not
expected
to
be
of
toxicological
concern.

3.6
Summary
of
Residues
for
Tolerance
Expression
and
Risk
Assessment
3.6.1
Tabular
Summary
Table
3.6.
Summary
of
Metabolites
and
Degradates
to
be
included
in
the
Risk
Assessment
and
Tolerance
Expression
Matrix
Residues
included
in
Risk
Assessment
Residues
included
in
Tolerance
Expression
Plants
Primary
Crop
Dimethipin
Dimethipin
Rotational
Crop
Dimethipin
Dimethipin
Livestock
Ruminant,
except
liver
Dimethipin
Dimethipin
Ruminant
liver
Dimethipin
plus
acetyl
dithiane
tetraoxide
Dimethipin
Poultry
not
applicable
­
no
residues
expected
not
applicable
­
no
tolerances
required
Drinking
Water
Dimethipin
Not
Applicable
3.6.2
Rationale
for
Inclusion
of
Metabolites
and
Degradates
Primary
Plant:

Dimethipin
per
se
was
found
to
comprise
74%
of
the
cotton
foliage
TRR
and
80%
of
the
cotton
seed
TRR.
No
additional
metabolites
were
identified.
The
residue
of
concern
for
the
tolerance
expression
and
risk
assessment
in
plants
is
dimethipin
per
se.

Livestock:

Poultry:
Dimethipin
per
se
was
not
detected
in
any
poultry
matrices
following
oral
administration
of
[
2,3­
14C]
dimethipin
to
hens
for
5
days
at
2772
ppm
(
27,720x
the
maximum
theoretical
dietary
burden).
Reduced
dimethipin
was
found
in
all
matrices
except
thigh
muscle
and
fat
at
0.98­
7.8%
TRR
(
0.21­
5.0
ppm).
The
only
metabolites
comprising
more
than
10%
of
the
TRR
for
a
given
matrix
were
Glu­
Cys­
S­
Harv
[
S­(
2,3­
dimethyl­
1,1,4,4­
tetraoxo­
1,4­
dithian­
yl)­
L­
cysteinyl­
 ­
glutamic
acid]
at
19­
36%
TRR
(
0.48­
7.5
ppm)
and
dimethipin
cysteine
conjugate
(
Harv­
S­
Cys)
at
up
to
21.5%
TRR
(
14
ppm).
Given
the
low
levels
of
radioactivity
found
at
the
highly
exaggerated
rate,
there
is
no
reasonable
expectation
of
finite
residues
of
dimethipin
or
its
metabolites
in
poultry.
15
Ruminant:
Dimethipin
per
se
was
not
detected
in
milk
or
tissues
of
goats
following
oral
administration
of
[
2,3­
14C]
dimethipin
to
lactating
goats
for
5
days
at
3.066,
1018.8
and
1290.0
ppm,
equivalent
to
0.5x,
177x
and
226x
the
maximum
theoretical
dietary
burden
(
MTDB).

In
milk,
dimethipin
cysteine
conjugate
(
Harv­
S­
Cys)
was
the
only
residue
identified
at
any
dose
level
(
34.8
­
52.8
%
TRR,
equivalent
to
0.001
to
0.002
ppm
at
the
low
dose;
and
25.2
­
50.6%
TRR,
equivalent
to
0.22
to
0.55
ppm,
at
the
high
doses).
Based
on
the
low
levels
seen
at
0.5x
the
MTDB
and
the
conservative
assumptions
used
to
calculate
the
MTDB
(
i.
e.,
assumed
50x
seed
residue
on
gin
byproducts
in
the
MTDB
calculation),
finite
residues
of
this
metabolite
would
not
be
expected
in
milk.

Reduced
dimethipin
was
identified
in
a
single
matrix,
muscle,
and
only
at
the
high
dose
(
21.9%
TRR,
equivalent
to
0.14
ppm).
Since
this
metabolite
was
present
in
the
rat
metabolism
study,
is
not
expected
to
occur
in
muscle
above
the
LOQ
at
a
1x
dose
and
was
not
found
in
any
other
matrix,
reduced
dimethipin
should
not
be
included
in
the
tolerance
expression
or
risk
assessment.

Ethane
disulfonic
acid
was
identified
as
a
major
metabolite
in
both
liver
and
kidney,
comprising
more
than
75%
of
the
TRR
(
0.11
ppm)
in
kidney
and
14.6%
of
the
TRR
(
0.038
ppm)
in
liver
at
the
low
(
0.5x)
dose.
However,
based
on
the
determination
that
this
metabolite
is
not
of
toxicological
concern,
it
should
not
be
included
in
the
tolerance
expression
or
risk
assessment.

Acetyl
dithiane
tetraoxide
was
identified
in
liver
at
levels
above
the
LOQ
at
both
the
low
and
high
doses
(
16.6%
TRR,
equivalent
to
0.045
ppm,
at
the
0.5x
dose).
Although
it
occurred
in
only
one
matrix,
the
dimethipin
Team
determined
that
it
should
be
included
in
the
dimethipin
risk
assessment
for
the
following
reasons:
(
1)
The
metabolite
is
similar
in
structure
to
the
parent
compound
and
may
be
of
toxicological
significance,
but
was
not
present
in
the
rat
metabolism
study;
(
2)
It
comprised
more
than
10%
of
the
TRR
in
liver;
and
(
3)
It
may
occur
in
liver
at
levels
above
the
LOQ.
The
Team
concluded
that
acetyl
dithiane
tetraoxide
should
not
be
included
in
the
tolerance
expression,
since
(
1)
the
metabolite
cannot
be
determined
by
multi­
residue
methods
(
dimethipin
is
completely
recovered
using
Multiresidue
Methods
Section
302
(
Luke
Method;
Protocol
D));
(
2)
it
was
found
in
only
one
matrix
at
10­
20%
of
the
TRR
at
the
low
dose;
(
3)
the
parent
compound
has
relatively
low
toxicity;
and
(
4)
Codex
does
not
include
the
metabolite
in
its
regulations.

Based
on
the
above
considerations,
HED
concludes
that
the
residue
of
concern
for
risk
assessment
is
dimethipin
per
se
in
all
animal
commodities
except
liver
and
dimethipin
plus
the
metabolite,
acetyl
dithiane
tetraoxide,
in
the
liver
of
ruminants.
The
residue
of
concern
for
the
tolerance
expression
in
animal
commodities
is
dimethipin
per
se.

Rotational
Crops:

In
the
submitted
confined
rotational
crop
study,
dimethipin
per
se
was
the
only
residue
identified
at
the
6­
month
plant
back
interval.
Dimethipin
product
labels
currently
bear
a
6­
month
plant
back
restriction.
At
the
one
month
plant
back
interval
in
the
confined
studies,
dimethipin
per
se
and
3
metabolites
were
identified.
Hydroxylated
dimethipin
(
metabolite
H­
5)
was
identified
at
low
16
levels
(
0.009
ppm)
in
a
single
matrix,
barley
straw;
dimethipin
cysteine
conjugate
(
H­
80)
and
a
mercaptolactic
acid
conjugate
were
identified
in
a
single
matrix,
immature
lettuce,
at
0.023
ppm
(
2.1%
TRR)
and
0.151
ppm
(
13.68%
TRR),
respectively.
Since
these
metabolites
occurred
at
low
levels
(
H­
5
and
H­
80)
and/
or
in
one
matrix
only
(
H­
5,
H­
80
and
the
mercaptolactic
acid
conjugate),
and
since
they
were
identified
only
at
the
30­
day
plant
back
interval,
the
residue
of
concern
for
rotational
crops
is
dimethipin
per
se.

Water:

No
major
transformation
products
were
identified
in
any
of
the
environmental
fate
studies.
2,3­
Dihydro­
5­
hydroxymethyl­
6­
methyl­
1,4­
dithiin­
1,1,4,4­
tetraoxide
(
H­
5)
was
present
as
a
minor
transformation
product
(
less
than
2%
of
the
applied
dimethipin)
in
the
aquaeous
photolysis
study
only.
The
saturated
carboxylic
acid
of
dimethipin
was
identified
in
the
anaerobic
aquatic
study
but
was
not
quantified.

Toxicity
information
is
not
available
for
the
H­
5
degradate.
However,
based
on
the
relatively
low
toxicity
of
the
parent
dimethipin
and
the
low
potential
for
exposure
to
this
degradate,
H­
5
is
not
considered
to
be
of
concern
for
human
health.
Dimethipin
degrades
slowly
in
the
environment,
and
dissipates
primarily
by
leaching,
coupled
with
photodegradation
at
the
soil
surface
and
metabolic
degradation
throughout
the
soil
column.
Photolysis
would
not
occur
in
groundwater,
and
although
some
dimethipin
would
reach
surface
water
through
runoff,
photolysis
only
occurs
in
the
upper
2­
3
inches
of
surface
water.
Therefore,
little
transformation
of
dimethipin
to
the
H­
5
degradate
is
expected.
Based
on
these
considerations,
the
residue
of
concern
for
drinking
water
is
dimethipin
per
se.

4.0
Hazard
Characterization/
Assessment
4.1
Hazard
Characterization
Acute
Toxicity:
The
acute
toxicity
data
base
for
dimethipin
is
considered
complete
for
acute
oral,
acute
dermal,
acute
inhalation,
dermal
and
eye
irritation,
and
dermal
sensitization.
Dimethipin
has
a
moderate
order
of
acute
toxicity
via
the
oral
(
Category
II)
and
inhalation
routes
(
Category
II).
It
has
a
low
order
of
acute
toxicity
via
the
dermal
(
Category
III)
route
of
exposure.
It
is
not
an
eye
or
skin
irritant,
or
a
dermal
sensitizer.
The
acute
toxicity
data
for
dimethipin
are
summarized
below
in
Table
4.1a.

Table
4.1a
Acute
Toxicity
Profile
­
Dimethipin
Guideline
No.
Study
Type
MRID(
s)
Results
Toxicity
Category
870.11
Acute
Oral
42429601
LD50
=
458
mg/
kg
(

)
LD50
=
546
mg/
kg
(

)
II
870.12
Acute
Dermal
42429602
LD50
>
5000
mg/
kg
III
17
870.13
Acute
Inhalation
42429603
LC50
=
1.2
mg/
L.
II
870.24
Primary
Eye
Irritation
70237
non­
irritant
IV
870.25
Primary
Dermal
Irritation
42429604
non­
irritant
IV
870.26
Dermal
Sensitization
42429605
not
a
sensitizer
 
Sub­
chronic
Toxicity:
No
treatment­
related
effects
on
mortality,
clinical
signs,
body
weight,
food
consumption,
pathology,
hematology
and
clinical
chemistry
were
observed
in
mice
following
dietary
administration
of
doses
of
up
to
300
mg/
kg/
day
for
28
days.

Decreased
body
weights
and
body
weight
gains
were
noted
in
female
rats
administered
dimethipin
in
the
diet
for
90
days
(
LOAEL
=
131
mg/
kg/
day;
NOAEL
=
3.1
mg/
kg/
day).
A
LOAEL
for
male
rats
was
not
established
(
NOAEL
=
220
mg/
kg/
day).
There
were
no
treatment­
related
effects
on
mortality,
clinical
signs,
food
consumption,
hematology,
clinical
chemistry,
or
pathology.

Chronic
Toxicity:
The
toxicity
database
for
dimethipin
indicates
that
reduced
body
weight
gain,
coupled
with
various
organ
effects
in
multiple
species,
are
the
major
toxic
effects
of
this
chemical.

In
a
104­
week
dietary
study
in
the
rat,
effects
were
observed
in
males
treated
with
77.6
mg/
kg/
day
(
mid­
dose)
and
161
mg/
kg/
day
(
high­
dose),
and
in
females
treated
with
50.3
mg/
kg/
day
(
mid­
dose)
and
103
mg/
kg/
day
(
high­
dose).
Liver
toxicity
was
indicated
by
increased
incidences
of
bile
duct
cysts
in
the
high­
dose
male
and
female
groups,
bile
duct
hyperplasia
in
the
mid­
and
high­
dose
female
groups,
eosinophilic
altered
foci
in
the
high­
dose
male
group,
and
elevated
serum
cholesterol
levels
in
males.
Chronic
progressive
nephropathy
was
exacerbated
in
mid­
and
high­
dose
rats
of
both
sexes
as
evidenced
by
increased
incidence
and
severity
of
the
lesion.
The
mean
absolute
kidney
weight
was
elevated
in
high­
dose
male
rats.
Toxicity
in
the
gastrointestinal
tract
was
manifested
by
elevated
incidences
and
severity
of
epithelial
hyperplasia
in
the
nonglandular
stomach
in
high­
dose
male
rats,
mineralization
in
the
glandular
stomach
of
mid­
and
high­
dose
female
rats,
epithelial
hyperplasia
of
the
duodenum
in
mid­
and
high­
dose
males
and
high­
dose
females,
and
crypt
abscesses
in
the
duodenum
of
mid­
and
high­
dose
male
rats.
In
addition
testicular
lesions
occurred
in
male
rats
fed
the
mid
and
high­
doses,
and
epididymal
hypospermia
occurred
in
high­
dose
males.
Effects
occurring
only
in
females
included
cardiovascular
toxicity
(
mineralization
of
the
heart
and
aortic
artery
(
mid
and
high
doses))
and
brain
degeneration
(
high­
doses).
The
NOAEL
in
males
is
2.18
mg/
kg/
day,
and
in
females
is
1.75
mg/
kg/
day.

In
a
carcinogenicity
study,
male
mice
administered
286
mg/
kg/
day
dimethipin
in
the
diet
exhibited
increased
mononuclear
inflammatory
cell
foci
in
the
trachea,
decreased
body
weight
gain,
and
decreased
food
efficiency.
The
NOAEL
is
400
ppm
for
males
(
56
mg/
kg/
day).
A
LOAEL
was
not
determined
for
females.
The
NOAEL
for
female
mice
was
2000
ppm
(
341
mg/
kg/
day).

In
a
52­
week
dietary
toxicity
study
in
the
dog,
decreased
body
weight
gain,
reduced
food
consumption,
and
a
negative
food
efficiency
were
observed
in
males
and
females
at
98.98
18
mg/
kg/
day
and
92.87
mg/
kg/
day,
respectively.
NOAELs
of
29.85
mg/
kg/
day
(
males)
and
34.42
mg/
kg/
day
(
females)
were
identified.

Developmental/
Reproductive
Toxicity:
Available
developmental
toxicity
data
provided
no
indication
of
increased
susceptibility
(
quantitative
or
qualitative)
of
rats
or
rabbits
to
in
utero
and/
or
postnatal
exposure
to
dimethipin.
No
treatment­
related
external,
visceral,
or
skeletal
malformations/
variations
were
noted
in
a
rat
developmental
toxicity
study.

In
a
two­
generation
rat
reproduction
study,
decreased
body
weights
and/
or
body
weight
gains
were
apparent
in
the
F
1a,
F
2a,
and
F
2b
pups.
The
offspring
toxicity
LOAEL
was
800
ppm
(
35.5­
115.7
mg/
kg/
day
for
males
and
31.2­
120.3
mg/
kg/
day
for
females).
The
offspring
toxicity
NOAEL
was
200
ppm
(
9.2­
28.7
mg/
kg/
day
for
males
and
11.8­
29.0
mg/
kg/
day
for
females).
Maternal
toxicity
consisted
of
decreased
body
weight
and
body
weight
gain
(
LOAEL
is
800
ppm
for
F
0
and
F
1
females
(
31.2­
120.3
mg/
kg/
day).
The
NOAEL
is
200
ppm
for
F
0
and
F
1
females
(
11.8­
29.0
mg/
kg/
day).
No
effects
were
noted
in
the
males
[
NOAEL

800
ppm
for
F
0
and
F
1
males
(
35.5­
115.7
mg/
kg/
day)].

Carcinogenicity/
Mutagenicity:
Dimethipin
has
been
classified
as
a
Group
C
(
possible
human)
carcinogen
by
the
HED
Cancer
Peer
Review
Committee.
The
classification
was
based
on
evidence
of
lung
adenomas
and
carcinomas
in
male
CD­
1
mouse.
The
Committee
concluded
that
the
original
rat
study
was
not
conducted
at
a
high
enough
dose
and
recommended
that
a
new
study
be
conducted.
The
results
of
the
new
study
indicated
no
evidence
of
carcinogenicity
in
the
rat.
Calculation
of
a
q1*
was
not
recommended
for
dimethipin.

Dimethipin
was
negative
in
a
mammalian
cytogenetic
assay
(
chromosome
aberration
in
Chinese
hamster
ovary
CHO
cells),
in
two
mouse
micronucleus
studies,
in
an
unscheduled
DNA
synthesis
assay
in
rat
hepatocytes,
in
a
bacterial
(
Salmonella
typhimurium/
E.
coli)
gene
mutation
assay,
and
in
a
sister
chromatid
exchange
assay
in
Chinese
hamster
ovary
CHO
cells.

Subchronic
and
chronic
toxicity
data
for
dimethipin
are
summarized
in
Table
4.1b.

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)
43065901
(
1993)

Acceptable/
guideline
0,
40,
1750,
or
3500
ppm
M:
0,
2.5,
108,
and
220
mg/
kg/
d
F:
0,
3.1,
131,
and
260
mg/
kg/
d
NOAEL
=
3.1
mg/
kg/
day
(

)
;
220
mg/
kg/
day
(

)

LOAEL
=
131
mg/
kg/
day
(

)
,
based
on
decreased
body
weight
and
body
weight
gain.
LOAEL
(

)
not
identified.
Table
4.1b
Subchronic,
Chronic
and
Other
Toxicity
Profile
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
19
870.3200
21/
28­
Day
dermal
toxicity
(
rat)
41944901
(
1991)

Acceptable/
Guideline
0,
10,
100,
or
1000
mg/
kg
bw/
day
systemic
NOAEL
=
1000
mg/
kg/
day
systemic
LOAEL
=
not
identified
870.3700a
Prenatal
developmental
in
Rat
93089032;
93089009
(
1990)

Unacceptable/
Guideline
(
Upgradable)

0,
30,
80,
or
160
mg/
kg
bw/
day
Maternal
NOAEL
=
30
mg/
kg/
day
LOAEL
=
80
mg/
kg/
day
based
on
decreased
maternal
body
weight
gain..

Developmental
NOAEL
=
160
mg/
kg/
day
LOAEL
=
Not
Identified.

870.3700b
Prenatal
developmental
in
Rabbit
93089033
(
1981),
93089010
(
1990),
44988701
(
1999)

Unacceptable/
Guideline
(
Upgradable)

0,
7.5,
20,
or
40
mg/
kg
bw/
day
Maternal
NOAEL
=
20
mg/
kg/
day
LOAEL
=
40
mg/
kg/
day
based
on
decreased
body
weight
gain..

Developmental
NOAEL
=
40
mg/
kg/
day
870.3800
Reproduction
and
fertility
effects
(
Rat)
93089034
(
1982),
93089011
(
1990)

Acceptable/
Guideline
0,
50,
200,
or
800
ppm
Parental/
Systemic
NOAEL
=
200
ppm
for
F0
and
F1
females
(
11.8­
29.0
mg/
kg/
day)
and

800
ppm
for
F0
and
F1
males
(
35.5­
115.7
mg/
kg/
day).

LOAEL
=
800
ppm
for
F0
and
F1
females
(
31.2­
120.3
mg/
kg/
day)
based
on
decreased
body
weights
and
body
weight
gains
and
was
not
identified
for
males.

Offspring
NOAEL
=
200
ppm
(
9.2­
28.7
mg/
kg/
day
for
males
and
11.8­
29.0
mg/
kg/
day
for
females).

LOAEL
=
800
ppm
(
35.5­
115.7
mg/
kg/
day
for
males
and
31.2­
120.3
mg/
kg/
day
for
females)
based
on
decreased
body
weights
and/
or
body
weight
gains
by
the
F1a,
F2a,
and
F2b
pups.
Table
4.1b
Subchronic,
Chronic
and
Other
Toxicity
Profile
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
20
870.4100b
Chronic
toxicity
(
dog)
93089030
(
1990),
93089008
(
1981)

Unacceptable/
Guideline
(
Upgradable)

0,
100,
300,
or
3000
ppm
M:
0,
8.92,
29.85,
and
98.98
mg/
kg
bw/
day
F:
0,
10.33,
34.42,
and
92.87
mg/
kg
bw/
day
for
females
NOAEL
=
29.85
mg/
kg/
day
(

)
;
34.42
mg/
kg/
day
(

)

LOAEL
=
98.98
mg/
kg/
day
(

)
;
92.87
mg/
kg/
day
(

)
,
based
on
decreased
body
weight
gain,
reduced
food
consumption
and
negative
food
efficiency.

870.4200
Carcinogenicity
(
rat)
43897601
(
1996)

Acceptable/
Guideline
M:
0,
40,
1750,
or
3500
ppm
(
0,
1.75,
77.6,
or
161
mg/
kg/
day)

F:
0,
40,
875,
or
1750
ppm
(
0,
2.18,
50.3,
or
103
mg/
kg/
day)
NOAEL
=
1.75
mg/
kg/
day
(

)
;
2.18
mg/
kg/
day
(

)

LOAEL
=
77.6
mg/
kg/
day
(

)
;
50.3
mg/
kg/
day
(

)
,
based
on
toxicity
in
the
kidney,
lungs,
duodenum,
and
testes
of
male
rats
and
depressed
body
weight
gain
and
toxicity
in
the
liver,
kidney,
glandular
stomach,
heart,
and
aortic
artery
of
female
rats.

No
evidence
of
carcinogenicity.

870.4300
Carcinogenicity
(
mouse)
93089031
(
1981),
93089008
(
1990)

Acceptable/
Guideline
0,
80,
400,
or
2000
ppm
M:
0,
11.3,
56,
or
286
mg/
kg
bw/
day
F:
0,
13.3,
68,
or
341
mg/
kg
bw/
day
NOAEL
=
56
mg/
kg/
day
(

)
;
341
mg/
kg/
day
(

)

LOAEL
=
286
mg/
kg/
day
(

)
,
based
on
increased
mononuclear
inflammatory
cell
foci
in
the
trachea,
decreased
body
weight
gain,
and
decreased
food
efficiency;
LOAEL
not
identified
in
females.

Carcinogenicity
­
Marginally
significant
(
p<
0.044)
increase
in
the
incidences
of
lung
carcinomas
and
adenomas
combined
compared
to
the
control
group
and
a
significant
positive
trend
for
lung
adenomas
in
male
mice.
Table
4.1b
Subchronic,
Chronic
and
Other
Toxicity
Profile
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
21
Gene
Mutation:
In
vitro
sister
chromatid
exchange
(
SCE)
assay
in
Chinese
hamster
ovary
CHO
cells
870.5900
3089036
(
1981)

93089015
(
1990)

42282705
(
1992)

Acceptable/
Guideline
0,
3.1,
9.3,
27.8,
83.3,
250.0
or
750.0
µ
g/
mL
with
metabolic
activation
(
S9­
mix):
0,
1.56,
3.13,
6.25,
12.50,
25.00
or
50.00
µ
g/
mL
without
S9­
mix.
There
was
no
evidence
of
SCE
induction
over
background.

Gene
Mutation:
In
vitro
Bacterial
Gene
Mutation
(
Bacterial
system,
Salmonella
typhimurium;
E.
coli)/
mammalian
activation
gene
mutation
assay
870.5100
93089035
(
1990)

93089012
(
1990)

Acceptable/
Guideline
0,
1,
10,
100,
500,
1000,
2500,
5000
or
10,000
µ
g/
plate
in
the
presence
and
absence
of
mammalian
metabolic
activation
(
S9­
mix)
There
was
no
evidence
of
induced
mutant
colonies
over
background.

Gene
Mutation:
In
Vitro
Mammalian
Cells
in
Culture
Gene
Mutation
assay
in
L5178Y
mouse
lymphoma
cells
870.5300
93089041
(
1981)

93089029
(
1990)

Unacceptable/
Guideline
0,
1.56,
12.5,
25.0,
50.0
or
75.0
µ
g/
mL
without
metabolic
activation
(
S9­
mix);
and
0,
12.5,
50.0,
75.0,
100.0
or
150.0
µ
g/
mL
with
S9­
mix.
In
the
second
assay,
0,
25.0,
50.0,
75.0,
100.0,
150.0
or
200.0
µ
g/
mL
with
S9­
mix
only
There
was
an
indication
of
mutant
induction
in
the
presence
of
S9­
mix
but
only
at
very
cytotoxic
doses
of
Harvade
(
N252).

Cytogenetics:
In
vivo
Mammalian
Cytogenetics
­
Micronucleus
Assay
870.5395
40479602
(
1984)

93089014
(
1990)

Acceptable/
Guideline
M:
0,
22.0,
73.3
or
220.0
mg/
kg
F:
0,
30,
100
or
300
mg/
kg
There
was
no
statistically
significant
increase
in
the
frequency
of
micronucleated
polychromatic
erythrocytes
in
bone
marrow
from
either
sex
at
any
dose.
Table
4.1b
Subchronic,
Chronic
and
Other
Toxicity
Profile
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
22
Cytogenetics:
In
Vivo
Mammalian
Cytogenetics
­
Erythrocyte
Micronucleus
assay
in
mice
870.5395
41708201
(
1986)

Acceptable/
Guideline
0
or
220
mg/
kg
There
was
no
statistically
significant
increase
in
the
frequency
of
micronucleated
polychromatic
erythrocytes
in
mouse
bone
marrow
at
any
harvest
time.

Other
Genotoxicity:
Unscheduled
DNA
Synthesis
in
Rat
Hepatocytes/
Mam
malian
Cells
­
in
vivo/
in
vitro
Procedure
870.5550
40479601
(
1987)

93089016
(
1990)

Acceptable/
Guideline
0,
100,
300
or
1000
mg/
kg
There
was
no
evidence
that
Harvade
increased
the
incidence
of
UDS
over
the
solvent
control
values
indicating
no
induction
of
DNA
damage.

870.6200a
Acute
neurotoxicity
screening
battery
Not
available
N/
A
870.6200b
Subchronic
neurotoxicity
screening
battery
Not
available
N/
A
Table
4.1b
Subchronic,
Chronic
and
Other
Toxicity
Profile
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
23
870.7485
Metabolism
and
pharmacokinetics
(
species)
41323301
(
1987),
41323302
(
1987),
41612401
(
1989),
93089017
(
1990),
and
93089018
(
1990),

Unacceptable/
Guideline
A
series
of
metabolism
studies
indicated
that
dimethipin
is
absorbed
from
the
gastrointestinal
tract.
Following
a
single
low
oral
dose,
~
59­~
66%
of
the
administered
dose
was
absorbed
in
male
and
female
rats,
respectively.
With
single
or
multiple
high
doses,
absorption
decreased
significantly
(~
37%
for
male
and
59%
for
females),
suggesting
absorption
was
rate­
limited.
Highest
levels
of
radioactivity
after
administration
of
radiolabeled
dimethipin
were
detected
in
the
gastrointestinal
tract,
liver,
kidneys
and
red
blood
cells.
Following
treatment,
~
57%
of
a
single
low­
dose
in
males
and
~
63%
in
females
was
recovered
in
the
urine
48­
96
hours
after
treatment
while
~
28%
of
the
dose
was
recovered
in
the
feces
of
these
rats.
Following
single
or
multiple
high
doses,
approximately
33%
of
the
dose
was
recovered
in
the
urine
of
male
rats
and
~
45%
in
the
urine
of
female
rats
48­
96
hours
after
dosing.

Of
that
amount
of
radiolabel
recovered
in
the
urine,
~
77%
was
composed
of
three
metabolites
identified
as
R­
4,
R­
5,
and
R­
6.
These
were
identified
as
a
cysteinylglycine
conjugate
of
the
parent
compound,
as
an
N­
acetylcysteinyl
conjugate
derived
from
cysteinylglycine
conjugate,
and
a
reductive
product
of
dimethipin
(
1,1,4,4­
tetraoxide,
2,3­
dimethyldithiane).
Also
identified
in
the
urine
were
polar
metabolites
which
were
not
further
characterized.
No
studies
were
conducted
to
identify
metabolites
in
the
feces
or
bile,
or
whether
radiolabel
was
eliminated
in
the
expired
air.

4.2
FQPA
Hazard
Considerations
4.2.1
Adequacy
of
the
Toxicity
Data
Base
The
toxicology
database
is
adequate
for
the
evaluation
of
risks
to
infants
and
children.
Relevant
studies
include
developmental
toxicity
studies
in
the
rat
and
rabbit
and
a
2­
generation
reproductive
toxicity
study
in
the
rat.
24
25
4.2.2
Evidence
of
Neurotoxicity
No
neurobehavioral
alterations
or
evidence
of
neuropathological
effects
were
observed
in
the
available
studies.

4.2.3
Developmental
Toxicity
Studies
Developmental
Rat
Study
EXECUTIVE
SUMMARY:
In
a
developmental
toxicity
study
(
MRID
93089032;
93089009),
N252
Technical
(
99.2%
a.
i.,
Lot
#
D10370)
in
corn
oil
was
administered
to
groups
of
at
least
25
BLU:(
SD)
BR
(
Sprague­
Dawley)
rats/
dose
by
gavage
at
dose
levels
of
0,
80,
400,
or
800
mg/
kg
bw/
day
from
days
6
through
15
of
gestation.
A
positive
control
group
of
29
rats
was
administered
250
mg/
kg
bw/
day
aspirin
from
gestation
days
(
GD)
6­
15.
Because
of
excessive
deaths
of
the
dams,
the
dose
levels
of
400
and
800
mg/
kg/
day
N252
Technical
were
terminated,
and
the
dose
groups
of
30
and
160
mg/
kg/
day
were
added.
Therefore,
the
test
groups
were
as
follows:
groups
of
28,
25,
25,
or
26
SD
rats
were
administered
N252
Technical
by
gavage
at
dose
levels
of
0,
30,
80,
or
160
mg/
kg
bw/
day,
respectively,
from
days
6
through
15
of
gestation.
On
GD
20,
all
dams
were
sacrificed,
subjected
to
gross
necropsy,
and
all
fetuses
examined
externally.
The
total
numbers
of
fetuses
examined
(
number
of
litters)
were
262
(
21),
243
(
22),
261
(
22),
and
243
(
22),
for
the
0,
30,
80,
160
mg/
kg
bw/
day
groups,
respectively,
and
196
(
19)
for
the
250
mg/
kg/
day
aspirin
group.
Approximately
one­
third
of
the
fetuses
were
examined
viscerally,
and
the
other
two­
thirds
of
the
fetuses
were
examined
for
skeletal
malformations/
variations.

At
the
discontinued
dose
levels
of
400
and
800
mg/
kg/
day,
maternal
toxicity
consisted
of
urine
seepage,
bloody
vaginal
discharge,
decreased
activity,
weight
loss,
and
death.

No
treatment­
related
deaths
or
clinical
signs
were
observed
in
dams
in
the
0,
30,
80,
or
160
mg/
kg/
day
groups.
The
30
and
160
mg/
kg/
day
dose­
groups
exhibited
statistically
decreased
mean
absolute
body
weights
throughout
the
study,
including
GD
0
(
90
and
93%
of
controls,
respectively;
p<
0.05
as
analyzed
by
the
reviewer
using
ANOVA
followed
by
Dunnet's
test).
These
lower
mean
absolute
body
weights
suggest
that
these
animals
were
younger
than
the
original
animals
used
at
study
initiation.
The
80
and
160
mg/
kg/
day
dose
groups
did
have
biologically
significant
decreases
in
mean
body
weight
gains
over
the
treatment
interval
of
GD
6­
15
(
77
and
71%
of
controls,
respectively;
statistical
analysis
not
conducted).
Body
weight
gains
during
the
post­
dosing
interval
of
GD
15­
20
were
comparable
to
controls.

Food
consumption
values
were
not
recorded,
and
no
gross
pathological
findings
were
noted
during
the
limited
gross
necropsy
of
treated
dams.

The
maternal
LOAEL
is
80
mg/
kg
bw/
day
based
on
decreased
maternal
body
weight
gain
during
the
dosing
interval.
The
maternal
NOAEL
is
30
mg/
kg
bw/
day.
26
No
definitive
N252
Technical­
related
effects
on
pregnancy
rates,
number
of
corpora
lutea,
pre­
or
postimplantation
losses,
resorptions/
dam,
fetuses/
litter,
fetal
body
weights,
or
fetal
sex
ratios
were
observed
in
the
treated
groups
as
compared
with
the
controls.

No
N252
Technical­
related
external,
visceral,
or
skeletal
malformations/
variations
were
observed.
The
developmental
NOAEL
is

160
mg/
kg
bw/
day,
and
a
developmental
LOAEL
could
not
be
established.

The
study
is
classified
Unacceptable/
Guideline
(
upgradable),
and
does
not
satisfy
the
guideline
requirement
for
a
developmental
toxicity
study
(
OPPTS
870.3700;
OECD
414)
in
the
rat
because
data
on
test
material
stability,
homogeneity,
and
concentration
in
the
dosing
medium
were
not
provided.
This
study
may
be
upgraded
and
found
to
be
acceptable
if
the
missing
data
are
obtained.

Developmental
Rabbit
Study
EXECUTIVE
SUMMARY:
In
a
developmental
toxicity
study
(
MRID
93089033)
N252
technical
(
98.3%
a.
i.,
batch/
lot
#
D10894)
was
administered
to
16
female
Dutch
belted
rabbits/
dose
by
gavage
at
dose
levels
of
0,
7.5,
20,
or
40
mg/
kg
bw/
day
from
days
6
through
27
of
gestation.
Additional
information
on
test
article
identity
was
provided
in
MRID
93089010.
Historical
control
data
(
MRID
44988701)
from
36
studies
conducted
between
1977­
1983
included
observations
from
uterine
examination;
results
were
given
as
percent
of
fetuses
and
litters
affected.
On
GD
28,
all
surviving
does
were
sacrificed
and
examined
grossly.
Each
fetus
was
weighed
and
examined
for
external
abnormalities.
Fetuses
were
examined
viscerally,
including
sex
determination.
The
brain
was
examined
by
a
mid­
coronal
slice,
and
the
heart
was
dissected
by
a
modification
of
the
Staples
method.
The
eviscerated,
skinned
carcasses
were
processed
for
skeletal
examination.

All
animals
survived
to
GD
28.
One
doe
in
each
of
the
control,
mid­,
and
high­
dose
groups
aborted
on
or
prior
to
termination
on
GD
28
and
was
sacrificed.
No
treatment­
related
clinical
signs
of
toxicity
were
observed
in
any
animal
and
gross
necropsy
was
unremarkable.
No
differences
in
absolute
body
weights
were
found
between
the
treated
and
control
groups
at
any
time
during
the
study.
However,
weight
gain
by
the
high­
dose
group
was
less
than
that
of
the
controls
throughout
the
treatment
interval.
The
high­
dose
group
had
a
mean
weight
loss
after
the
initiation
of
dosing
(
GD
6­
12)
and
an
overall
weight
gain
for
the
treatment
interval
only
2%
of
the
control
level.

Therefore,
the
maternal
toxicity
LOAEL
for
N252
in
rabbits
is
40
mg/
kg/
day
based
on
decreased
body
weight
gain
and
the
maternal
toxicity
NOAEL
is
20
mg/
kg/
day.

No
statistically
significant
differences
were
noted
between
the
treated
and
control
groups
for
numbers
of
corpora
lutea,
implantations,
live
fetuses,
or
resorptions,
fetal
sex
ratios,
or
pre­
or
post­
implantation
losses.
Fetal
body
weights
were
similar
between
the
treated
and
control
27
groups.
No
dose­
or
treatment­
related
external
or
visceral
malformations/
variations
were
observed
in
any
fetus
from
any
group.
The
slight
increase
in
the
incidence
of
scoliosis
was
not
considered
treatment­
related
based
on
historical
control
data.

Therefore,
the
developmental
toxicity
NOAEL
for
N252
in
rabbits
is
40
mg/
kg/
day.

The
developmental
toxicity
study
in
the
rabbit
is
classified
Unacceptable/
Guideline
(
upgradable)
and
does
not
satisfy
the
guideline
requirements
for
a
developmental
toxicity
study
(
OPPTS
870.3700;
OECD
414)
in
rabbits.
The
dosing
solutions
were
not
analyzed
for
homogeneity,
stability,
or
concentration.
These
data
may
have
been
submitted
separately,
but
were
not
available
to
the
reviewer.

4.2.4
Reproductive
Toxicity
Study
EXECUTIVE
SUMMARY:
In
a
two­
generation
reproduction
study
(
MRID
93089034),
N252
(
Dimethipin;
99.7%
a.
i.,
lot
#
D10894)
was
administered
to
15
male
and
25
female
CD
®
(
SD)
BR
rats/
dose
in
the
diet
at
concentrations
of
0,
50,
200,
or
800
ppm.
Additional
information
on
test
article
identity
was
provided
in
MRID
93089011.
Two
litters
were
produced
in
each
generation;
F
1
animals
were
randomly
selected
from
the
B
litters.
The
animals
were
mated
1:
2
(
male:
female)
within
dose
groups.
Premating
compound
intake
(
mean
values)
for
the
treated
F
0
parental
animals
were
2.5­
7.7,
9.4­
28.7,
and
39.4­
115.7
mg/
kg/
day,
respectively,
for
males
and
3.1­
7.4,
12.7­
29.0,
and
51.1­
120.3
mg/
kg/
day,
respectively,
for
females.
Premating
doses
for
the
treated
F
1
parental
animals
were
2.4­
6.1,
9.2­
24.8,
and
35.5­
96.0
mg/
kg/
day,
respectively,
for
males
and
3.0­
5.9,
11.8­
24.9,
and
31.2­
96.4
mg/
kg/
day,
respectively,
for
females.
F
0
and
F
1
parental
animals
were
administered
test
or
control
diet
for
15
or
17
weeks,
respectively,
prior
to
mating,
throughout
mating,
gestation,
and
lactation
of
two
litters,
and
until
sacrifice.

No
treatment­
related
deaths,
clinical
signs
of
toxicity,
or
gross
or
microscopic
lesions
were
observed
in
any
animal
during
the
study.
No
effects
on
body
weights,
body
weight
gains,
or
food
consumption
were
observed
in
the
low­
and
mid­
dose
groups
of
either
generation.

Body
weights
and
body
weight
gains
of
the
high­
dose
F
0
and
F
1
females
were
significantly
(
p

0.05
or
0.01)
less
than
those
of
the
controls
during
premating.
Absolute
body
weights
for
the
F
0
females
were
91­
93%
of
controls
during
weeks
9­
15
and
for
the
F
1
females
were
89­
94%
of
controls
during
weeks
7­
17.
Weekly
body
weight
gains
for
the
F
0
females
were
not
affected
by
treatment,
however,
overall
premating
weight
gain
by
the
high­
dose
group
was
89%
of
the
control
group
level.
Body
weight
gains
for
the
F
1
animals
were
less
than
control
levels
for
weeks
2,
4,
and
11
with
overall
premating
weight
gain
by
the
high­
dose
group
80%
of
the
control
group
level.
The
lower
absolute
body
weights
for
high­
dose
females
of
both
generations
continued
into
gestation
and
lactation
of
both
litters.
Food
consumption
by
the
high­
dose
F
0
females
was
significantly
(
92­
94%
of
controls;
p

0.05
or
0.01)
less
than
that
of
the
controls
for
premating
weeks
6
and
8­
10.
Food
consumption
by
the
high­
dose
F
1
females
was
significantly
(
p

0.05
or
0.01)
less
than
that
of
the
controls
for
premating
weeks
6­
9
(
91­
94%
of
controls),
11­
15
(
89­
91%
of
controls),
and
17
(
54%
of
controls).
The
parental
systemic
LOAEL
is
800
ppm
for
F0
and
28
F1
females
(
31.2­
120.3
mg/
kg/
day)
based
on
decreased
body
weights
and
body
weight
gains
and
was
not
identified
for
males.
The
parental
systemic
NOAEL
is
200
ppm
for
F0
and
F1
females
(
11.8­
29.0
mg/
kg/
day)
and

800
ppm
for
F0
and
F1
males
(
35.5­
115.7
mg/
kg/
day).

No
treatment­
related
differences
in
mating,
fertility,
or
gestation
indices
were
seen
between
the
treated
and
control
groups
of
either
generation
during
the
production
of
both
litters.
The
precoital
interval
and
the
gestation
length
of
the
treated
groups
were
comparable
to
the
control
groups
during
the
production
of
both
litters
in
both
generations.
The
reproductive
toxicity
NOAEL
for
males
and
females
is

800
ppm
(
35.5­
115.7
and
31.2­
120.3
mg/
kg/
day,
respectively)
and
the
reproductive
toxicity
LOAEL
was
not
identified.

For
the
A
and
B
litters
of
the
F
1
and
F
2
generations,
live
birth
and
viability
indices,
mean
litter
sizes,
sex
ratios,
and
frequency
and
type
of
clinical
signs
were
similar
between
the
treated
and
control
groups.
Absolute
body
weights
of
all
low­
and
mid­
dose
pups
and
high­
dose
F
1b
and
F
2a
pups
were
not
affected
by
treatment.
High­
dose
F
1a
pups
had
significantly
(
p

0.01)
lower
body
weights
on
lactation
days
14
and
21
compared
with
the
controls
as
a
result
of
weight
gains
79­
84%
of
the
control
group
levels
during
lactations
days
4­
21.
Body
weight
gains
of
the
high­
dose
F
2a
pups
were
83%
of
controls
(
p

0.05)
for
lactation
days
14­
21.
Body
weight
of
the
high­
dose
F
2b
pups
were
significantly
(
84­
86%;
p

0.05)
less
than
those
of
the
controls
on
lactation
days
4­
14
due
to
a
weight
gain
of
75%
(
p

0.01)
of
the
control
level
on
day
4.
No
dose­
or
treatmentrelated
differences
were
seen
in
organ
weights
or
gross
or
microscopic
lesions
between
treated
and
control
weanlings
of
either
generation.
The
offspring
toxicity
LOAEL
is
800
ppm
(
35.5­
115.7
mg/
kg/
day
for
males
and
31.2­
120.3
mg/
kg/
day
for
females)
based
on
decreased
body
weights
and/
or
body
weight
gains
by
the
F1a,
F2a,
and
F2b
pups.
The
offspring
toxicity
NOAEL
is
200
ppm
(
9.2­
28.7
mg/
kg/
day
for
males
and
11.8­
29.0
mg/
kg/
day
for
females).

This
study
is
Acceptable/
Guideline
and
satisfies
the
guideline
requirement
for
a
two­
generation
reproduction
study
(
OPPTS
870.3800;
OECD
416)
in
rats.

4.2.5
Additional
Information
from
Literature
Sources
No
additional
information
was
identified
from
literature
sources.

4.2.6
Pre­
and/
or
Postnatal
Toxicity
4.2.6.1
Determination
of
Susceptibility
There
is
no
indication
of
increased
susceptibility
of
fetuses
or
offspring
in
the
developmental
and
reproduction
studies.
29
4.2.6.2
Degree
of
Concern
Analysis
and
Residual
Uncertainties
for
Pre
and/
or
Post­
natal
Susceptibility
There
is
no
degree
of
concern
and
there
are
no
residual
uncertainties.
Although
the
developmental
toxicity
studies
are
unacceptable
(
upgradable
pending
receipt
of
absent
data
on
homogeneity,
stability,
and
concentration),
the
missing
data
will
not
impact
the
conclusions
of
the
studies.
No
quantitative
or
qualitative
sensitivity
was
observed
in
the
rat
and
rabbit
developmental
studies
or
in
the
2­
generation
reproduction
study
in
the
rat.
Based
on
the
lack
of
evidence
of
pre­
and/
or
postnatal
susceptibility
resulting
following
exposure
to
dimethipin,
and
considering
the
lack
of
residual
uncertainties
for
pre­
and/
or
postnatal
toxicity,
no
special
FQPA
safety
factor
is
needed
(
i.
e.,
1X).
There
is
no
concern
for
developmental
neurotoxicity
resulting
from
exposure
to
dimethipin.

4.3
Recommendation
for
a
Developmental
Neurotoxicity
Study
4.3.1
Evidence
that
supports
requiring
a
Developmental
Neurotoxicity
study
There
was
no
evidence
of
developmental
toxicity
in
the
developmental
toxicity
studies
in
the
rat
and
rabbit.
No
neurobehavioral
alterations
or
evidence
of
neuropathological
effects
were
observed
in
the
available
studies.

4.3.2
Evidence
that
supports
not
requiring
a
Developmental
Neurotoxicity
study
None.

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

Not
applicable.
A
Developmental
Neurotoxicity
study
is
not
recommended.

4.4
Hazard
Identification
and
Toxicity
Endpoint
Selection
4.4.1
Acute
Reference
Dose
(
aRfD)
­
Females
age
13­
49
An
endpoint
attributable
to
a
single
exposure
was
not
identified
from
the
available
database.

4.4.2
Acute
Reference
Dose
(
aRfD)
­
General
Population
30
An
endpoint
attributable
to
a
single
exposure
was
not
identified
from
the
available
database.

4.4.3
Chronic
Reference
Dose
(
cRfD)

The
chronic
reference
dose
(
cRfD)
for
the
general
population
was
selected
from
a
combined
chronic
toxicity/
carcinogenicity
feeding
study
in
the
rat.
The
proposed
study
is
suitable
for
a
chronic
exposure
duration.
The
endpoint
was
based
on
toxicity
in
the
kidney,
lungs,
duodenum,
and
testes
of
male
rats
and
depressed
body
weight
gain
and
toxicity
in
the
liver,
kidney,
glandular
stomach,
heart,
and
aortic
artery
of
female
rats.
The
LOAEL
in
males
is
77.6
mg/
kg/
day
and
the
LOAEL
in
females
is
50.3
mg/
kg/
day.
The
NOAEL
in
males
is
1.75
mg/
kg/
day
and
the
NOAEL
in
females
is
2.18
mg/
kg/
day.
The
chronic
RfD
was
derived
from
the
NOAEL
of
2.18
mg/
kg/
day
in
females.
Application
of
an
uncertainty
factor
of
100
results
in
a
chronic
RfD
of
0.0218
mg/
kg/
day.

EXECUTIVE
SUMMARY:
In
a
chronic
toxicity
study
(
MRID
43897601),
Harvade
®
Technical
(
98.5%
a.
i.)
was
administered
in
the
diet
to
60
male
rats
(
Crl:
CD
®
BR/
VAF/
Plus)
at
concentrations
of
0,
40,
1750,
or
3500
ppm
(
0,
1.75,
77.6,
or
161
mg/
kg/
day)
and
60
female
rats
at
concentrations
of
0,
40,
875,
or
1750
ppm
(
0,
2.18,
50.3,
or
103
mg/
kg/
day)
for
104
weeks.
Ten
animals
per
sex
per
dose
were
killed
at
12
months
for
interim
evaluations.

Treatment
related
(
statistically
significant
(
p<
0.05
or
<
0.01),
biologically
significant,
and
doserelated
effects
occurred
in
the
liver,
kidney,
lungs,
and
gastrointestinal
tract
at
the
mid­
and
highdose
levels
for
male
(
1750
and
3500
ppm)
and
female
rats
(
875
and
1750
ppm).
Effects
were
seen
also
in
the
cardiovascular
system
and
brain
of
females
and
in
the
reproductive
organs
of
males
receiving
the
mid
and
high
doses.
High­
dose
male
rats
weighed
up
to
14%
less
than
controls
up
to
week
102
of
the
study
and
20%
less
at
week
104;
mid­
dose
females
weighed
up
to16%
less
than
controls
and
the
high­
dose
females
weighed
up
to19%
less
than
controls
during
the
study.
Body
weight
gain
was
depressed
by
24%
in
the
high­
dose
male
group
and
by
13
and
29%
in
the
mid­
and
high­
dose
female
groups
overall
compared
with
controls.
There
was
no
accompanying
decrease
in
food
consumption.
Liver
toxicity
was
indicated
by
increased
incidences
of
bile
duct
cysts
in
the
high­
dose
male
and
female
groups,
bile
duct
hyperplasia
in
the
mid­
and
high­
dose
female
groups,
eosinophilic
altered
foci
in
the
high­
dose
male
group,
and
elevated
serum
cholesterol
levels
in
males.
Chronic
progressive
nephropathy
was
exacerbated
in
mid­
and
high­
dose
rats
of
both
sexes
as
evidenced
by
increased
incidence
and
severity
of
the
lesion.
The
mean
absolute
kidney
weight
was
elevated
in
high­
dose
male
rats.
Toxicity
in
the
gastrointestinal
tract
was
manifested
by
elevated
incidences
and
severity
of
epithelial
hyperplasia
in
the
nonglandular
stomach
in
high­
dose
male
rats,
mineralization
in
the
glandular
stomach
of
mid­
and
high­
dose
female
rats,
epithelial
hyperplasia
of
the
duodenum
in
mid­
and
high­
dose
males
and
high­
dose
females,
and
crypt
abscesses
in
the
duodenum
of
mid­
and
high­
dose
male
rats.
In
addition
testicular
lesions
occurred
in
male
rats
fed
the
mid
and
high­
doses,
and
epididymal
hypospermia
occurred
in
high­
dose
males.
Effects
occurring
only
in
females
included
cardiovascular
toxicity
(
mineralization
of
the
heart
and
aortic
artery
(
mid
and
high
doses))
and
brain
degeneration
(
high­
doses).
No
treatment­
related
clinical
signs
of
toxicity,
ophthalmic
effects,
hematologic
effects,
or
changes
in
urinalysis
parameters
occurred
in
male
or
females
rats
31
fed
the
test
material.
There
were
no
treatment­
related
effects
in
male
or
female
rats
fed
40
ppm
of
the
test
material.

The
LOAEL
is
1750
ppm
(
77.6
mg/
kg/
day)
for
males
and
875
ppm
(
50.3
mg/
kg/
day)
for
females,
based
on
toxicity
in
the
kidney,
lungs,
duodenum,
and
testes
of
male
rats
and
depressed
body
weight
gain
and
toxicity
in
the
liver,
kidney,
glandular
stomach,
heart,
and
aortic
artery
of
female
rats.
The
corresponding
NOAEL
is
40
ppm
(
1.75
and
2.18
mg/
kg/
day,
respectively)
for
male
and
female
rats.

There
was
no
evidence
of
potential
carcinogenicity
of
the
test
material
in
this
study.
No
neoplastic
lesions
showed
increased
incidences
that
were
significantly
different
from
the
incidences
observed
in
control
animals.
The
doses
were
adequate
for
testing
carcinogenicity
based
on
treatment­
related
toxicity
seen
in
the
mid­
and
high­
dose
groups.

This
study
is
classified
as
acceptable
and
it
satisfies
the
guideline
requirements
for
a
combined
chronic
toxicity/
oncogenicity
study
(
§
83­
5).
There
were
no
noteworthy
deficiencies
in
this
study.

Uncertainty
Factor(
s):
100
(
10X
for
intraspecies
variation,
10X
for
interspecies
extrapolation).

Comments
about
Study/
Endpoint/
Uncertainty
Factor:
This
endpoint
is
of
the
appropriate
route
and
duration
of
exposure
and
applies
to
the
population
of
concern.

4.4.4
Incidental
Oral
Exposure
(
Short
and
Intermediate
Term)

Incidental
oral
endpoints
were
not
selected
since
there
are
no
residential
uses.

4.4.5
Dermal
Absorption
No
dermal
absorption
studies
on
dimethipin
are
available.

4.4.6
Dermal
Exposure
(
Short,
Intermediate
and
Long
Term)

Short­
and
Intermediate­
Term
Dermal
Endpoints:
No
hazard
was
identified;
therefore,
no
quantification
is
required.
Systemic
toxicity
was
not
seen
at
the
limit
dose
in
a
dermal
toxicity
study
in
the
rat.
Additionally,
there
are
no
developmental
concerns.

Long­
Term
Dermal
Endpoints:
Based
on
use
pattern,
no
long­
term
dermal
exposure
is
anticipated.

4.4.7
Inhalation
Exposure
(
Short,
Intermediate
and
Long
Term)
32
Short­
Term
Inhalation
Endpoint:
The
short­
term
inhalation
endpoint
was
based
on
the
maternal
NOAEL
of
20
mg/
kg/
day
identified
in
an
oral
developmental
rabbit
study.
The
maternal
LOAEL
of
40
mg/
kg/
day
was
based
on
decreased
body
weight
gain.

Comments
about
Study/
Endpoint:
This
study
was
selected
for
determination
of
the
short­
term
inhalation
endpoint
because
the
duration
of
the
study
is
appropriate
to
a
short­
term
exposure
scenario
and
a
clear
NOAEL
was
identified
for
the
endpoint.

Intermediate­
Term
Inhalation
Endpoint:
The
2­
generation
reproduction
study
in
the
rat
was
used
for
the
selection
of
the
intermediate­
term
inhalation
endpoint,
which
was
based
on
a
parental
systemic
NOAEL
of
11.8
mg/
kg/
day
(
F0
and
F1
females).
The
LOAEL
for
F0
and
F1
females
(
31.2­
120.3
mg/
kg/
day)
was
based
on
decreased
body
weights
and
body
weight
gains.

Comments
about
Study/
Endpoint:
This
study
was
selected
for
determination
of
the
intermediateterm
inhalation
endpoint
because
the
duration
of
the
study
is
appropriate
to
an
intermediate­
term
exposure
scenario
and
a
clear
NOAEL
was
identified
for
the
endpoint.

Long­
Term
Inhalation
Endpoint:
Based
on
use
pattern,
no
long­
term
inhalation
exposure
is
anticipated.

4.4.8
Margins
of
Exposure
The
target
Margins
of
Exposure
(
MOEs)
for
occupational
exposure
risk
assessments
are
as
follows:

Route
of
Exposure
Duration
of
Exposure
Short­
Term
(
1­
30
Days)
Intermediate­
Term
(
1
­
6
Months)
Long­
Term
(>
6
Months)

Dermal
 
 
 
Inhalation
100
100
 
For
occupational
exposure,
short­
term
and
intermediate­
term
inhalation
exposure
risk
assessments,
a
MOE
of
100
is
required.
The
MOE
is
based
on
the
conventional
uncertainty
factor
of
100X
(
10X
for
intraspecies
variation
and
10X
for
interspecies
extrapolation).

There
are
no
residential
uses
at
the
present
time.

4.4.9
Recommendation
for
Aggregate
Exposure
Risk
Assessments
33
In
accordance
with
the
FQPA,
HED
must
consider
and
aggregate
(
add)
pesticide
exposures
and
risks
from
three
major
sources:
food,
drinking
water,
and
residential
exposures.
In
this
case,
since
dimethipin
is
registered
only
for
agricultural
uses,
no
residential
exposures
are
anticipated.
Therefore,
the
aggregate
exposure
risk
assessment
for
dimethipin
considers
only
exposures
and
risks
from
residues
of
dimethipin
in
food
and
drinking
water.

4.4.10
Classification
of
Carcinogenic
Potential
Dimethipin
has
been
classified
as
a
Group
C
(
possible
human)
carcinogen
by
the
Toxicology
Peer
Review
Committee.
The
classification
was
based
on
evidence
of
lung
adenomas
and
carcinomas
in
male
CD­
1
mouse.
The
Committee
concluded
that
the
original
rat
study
was
not
conducted
at
a
high
enough
dose
and
recommended
that
a
new
study
be
conducted.
The
results
of
the
new
study
indicated
no
evidence
of
carcinogenicity
in
the
rat.
Calculation
of
a
q1*
was
not
recommended
for
dimethipin,
based
on
the
weight­
of­
evidence
(
i.
e.,
tumors
at
the
HDT
in
only
one
sex,
strain,
species
and
only
one
experiment;
weak
mutagenicity
of
dimethipin;
and
lack
of
structural
congener
information).

Table
4.4.
Summary
of
Toxicological
Doses
and
Endpoints
for
Chemical
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
(
females
13­
49)
Not
applicable.
Not
applicable.
No
appropriate
acute
endpoint
identified
for
these
groups
(
i.
e.,
no
toxic
effect
attributable
to
a
single
dose
identified).
Acute
Dietary
(
general
population)

Chronic
Dietary
(
all
populations)
NOAEL
=
2.18
mg/
kg/
day
UF
=
100
(
10x
for
intraspecies
variation,
10x
for
interspecies
extrapolation)

Chronic
RfD
=
0.0218
mg/
kg/
day
1X
cPAD
=
0.0218
mg/
kg/
day
(
cRfD/
FQPA
SF
=
cPAD
=
0.0218/
1
=
0.0218)
ChronicToxicity/
Carcinogenicity
Study
in
the
Rat
LOAEL
=
50.3
mg/
kg/
day
,
based
on
toxicity
in
the
kidney,
lungs,
duodenum,
and
testes
of
male
rats
and
depressed
body
weight
gain
and
toxicity
in
the
liver,
kidney,
glandular
stomach,
heart,
and
aortic
artery
of
female
rats.

Incidental
Oral
Short­
Term
(
1
­
30
days)
Not
applicable.
Not
applicable.
Not
required
­
no
residential
uses.
Table
4.4.
Summary
of
Toxicological
Doses
and
Endpoints
for
Chemical
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
34
Incidental
Oral
Intermediate­
Term
(
1
­
6
months)

Dermal
Short­
Term
(
1
­
30
days)
Not
applicable.
Not
applicable.
No
hazard
was
identified;
therefore
no
quantification
is
required.
Systemic
toxicity
not
seen
at
the
limit
dose
in
a
Dermal
Toxicity
Study.
Additionally,
there
are
no
developmental
concerns
and
no
anticipated
residential
exposure.
Residential
Occupational
Dermal
Intermediate­
Term
(
1
­
6
months)

Not
applicable.
Not
applicable.
Not
required
­
no
residential
uses.
Residential
Occupational
Not
applicable.
Not
applicable.
No
hazard
was
identified;
therefore
no
quantification
is
required.
Systemic
toxicity
not
seen
at
the
limit
dose
in
a
Dermal
Toxicity
Study.
Additionally,
there
are
no
developmental
concerns.

Dermal
Long­
Term
(>
6
mos.)
Not
applicable
Not
applicable
No
residential
uses.
Based
on
use
pattern,
no
long
term
occupational
exposure
is
anticipated.
Residential
Occupational
Inhalation
Short­
Term
(
1
­
30
days)
NOAEL
=
20
mg/
kg/
day
1X
LOC:
MOE
=
100
(
10x
for
intraspecies
variation,
10x
for
interspecies
extrapolation)
Developmental
Study
in
the
Rabbit
LOAEL
=
40
mg/
kg/
day,
based
on
decreased
body
weight
gain.

Occupational
Residential
Not
applicable
Not
applicable
Not
required
­
no
residential
uses.
Table
4.4.
Summary
of
Toxicological
Doses
and
Endpoints
for
Chemical
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
35
Inhalation
Intermediate­
Term
(
1
­
6
months)
NOAEL
=
11.8
mg/
kg/
day
1X
LOC:
MOE
=
100
(
10x
for
intraspecies
variation,
10x
for
interspecies
extrapolation)
Two­
generation
reproduction
study
in
the
rat
LOAEL
=
31.2­
120.3
mg/
kg/
day,
based
on
decreased
bodyweight/
bodyweight
gain
in
F0
&
F1
females.
Occupational
Residential
Not
applicable.
Not
applicable.
Not
required
­
no
residential
uses.

Inhalation
Long­
Term
(>
6
months)

Residential
Not
applicable.
Not
applicable.
Not
required
­
no
residential
uses
and
no
long­
term
inhalation
exposure
anticipated.

Occupational
Not
applicable
Not
applicable
Based
on
use
pattern,
no
long
term
occupational
exposure
is
anticipated.

Cancer
(
oral,
dermal,
inhalation)
Classification:
Class
C
­
quantification
not
recommended.

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
*
Refer
to
Section
4.5
4.5
Special
FQPA
Safety
Factor
Based
on
the
above­
discussed
hazard
and
exposure
data,
no
special
FQPA
safety
factor
is
needed
(
i.
e.,
1X)
and
there
are
no
residual
uncertainities
for
pre­
and/
or
post­
natal
toxicity.


The
dietary
food
exposure
assessment
utilizes
tolerance
level
or
higher
residues
and
100%
crop
treated
(
CT)
information
for
all
commodities.
By
using
these
screening­
level
assessments,
chronic
exposures/
risks
will
not
be
underestimated.
36

The
dietary
drinking
water
assessment
(
Tier
1
estimates)
utilizes
values
generated
by
models
and
associated
modeling
parameters
which
are
designed
to
provide
conservative,
health
protective,
high­
end
estimates
of
water
concentrations.

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).

In
the
available
toxicity
studies
on
dimethipin,
there
was
no
estrogen,
androgen,
and/
or
thyroid
mediated
toxicity.
When
additional
appropriate
screening
and/
or
testing
protocols
being
considered
under
the
Agency's
EDSP
have
been
developed,
dimethipin
may
be
subjected
to
further
screening
and/
or
testing
to
better
characterize
effects
related
to
endocrine
disruption.

5.0
Public
Health
Data
5.1
Incident
Reports
According
to
a
review
of
dimethipin
incident
reports
(
Jerome
Blondell,
05/
20/
04,
DP293579),
relatively
few
incidents
of
illness
have
been
reported
due
to
dimethipin.
This
conclusion
is
based
on
information
from
the
following
data
sources:

I.
OPP
Incident
Data
System
(
1992
to
the
present)
:
No
reports
II.
Poison
Control
Center
Data
­
1993
through
2001:
There
was
only
one
report
of
an
exposure
to
dimethipin.
This
occupational
exposure
involved
a
forty­
three
year
old
man
who
ingested
the
product
and
reported
throat
irritation
and
itching.
No
further
information
on
the
disposition
of
the
case
was
reported.

III.
California
Data
­
1982
through
2002:
No
reports
37
IV.
National
Pesticide
Information
Center:
On
the
list
of
the
top
200
chemicals
for
which
NPIC
received
calls
from
1984­
1991,
inclusively,
dimethipin
was
not
reported
to
be
involved
in
human
incidents.

V.
National
Institute
of
Occupational
Safety
and
Health's
Sentinel
Event
Notification
System
for
Occupational
Risks
(
NIOSH
SENSOR)
1998­
2002:
No
reports
VI.
Scientific
Literature:
No
scientific
literature
was
located
concerning
acute
poisoning
due
to
exposure
to
dimethipin.

5.2
Other
Dimethipin
is
not
included
in
the
Agricultural
Health
Survey
(
AHS)
Applicator
questionnaire
and
is
not
on
the
current
National
Health
and
Nutrition
Examination
Survey
(
NHANES)
list.

6.0
Exposure
Characterization/
Assessment
6.1
Dietary
Exposure/
Risk
Pathway
6.1.1
Residue
Profile
The
nature
of
the
residue
in
plants
and
livestock
is
adequately
understood
based
on
metabolism
studies
with
cotton,
goats,
and
hens.
The
residue
of
concern
for
tolerance
enforcement
is
dimethipin
per
se
for
both
plant
and
livestock
commodities.
The
residue
of
concern
for
risk
assessment
is
dimethipin
per
se
for
plant
commodities
and
livestock
commodities
except
liver.
The
residues
of
concern
for
risk
assessment
for
the
liver
of
cattle,
goats,
hogs
and
sheep
are
dimethipin
plus
acetyl
dithiane
tetraoxide.
A
conservative
residue
value
for
liver
for
risk
assessment
purposes
was
calculated
by
multiplying
the
total
amount
of
dimethipin
and
acetyl
dithiane
tetraoxide
(
0.0
ppm
dimethipin
and
0.045
ppm)
found
in
the
liver
in
the
ruminant
metabolism
study
at
1/
2x
the
maximum
theoretical
dietary
burden
(
MTDB)
for
cattle
by
2
(
0.045
ppm
x
2
=
0.09,
rounded
to
0.1ppm).

Tolerances
are
established
under
40
CFR
§
180.406
(
a)
for
residues
of
dimethipin
(
2,3­
dihydro­
5,6­
dimethyl­
1,4­
dithiin
1,1,4,4­
tetraoxide;
CAS
Reg.
No.
55290­
64­
7)
per
se
in/
on
cotton,
undelinted
seed
at
0.5
ppm,
cotton
hulls
at
0.7
ppm,
and
the
fat,
meat,
and
meat
byproducts
of
cattle,
goats,
hogs,
horses,
and
sheep,
each
at
0.02
ppm.
There
are
no
tolerances
established
for
dimethipin
residues
in
poultry
tissues
or
eggs
as
the
Agency
has
concluded
that
there
is
no
reasonable
expectation
of
finite
residues
(
40
CFR
§
180.6(
a)(
3))
of
dimethipin
in
poultry
commodities
based
on
the
current
registered
uses.

Crop
field
trials
conducted
in
several
different
states
indicate
that
residues
of
dimethipin
are
not
likely
to
exceed
the
established
tolerance
of
0.5
ppm
in/
on
cottonseed
when
dimethipin
is
used
38
according
to
label
directions.
Processing
studies
indicate
that
residues
of
dimethipin
do
not
concentrate
in
cottonseed
meal,
hulls,
or
refined
oil.
The
field
trial
and
processing
studies
for
dimethipin
satisfy
the
reregistration
requirements
for
these
magnitude
of
the
residue
studies.

Data
must
be
submitted
for
cotton
gin
byproducts,
a
cattle
feed
item.
In
the
absence
of
data,
HED
assumed
residues
in
gin
byproducts
of
50x
the
cottonseed
tolerance
in
calculating
the
maximum
theoretical
dietary
burden
(
MTDB)
for
cattle.
The
50x
value
is
considered
worst­
case
and
is
based
on
a
comparison
of
established
tolerances
for
cottonseed
and
cotton
gin
byproducts
for
pesticides
where
separate
tolerances
for
cottonseed
and
gin
byproducts
have
been
established.

Feeding
study
data,
reflecting
exaggerated
dosing
levels,
indicate
that
there
is
no
expectation
of
finite
residues
in
the
fat,
meat,
or
meat
byproducts
of
cattle,
goats,
horses,
hogs
or
sheep.
However,
HED
recommends
that
the
tolerances
for
dimethipin
in
livestock
meat
and
meat
byproducts
be
retained
in
order
to
harmonize
with
the
established
Codex
MRLs.
The
U.
S.
tolerances
for
livestock
meat
and
meat
byproducts
and
Codex
MRLs
for
mammalian
meat
and
edible
offal
are
established
at
0.02
ppm,
which
is
at
or
about
the
limit
of
quantitation.
HED
recommends
that
tolerances
for
dimethipin
in
the
fat
of
cattle,
goats,
horses,
hogs
and
sheep
be
revoked
as
there
is
no
expectation
of
finite
residues
in
these
commodities
and
there
are
no
Codex
MRLs
established.
There
is
no
U.
S.
tolerance
for
dimethipin
in
milk.
A
tolerance
for
milk
is
not
required
as
there
is
no
expectation
of
finite
residues
of
dimethipin
in
milk.

Adequate
enforcement
methodology
is
available
to
enforce
dimethipin
tolerances.
PAM
Vol.
II
lists
two
methods,
Method
I
for
cottonseed
and
Method
II
for
livestock
tissues
and
eggs.
The
stated
detection
limits
are
0.1
ppm
for
cottonseed
and
0.02
ppm
for
livestock
commodities.

6.1.2
Chronic
Dietary
Exposure
and
Risk
Reference:
Dimethipin
Chronic
Dietary
Exposure
Assessment
for
the
Reregistration
Eligibility
Decision,
DP
Barcode:
D303935,
Susan
Stanton,
08/
18/
04
A
chronic
dietary
risk
assessment
was
conducted
using
the
Lifeline
Model
Version
2.0
and
the
Dietary
Exposure
Evaluation
Model
(
DEEM­
FCID
 
)
,
Version
2.03,
which
use
food
consumption
data
from
the
USDA's
Continuing
Surveys
of
Food
Intakes
by
Individuals
(
CSFII)
from
1994­
1996
and
1998.
In
this
analysis
the
chronic
dietary
exposure
and
risk
estimates
resulting
from
food
intake
were
determined
for
the
general
U.
S.
population
and
various
population
subgroups.
An
endpoint
of
concern
attributable
to
a
single
dose
was
not
identified
for
dimethipin;
therefore,
an
acute
RfD
was
not
established
and
an
acute
dietary
risk
assessment
was
not
conducted.

The
resulting
food
exposure
estimates
using
the
Lifeline
 
software
were
less
than
1%
of
the
cPAD
for
the
U.
S.
population
and
all
population
subgroups.
Dimethipin
food
exposure
was
estimated
at
0.000042
mg/
kg/
day
for
the
U.
S.
population
(<
1%
of
the
cPAD)
and
0.000083
mg/
kg/
day
(<
1%
39
of
the
cPAD)
for
the
most
highly
exposed
population
subgroup
(
children,
3­
5
years
old).
DEEMFCID
yielded
similar
results.

The
chronic
analysis
assumed
100%
crop
treated,
DEEM
 
(
ver
7.76)
default
processing
factors,
and
tolerance­
level
residues
(
Tier
1)
for
all
commodities,
except
the
liver
of
cattle,
goats,
hogs
and
sheep.

Liver:
The
residues
of
concern
for
risk
assessment
in
liver
are
dimethipin
and
its
metabolite,
acetyl
dithiane
tetraoxide.
A
conservative
residue
value
for
liver
was
calculated
by
multiplying
the
total
amount
of
dimethipin
and
acetyl
dithiane
tetraoxide
(
0.0
ppm
dimethipin
and
0.045
ppm
acetyl
dithiane
tetraoxide)
found
in
the
liver
in
the
ruminant
metabolism
study
at
1/
2x
the
maximum
theoretical
dietary
burden
(
MTDB)
for
cattle
by
2
and
rounding
to
0.1
ppm
(
0.045
ppm
x
2
=
0.09,
rounded
to
0.1ppm).
This
value
is
considered
conservative
because
of
the
worst­
case
assumptions
that
went
into
calculation
of
the
MTDB
for
cattle.
Residue
data
for
the
cattle
feed
item,
cotton
gin
byproducts,
have
not
been
submitted;
however,
it
is
unlikely
that
residues
of
dimethipin
in
cotton
gin
byproducts
would
exceed
residues
in
cotton
seed
by
more
than
a
factor
of
50X.
A
review
of
existing
tolerances
for
13
pesticides
with
both
cotton
seed
and
cotton
gin
byproducts
tolerances
found
a
1X
to
50X
difference
between
cotton
seed
and
cotton
gin
byproducts
tolerances
with
an
average
difference
of
22X.
Based
on
this
information,
the
MTDB
of
dimethipin
to
cattle
was
calculated
assuming
a
worst­
case
estimate
of
residues
of
dimethipin
in/
on
cotton
gin
byproducts
at
25
ppm
(
equivalent
to
50X
the
cotton
seed
tolerance
of
0.5
ppm)
(
Dimethipin,
Residue
Chemistry
Considerations
for
Reregistration
Eligibility
Decision,
Case
No.
3063.
DP
Barcode:
293580,
Danette
Drew,
07/
22/
04).
The
MTDB
of
dimethipin
to
cattle
is
also
considered
conservative,
because
it
assumes
cotton
gin
byproducts
would
comprise
20%
of
the
diet
of
all
beef
and
dairy
cattle.
In
fact,
cotton
gin
byproducts
is
a
relatively
minor
feed
item
of
significance
in
certain
regional
areas
only.
In
most
areas,
cotton
gin
byproducts
would
be
a
minor
contributor
or
non­
contributor
to
the
diet
of
beef
and
dairy
cattle.
This
is
especially
true
for
dimethipin,
since
less
than
5%
of
the
cotton
crop
is
treated.
It
should
be
noted
that
HED
is
currently
reviewing
public
comments
regarding
the
feeding
of
cotton
gin
byproducts
to
livestock
and
may
revise
(
i.
e.,
lower)
its
estimate
of
the
maximum
amount
in
livestock
diets
in
the
future.
40
Table
6.1.
Result
of
Chronic
Dietary
Exposure
and
Risk
Estimates
for
Dimethipin
Population
Subgroupa
cPAD
(
mg/
kg/
day)
Exposure
(
mg/
kg/
day)
b
%
cPAD
Lifeline
DEEMFCID
Lifeline
DEEMFCID
General
U.
S.
Population
0.0218
0
0.00004
<
1.0
<
1.0
All
Infants
(<
1
year
old)
0
0.00002
<
1.0
<
1.0
Children
1­
2
years
old
0.0001
0.00008
<
1.0
<
1.0
Children
3­
5
years
old
0.0001
0.00009
<
1.0
<
1.0
Children
6­
12
years
old
0.0001
0.00006
<
1.0
<
1.0
Youth
13­
19
years
old
0
0.00004
<
1.0
<
1.0
Adults
20­
49
years
old
0
0.00004
<
1.0
<
1.0
Adults
50+
years
old
0
0.00003
<
1.0
<
1.0
Females
13­
49
years
old
0
0.00003
<
1.0
<
1.0
a
The
values
for
the
population
with
the
highest
risk
are
bolded.

b
Reported
to
2
significant
figures.

6.2
Water
Exposure/
Risk
Pathway
References:
Tier
I
Estimated
Environmental
Concentrations
of
Dimethipin,
for
use
in
Human
Health
Risk
Assessment;
DP
Barcode:
D293574,
Larry
Liu,
06/
22/
04;
Personal
Communications
­
Larry
Liu
and
Michael
Barrett
(
8/
19/
04
&
8/
20/
04)

Water
models
were
used
to
assess
potential
exposure
to
dimethipin
from
consumption
of
contaminated
drinking
water.
Tier
1
Estimated
Environmental
Concentrations
(
EECs)
for
dimethipin
were
generated
using
FIRST
for
surface
water
and
SCI­
GROW
for
groundwater.
FIRST
is
a
relatively
new
screening
model
which
provides
high­
end
estimates
of
the
concentrations
that
might
be
found
in
a
small
drinking
water
reservoir
due
to
use
of
the
pesticide.
Input
parameters
for
FIRST
were
based
on
application
to
cotton
at
the
maximum
seasonal
rate
of
0.562
lb.
a.
i./
A.
SCI­
GROW
is
a
screening
model
which
provides
worst­
case
estimates
of
groundwater
concentrations
if
the
pesticide
is
used
at
the
maximum
allowable
rate
in
areas
where
groundwater
is
exceptionally
vulnerable
to
contamination.

Using
input
parameters
for
FIRST
and
SCI­
GROW
of
a
maximum
seasonal
use
rate
of
0.562
lb
ai/
A,
a
K
oc
of
1,
and
a
half­
life
of
408
days,
the
Tier
1
acute
and
chronic
(
non­
cancer)
EECs
for
dimethipin
in
surface
water
are
11.9
ppb
and
7.3
ppb,
respectively.
The
Tier
1EEC
(
acute
and
chronic)
for
dimethipin
in
ground
water
is
423.2
ppb.
The
disparity
between
estimated
levels
of
dimethipin
in
ground
and
surface
water
may
be
attributed
to
dimethipin's
physico­
chemical
properties
and
the
limitations
of
the
drinking
water
screening
models.
Dimethipin
has
an
extremely
low
adsorption
coefficient
(
Koc
=
1)
indicating
a
high
leaching
potential.
It
is
also
very
persistent,
as
indicated
by
its
aerobic
soil
metabolism
half­
life
of
408
days.
These
characteristics
of
high
mobility
and
persistence
account,
in
part,
for
the
relatively
high
estimated
residue
level
in
groundwater.
41
The
high
residue
estimate
for
groundwater
is
also
due,
in
part,
to
the
limitations
of
the
SCIGROW
model
itself.
Dimethipin's
K
oc
value
of
1
is
very
low
and
outside
the
range
of
K
oc
values
used
in
the
development
of
SCI­
GROW.
According
to
EFED's
Dr.
Michael
Barrett,
the
developer
of
SCI­
GROW,
the
model
tends
to
overestimate
leaching
below
a
K
oc
of
10;
and
it
is
more
appropriate
to
run
the
model
using
a
K
oc
of
10
as
a
reasonable
worst
case
in
estimating
residues
of
dimethipin
in
groundwater.
When
the
model
is
re­
run
with
a
K
oc
of
10,
the
resulting
estimated
concentration
of
dimethipin
in
groundwater
is
99
ppb,
compared
to
423
ppb
using
a
K
oc
of
1.

Based
on
the
conservative,
screening
nature
of
the
SCI­
GRO
model
and
the
limitations
on
its
reliability
for
pesticides
with
very
low
K
oc
values,
HED
believes
the
EEC
of
99
ppb
is
a
more
reliable
estimate
of
dimethipin
residues
in
ground
water
and
should
therefore
be
used
for
determining
risk
from
consumption
of
dimethipin­
contaminated
drinking
water.

6.3
Residential
(
Non­
Occupational)
Exposure/
Risk
Pathway
Dimethipin
is
registered
for
use
only
on
the
agricultural
site,
cotton.
There
are
no
residential
uses
and,
therefore,
no
anticipated
exposures
in
or
around
homes
or
recreational
areas.

6.3.1
Home
Uses
­
Not
applicable.

6.3.2
Recreational
Uses
­
Not
applicable.

6.3.3
Other
(
Spray
Drift,
etc.)

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

7.0
Aggregate
Risk
Assessments
and
Risk
Characterization
In
accordance
with
the
FQPA,
HED
must
consider
and
aggregate
(
add)
pesticide
exposures
and
risks
from
three
major
sources:
food,
drinking
water,
and
residential
exposures.
In
an
aggregate
42
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.

For
most
pesticide
active
ingredients,
water
monitoring
data
are
considered
inadequate
to
determine
surface
and
ground
water
drinking
water
exposure
estimates,
so
model
estimates
have
been
used
to
estimate
residues
in
drinking
water
(
EDWCs).
In
order
to
determine
if
aggregate
risks
are
of
concern,
HED
then
calculates
drinking
water
levels
of
comparison,
or
DWLOCs.
The
DWLOC
is
the
maximum
amount
of
a
pesticide
in
drinking
water
that
would
be
acceptable
in
light
of
combined
exposure
from
food
and
residential
pathways.
The
calculated
DWLOCs
are
then
compared
to
the
EDWCs
provided
by
EFED;
if
model­
derived
EDWCs
exceed
the
DWLOCs
for
surface
or
ground
water,
there
may
be
a
concern
for
dietary
exposure
to
residues
in
drinking
water,
and
monitoring
data
may
be
required.

7.1
Acute
Aggregate
Risk
An
acute
aggregate
risk
assessment
was
not
conducted
because
an
endpoint
of
concern
attributable
to
a
single
dose
was
not
identified.

7.2
Short­
Term
Aggregate
Risk
A
short­
term
aggregate
risk
assessment
was
not
conducted
because
there
are
no
existing
or
proposed
residential
uses
for
dimethipin.

7.3
Intermediate­
Term
Aggregate
Risk
An
intermediate­
term
aggregate
risk
assessment
was
not
conducted
because
there
are
no
existing
or
proposed
residential
uses
for
dimethipin.

7.4
Long­
Term
Aggregate
Risk
A
long­
term
(
chronic)
aggregate
risk
assessment
was
conducted
for
dimethipin.
The
chronic
assessment
considered
exposures
from
food
and
water
only,
because
there
are
no
residential
uses
and
no
residential
exposures
anticipated
for
this
chemical.
Since
adequate
water
monitoring
data
are
not
available
to
estimate
levels
of
dimethipin
in
drinking
water,
HED
calculated
DWLOCs
and
compared
them
to
the
modeled
EDWCs
for
surface
and
ground
water
to
determine
whether
aggregate
chronic
risks
are
of
concern.

The
results
of
the
deterministic,
Tier
1
dietary
exposure
assessment
indicate
that
dietary
exposures
to
dimethipin
in
food
are
very
low
and
well
below
HED's
level
of
concern
(
100%
of
the
cPAD).
Dimethipin
food
exposure
is
estimated
at
0.000042
mg/
kg/
day
for
the
U.
S.
population
(<
1%
of
43
the
cPAD)
and
0.000083
mg/
kg/
day
(<
1%
of
the
cPAD)
for
the
most
highly
exposed
population
subgroup
(
children,
3­
5
years
old)
using
the
LifeLine
model.
DEEM­
FCID
yielded
nearly
identical
results.

HED
used
the
LifeLine
exposure
estimates
to
calculate
chronic
DWLOCs
for
the
U.
S.
population
and
various
population
subgroups.
The
calculated
DWLOCS
ranged
from
762
ppb
for
adults
to
217
ppb
for
children.
The
Tier
1
chronic
surface
water
EDWC
(
7.3
ppb)
generated
by
EFED
is
well
below
HED's
calculated
DWLOCs
for
chronic
exposure
to
dimethipin
for
the
U.
S.
population
and
each
population
subgroup.
The
chronic
ground
water
EDWC
(
99
ppb)
generated
by
SCI­
GROW
using
a
K
oc
value
of
10
is
also
below
HED's
calculated
DWLOCs
for
the
U.
S.
population
and
all
population
subgroups.

Based
on
these
considerations,
HED
is
reasonably
certain
that
the
chronic
aggregate
risk
associated
with
the
use
of
dimethipin
does
not
exceed
HED's
level
of
concern
for
the
overall
U.
S.
population
or
population
subgroups,
including
infants
and
children.

Table
7.4
summarizes
the
estimated
chronic
aggregate
exposures
to
dimethipin
residues.

Table
7.4.
Aggregate
Risk
Assessment
for
Chronic
(
Non­
Cancer)
Exposure
to
Dimethipin
Population
Subgroup1
Chronic
Scenario
cPAD
mg/
kg/
day
Chronic
Food
Exp
mg/
kg/
day
Max
Chronic
Water
Exp
mg/
kg/
day2
Ground
Water
EDWC
(
ppb)
3
Surface
Water
EDWC
(
ppb)
3
Chronic
DWLOC
(
ppb)

U.
S.
Population
0.0218
0
0.021758
99
7.3
762
All
Infants
(<
1
year
old)
0.0218
0
0.021785
99
7.3
218
Children
1­
2
years
0.0218
0
0.021724
99
7.3
217
Children
3­
5
years
0.0218
0
0.021717
99
7.3
217
Children
6­
12
0.0218
0
0.02174
99
7.3
217
Youth
13­
19
0.0218
0
0.021757
99
7.3
653
Adults
20­
49
0.0218
0
0.021762
99
7.3
762
Females
13­
49
years
0.0218
0
0.021757
99
7.3
653
Table
7.4.
Aggregate
Risk
Assessment
for
Chronic
(
Non­
Cancer)
Exposure
to
Dimethipin
Population
Subgroup1
Chronic
Scenario
cPAD
mg/
kg/
day
Chronic
Food
Exp
mg/
kg/
day
Max
Chronic
Water
Exp
mg/
kg/
day2
Ground
Water
EDWC
(
ppb)
3
Surface
Water
EDWC
(
ppb)
3
Chronic
DWLOC
(
ppb)

44
Adults
50+
years
0.0218
0
0.021763
99
7.3
762
1Body
wts.
used
to
calculate
DWLOCs:
70
kg
(
U.
S.
Population,
Adults
20­
49
years
and
Adults
50+
years);
60
kg
(
Females
13­
49
years
and
Youth
13­
19
years);
and
10
kg.
(
Infants
and
Children).
Water
consumption
was
assumed
to
be
2
L/
day
for
adults
and
youths
(
13­
19)
and
1
L/
day
for
infants
and
children.

2Maximum
Chronic
Water
Exposure
(
mg/
kg/
day)
=
[
Chronic
PAD
(
mg/
kg/
day)
­
Chronic
Dietary
Exposure
(
mg/
kg/
day)]

3
Based
on
application
to
cotton
at
the
maximum
seasonal
rate
of
0.562
lb.
a.
i./
A.
and
a
K
oc
value
of
10.
The
K
oc
of
10
was
used
instead
of
dimethipin's
K
oc
value
of
1
to
adjust
for
SCI­
GROW's
tendency
to
overestimate
residues
for
chemicals
with
low
K
oc
values.

4
Chronic
DWLOC(

g/
L)
=
[
maximum
chronic
water
exposure
(
mg/
kg/
day)
x
body
weight
(
kg)]

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

7.5
Cancer
Risk
Quantification
of
the
cancer
risk
is
not
recommended
for
dimethipin.
Therefore,
an
aggregate
cancer
assessment
was
not
conducted.

8.0
Cumulative
Risk
Characterization/
Assessment
Unlike
other
pesticides
for
which
EPA
has
followed
a
cumulative
risk
approach
based
on
a
common
mechanism
of
toxicity,
EPA
has
not
made
a
common
mechanism
of
toxicity
finding
as
to
dimethipin
and
any
other
substances
and
dimethipin
does
not
appear
to
produce
a
toxic
metabolite
produced
by
other
substances.
For
the
purposes
of
this
tolerance
action,
therefore,
EPA
has
not
assumed
that
dimethipin
has
a
common
mechanism
of
toxicity
with
other
substances.
For
information
regarding
EPA's
efforts
to
determine
which
chemicals
have
a
common
mechanism
of
toxicity
and
to
evaluate
the
cumulative
effects
of
such
chemicals,
see
the
policy
statements
released
by
EPA's
Office
of
Pesticide
Programs
concerning
common
mechanism
determinations
and
procedures
for
cumulating
effects
from
substances
found
to
have
a
common
mechanism
on
EPA's
website
at
http://
www.
epa.
gov/
pesticides/
cumulative/.
45
9.0
Occupational
Exposure/
Risk
Pathway
Reference:
Occupational
and
Residential
Exposure
Assessment
and
Recommendations
for
the
Reregistration
Eligibility
Decision
Document
for
Dimethipin.
DP
Barcode
D332596.
S.
Tadayon.
06/
08/
04.

9.1
Short/
Intermediate/
Long­
Term
Handler
Risk
Occupational
handlers
may
be
exposed
through
the
following
routes
during
mixing,
loading
and
application
of
dimethipin
using
aerial,
groundboom
or
high
pressure
handwand
equipment
and
during
flagging
operations
for
spray
applications:


Dermal:
Although
dermal
exposure
is
expected,
short­
and
intermediate­
term
dermal
endpoints
were
not
identified
due
to
the
lack
of
dermal,
systemic,
and
developmental
toxicity
concerns.
A
long­
term
dermal
endpoint
was
not
identified;
nor
would
long­
term
dermal
occupational
exposure
be
expected.
Therefore
dermal
exposure
was
not
assessed.


Inhalation:
Even
though
the
volatility
of
this
chemical
is
very
low,
based
on
the
use
patterns
for
dimethipin,
both
short­
and
intermediate­
term
inhalation
exposure
may
occur.
Long­
term
inhalation
exposure
is
not
anticipated.
A
shortterm
inhalation
endpoint
was
selected
based
on
the
maternal
NOAEL
of
20
mg/
kg/
day
from
an
oral
developmental
rabbit
study.
The
maternal
LOAEL
of
40
mg/
kg/
day
was
based
on
decreased
body
weight
gain.
An
intermediate­
term
inhalation
endpoint
was
selected
using
the
NOAEL
of
11.8
mg/
kg/
day
(
F0
and
F1
females)
from
a
2­
generation
reproduction
study
in
the
rat.
The
LOAEL
for
F0
and
F1
females
(
31.2­
120.3
mg/
kg/
day)
was
based
on
decreased
body
weights
and
body
weight
gains.

Handler
exposure
and
risk
were
estimated
for
the
following
scenarios:
(
1)
mixing/
loading
liquids
for
aerial
application,
(
2)
mixing/
loading
liquids
for
groundboom
application
,
(
3)
mixing/
loading
liquids
for
high­
pressure
handwand
application,
(
4)
aerial
spray
application,
(
5)
groundboom
spray
application,
(
6)
high­
pressure
handwand
spray
application
and
(
7)
flagging
for
spray
applications.

No
chemical­
specific
handler
exposure
data
were
submitted
to
the
Agency
in
support
of
the
reregistration
of
dimethipin.
It
is
the
policy
of
HED
to
use
data
from
the
Pesticide
Handlers
Exposure
Database
(
PHED)
Version
1.1,
as
presented
in
the
PHED
Surrogate
Exposure
Guide
(
8/
98),
when
chemical­
specific
monitoring
data
are
not
available.
PHED
data
were
used
with
other
HED
standard
values
for
areas
treated
per
day,
body
weight
and
the
level
of
personal
protective
equipment
(
PPE)
to
assess
handler
exposures
to
dimethipin.
For
all
exposure
scenarios
except
aerial
spray
application,
baseline
PPE
(
i.
e.,
no
respirator)
were
assumed.
This
assumption
is
consistent
with
PPE
requirements
on
dimethipin
labels
(
gloves,
but
not
respirators,
are
46
required).
For
aerial
spray
application
(
fixed
wing
aircraft),
HED
assumed
the
use
of
engineering
controls
(
i.
e.,
closed­
cockpit).
Engineering
controls
were
assumed
because
of
the
insufficient
number
of
data
points
for
fixed­
wing,
open­
cockpit
aircraft
in
the
PHED.

Using
the
above
assumptions,
all
of
the
calculated
occupational
handler
MOEs
are
greater
than
HED's
target
of
100
and,
therefore,
are
not
of
concern.
Short­
term
inhalation
MOEs
range
from
1,500
(
mixing/
loading
liquids
for
aerial
application)
to
1,300,000
(
mixing/
loading
liquids
for
highpressure
handwand
application).
Intermediate­
term
inhalation
MOEs
range
from
880
(
mixing/
loading
liquid
for
aerial
application)
to
770,000
(
mixing/
loading
liquids
for
high­
pressure
handwand
application).

Table
9.1.1
Short­
and
Intermediate­
Term
Occupational
Exposure
and
Risk
Estimates
for
Dimethipin.
The
short­
term
inhalation
NOAEL
is
20
mg/
kg/
day.
The
long­
term
inhalation
NOAEL
is
11.8
mg/
kg/
day.

Exposure
Scenario
(
Scenario
#)
Crop
Daily
Area
Treated
(
Acres
or
Gals./
Day)
Daily
Inhalation
Dose
(
mg/
kg/
day)
Short­
Term
Inhalation
MOE
Intermediat
e­
Term
Inhalation
MOE
Mixer/
Loader
Mixing/
loading
Liquids
for
Aerial
Application
(
1)
Cotton
1200
acres
0.013
1,500
880
Mixing/
loading
Liquids
for
Groundboom
Application
(
2)
200
acres
0.0022
8,900
5,300
Mixing/
loading
Liquids
for
High­
pressure
Handwand
Application
(
3)
Apple
1,000
gals.
0.000015
1,300,000
770,000
Applicator
Aerial
Spray
Application
(
4)
Cotton
1200
0.00076
26,000
(
engineering
control)
15,000
(
engineering
control)

Groundboom
Spray
Application
(
5)
Cotton
200
0.0014
14,000
8,500
High­
pressure
Handwand
Spray
Application
(
6)
Apple
1,000
gals.
0.001
20,000
12,000
Flagger
Flagging
for
Spray
Applications
(
7)
Cotton
350
0.0011
17,000
10,000
9.2
Short/
Intermediate/
Long­
Term
Postapplication
Risk
EPA
did
not
assess
risk
from
occupational
postapplication
dermal
exposure,
since
no
short­
or
intermediate­
term
dermal
endpoint
of
concern
was
identified
and
long­
term
dermal
exposures
are
47
not
expected
for
tasks
involving
cotton
use
patterns.
Postapplication
inhalation
exposure
is
expected
to
be
negligible;
therefore,
a
risk
assessment
for
this
route
was
also
not
conducted.

The
toxicity
categories
of
the
active
ingredient
for
acute
dermal
toxicity,
eye
and
skin
irritation
potential
are
used
to
determine
the
interim
REI
(
Restricted­
entry
Interval).
The
classification
of
dimethipin
in
category
III
for
dermal
irritation
potential
requires
a
12­
hour
REI.

10.0
Data
Needs
and
Label
Requirements
10.1
Toxicology

870.3700a:
Data
must
be
submitted
on
test
material
stability,
homogeneity,
and
concentration
in
the
dosing
medium.


870.3700b:
Data
must
be
submitted
on
test
material
stability,
homogeneity,
and
concentration
in
the
dosing
medium.


870.4100b:
Data
must
be
submitted
on
historical
controls,
and
diet
homogeneity
and
stability.

10.2
Residue
Chemistry

860.1500:
Data
must
be
submitted
depicting
dimethipin
residues
in
cotton
gin
byproducts
which
include
burrs,
leaves,
stem,
lint,
immature
seeds
and
sand
(
dirt)
obtained
from
ginning
cotton.


860.1850:
To
demonstrate
the
storage
stability
of
the
samples
used
in
the
supplemental
confined
rotational
crop
submission,
the
registrant
must
submit
additional
data/
information
comparing
the
chromatographic
profiles
of
the
stored
samples
with
those
of
the
original
analyses
(
see
D219060and
D223855,
DERs
4376801,
43768202,
and
43931301).


860.1900:
Additional
storage
stability
data
are
required
to
support
the
limited
field
rotational
crop
studies
(
see
D225417,
DERs
43979102
and
43979101).
HED
notes
that
crop
field
trial
data
for
cotton
gin
byproducts
and
extensive
field
rotational
crop
studies
are
required;
storage
stability
data
to
support
those
studies
will
be
required
unless
samples
are
analyzed
within
one
month
of
collection.


860.1900:
The
available
limited
rotational
crop
studies
indicate
the
potential
for
dimethipin
residues
in
certain
rotated
crops
at
the
established
plantback
interval
(
6
months).
Extensive
field
rotational
crop
studies
must
48
be
submitted
for
all
crops,
except
leafy
vegetables,
for
which
the
registrant
wishes
to
allow
a
6­
month
plantback
interval.
In
the
submitted
studies,
residues
of
dimethipin
were
below
the
LOQ
(<
0.02
ppm)
to
0.031
ppm
in
lettuce,
<
0.02
ppm
in
carrot
roots,
0.034­
0.071
ppm
in
carrot
tops,
0.027­
0.039
ppm
in
wheat
forage,
<
0.02
ppm
in
wheat
grain,
and
<
0.02­
0.023
ppm
in
wheat
straw
planted
one
month
after
application
of
dimethipin.
Residues
of
dimethipin
were
below
the
LOQ
(<
0.02
ppm)
in
lettuce,
<
0.02­
0.024
ppm
in
carrot
roots,
<
0.02­
0.180
ppm
in
carrot
tops,
<
0.02
ppm
in
oat
forage,
<
0.02
ppm
in
oat
grain,
and
<
0.02­
0.021
ppm
in
oat
straw
planted
six
months
after
dimethipin
application.
At
both
plantback
intervals,
residues
were
highest
in
carrot
tops.

10.3
Occupational
and
Residential
Exposure
­
None
References:

Dimethipin,
Residue
Chemistry
Considerations
for
Reregistration
Eligibility
Decision,
Case
No.
3063.
DP
Barcode:
293580,
Danette
Drew,
07/
22/
04
Dimethipin
Chronic
Dietary
Exposure
Assessment
for
the
Reregistration
Eligibility
Decision,
DP
Barcode:
D303935,
Susan
Stanton,
08/
18/
04
Occupational
and
Residential
Exposure
Assessment
and
Recommendations
for
the
Reregistration
Eligibility
Decision
Document
for
Dimethipin,
DP
Barcode
D332596,
S.
Tadayon,
06/
08/
04
Tier
I
Estimated
Environmental
Concentrations
of
Dimethipin
for
use
in
Human
Health
Risk
Assessment;
DP
Barcode:
D293574,
Larry
Liu,
06/
22/
04
49
Appendices
1.0
TOXICOLOGY
DATA
REQUIREMENTS
The
requirements
(
40
CFR
158.340)
for
food
use
for
dimethipin
are
in
Table
1.
Use
of
the
new
guideline
numbers
does
not
imply
that
the
new
(
1998)
guideline
protocols
were
used.

Test
Technical
Required
Satisfied
870.1100
Acute
Oral
Toxicity
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.

870.1200
Acute
Dermal
Toxicity
.
.
.
.
.
.
.
.
.
.
.
.
.

870.1300
Acute
Inhalation
Toxicity
.
.
.
.
.
.
.
.
.
.
.

870.2400
Primary
Eye
Irritation
.
.
.
.
.
.
.
.
.
.
.
.
.
.

870.2500
Primary
Dermal
Irritation
.
.
.
.
.
.
.
.
.
.
.

870.2600
Dermal
Sensitization
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
yes
yes
yes
yes
yes
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
­

­

870.3700a
Developmental
Toxicity
(
rodent)
.
.
.
.
.

870.3700b
Developmental
Toxicity
(
nonrodent)
.
.
.

870.3800
Reproduction
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
yes
yes
yes
yes
yes
yes
870.4100a
Chronic
Toxicity
(
rodent)
.
.
.
.
.
.
.
.
.
.
.

870.4100b
Chronic
Toxicity
(
nonrodent)
.
.
.
.
.
.
.
.

870.4200a
Oncogenicity
(
rat)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.

870.4200b
Oncogenicity
(
mouse)
.
.
.
.
.
.
.
.
.
.
.
.
.
.

870.4300
Chronic/
Oncogenicity
.
.
.
.
.
.
.
.
.
.
.
.
.
.
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
Test
Technical
Required
Satisfied
50
870.5100
Mutagenicity
 
Gene
Mutation
­
bacterial
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.

870.5300
Mutagenicity
 
Gene
Mutation
­
mammalian
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.

870.5xxx
Mutagenicity
 
Structural
Chromosomal
Aberrations
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.

870.5550
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
no
no
no
­

­

870.7485
General
Metabolism
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.

870.7600
Dermal
Penetration
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
yes
no
yes
­

Special
Studies
for
Ocular
Effects
Acute
Oral
(
rat)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.

Subchronic
Oral
(
rat)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.

Six­
month
Oral
(
dog)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
no
no
no
­

­

­

2.0
NON­
CRITICAL
TOXICOLOGY
STUDIES
STUDY
TYPE:
Carcinogenicity
feeding
­
mouse
[
OPPTS
870.4200b
(
§
83­
2(
b))];
OECD
451.

EXECUTIVE
SUMMARY:
In
a
18­
month
oral
carcinogenicity
study
(
MRID
93089031),
N252
(
97.8%
a.
i.,
Lot
#
BL
8461)
was
administered
to
a
total
of
50
CD
®
­
1
mice/
sex/
dose
in
the
diet
at
concentrations
of
0,
80,
400,
or
2000
ppm
(
equivalent
to
0,
11.3,
56,
or
286
mg/
kg
bw/
day
for
males
and
0,
13.3,
68,
or
341
mg/
kg
bw/
day
for
females).

There
were
no
treatment­
related
effects
on
mortality.
The
body
weight
gain
of
males
at
2000
ppm
was
75%
(
p<
0.05)
of
the
control
after
13
weeks
of
treatment
and
81%
after
18
months.
The
body
weight
gain
in
females
at
2000
ppm
was
80%
(
NS)
of
the
control
at
13
weeks
and
comparable
to
the
controls
at
18
months.
Food
efficiency
over
the
first
53
weeks
of
the
study
was
decreased
by
23%
in
males
at
2000
ppm
compared
to
the
control.
Food
consumption
was
comparable
to
the
control
groups.
Erythrocyte
counts
were
increased
by
19­
25%
in
treated
mice
compared
to
the
control
groups,
but
the
difference
was
statistically
significant
only
in
females
at
51
80
ppm.
Increases
in
hematocrit
and
hemoglobin
concentration
were
also
seen
in
treated
mice,
but
the
changes
were
not
significantly
different
from
the
control.
No
significant
treatment­
related
changes
were
seen
in
absolute
or
relative
(
to
body
weight)
organ
weights.
Microscopic
examination
revealed
significantly
increased
incidences
of
tracheal
mononuclear
inflammatory
cell
foci
in
males
at
2000
ppm
(
26%,
p<
0.05)
compared
to
the
control
group
(
8%).
Increased
inflammatory
cell
foci
incidences
were
not
seen
in
treated
females
compared
to
the
control
group.

A
number
of
findings
were
negatively
correlated
with
treatment
including
incidences
of
liver
microgranulomas
and
nonsuppurative
pericholangitis
in
males;
pulmonary
perivascular
lymphoid
hyperplasia
and
focal
pneumonitis,
dilated
kidney
tubules,
regenerative
kidney
tubule
epithelium,
and
cystic
ovarian
follicles
in
females.

The
LOAEL
for
N252
in
male
mice
is
2000
ppm
(
286
mg/
kg/
day)
based
on
increased
mononuclear
inflammatory
cell
foci
in
the
trachea,
decreased
body
weight
gain,
and
decreased
food
efficiency.
A
LOAEL
was
not
determined
for
females.
The
NOAEL
is
400
ppm
for
males
(
56
mg/
kg/
day)
and
2000
ppm
for
females
(
341
mg/
kg/
day).

Treatment
of
CD
®
­
1
male
mice
with
a
dietary
level
of
2000
ppm
N252
for
18
months
resulted
in
a
marginally
significant
(
p<
0.044)
increase
in
the
incidences
of
lung
carcinomas
and
adenomas
combined
compared
to
the
control
group
and
a
significant
positive
trend
for
lung
adenomas.

This
carcinogenicity
study
in
the
mouse
is
Acceptable/
Guideline
and
satisfies
guideline
requirements
for
a
carcinogenicity
study
[
OPPTS
870.4200b;
OECD
451]
in
mice.
Although
toxicity
and
neoplastic
effects
were
seen
in
males,
the
animals,
and
especially
females,
could
have
tolerated
higher
doses.
A
comparison
of
tumor
incidences
in
historic
controls
would
have
been
helpful.

STUDY
TYPE:
Chronic
toxicity
­
dog
feeding
OPPTS
870.4100b
[
§
83­
1b]
OECD
452.

EXECUTIVE
SUMMARY:
In
a
chronic
toxicity
study
(
MRID
93089030),
N252
(
99.7%
a.
i.,
Control
D
­
10894)
was
administered
to
6
beagle
dogs/
sex/
dose
in
the
diet
at
concentrations
of
0,
100,
300,
or
3000
ppm
(
equivalent
to
0,
8.92,
29.85,
and
98.98
mg/
kg
bw/
day
for
males
and
0,
10.33,
34.42,
and
92.87
mg/
kg
bw/
day
for
females,
respectively)
for
52
weeks.
An
independent
summary
(
MRID
93089007)
of
the
materials/
methods
and
results
of
the
aforementioned
primary
study
was
also
available
and
concurred
with
the
study
reports
conclusions.

At
3000
ppm
N252,
females
showed
a
statistically
significant
decrease
in
body
weight
gain
(
20.8%
at
52
weeks;
p
<
0.01)
and
males
exhibited
a
statistically
significant
decrease
(
7.8%
at
52
weeks;
p<
0.05).
Food
consumption
was
markedly
reduced
in
females
and
moderately
reduced
in
males
at
3000
ppm.
Irregular
heartbeat
was
observed
in
most
of
the
3000
ppm
dogs
prior
to
sacrifice.
Four
dogs
in
the
3000
ppm
treatment
group
(
1
male
and
3
females)
died
or
were
sacrificed
in
extremis
during
the
study;
the
deaths
could
not
be
directly
attributed
to
the
treatment.
Although
the
deaths
could
not
be
directly
attributed
to
the
treatment
based
upon
the
52
clinical
chemistry
and
gross
pathology
correlates,
food
efficiency
was
negative
for
both
males
and
females
in
the
high­
dose
group
thereby
suggesting
a
compound­
related
effect.
There
were
no
remarkable
treatment­
related
gross
or
microscopic
lesions,
and
no
alterations
in
hematologic
and
clinical
chemistry
parameters
in
any
of
the
dogs.
Relative
weights
of
various
organs
were
significantly
increased
(
p
<
0.05
or
p
<
0.01)
in
both
male
and
female
dogs
in
the
1000
and
3000
ppm
treatment
groups.
However,
corresponding
absolute
organ
weights
were
not
significantly
increased
compared
to
controls,
indicating
increased
relative
organ
weights
were
likely
a
function
of
decreased
body
weight.

The
N252
LOAEL
for
male
and
female
beagle
dogs
is
3000
ppm
(
98.98
and
92.87
mg/
kg
bw/
day,
respectively)
based
upon
decreased
body
weight
gain,
reduced
food
consumption,
and
a
negative
food
efficiency.
The
NOAEL
is
1000
ppm
(
29.85
and
34.42
mg/
kg
bw/
day
for
males
and
females,
respectively).

This
chronic
study
is
Unacceptable/
Guideline
and
does
not
satisfy
the
guideline
requirement
for
a
chronic
oral
study
[
OPPTS
870.4100,
OECD
452]
in
dogs.
This
study
may
be
upgradable
to
acceptable
pending
submission
of
historical
control
data,
diet
homogeneity
and
stability,
and
replacement
of
illegible
data.

STUDY
TYPE:
21­
Day
Dermal
Toxicity
­
Rat
[
OPPTS
870.3200
(
§
82­
2)]
OECD
410.

EXECUTIVE
SUMMARY:

In
a
21­
day
dermal
toxicity
study
(
MRID
41944901),
Harvade
®
Technical
(
Dimethipin;
98.62%
a.
i.,
Lot
#
R047232)
was
applied
to
the
intact
shaved
skin
of
6
CD
®
rats/
sex/
dose
at
dose
levels
of
0,
10,
100,
or
1000
mg/
kg
bw/
day,
6
hours/
day
for
7
days/
week
during
a
21­
day
period.

There
were
no
treatment­
related
effects
on
mortality,
clinical
signs,
body
weight,
food
consumption,
hematology,
clinical
chemistry,
or
gross
pathology,
and
there
were
no
observations
of
dermal
irritation
(
erythema
or
edema).
At
the
highest
dose
level,
relative
(
to
body)
liver
weights
were
increased
in
both
males
and
females
(
20
and
15%
greater
than
controls,
respectively;
p<
0.01).
Treatment­
related
histopathological
changes
were
limited
to
diffuse
trace
hyperkeratosis
of
treated
skin
in
6/
6
high­
dose
males
and
2/
6
high­
dose
females
(
vs.
none
of
the
controls).
Multifocal
trace
hyperkeratosis
of
treated
skin
was
noted
in
5/
6
low­
and
mid­
dose
males
and
2/
6
mid­
and
high­
dose
females
but
was
not
considered
toxicologically
significant.
The
dermal
LOAEL
is
1000
mg/
kg
bw/
day,
based
on
diffuse
trace
hyperkeratosis
of
treated
skin.
The
dermal
NOAEL
is
100
mg/
kg
bw/
day.
The
systemic
NOAEL
is
1000
mg/
kg
bw/
day
and
the
systemic
LOAEL
is
not
identified.

This
21­
day
dermal
toxicity
study
in
the
rat
is
Acceptable/
Guideline
and
satisfies
the
guideline
requirement
for
a
21­
day
dermal
toxicity
study
(
OPPTS
870.3200;
OECD
410).
53
54
STUDY
TYPE:
28­
Day
Oral
Toxicity
Feeding­
Mouse;
OPPTS
870.3100
[
§
82­
1a];
OECD
408.

EXECUTIVE
SUMMARY:

In
a
28­
day
oral
toxicity
study
(
MRID
00160460)
N­
252
Harvade
technical
(
Dimethipin;
purity
and
batch/
lot
#
not
reported)
was
administered
to
10
albino
mice/
sex/
group
in
the
diet
at
dietary
concentrations
of
0,
250,
500,
1000,
or
2000
ppm
(
by
standard
conversion
factor,
equivalent
to
0,
37.5,
75,
150,
or
300
mg/
kg
bw/
day).

There
were
no
treatment­
related
effects
on
mortality,
clinical
signs,
body
weight,
food
consumption,
or
gross
pathology.
Hematology,
clinical
chemistry,
and
histopathology
were
not
evaluated.
Males
treated
at
1000
and
2000
ppm
had
increased
absolute
liver
weights
(
115%
and
127%
of
controls,
respectively;
p<
0.05
for
2000
ppm
only)
and
increased
relative
liver
weights
(
106%
and
120%
of
controls,
respectively;
p<
0.05
for
2000
ppm
only).
Females
treated
at
500,
1000,
and
2000
ppm
had
increased
absolute
liver
weights
(
118,
110,
and
116%
of
controls,
respectively;
p<
0.05
except
at
1000
ppm)
and
increased
relative
liver
weights
(
113,
108,
and
118%
of
controls,
respectively;
p<
0.05
except
at
1000
ppm).
These
increases
were
considered
treatment­
related
adaptive
responses
and
not
considered
toxicologically
significant,
especially
in
the
absence
of
a
clear
dose­
response
pattern.
The
LOAEL
is
not
identified
and
the
NOAEL
is
2000
ppm
(
300
mg/
kg
bw/
day
by
standard
conversion
factor).

This
28­
day
oral
toxicity
study
in
the
mouse
is
classified
Acceptable/
Non­
guideline
and
fulfills
its
intended
purpose
as
a
range­
finding
study.
Alone
it
does
not
satisfy
the
guideline
requirements
for
a
90­
day
oral
toxicity
study
in
a
rodent
species
(
OPPTS
870.3100;
OECD
408).

STUDY
TYPE:
90­
Day
Oral
Toxicity
(
feeding)­
rats
[
OPPTS
870.3100
(
§
82­
1a)]
(
rodent)
OECD
408.

EXECUTIVE
SUMMARY:
In
a
90­
day
oral
toxicity
study
(
MRID
43065901),
dimethipin
(
98.51%
a.
i.,
batch/
lot
#
204R026)
was
administered
to
10
Crl:
CD
BR
VAF/
Plus
rats/
sex/
dose
in
the
diet
at
concentrations
of
0,
40,
1750,
or
3500
ppm
(
equivalent
to
0,
2.5,
108,
and
220
mg/
kg
bw/
day
in
males
and
0,
3.1,
131,
and
260
mg/
kg
bw/
day
in
females).
There
were
no
treatmentrelated
effects
on
mortality,
clinical
signs,
food
consumption,
hematology,
clinical
chemistry,
or
gross
or
microscopic
pathology.
At
the
end
of
the
study,
body
weight
of
the
1750­
and
3500­
ppm
females
was
reduced
by
10%
and14%,
respectively,
compared
to
controls,
while
body
weight
of
treated
males
was
unaffected.
Total
body
weight
gain
by
the
1750­
and
3500­
ppm
females
was
reduced
by
21%
and
29%,
respectively,
while
total
body
weight
gain
by
males
was
comparable
to
that
of
controls.

Under
the
conditions
of
this
study,
the
LOAEL
for
dimethipin
in
rats
was
not
established
for
males,
and
is
1750
ppm
(
131
mg/
kg/
day)
for
females,
based
on
decreased
body
weight
and
body
weight
gain.
The
NOAEL
is
3500
ppm
(
220
mg/
kg/
day)
for
males,
and
40
ppm
(
3.1
mg/
kg/
day)
for
females.
55
This
90­
day
oral
toxicity
study
in
the
rat
is
Acceptable/
Guideline,
and
satisfies
the
guideline
requirement
for
a
90­
day
oral
toxicity
study
(
OPPTS
870.3100;
OECD
408)
in
rats.

STUDY
TYPE:
In
vitro
Mammalian
Cytogenetics
in
Chinese
hamster
ovary
CHO
cells
[
OPPTS
870.5375
(
§
84­
2)]
OECD
473
EXECUTIVE
SUMMARY:
In
a
mammalian
cell
cytogenetics
(
Chromosomal
aberrations)
assay
(
MRID
133302
and
93089013),
Chinese
hamster
ovary
CHO­
K1­
BH
4
cell
cultures
were
exposed
to
Harvade
®
technical
(
100%
a.
i.,
batch
#
not
provided)
in
DMSO
at
concentrations
of
0,
5,
25
or
50
µ
g/
mL
for
5
hours
with
and
without
metabolic
activation
(
S9­
mix)
and
harvested
6
­
8
and
14
­
18
hours
post­
exposure.
Duplicate
cultures
were
used
at
each
test
material
concentration
and
for
the
solvent
and
positive
controls.
The
S9­
fraction
was
obtained
from
Aroclor
1254
induced
rat
liver.
The
rat
strain
and
sex
were
not
identified.

Harvade
®
technical
was
tested
up
to
cytotoxic
concentrations.
Cytotoxicity,
as
based
on
a
reduction
of
the
mitotic
index,
was
seen
at
concentrations
of
33
µ
g/
mL
and
higher.
No
statistically
significant
increase
in
the
percentage
of
cells
with
structural
aberrations
(
excluding
gaps)
over
solvent
control
values
was
seen
at
any
concentration,
with
or
without
S9­
mix.
The
positive
control
used
in
the
experiment
with
activation,
dimethylnitrosamine
(
DMN),
gave
abnormally
low
values
in
the
original
assay;
therefore,
this
part
of
the
study
was
repeated
at
the
same
test
material
concentrations
and
with
two
different
lots
of
DMN.
The
positive
control
values
were
acceptable
with
both
lots
of
DMS
in
the
repeat
assay
and
no
statistically
significant
increase
in
the
percentage
of
cells
with
structural
aberrations
(
excluding)
gaps
was
seen
at
any
test
material
concentration.
The
solvent
and
positive
controls
induced
the
appropriate
responses.
There
was
no
evidence
that
the
test
material
increased
the
incidence
of
chromosome
aberrations
over
background
levels.

This
study
is
classified
as
Acceptable/
Guideline
and
satisfies
the
guideline
requirement
for
Test
Guideline
OPPTS
870.5375;
OECD
473
for
in
vitro
cytogenetic
mutagenicity
data.

STUDY
TYPE:
Other
Genotoxicity:
Unscheduled
DNA
Synthesis
in
Rat
Hepatocytes/
Mammalian
Cells
­
in
vivo/
in
vitro
Procedure
[
OPPTS
870.5550
(
§
84­
2)]

EXECUTIVE
SUMMARY:
In
an
in
vivo/
in
vitro
unscheduled
DNA
synthesis
(
UDS)
assay
(
MRIDs
40479601
and
93089016)
in
rat
hepatocytes,
Harvade,
in
1.25%
methylcellulose,
was
administered
by
gavage
to
three
male
Wistar
rats
per
test
group
in
two
experiments
at
doses
of
0,
100,
300
or
1000
mg/
kg
body
weight.
The
test
material
was
delivered
in
a
volume
of
10
mL/
kg.
Hepatocytes
were
isolated
at
2
hours
post­
treatment
in
the
first
experiment
and
at
12
hours
posttreatment
in
the
second
experiment
and
cultured
for
determination
of
tritiated
thymidine
incorporation
using
the
autoradiographic
procedure.
The
positive
control
was
methylmethanesulfonate
(
MMS)
in
the
first
experiment
and
2­
acetylaminofluorene
(
2­
AAF)
in
the
second
experiment.
56
The
upper
dose
of
Harvade
used
was
considered
near
the
LD
50
in
rats.
No
mortality
occurred
during
the
study
but
all
rats
dosed
at
1000
mg/
kg
were
lethargic
and
lachrymating
1
to
2
hours
after
treatment.
The
rats
appeared
normal
by
12
hours
after
treatment.
The
mean
net
nuclear
grain
counts
were
below
zero
and
also
below
the
solvent
control
values
of
­
1.15
±
0.57
at
2
hours
and
­
0.98
±
0.21
at
12
hours
at
all
test
material
concentrations
at
both
treatment
times.
Also,
little
difference
in
the
percentage
of
cells
in
repair
(
defined
as
a
cell
with
a
net
nuclear
grain
count
of
five
or
more)
was
seen
between
test
material
and
solvent
control
groups.
The
mean
net
nuclear
grain
count
of
the
MMS
positive
control
was
3.66
±
1.16
and
that
of
the
2­
AAF
positive
control
was
4.93
±
0.23.
The
solvent
and
positive
control
values
were
appropriate.
There
was
no
evidence
that
Harvade
increased
the
incidence
of
UDS
over
the
solvent
control
values
indicating
no
induction
of
DNA
damage.

This
study
is
classified
as
an
Acceptable/
Guideline
study.
It
satisfies
the
guideline
requirements
in
[
OPPTS
870.5550
(
§
84­
2)].

STUDY
TYPE:
In
Vivo
Mammalian
Cytogenetics
­
Erythrocyte
Micronucleus
assay
in
mouse
bone
marrow
[
OPPTS
870.5395
(
§
84­
2)]
OECD
474.

EXECUTIVE
SUMMARY:
In
a
Swiss
CD­
1
mouse
bone
marrow
micronucleus
assay
(
MRID
40479602),
five
mice/
sex/
dose
were
treated
orally
on
two
occasions
24
hours
apart
with
Dimethipin
technical
(
98.9%
a.
i.,
batch
#
SI
251).
Males
received
two
doses
of
test
material
at
0,
22.0,
73.3
or
220.0
mg/
kg
body
weight
and
females
received
two
doses
at
0,
30,
100
or
300
mg/
kg.
Bone
marrow
cells
were
harvested
at
6
hours
after
the
second
treatment.
The
vehicle
was
0.5%
Carboxymethylcellulose
(
CAC).

Dimetipin
technical
was
tested
to
toxic
concentrations.
One
male
in
the
220
mg/
kg
dose
group
died
a
short
time
after
the
first
dose
and
all
females
in
the
300
mg/
kg
dose
group
appeared
sedated
several
hours
after
the
first
dose
and
were
found
dead
the
following
day.
The
incidence
of
micronucleated
PCEs
was
slightly
increased
over
the
solvent
control
value
in
the
high
dose
males,
but
not
in
any
other
treatment
group,
in
the
initial
scoring
(
data
not
presented).
The
slides
from
the
high
dose
males
and
those
from
the
male
and
female
solvent
control
groups
were
recoded
and
rescored.
No
increase
in
the
incidence
of
micronucleated
PCEs
over
the
solvent
control
value
was
seen
in
the
combined
data
from
the
initial
and
repeat
scoring
of
slides
from
the
high
dose
males.
The
Mitomycin
C
positive
control
induced
statistically
significant
increases
in
the
mean
incidence
of
micronucleated
PCEs
per
1000
PCE
in
both
males
and
females
over
the
respective
solvent
control
values
and
the
solvent
control
values
were
appropriate.
The
PCE/
NCE
ratios
were
similar
in
the
solvent
control
and
test
material
treated
groups
and
did
not
indicate
bone
marrow
cytotoxicity.
There
was
no
statistically
significant
increase
in
the
frequency
of
micronucleated
polychromatic
erythrocytes
in
bone
marrow
from
either
sex
at
any
dose.

This
study
is
classified
as
Acceptable/
Guideline
and
satisfies
the
guideline
requirement
for
Test
Guideline
OPPTS
870.5395;
OECD
474
for
in
vivo
cytogenetic
mutagenicity
data.
57
STUDY
TYPE:
In
Vivo
Mammalian
Cytogenetics
­
Erythrocyte
Micronucleus
assay
in
mice;
[
OPPTS
870.5395
(
§
84­
2)]
OECD
474.

EXECUTIVE
SUMMARY:
In
a
Swiss
CD­
1
mouse
bone
marrow
micronucleus
assay
(
MRID
41708201),
five
mice/
sex/
dose/
harvest
time
were
treated
once
orally
with
Dimethipin
Technical
(
98.8%
a.
i.,
batch/
lot
#
not
provided)
in
0.5%
carboxymethyl
cellulose
(
CMC)
at
a
dose
of
0
or
220
mg/
kg
body
weight.
Bone
marrow
cells
were
harvested
at
24,
48
and
72
hours
posttreatment

Dimethipin
Technical
was
tested
at
a
toxic
concentration
with
27
of
30
mice
showing
piloerection
and
9
of
15
male
mice
having
reduced
body
temperature
following
treatment.
Bone
marrow
cytotoxicity,
as
based
on
an
elevated
NCE/
PCE
ratio,
was
seen
in
test
material
treated
mice
at
48
and
72
hours
post­
treatment.
At
least
1000
PCEs
per
mouse
were
scored
for
micronuclei.
There
was
no
statistically
significant
increase
in
the
incidence
of
micronucleated
polychromatic
erythrocytes
(
PCEs)
over
the
concurrent
solvent
control
value
in
either
sex
at
any
harvest
time.
The
solvent
and
positive
control
induced
the
appropriate
responses.
There
was
no
statistically
significant
increase
in
the
frequency
of
micronucleated
polychromatic
erythrocytes
in
mouse
bone
marrow
at
any
harvest
time.

This
study
is
classified
as
Acceptable/
Guideline
and
satisfies
the
guideline
requirement
for
Test
Guideline
OPPTS
870.5395;
OECD
474
for
in
vivo
cytogenetic
mutagenicity
data.

STUDY
TYPE:
In
vitro
Bacterial
Gene
Mutation
(
Bacterial
system,
Salmonella
typhimurium;
E.
coli)/
mammalian
activation
gene
mutation
assay;
OPPTS
870.5100
[
§
84­
2];
OECD
471
(
formerly
OECD
471
&
472).

EXECUTIVE
SUMMARY:
In
a
reverse
gene
mutation
assay
in
bacteria
(
MRID
93089035
and
93089012),
strains
TA98,
TA100,
TA1535,
TA1537
and
TA1538
of
S.
typhimurium
were
exposed
to
Harvade
(
N252)(
98%
a.
i.,
lot
#
D­
11401)
in
DMSO
at
concentrations
of
0,
1,
10,
100,
500,
1000,
2500,
5000
or
10,000
µ
g/
plate
in
the
presence
and
absence
of
mammalian
metabolic
activation
(
S9­
mix).
A
second
assay
was
conducted
using
TA98
and
TA100
without
S9­
mix
and
a
third
assay
conducted
using
TA98
and
TA1538
with
S9­
mix.
All
plating
was
in
duplicate.
The
S9­
fraction
was
obtained
from
Aroclor
1254
induced
male
Sprague­
Dawley
rat
liver.
MRID
93089035
is
a
reformat
prepared
by
Uniroyal
Chemical
Co.,
Inc.
dated
July
5,
1990
of
the
original
study
dated
March
18,
1981.
MRID
93089012
is
a
summary
prepared
by
D.
L.
Story
dated
June
14,
1990.

Harvade
(
N252)
was
tested
up
to
10,000
µ
g/
plate,
twice
the
accepted
limit
concentration
of
5000
µ
g/
plate.
The
test
material
was
slightly
cytotoxic
to
TA1537
at
10,000
µ
g/
plate.
The
number
of
revertants
per
plate
was
not
increased
over
the
respective
solvent
control
value
at
any
test
material
concentration,
with
or
without
S9­
mix,
in
any
bacterial
strain.
The
tests
with
TA98
and
TA100
without
S9­
mix
were
repeated
because
of
a
low
positive
control
value
in
TA100
and
low
number
of
revertants
per
plate
at
several
test
material
concentrations
in
TA98.
The
tests
with
TA98
and
TA1538
with
S9­
mix
were
repeated
because
of
a
low
positive
control
value
in
58
TA1538
and
fungal
contamination
of
one
duplicate
plate
of
the
TA98
solvent
control.
The
repeat
assays
were
acceptable
and
confirmed
the
negative
results
of
the
initial
assay.
The
solvent
and
positive
controls
induced
the
appropriate
responses
in
the
corresponding
strains.
There
was
no
evidence
of
induced
mutant
colonies
over
background.

This
study
is
classified
as
Acceptable/
Guideline
and
satisfies
the
intent
of
the
guideline
requirement
for
Test
Guideline
OPPTS
870.5100;
OECD
471
for
in
vitro
mutagenicity
(
bacterial
reverse
gene
mutation)
data.

STUDY
TYPE:
In
Vitro
Mammalian
Cells
in
Culture
Gene
Mutation
assay
in
L5178Y
mouse
lymphoma
cells;
OPPTS
870.5300
[
§
84­
2];
OECD
476.

EXECUTIVE
SUMMARY:
In
a
mammalian
cell
gene
mutation
assay
at
the
TK
locus
(
MRID
93089041
and
93089029),
mouse
lymphoma
L5178Y
TK
±
cells
cultured
in
vitro
were
exposed
for
four
hours
to
Harvade
(
N252)
(
98%
a.
i.,
batch
No.
D­
11401)
in
DMSO
in
two
independent
assays.
In
the
first
assay,
cells
were
exposed
at
concentrations
of
0,
1.56,
12.5,
25.0,
50.0
or
75.0
µ
g/
mL
without
metabolic
activation
(
S9­
mix)
and
at
concentrations
of
0,
12.5,
50.0,
75.0,
100.0
or
150.0
µ
g/
mL
with
S9­
mix.
In
the
second
assay,
cells
were
exposed
at
concentrations
of
0,
25.0,
50.0,
75.0,
100.0,
150.0
or
200.0
µ
g/
mL
with
S9­
mix
only.
The
S9­
fraction
was
obtained
from
Aroclor
1254
induced
male
Fischer
344
rat
liver.

Harvade
(
N252)
was
tested
up
to
cytotoxic
concentrations.
In
the
first
mutation
assay,
the
test
material
reduced
the
percent
relative
growth
to
9.5%
at
75.00
µ
g/
mL
without
S9­
mix
and
to
6.1%
at
150
µ
g/
mL
with
S9­
mix.
The
mutant
frequency
did
not
exceed
the
background
mutant
frequency
or
approach
the
minimum
for
a
positive
response
(
calculated
as
32.6
x
10­
6
for
the
current
test)
at
any
test
material
concentration
without
S9­
mix.
However,
in
the
presence
of
S9­
mix,
weak
mutagenicity
was
seen
at
test
material
concentrations
of
75.0
µ
g/
mL
and
higher.
The
highest
mutant
frequency
of
56.4
x
10­
6
was
seen
at
100
µ
g/
mL.
The
minimum
mutant
frequency
for
a
positive
response
with
S9­
mix
was
calculated
as
41.1
x
10­
6.
In
the
confirmatory
assay
conducted
in
the
absence
of
S9­
mix
only,
positive
results
were
again
seen
at
test
material
concentrations
of
75.0
µ
g/
mL
and
higher.
The
mutant
frequencies
ranged
from
47.0
x
10­
6
at
75.0
µ
g/
mL
to
127.9
x
10­
6
at
200
µ
g/
mL,
exceeding
the
minimum
value
for
a
positive
response
for
the
test
of
43.9
x
10­
6.
The
positive
results,
however,
were
seen
only
at
very
cytotoxic
concentrations,
at
cell
survivals
less
than
10%
in
most
cases.
The
mutant
frequency
reached
a
doubling
of
that
calculated
as
minimal
for
a
positive
response
in
the
repeat
assay
only
at
relative
growth
rates
of
2.4%,
3.9%
and
1.6%.
Results
at
such
low
survival
rates
are
unreliable.
In
addition,
the
current
acceptance
criteria
for
this
assay
require
data
on
colony
sizing
and
some
indication
that
pH
and
osmolality
of
the
treatment
medium
did
not
affect
the
results.
This
information
was
not
provided.
The
testing
laboratory's
protocol
specifies
that
either
BrdU
or
TFT
could
be
used
as
the
selective
agent
but
the
investigators
did
not
report
which
was
used
in
this
study.
The
solvent
and
positive
controls
(
Ethyl
methanesulfonate
without
S9­
mix
and
Dimethylnitrosamine
with
S9­
mix)
induced
the
appropriate
responses.
There
was
an
indication
of
mutant
induction
in
the
presence
of
S9­
mix
but
only
at
very
cytotoxic
doses
of
Harvade
(
N252).
59
This
study
is
classified
as
Unacceptable/
Guideline.
It
does
not
satisfy
the
guideline
requirement
for
Test
Guideline
OPPTS
870.5300,
OECD
476
for
in
vitro
mutagenicity
(
mammalian
forward
gene
mutation)
data.

3.0
METABOLISM
CONSIDERATIONS
1.01
Introduction
1.1
Description
of
Issues
­
What
are
the
residues
of
concern
for
the
tolerance
expression
and
risk
assessment
in
plant
commodities,
animal
commodities,
rotational
crops
and
water?

1.2
Team
Proposal
­
The
Team
proposes
that:


for
the
tolerance
expression
and
risk
assessment
in
plant
commodities
the
residue
of
concern
is
dimethipin
per
se.


for
the
tolerance
expression
in
animal
commodities
the
residue
of
concern
is
dimethipin
per
se.
The
residue
of
concern
for
risk
assessment
is
dimethipin
per
se
in
all
animal
commodities
except
liver
and
dimethipin
plus
the
metabolite,
acetyl
dithiane
tetraoxide,
in
the
liver
of
cattle,
goats,
horses
and
sheep.


the
residue
of
interest
in
rotational
crops
is
dimethipin
per
se.


the
residue
of
concern
in
water
for
risk
assessment
is
dimethipin
per
se.

2.0
Nature
of
the
Residue
Studies
in
Plants
Metabolism
was
studied
only
in
cotton
because
dimethipin
is
registered
only
for
food
use
on
cotton.

2.1.1
Executive
Summary
of
Plant
Study
No.
1
[
MRID
43436901]

Greenhouse­
grown
cotton
was
treated
with
[
2,3­
14C]
dimethipin
at
1.22
lb
ai/
A
and
3.06
lb
ai/
A
(
2.2x
and
5.4x
the
maximum
seasonal
rate)
two
weeks
prior
to
harvest.
Total
radioactive
residues
were
97.1
ppm
in
foliage
and
0.291
ppm
in
seeds
from
plants
treated
at
the
2.2x
rate,
and
341.3
ppm
in
foliage
and
1.42
ppm
in
seeds
from
plants
treated
at
the
5.4x
rate.
Matrices
from
the
2.2x
treated
plants
were
subjected
to
extraction
and
characterization/
identification.
Dimethipin
per
se
was
found
to
comprise
74%
of
foliage
radioactivity
and
80%
of
seed
radioactivity;
no
additional
metabolites
were
identified.
60
2.1.2
Tabular
Summary
of
Plant
Study
No.
1
Table
2.1.2
Summary
of
Characterization
and
Identification
of
Radioactive
Residues
in
Cotton
MATRIX
TRR
Recovery
%
Extractable
TRR
Dimethipin1
Cotton
Foliage
95.2%
74
Cotton
Mature
Seeds
86.2%
80
1No
additional
metabolites
were
identified.

3.0
Nature
of
the
Residue
in
Livestock
3.1.1
Executive
Summary
of
Ruminant
Study
[
MRID
43922101]

Three
lactating
goats
were
orally
administered
a
gelatin
capsule
containing
either
[
14C]
dimethipin
or
a
mixture
of
[
14C
and
13C]
dimethipin
once
daily
for
five
consecutive
days.
The
administered
dose
levels
of
dimethipin
in
the
diet
were
3.066
ppm
(
low
dose)
for
the
first
goat,
1010.8
ppm
(
high
dose)
for
the
second
goat,
and
1290.0
ppm
(
high
dose)
for
the
third
goat.
The
daily
feeding
levels
were,
respectively,
equivalent
to
0.5x,
177x
and
226x
the
maximum
theoretical
dietary
burden
of
5.7
ppm
for
dairy
cattle
(
based
on
residues
in
cottonseed
meal
at
the
0.5
ppm
tolerance
level
and
a
high
end
estimate
of
cotton
gin
trash
residues
at
25
ppm).

The
TRR
were
0.005­
0.006
ppm
in
milk,
0.27
ppm
in
liver,
0.15
ppm
in
kidney,
0.002
ppm
in
muscle,
and
0.001
ppm
in
fat
from
the
goat
dosed
at
3.066
ppm,
0.68­
1.20
ppm
in
milk,
78.5
ppm
in
liver,
28.4
ppm
in
kidney,
0.64
ppm
in
muscle,
and
0.32
ppm
in
fat
from
the
goat
dosed
at
1010.8
ppm,
and
3.13­
4.26
ppm
in
milk,
45.0
ppm
in
liver,
55.2
ppm
in
kidney,
2.04
ppm
in
muscle,
and
0.99
ppm
in
fat
from
the
goat
dosed
at
1290.0
ppm.

Dimethipin
was
not
detected
in
milk
and
tissues
from
the
goat
dosed
at
3.066
ppm.
In
milk
from
this
goat,
dimethipin
cysteine
conjugate
(
34.8­
52.8%
TRR,
0.001­
0.002
ppm)
was
the
only
residue
identified.
In
kidney,
the
only
metabolite
identified
was
ethane
disulfonic
acid
(
75.6%
TRR,
0.11
ppm).
In
liver,
two
metabolites
were
identified:
ethane
disulfonic
acid
(
14.6%
TRR,
0.38
ppm)
and
acetyl
dithiane
tetraoxide
(
16.6%
TRR,
0.045
ppm).
No
attempts
were
made
to
characterize/
identify
radioactive
residues
in
fat
and
muscle
because
the
total
radioactive
residues
in
these
tissues
were
0.001
and
0.002
ppm,
respectively.

The
parent
dimethipin
was
also
not
detected
in
the
milk
and
tissues
of
the
goats
dosed
at
higher
levels.
Dimethipin
cysteine
conjugate
was
also
the
only
residue
identified
in
milk
(
25.2­
50.6%
TRR,
0.22­
0.55
ppm).
In
kidney,
ethane
disulfonic
acid
(
27.6%
TRR,
7.8
ppm)
and
acetyl
dithiane
tetraoxide
(
32.3%
TRR,
9.2
ppm)
were
identified.
In
muscle,
reduced
dimethipin
(
2,3­
61
dimethyl­
1,1,4,4­
tetraoxo­
1,4­
dithiane;
21.9%
TRR,
0.140
ppm)
was
identified.
In
liver,
ethane
disulfonic
acid
(
44.8%
TRR,
20.1
ppm)
was
identified.
Based
on
several
fractionation
and
extraction
procedures
employed
in
the
study,
the
registrant
believes
that
majority
of
radioactive
residues
in
kidney
and
liver
were
covalently
bound
to
proteins.

3.1.2
Tabular
Summary
of
Ruminant
Study
Table
3.1.2a
Distribution,
characterization
and
identification
of
total
radioactive
residues
in
milk
and
tissues
from
goats
dosed
with
[
14C]
dimethipin
at
3.066
ppm
(
low
dose)
in
the
diet
for
five
consecutive
days.

Fraction
%
TRR
ppm
Characterization/
Identification
a
Milk,
Day
1
(
TRR
=
0.005
ppm)

Aqueous
81.3
0.004
Anion­
exchange
HPLC
analysis
resolved:

dimethipin­
cysteine
52.8%
TRR
0.002
ppm
Nonextractable
NR
b
NR
Not
further
analyzed
(
N/
A).

Milk,
Day
2
(
TRR
=
0.005
ppm)

Aqueous
76.5
0.004
Anion­
exchange
HPLC
analysis
resolved:

dimethipin­
cysteine
34.8%
TRR
0.001
ppm
Nonextractable
NR
NR
N/
A.

Milk,
Day
3
(
TRR
=
0.006
ppm)

Aqueous
72.3
0.004
Anion­
exchange
HPLC
analysis
resolved:

dimethipin­
cysteine
44.2%
TRR
0.002
ppm
Nonextractable
NR
NR
N/
A.

Milk,
Day
4
(
TRR
=
0.006
ppm)

Aqueous
70.3
0.004
Anion­
exchange
HPLC
analysis
resolved:

dimethipin­
cysteine
41.1%
TRR
0.002
ppm
Nonextractable
NR
NR
N/
A.

Milk,
Day
5
(
TRR
=
0.005
ppm)

Aqueous
69
0.003
Anion­
exchange
HPLC
analysis
resolved:

dimethipin­
cysteine
38.5%
TRR
0.001
ppm
Nonextractable
NR
NR
N/
A.

Kidney
(
TRR
=
0.15
ppm)

Aqueous
99.7
0.15
Anion­
exchange
HPLC
analysis
resolved:

Ethane
disulfonic
acid
75.6%
TRR
0.11
ppm
Ion­
pairing
HPLC
analysis
resolved:

Ethane
disulfonic
acid
69.6%
TRR
0.10
ppm
Nonextractable
1.46
0.014
N/
A.

Liver
(
TRR
=
0.27
ppm)
­
Trypsin/
pepsin
digest/
RP
C18
Water
36.5
0.098
Subjected
to
amino
SPE
cleanup
with
the
following
fractions
isolated
for
HPLC
analysis.

Water
12.6
0.034
Anion­
exchange
HPLC
analysis
resolved:

Ethane
disulfonic
acid
0.8%
TRR
0.002
ppm
Unknown
Rt
=
3­
5
mins
3.6%
TRR
0.010
ppm
Unknown
Rt
=
23­
25
mins
4.7%
TRR
0.013
ppm
Unknown
Rt
=
26­
28
mins
0.6%
TRR
0.002
ppm
Table
3.1.2a
Distribution,
characterization
and
identification
of
total
radioactive
residues
in
milk
and
tissues
from
goats
dosed
with
[
14C]
dimethipin
at
3.066
ppm
(
low
dose)
in
the
diet
for
five
consecutive
days.

Fraction
%
TRR
ppm
Characterization/
Identification
a
62
1%
TFA
7.4
0.027
Anion­
exchange
HPLC
analysis
resolved:

Ethane
disulfonic
acid
1.3%
TRR
0.003
ppm
Unknown
Rt
=
3­
5
mins
1.6%
TRR
0.004
ppm
Unknown
Rt
=
23­
25
mins
0.5%
TRR
0.001
ppm
Unknown
Rt
=
26­
28
mins
1.6%
TRR
0.004
ppm
Unknown
Rt
=
36­
38
mins
0.7%
TRR
0.002
ppm
25%
TFA
17
0.045
Anion­
exchange
HPLC
analysis
resolved:

Ethane
disulfonic
acid
12.1%
TRR
0.032
ppm
Unknown
Rt
=
23­
25
mins
1.4%
TRR
0.004
ppm
25%
Aqueous
methanol
48.6
0.13
Subjected
to
amino
SPE
cleanup
with
the
following
fractions
isolated
for
HPLC
analysis.

Water
25.1
0.067
Anion­
exchange
HPLC
analysis
resolved:

Acetyl
dithiane
tetraoxide
14.9%
TRR
0.040
ppm
Unknown
Rt
=
23­
25
mins
5.5%
TRR
0.015
ppm
1%
TFA
18.6
0.05
Anion­
exchange
HPLC
analysis
resolved:

Acetyl
dithiane
tetraoxide
1.7%
TRR
0.005
ppm
Unknown
Rt
=
3­
5
mins
2.3%
TRR
0.006
ppm
Unknown
Rt
=
26­
28
mins
5.1%
TRR
0.014
ppm
Unknown
Rt
=
33­
34
mins
2.1%
TRR
0.006
ppm
Unknown
Rt
=
35
mins
1.2%
TRR
0.003
ppm
Unknown
Rt
=
36­
38
mins
1.7%
TRR
0.005
ppm
Subjected
to
non­
specific
protease
digestion.

Protease
digest
NR
NR
Anion­
exchange
HPLC
analysis
resolved:

Acetyl
dithiane
tetraoxide
1.6%
TRR
0.004
ppm
Unknown
Rt
=
4­
5
mins
7.2%
TRR
0.019
ppm
Unknown
Rt
=
22
mins
0.9%
TRR
0.002
ppm
Unknown
Rt
=
23­
24
mins
4.2%
TRR
0.011
ppm
Unknown
Rt
=
26­
27
mins
1.5%
TRR
0.004
ppm
25%
TFA
4.6
0.012
Anion­
exchange
HPLC
analysis
resolved:

Ethane
disulfonic
acid
0.4%
TRR
0.001
ppm
Unknown
Rt
=
3­
5
mins
2.0%
TRR
0.005
ppm
Unknown
Rt
=
17­
19
mins
0.3%
TRR
0.001
ppm
Unknown
Rt
=
26­
28
mins
0.6%
TRR
0.002
ppm
50%
Aqueous
methanol
14.1
0.038
Anion­
exchange
HPLC
analysis
resolved:

Unknown
Rt
=
17­
19
mins
1.3%
TRR
0.003
ppm
Unknown
Rt
=
36­
38
mins
2.7%
TRR
0.007
ppm
Unknown
Rt
=
41­
43
mins
2.4%
TRR
0.006
ppm
Unknown
Rt
=
44­
47
mins
2.3%
TRR
0.006
ppm
Nonextractable
NR
NR
N/
A.

aRefer
to
Table
3.4
for
the
structures
of
identified
metabolites.

bNR
=
not
reported.
63
Table
3.1.2b
Distribution,
characterization
and
identification
of
total
radioactive
residues
in
milk
and
tissues
from
goats
dosed
with
[
14C]
dimethipin
at
1010.8
ppm
(
high
dose)
or
with
a
mixture
of
[
14C
and
13C]
dimethipin
at
1290
ppm
in
the
diet
for
five
consecutive
days.

Fraction
%
TRR
ppm
Characterization/
Identification
a
Milk,
Day
1
(
TRR
=
0.68
ppm)

Aqueous
86.4
0.588
Ion­
pairing
HPLC
analysis
resolved:

dimethipin­
cysteine
32.9%
TRR
0.22
ppm
Unknown
#
1
15.4%
TRR
0.10
ppm
Unknown
#
2
8.2%
TRR
0.056
ppm
Nonextractable
NR
b
NR
Extracted
with
hexane.

Hexane
3.7
0.025
Not
further
analyzed
(
N/
A).

Nonextractable
NR
NR
N/
A.

Milk,
Day
2
(
TRR
=
1.20
ppm)

Aqueous
88.4
1.061
Ion­
pairing
HPLC
analysis
resolved:

dimethipin­
cysteine
25.2%
TRR
0.30
ppm
Unknown
#
1
20.3%
TRR
0.24
ppm
Unknown
#
2
9.3%
TRR
0.11
ppm
Nonextractable
NR
NR
Extracted
with
hexane.

Hexane
3.5
0.042
N/
A.

Nonextractable
NR
NR
N/
A.

Milk,
Day
3
(
TRR
=
1.12
ppm)

Aqueous
92.8
1.039
Ion­
pairing
HPLC
analysis
resolved:

dimethipin­
cysteine
35.8%
TRR
0.40
ppm
Unknown
#
1
20.7%
TRR
0.23
ppm
Unknown
#
2
11.9%
TRR
0.13
ppm
Nonextractable
NR
NR
Extracted
with
hexane.

Hexane
4.9
0.055
N/
A.

Nonextractable
NR
NR
N/
A.

Milk,
Day
4
(
TRR
=
0.99
ppm)

Aqueous
88.5
0.876
Ion­
pairing
HPLC
analysis
resolved:

dimethipin­
cysteine
39.3%
TRR
0.39
ppm
Unknown
#
1
16.7%
TRR
0.17
ppm
Unknown
#
2
12.1%
TRR
0.12
ppm
Nonextractable
NR
NR
Extracted
with
hexane.

Hexane
5.3
0.052
N/
A.

Nonextractable
NR
NR
N/
A.

Milk,
Day
5
(
TRR
=
1.08
ppm)

Aqueous
89.7
0.969
Ion­
pairing
HPLC
analysis
resolved:

dimethipin­
cysteine
50.6%
TRR
0.55
ppm
Unknown
#
1
11.6%
TRR
0.13
ppm
Unknown
#
2
8.2%
TRR
0.088
ppm
Nonextractable
NR
NR
Extracted
with
hexane.

Hexane
5.4
0.058
N/
A.

Nonextractable
NR
NR
N/
A.

Fat
(
TRR
=
0.32
ppm)
Table
3.1.2b
Distribution,
characterization
and
identification
of
total
radioactive
residues
in
milk
and
tissues
from
goats
dosed
with
[
14C]
dimethipin
at
1010.8
ppm
(
high
dose)
or
with
a
mixture
of
[
14C
and
13C]
dimethipin
at
1290
ppm
in
the
diet
for
five
consecutive
days.

Fraction
%
TRR
ppm
Characterization/
Identification
a
64
Hexane
6.4
0.02
Partitioned
with
ACN
and
methanol;
partitioned
phases
were
combined
with
the
ACN
and
methanol
extracts
of
the
nonextractable.

Nonextractable
NR
NR
Sequentially
extracted
with
ACN
and
methanol;
extracts
combined
with
ACN
and
methanol
partitioned
phases
of
the
hexane
extract.

Methanol/
ACN
28.1
0.09
Ion­
pairing
HPLC
analysis
resolved:

Unknown
­
early
eluting
11.5%
TRR
0.004
ppm
Partitioned
with
hexane.

Hexane
2.9
0.0093
N/
A.

Precipitate
23.3
0.075
N/
A.

Nonextractable
37.5
0.012
N/
A.

Kidney
(
TRR
=
28.4
ppm)

Aqueous
104.4
29.65
Anion­
exchange
HPLC
analysis
resolved:

Ethane
disulfonic
acid
34.2%
TRR
9.7
ppm
Ion­
pairing
HPLC
analysis
resolved:

Ethane
disulfonic
acid
30.5%
TRR
8.7
ppm
Hydrolyzed
with
HCl­
BuOH.

BuOH/
HCl
91.7
26.04
Reverse
phase
HPLC
analysis
resolved:

Ethane
disulfonic
acid
18.3%
TRR
5.2
ppm
Acetyl
dithiane
tetraoxide
34.6%
TRR
9.8
ppm
Ion­
pairing
HPLC
analysis
resolved:

Ethane
disulfonic
acid
27.6%
TRR
7.8
ppm
Acetyl
dithiane
tetraoxide
32.3%
TRR
9.2
ppm
Nonextractable
NR
NR
N/
A.

Liver
(
13C/
14C
Label;
TRR
=
44.9
ppm)

Trypsin/
pepsin
digest
106
45
Reverse
phase
HPLC
analysis
resolved:

Acetyl
dithiane
tetraoxide
11.3%
TRR
5.1
ppm
Unknown
Rt
=
3­
5
mins
51.5%
TRR
23.1
ppm
Unknown
Rt
=
29­
31
mins
7.9%
TRR
3.5
ppm
Subsample
1:
Supernatant
was
subjected
to
C18
column
chromatography
and
the
water
fraction
(
106%
TRR,
44.9
ppm)
was
subjected
to
bonded­
phase
amino
SPE
cleanup;
the
25%
TFA
fraction
(
75.8%
TRR,
34.0
ppm)
was
subjected
to
anion­
exchange
SPE
with
the
following
fractions
isolated
for
HPLC
analysis.

Subsample
2:
A
subsample
was
hydrolyzed
with
BuOH­
HCl
and
TFA.

Subsample
1
2.5%
TFA
22.9
10.3
Anion­
exchange
HPLC
analysis
resolved:

Ethane
disulfonic
acid8.5%
TRR
3.8
ppm
Unknown
Rt
=
14­
15
mins
1.8%
TRR
0.79
ppm
Unknown
Rt
=
21­
22
mins
3.8%
TRR
1.7
ppm
Unknown
Rt
=
23­
25
mins
2.6%
TRR
1.1
ppm
Unknown
Rt
=
26­
29
mins
1.7%
TRR
0.77
ppm
Table
3.1.2b
Distribution,
characterization
and
identification
of
total
radioactive
residues
in
milk
and
tissues
from
goats
dosed
with
[
14C]
dimethipin
at
1010.8
ppm
(
high
dose)
or
with
a
mixture
of
[
14C
and
13C]
dimethipin
at
1290
ppm
in
the
diet
for
five
consecutive
days.

Fraction
%
TRR
ppm
Characterization/
Identification
a
65
5.0%
TFA
50.9
22.8
Anion­
exchange
HPLC
analysis
resolved:

Ethane
disulfonic
acid
36.3%
TRR
16.3
ppm
Unknown
Rt
=
21­
22
mins
3.9%
TRR
1.7
ppm
Subsample
2
BuOH/
HCl
hydrolysate
NR
NR
Reverse
phase
HPLC
analysis
resolved:

Acetyl
dithiane
tetraoxide
20.4%
TRR
9.2
ppm
Unknown
Rt
=
3­
5
mins
13.1%
TRR
5.9
ppm
Unknown
Rt
=
8­
9
mins
5.9%
TRR
2.6
ppm
Unknown
Rt
=
18­
20
mins
26.3%
TRR
11.8
ppm
Unknown
Rt
=
29­
31
mins
7.0%
TRR
3.1
ppm
TFA
NR
NR
Reverse
phase
HPLC
analysis
resolved:

Acetyl
dithiane
tetraoxide
19.3%
TRR
8.7
ppm
Unknown
Rt
=
3­
5
mins
19.2%
TRR
8.6
ppm
Unknown
Rt
=
18­
20
mins
24.7%
TRR
11.1
ppm
Unknown
Rt
=
29­
31
mins
6.1%
TRR
2.7
ppm
Nonextractable
NR
NR
N/
A.

Muscle
(
TRR
=
0.64
ppm)
­
HCl­
BuOH
hydrolysis
and
SPE
cleanup
Aqueous
27
0.17
Ion­
pairing
HPLC
analysis
resolved:

Unknown
Rt
=
5
mins
16.7%
TRR
0.107
ppm
Unknown
Rt
=
11
mins
1.5%
TRR
0.009
ppm
Anion­
exchange
HPLC
analysis
resolved:

Unknown
Rt
=
26
mins
4.0%
TRR
0.025
ppm
Unknown
Rt
=
41
mins
1.8%
TRR
0.012
ppm
Unknown
Rt
=
54
mins
7.1%
TRR
0.045
ppm
Unknown
Rt
=
57
mins
2.7%
TRR
0.017
ppm
Methanol
59.6
0.38
Ion­
pairing
HPLC
analysis
resolved:

Reduced
dimethipin
21.9%
TRR
0.140
ppm
Unknown
Rt
=
7
mins
2.8%
TRR
0.018
ppm
Unknown
Rt
=
11
mins
6.2%
TRR
0.040
ppm
Unknown
Rt
=
15
mins
7.2%
TRR
0.046
ppm
Unknown
Rt
=
35
mins
3.6%
TRR
0.023
ppm
Anion­
exchange
HPLC
analysis
resolved:

Reduced
dimethipin
22.9%
TRR
0.146
ppm
Unknown
Rt
=
17
mins
7.3%
TRR
0.047
ppm
Unknown
Rt
=
26
mins
2.9%
TRR
0.018
ppm
Unknown
Rt
=
61
mins
6.5%
TRR
0.041
ppm
Ethyl
acetate
4.8
0.031
N/
A.

Nonextractable
NR
NR
N/
A.

aRefer
to
Table
3.4
for
the
structures
of
identified
metabolites.

bNR
=
not
reported.

3.1.3
Executive
Summary
of
Poultry
Study
[
MRID
42706001]

Two
groups
of
hens
were
orally
dosed
with
[
14C]
dimethipin
for
five
consecutive
days.
Five
hens
(
Group­
I)
received
a
low
dose
(
203.5
ppm)
of
[
14C]
dimethipin
with
a
specific
activity
of
0.6592
66
mCi/
mmole
(
6906
dpm/

g),
and
two
hens
(
Group­
II)
received
a
high
dose
(
2772
ppm)
with
a
specific
activity
of
0.1341
mCi/
mmole
(
1405
dpm/

g).
The
low
and
high
doses
were
equivalent
to
2035x
and
27,720x
the
maximum
theoretical
dietary
burden
for
poultry
of
0.1
ppm,
calculated
based
on
the
cottonseed
meal
tolerance
of
0.5
ppm.
The
[
14C]
dimethipin
had
a
radiochemical
purity
of
>
95%.
The
position
of
the
radiolabel
was
at
the
2­
and
3­
carbons
in
the
dithiin
ring.
Five
additional
hens
were
used
as
controls.

The
TRR
were
0.12­
12
ppm
in
egg
whites,
0.34­
16
ppm
in
egg
yolks,
2.4
ppm
in
fat,
10
ppm
in
thigh
muscle,
10
ppm
in
breast
muscle,
39
ppm
in
kidney,
and
65
ppm
in
liver.
Dimethipin
per
se
was
not
detected
in
any
poultry
matrices,
however
reduced
dimethipin
was
found
in
all
matrices
except
thigh
muscle
and
fat,
0.98­
7.8%
TRR
(
0.21­
5.0
ppm).
In
all
matrices
except
liver,
the
predominant
metabolite
was
Glu­
Cys­
S­
Harv
[
S­(
2,3­
dimethyl­
1,1,4,4­
tetraoxo­
1,4­
dithian­
yl)­
Lcysteinyl
 ­
glutamic
acid],
at
19­
36%
TRR
(
0.48­
7.5
ppm);
this
metabolite
was
found
in
liver
at
7.4%
TRR
(
4.8
ppm).
The
most
significant
liver
metabolite
was
dimethipin
cysteine
conjugate
(
Harv­
S­
Cys),
at
21.5%
TRR
(
14
ppm);
this
metabolite
was
found
in
all
other
matrices
except
fat,
at
0.1­
7.0%
TRR
(
0.01­
2.8
ppm).
The
major
metabolic
pathway
proposed
by
the
registrant
involved
the
formation
of
thioethers
of
dimethipin;
other
minor
pathways
involved
reduction
and
hydroxylation
of
dimethipin.
67
3.1.4
Tabular
Summary
of
Poultry
Study
Table
3.1.4
Characterization/
Identification
of
14C­
residues
in
egg
and
tissues
from
hens
fed
uniformly
labeled
[
14C]
dimethipin
at
the
high
dose
(
2772
ppm).

Metabolite
ID
Egg
White
Egg
Yolk
Liver
Kidney
Gizzard
Breast
Muscle
Thigh
Muscle
Fat
%
TRR
PPM
(
6.6)
%
TRR
PPM
(
6.9)
%
TRR
PPM
(
65)
%
TRR
PPM
(
39)
%
TRR
PPM
(
20)
%
TRR
PPM
(
10)
%
TRR
PPM
(
10)
%
TRR
PPM
(
2.4)

Reduced
dimethipin
7.8
0.51
4.7
0.33
7.6
5.0
0.98
0.34
2.5
0.51
2.1
0.21
­
­
­
­

Harv­
S­
Methyl
­
a
­
0.62
0.04
7.3
4.7
­
­
­
­
­
­
­
­
­
­

Harv­
prim­

OH
2.3
0.15
2.9
0.20
3.1
2.0
­
­
0.77
0.15
­
­
­
­
­
­

Harv­
tert­
OH
1.2
0.08
­
­
2.9
1.9
4.4
1.7
­
­
­
­
­
­
­
­

Harv­
SOMethyl
6.0
0.40
0.95
0.07
0.95
0.62
1.2
0.48
­
­
0.20
0.02
­
­
­
­

Harv­
S­
Cys
0.10
0.01
3.9
0.27
21.5
14
7.0
2.8
11
2.2
2.3
0.23
5.0
0.50
­
­

Harv­
GSH
3.4
0.23
8.1
0.56
5.9
3.9
3.5
1.4
4.1
0.83
1.0
0.10
4.3
0.43
­
­

Glu­
Cys­

SHarv
25
1.7
36
2.5
7.4
4.8
19
7.5
21
4.3
32
3.2
28
2.8
20
0.48
Harv­
SAcetate
­
­
6.8
0.47
­
­
­
­
­
­
0.60
0.06
­
­
­
­

Harv­
SH
3.8
0.25
0.92
0.60
0.92
0.60
­
­
0.71
0.14
­
­
­
­
­
­

Identified
49.6
3.27
64.9
4.48
57.7
37.8
36.08
16.32
39.98
8.13
38.2
3.82
37.3
3.73
20
0.48
Unknown
#
1
0.25
0.017
­
­
1.3
0.82
­
­
0.29
0.059
0.13
0.013
1.7
0.17
3.1
0.074
Unknown
#
2
1.1
0.07
7.6
0.53
3.1
2.0
17
6.5
15
3.1
28
2.8
16
1.6
­
­

Unknown
#
3
­
­
­
­
0.45
0.29
­
­
­
­
­
­
­
­
­
­

Unknown
#
4
­
­
­
­
2.4
1.6
2.8
1.1
­
­
2.2
0.22
­
­
­
­

Unknown
#
5
­
­
­
­
0.58
0.38
1.6
0.6
­
­
­
­
­
­
­
­

Unknown
#
6
­
­
5.0
0.34
0.36
0.24
­
­
­
­
­
­
­
­
­
­

Unknown
#
7
3.8
0.25
­
­
­
­
­
­
­
­
­
­
­
­
­
­

Unknown
#
8
12
0.82
4.1
0.28
0.91
0.59
4.0
1.6
8.8
1.7
3.4
0.34
3.6
0.36
­
­

Unknown
#
9
­
­
­
­
0.25
0.16
­
­
0.86
0.17
­
­
0.51
0.051
­
­
Table
3.1.4
Characterization/
Identification
of
14C­
residues
in
egg
and
tissues
from
hens
fed
uniformly
labeled
[
14C]
dimethipin
at
the
high
dose
(
2772
ppm).
68
Characterized
17.15
1.16
16.7
1.15
9.35
6.08
25.4
9.8
24.95
5.03
33.73
3.37
21.81
2.18
3.1
0.074
Totalb
66.75
4.43
81.6
5.63
67.1
43.88
61.48
26.12
64.93
13.16
71.93
7.19
59.11
5.91
23.1
0.55
Baselinec
20
1.3
15
1.1
26
17
12
4.7
31.0
5.0
14
1.4
13
1.3
16
0.39
Boundd
20
1.3
1.9
0.13
1.3
0.85
2.3
0.86
1.3
0.26
0.96
0.096
2.1
0.22
24
0.58
a
None
reported.

b
Includes
identified
and
characterized
residues.

c
Baseline
radioactivity
refers
to
radioactivity
which
did
not
elute,
or
eluted
but
was
not
associated
with
a
specific
peak.

d
Bound
residues
remaining
after
enzyme
hydrolysis.
There
is
a
discrepancy
in
the
registrant's
report
regarding
the
bound
residues
in
fat
(
the
bound
TRR
is
either
5%
or
24%
of
the
total).
69
4.0
Confined
Rotational
Crop
Studies
4.1
Summary
of
Rotational
Crop
Studies
Two
confined
rotational
crop
studies
[
MRID
42666301,
42757801,
43768201,
43768202
and
43931301]
and
two
limited
field
rotational
crop
studies
[
MRID
43979101
and
43979102]
were
submitted.

In
the
confined
studies
[
14C]
Dimethipin
was
applied
to
the
soil
at
0.54
lb
ai/
A
(
1x
the
maximum
seasonal
rate),
and
rotational
crops
of
lettuce,
carrots,
and
barley
were
planted
30
and
183
days
after
application.
Samples
of
immature
and
mature
lettuce;
immature
and
mature
carrot
root
and
top;
and
barley
forage,
grain,
and
straw
were
collected.
In
samples
from
the
30­
day
plant
back
interval,
dimethipin
was
identified
in
immature
and
mature
lettuce
(
0.064­
0.091
ppm),
mature
carrot
tops
(
0.024
ppm),
immature
and
mature
carrot
root
(
0.016­
0.039
ppm),
barley
forage
(
0.025
ppm),
and
barley
straw
(
0.012
ppm).
Hydroxylated
dimethipin
(
metabolite
H­
5)
was
identified
at
low
levels
(
0.009
ppm)
in
barley
straw.
Two
additional
metabolites,
dimethipin
cysteine
conjugate
(
H­
80)
and
a
mercaptolactic
acid
conjugate,
were
identified
in
immature
lettuce
at
0.023
ppm
(
2.1%
TRR)
and
0.151
ppm
(
13.68%
TRR),
respectively.
In
samples
from
the
183­
day
plant
back
interval,
dimethipin
was
identified
in
immature
carrot
tops
(
0.041
ppm)
but
was
not
identified
in
any
other
matrix.
No
additional
metabolites
were
identified
at
the
183­
day
plant
back
interval.

5.0
Analytical
Methodology
For
enforcement
of
tolerances
for
residues
of
dimethipin,
PAM
Vol.
II
lists
two
methods,
Method
I
for
cottonseed
and
Method
II
for
animal
tissues
and
eggs.
The
stated
detection
limits
are
0.1
ppm
for
cottonseed
and
0.02
ppm
for
animal
commodities.
In
Method
I,
samples
are
extracted
with
methanol/
water,
the
extract
is
washed
with
hexane
to
remove
oil,
the
residues
are
partitioned
into
chloroform,
the
chloroform
extract
is
evaporated
to
dryness
and
redissolved
in
benzene/
chloroform,
and
the
extract
is
cleaned
up
on
a
Florisil/
alumina
column
prior
to
analysis
using
GC/
FPD.
In
Method
II,
samples
are
extracted
with
acetonitrile,
the
extract
is
washed
with
petroleum
ether,
the
acetonitrile
phase
is
evaporated
to
dryness
and
redissolved
in
benzene/
chloroform,
and
the
extract
is
cleaned
up
on
a
Florisil/
alumina
column
prior
to
analysis
by
GC/
MS
with
selected
ion
monitoring.

The
registrant
has
submitted
a
revised
version
of
the
enforcement
method
for
cottonseed
to
include
instructions
for
the
analysis
of
cottonseed
processed
commodities,
the
use
of
toluene
instead
of
benzene
as
a
solvent,
and
a
GPC
cleanup
step.
The
revised
method
has
undergone
adequate
independent
laboratory
validation.
The
requested
waiver
of
the
requirement
for
additional
method
validation
(
including
Agency
method
validation)
for
this
method
has
been
approved.
The
method
(
in
MRID
43109801)
should
be
forwarded
to
FDA
for
publication
in
PAM
Vol.
II
as
a
replacement
for
Method
I.
70
The
FDA
PESTDATA
database
dated
11/
01
(
PAM
Volume
I,
Appendix
I)
indicates
that
dimethipin
is
completely
recovered
using
Multiresidue
Methods
Section
302
(
Luke
Method;
Protocol
D)
but
is
not
recovered
using
Section
303
(
Mills,
Onley,
and
Gaither
Method;
Protocol
E,
nonfatty
food)
or
Section
304
(
Mills
Method;
Protocol
F,
fatty
food).

6.0
Summary
of
Magnitude
of
Residue
(
MOR)
Studies
6.1
Plants
[
MRIDs:
42920901,
42920902,
42920903,
43184101,42467001,
42467002]

Field
Trials:
Residues
of
dimethipin
were
<
0.10­
0.215
ppm
in/
on
cottonseed
treated
with
two
applications
of
the
4.9
lb/
gal
FlC
formulation
at
0.3125
lb
ai/
A
and
0.2344
lb
ai/
A
(
1x
the
maximum
registered
seasonal
rate);
tests
were
conducted
in
AR,
GA,
LA,
MS,
TN,
and
TX.
Additional
data,
from
field
trials
conducted
in
CA,
GA,
MS,
and
TX,
indicate
that
the
residues
of
dimethipin
are
not
likely
to
exceed
the
established
tolerance
of
0.5
ppm
in/
on
cottonseed
harvested
7
days
following
two
broadcast
foliar
applications
of
the
4.9
lb/
gal
FlC
formulation
at
0.31
and
0.23
lb
ai/
A
(
1x
the
maximum
registered
seasonal
rate);
dimethipin
residues
were
<
0.10­
0.260
ppm.

Data
must
be
submitted
depicting
dimethipin
residues
in
cotton
gin
byproducts
which
include
burrs,
leaves,
stem,
lint,
immature
seeds
and
sand
(
dirt)
obtained
from
ginning
cotton.

Processed
Food
and
Feed:
The
available
processing
data
indicate
that
residues
of
dimethipin
do
not
concentrate
in
cottonseed
meal
(
average
processing
factor
of
<
0.22x),
hulls
(
average
processing
factor
of
0.96x),
or
refined
oil
(
average
processing
factor
of
<
0.22x)
processed
from
cotton
treated
at
2x
the
maximum
seasonal
rate.

6.2
Livestock
[
MRIDs:
43966401,
44147201,
44147202]

Cattle
A
dairy
cattle
feeding
study
with
dimethipin
has
been
conducted.
Dimethipin
was
administered
orally
to
11
Holstein
dairy
cattle
daily
for
28
days.
Dosing
was
made
at
5,
16,
and
55
ppm
in
the
feed,
equivalent
to
approximately
1x,
3x,
and
10x
the
tentative
maximum
theoretical
dietary
burden
to
beef
and
dairy
cattle.
Milk
samples
were
collected
twice
daily.
Cows
were
sacrificed
within
24
hours
of
the
final
dose,
and
samples
of
milk,
muscle,
liver,
and
kidney
were
collected.
Residues
of
dimethipin
were
below
the
limit
of
quantitation
(<
0.01
ppm)
in
samples
of
milk
(
collected
on
study
days
0,
7,
14,
21,
and
28),
muscle,
liver,
and
kidney
from
the
55­
ppm
dosing
group.
As
a
result,
samples
of
cattle
commodities
from
the
5­
and
16­
ppm
dosing
groups
were
not
analyzed.

The
registrant
did
not
collect
or
analyze
samples
of
fat
from
dosed
cattle
in
this
study.
Based
on
the
available
goat
metabolism
data,
which
indicated
that
total
radioactive
residues
were
lowest
in
fat
(
as
compared
with
muscle,
liver,
and
kidney)
following
dosing
with
[
14C]
dimethipin
at
levels
71
similar
to
and
greatly
exceeding
those
of
the
feeding
study,
data
depicting
dimethipin
residues
in
cattle
fat
are
not
required.

The
registrant
also
submitted
data
from
analyses
of
kidney
samples,
from
the
above
described
feeding
study,
for
residues
of
a
dimethipin
metabolite,
1,2­
ethanedisulfonic
acid
(
EDSA).
Residues
of
EDSA
were
below
the
LOQ
(<
0.100
ppm)
in
samples
of
kidney
from
cattle
in
the
5­
ppm
dosing
group,
0.218­
0.376
ppm
in
kidney
from
the
16­
ppm
dosing
group,
and
0.315­
0.663
ppm
in
kidney
from
the
55­
ppm
dosing
group.
The
results
for
kidney
samples
from
the
55­
ppm
dosing
group
were
confirmed
by
a
second
laboratory;
residues
were
determined
to
be
0.22­
0.54
ppm
in
these
samples.

Poultry
Based
on
the
results
of
the
poultry
metabolism
study,
the
Agency
has
concluded
that
dimethipin
residues
in
poultry
may
be
classified
under
40
CFR
§
180.6(
a)(
3);
i.
e.,
there
is
no
reasonable
expectation
of
finite
residues
in
poultry
commodities.
Therefore,
no
poultry
feeding
study
is
required.

7.0
International
Considerations
The
Codex
Alimentarius
Commission
has
established
several
maximum
residue
limits
(
MRLs)
for
residues
of
dimethipin
in/
on
various
commodities.
The
Codex
MRLs
are
expressed
in
terms
of
dimethipin
per
se.
The
Codex
MRL
and
the
U.
S.
tolerance
expressions
are
compatible.

A
comparison
of
the
Codex
MRLs
and
the
corresponding
reassessed
U.
S.
tolerances
is
presented
in
Table
3.8.
The
U.
S.
tolerance
and
Codex
MRL
are
identical
in
magnitude
for
cottonseed
and
livestock
meat
commodities.
There
are
several
Codex
MRLs
for
which
there
are
no
U.
S.
tolerances,
either
because
no
U.
S.
registrations
exist
(
plant
RAC
MRLs)
or
because
U.
S.
tolerances
are
not
needed
(
processed
commodity,
poultry
commodities
and
milk
MRLs).

There
are
no
Canadian
MRLs
established
for
dimethipin.
There
are
Mexican
MRLs
for
"
dimetipin"
on
cottonseed
(
0.5
mg/
kg)
and
potato
(
0.05
mg/
kg).

Table
7.0
Codex
MRLs
and
applicable
U.
S.
tolerances
for
dimethipin.
Recommendations
are
based
on
conclusions
following
reassessment
of
U.
S.
tolerances.

Codex
Reassessed
U.
S.
Tolerance,
ppm
Recommendation
And
Comments
Commodity,
As
Defined
MRL
(
mg/
kg)
Step
Cotton
seed
0.5
CXL
0.5
Harmonized.

Cotton
seed
oil,
Crude
0.1
CXL
­­
No
separate
tolerance
established
in
U.
S.
for
cotton
seed
oil.
Table
7.0
Codex
MRLs
and
applicable
U.
S.
tolerances
for
dimethipin.
Recommendations
are
based
on
conclusions
following
reassessment
of
U.
S.
tolerances.

Codex
Reassessed
U.
S.
Tolerance,
ppm
Recommendation
And
Comments
Commodity,
As
Defined
MRL
(
mg/
kg)
Step
72
Cotton
seed
oil,
Edible
0.02(*)
1
CXL
­­
No
separate
tolerance
established
in
U.
S.
for
cotton
seed
oil.

Edible
offal
(
mammalian)
0.02(*)
CXL
0.02
U.
S
tolerances
established
for
meat
by­
products.

Eggs
0.02(*)
CXL
­­
U.
S.
tolerances
not
necessary
for
poultry
and
egg
commodities.

Linseed
0.2
CXL
­­
No
U.
S.
registrations
for
use
on
linseed.

Meat
(
from
mammals
other
than
marine
mammals)
0.02(*)
CXL
0.02
Harmonized.

Milks
0.02(*)
CXL
­­
U.
S.
tolerances
not
necessary
for
milk.

Potato
0.05(*)
CXL
­­
No
U.
S.
registrations
for
use
on
potato.

Poultry
meat
0.02(*)
CXL
­­
U.
S.
tolerances
not
necessary
for
poultry
commodities.

Poultry,
Edible
offal
of
0.02(*)
CXL
­­
U.
S.
tolerances
not
necessary
for
poultry
commodities.

Rape
seed
0.1
CXL
­­
No
U.
S.
registrations
for
use
on
rape
seed.

Sunflower
seed
0.5
CXL
­­
No
U.
S.
registrations
for
use
on
sunflower.

Sunflower
seed
oil,
Crude
0.1
CXL
­­
No
U.
S.
registrations
for
use
on
sunflower.

Sunflower
seed
oil,
Edible
0.02
CXL
­­
No
U.
S.
registrations
for
use
on
sunflower.

8.0
Environmental
Degradation
8.1
Environmental
Persistence
73
Dimethipin
degrades
slowly
under
laboratory
and
field
conditions,
with
the
apparent
primary
route
of
dissipation
in
the
field
being
leaching
coupled
with
photodegradation
at
the
soil
surface
and
metabolic
degradation
throughout
the
soil
column.

In
buffered
aqueous
solutions,
Dimithipin
was
stable
to
hydrolysis
with
half­
lives
>
2
years
at
pHs
3­
9
and
photodegraded
slowly
to
very
slowly
with
half­
lives
ranging
from
60
days
(
pH
5)
to
224
days
(
pH
7)
at
pH
5­
9.
In
sandy
loam
soil,
dimethipin
photodegraded
with
a
half­
life
of
75
days.
In
metabolism
studies,
dimethipin
degraded
under
aerobic
conditions
with
a
half­
life
of
408
days
and
under
anaerobic
aquatic
conditions
with
a
half­
life
of
277
days.

Octanol/
water
partitioning
(
Kow)
data
provided
by
the
registrant
indicate
a
low
potential
for
dimethipin
to
accumulate
in
fish
(
Kow
for
dimethipin
=
0.66).

8.2
Expected
Mobility
Dimethipin
has
very
high
mobility
in
soils
ranging
from
sand
to
clay,
with
Freundlich
adsorption
coefficients
of

0.09.
In
field
studies
using
bare
ground
and
cropped
plots,
dimethipin
leached
to
a
depth
of
75­
90
cm.

Volatilization
is
not
expected
to
be
a
significant
since
the
reported
vapor
pressure
is
<
3.87
x
10­
7
mm
Hg
at
24

C.

8.3
Environmental
Metabolites
No
major
transformation
products
were
identified
in
any
environmental
fate
study.
2,3­
Dihydro­
5­
hydroxymethyl­
6­
methyl­
1,4­
dithiin­
1,1,4,4­
tetraoxide
(
H­
5)
was
a
minor
transformation
product
at
<
2%
of
the
applied
in
the
photodegradation
in
water
study
only.
The
saturated
carboxylic
acid
of
dimethipin
was
identified
in
the
anaerobic
aquatic
study
but
was
not
quantified.

Table
8.3
Summary
of
Environmental
Fate
Studies
for
Dimethipin
Degradate
Maximum
Degradate
Concentration
(%
of
applied)
in
Study:

Hydrolysis
(
161­
1)
Aqueous
Photo.

(
161­
2)
Soil
Photo.

(
161­
3)
Aerobic
Soil
(
162­
1)
Anaerobic
Aquatic
(
162­
3)
Field
Diss.

(
164­
1)

2,3­
Dihydro­
5­
hydroxymethyl­
6­
methyl­
1,4­
dithiin­
1,1,4,4­
tetraoxide
(
aka
H­
5)
Not
detected
2%
@
pH
5
0.8%
@
pH
9
Not
detected
Not
detected
Not
detected
Not
analyzed
Table
8.3
Summary
of
Environmental
Fate
Studies
for
Dimethipin
Degradate
Maximum
Degradate
Concentration
(%
of
applied)
in
Study:

Hydrolysis
(
161­
1)
Aqueous
Photo.

(
161­
2)
Soil
Photo.

(
161­
3)
Aerobic
Soil
(
162­
1)
Anaerobic
Aquatic
(
162­
3)
Field
Diss.

(
164­
1)

74
Saturated
carboxylic
acid
of
Dimethipin
Not
analyzed
Not
detected
Not
detected
Detected,
but
not
quantified
Not
detected
Not
analyzed
4.0
TOLERANCE
REASSESSMENT
SUMMARY
The
tolerances
listed
in
40
CFR
§
180.406(
a)
are
expressed
in
terms
of
dimethipin
(
2,3­
dihydro­
5,6­
dimethyl­
1,4­
dithiin
1,1,4,4­
tetraoxide;
CAS
Reg.
No.
55290­
64­
7)
per
se.
The
current
tolerance
expression
is
adequate.

Tolerances
Listed
Under
40
CFR
§
180.406(
a):

Adequate
residue
data
have
been
submitted
to
reassess
the
established
tolerance
for
undelinted
cotton
seed;
the
tolerance
is
reassessed
at
the
same
level.

The
available
processing
data
indicate
that
dimethipin
residues
do
not
concentrate
in
cotton
hulls.
The
established
tolerance
for
cotton
hulls
should
be
revoked.

Although
feeding
study
data,
reflecting
exaggerated
dosing
levels,
indicate
that
there
are
no
expectation
of
finite
residues
in
the
fat,
meat,
or
meat
byproducts
of
cattle,
goats,
horses,
hogs
or
sheep,
HED
recommends
that
the
tolerances
for
dimethipin
in
livestock
meat
and
meat
byproducts
not
be
revoked
in
order
to
harmonize
with
the
established
Codex
MRLs.
The
U.
S.
tolerances
for
livestock
meat
and
meat
byproducts
and
Codex
MRLs
for
mammalian
meat
and
edible
offal
are
established
at
0.02
ppm,
which
is
at
or
about
the
limit
of
quantitation.

The
U.
S.
tolerances
for
dimethipin
in
the
fat
of
cattle,
goats,
horses,
hogs
and
sheep
should
be
revoked
as
there
is
no
expectation
of
finite
residues
in
these
commodities
and
there
are
no
Codex
MRLs
established.

There
is
no
U.
S.
tolerance
for
dimethipin
in
milk.
A
tolerance
for
milk
is
not
required
as
there
is
no
expectation
of
finite
residues
of
dimethipin
in
milk.

Tolerances
To
Be
Proposed
Under
40
CFR
§
180.406(
a):

A
tolerance
must
be
proposed
for
cotton
gin
byproducts;
adequate
crop
field
trial
data
must
be
submitted
before
the
appropriate
tolerance
level
may
be
determined.
75
A
summary
of
dimethipin
tolerance
reassessments
is
presented
in
Table
4.0.

Table
4.0.
Tolerance
Reassessment
Summary
for
Dimethipin.

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

Tolerances
Listed
Under
40
CFR
§
180.406(
a):

Cotton,
undelinted
seed
0.5
<
0.10­
0.260
0.5
Cotton,
hulls
0.7
average
processing
factor
=
0.95x
Revoke
No
tolerance
for
cotton
hulls
is
necessary
because
residues
do
not
concentrate.

Cattle,
fat
0.02
<
0.01
at
a
9.6x
dosing
level
Revoke
The
available
feeding
study
data,
reflecting
exaggerated
dosing
levels,
indicate
that
there
is
no
expectation
of
finite
residues.
However,
tolerances
should
be
maintained
for
meat
and
meat
byproducts
to
harmonize
with
CODEX
MRLs.
Tolerances
for
fat
should
be
revoked
(
No
CODEX
MRL).
Cattle,
meat
0.02
0.02
Cattle,
meat
byproducts
0.02
0.02
Goat,
fat
0.02
Revoke
Goat,
meat
0.02
0.02
Goat,
meat
byproducts
0.02
0.02
Hog,
fat
0.02
Revoke
Hog,
meat
0.02
0.02
Hog,
meat
byproducts
0.02
0.02
Horse,
fat
0.02
Revoke
Horse,
meat
0.02
0.02
Horse,
meat
byproducts
0.02
0.02
Sheep,
fat
0.02
Revoke
Sheep,
meat
0.02
0.02
Sheep,
meat
byproducts
0.02
0.02
Tolerances
to
Be
Proposed
under
40
CFR
180.406(
a):

Cotton,
gin
byproducts
­­
­­
TBD1
1
TBD
=
To
be
determined.
Additional
residue
crop
field
trial
data
are
required.
