Page
1
of
64
UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
OFFICE
OF
PREVENTION,
PESTICIDES
AND
TOXIC
SUBSTANCES
Date:
07/
07/
2005
MEMORANDUM
SUBJECT:
Napropamide:
Final
HED
Chapter
of
the
Reregistration
Eligibility
Decision
(
RED)
Document.
PC
Code:
103001,
Case
#:
2450,
DP
Barcode:
D312976
Regulatory
Action:
Phase
4
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:
Demson
Fuller;
Chemical
Review
Manager
Reregistration
Branch
I
SRRD
(
7508C)

The
attached
risk
assessment
for
napropamide
has
been
revised
to
incorporate
review
of
additional
product
chemistry
data
and
residue
field
trial
data
for
basil.
These
data
were
submitted
by
the
registrant,
United
Phosphorus,
Inc.,
and/
or
USDA's
IR­
4
program
in
response
to
HED's
Page
2
of
64
preliminary,
Phase
1
risk
assessment.

Since
the
preliminary
risk
assessment
was
completed,
the
registrant
has
proposed
several
label
changes,
including
a
reduction
in
the
maximum
application
rate
for
cranberries.
The
registrant
has
also
indicated
that
the
company
will
not
support
existing
tolerances
for
cucurbit
vegetables
and
coffee.
The
changes
proposed
by
the
registrant
would
result
in
lower
estimates
of
dietary
and
non­
dietary
exposure
to
napropamide.
However,
because
the
estimated
risks
based
on
HED's
previous
exposure
assessments
are
well
below
our
level
of
concern,
a
revised
risk
assessment
reflecting
the
proposed
changes
is
not
warranted
and
has
not
been
conducted.
Page
3
of
64
Table
of
Contents
1.0
Executive
Summary
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6
2.0
Ingredient
Profile
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9
2.1
Summary
of
Registered/
Proposed
Uses
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9
2.2
Structure
and
Nomenclature
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9
2.3
Physical
and
Chemical
Properties
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10
3.0
Metabolism
Assessment
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11
3.1
Comparative
Metabolic
Profile
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11
3.2
Nature
of
the
Residue
in
Foods
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12
3.2.1.
Description
of
Primary
Crop
Metabolism
.
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12
3.2.2
Description
of
Livestock
Metabolism
.
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13
3.2.3
Description
of
Rotational
Crop
Metabolism,
including
identification
of
major
metabolites
and
specific
routes
of
biotransformation
.
.
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.
14
3.3
Environmental
Degradation
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15
3.4
Toxicity
Profile
of
Major
Metabolites
and
Degradates
.
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15
3.5
Summary
of
Residues
for
Tolerance
Expression
and
Risk
Assessment
.
.
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16
3.5.1
Tabular
Summary
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16
3.5.2
Rationale
for
Inclusion
of
Metabolites
and
Degradates
.
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16
4.0
Hazard
Characterization/
Assessment
.
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17
4.1
Hazard
Characterization
.
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17
4.2
FQPA
Hazard
Considerations
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22
4.2.1
Adequacy
of
the
Toxicity
Data
Base
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22
4.2.2
Evidence
of
Neurotoxicity
.
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22
4.2.3
Developmental
Toxicity
Studies
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22
4.2.4
Reproductive
Toxicity
Study
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23
4.2.5
Additional
Information
from
Literature
Sources
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23
4.2.6
Pre­
and/
or
Postnatal
Toxicity
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23
4.2.6.1
Determination
of
Susceptibility
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23
4.2.6.2
Degree
of
Concern
Analysis
and
Residual
Uncertainties
for
Pre
and/
or
Post­
natal
Susceptibility
.
.
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23
4.3
Recommendation
for
a
Developmental
Neurotoxicity
Study
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24
4.3.1
Evidence
that
supports
requiring
a
Developmental
Neurotoxicity
study
.
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24
4.3.2
Evidence
that
supports
not
requiring
for
a
Developmental
Neurotoxicity
study
.
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24
4.4
Hazard
Identification
and
Toxicity
Endpoint
Selection
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24
4.4.1
Acute
Reference
Dose
(
aRfD)
­
Females
age
13­
49
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24
4.4.2
Acute
Reference
Dose
(
aRfD)
­
General
Population
.
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24
Page
4
of
64
4.4.3
Chronic
Reference
Dose
(
cRfD)
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24
4.4.4
Incidental
Oral
Exposure
(
Short
and
Intermediate
Term)
.
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25
4.4.5
Dermal
Absorption
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27
4.4.6
Dermal
Exposure
(
Short,
Intermediate
and
Long
Term)
.
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27
4.4.7
Inhalation
Exposure
(
Short,
Intermediate
and
Long
Term)
.
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29
4.4.8
Margins
of
Exposure
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31
4.4.9
Recommendation
for
Aggregate
Exposure
Risk
Assessments
.
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32
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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34
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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38
6.2
Water
Exposure/
Risk
Pathway
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39
6.3
Residential
(
Non­
Occupational)
Exposure/
Risk
Pathway
.
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41
6.3.1
Residential
Handler
Exposures
.
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41
6.3.1.1
Handler
Exposure
Scenarios
.
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41
6.3.1.2
Data
and
Assumptions
For
Handler
Exposure
Scenarios
42
6.3.1.3
Residential
Handler
Exposure
and
Risk
Estimates
.
.
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43
6.3.2
Residential
Postapplication
Exposures
.
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43
6.3.2.1
Residential
Postapplication
Exposure
Scenarios
.
43
6.3.2.2
Data
&
Assumptions
for
Residential
Postapplication
Exposure
Scenarios
.
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44
6.3.2.3
Residential
Postapplication
Exposure
and
Risk
Estimates
45
6.3.3
Other
(
Spray
Drift,
etc.)
.
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49
7.0
Aggregate
Risk
Assessments
and
Risk
Characterization
.
.
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49
7.1
Acute
Aggregate
Risk
.
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50
7.2
Short­
Term
Aggregate
Risk
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50
7.3
Intermediate­
Term
Aggregate
Risk
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51
7.4
Long­
Term
Aggregate
Risk
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51
7.5
Cancer
Risk
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51
8.0
Cumulative
Risk
Characterization/
Assessment
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52
9.0
Occupational
Exposure/
Risk
Pathway
.
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53
Page
5
of
64
9.1
Short/
Intermediate/
Long­
Term
Handler
Risk
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53
9.2
Short/
Intermediate/
Long­
Term
Postapplication
Risk
.
.
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57
10.0
Data
Needs
and
Label
Requirements
.
.
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58
10.1
Toxicology
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58
10.2
Residue
and
Product
Chemistry
Deficiencies
.
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58
10.3
Occupational
and
Residential
Exposure
.
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58
References:
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59
Appendices
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60
Page
6
of
64
1.0
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
napropamide
and
has
conducted
a
human
health
risk
assessment
in
support
of
the
Reregistration
Eligibility
Decision
(
RED)
for
this
active
ingredient.

Use
Information
Napropamide
[
N,
N­
diethyl­
2­(
1­
naphthalenyloxy)
propionamide]
is
a
selective
preemergence
herbicide
belonging
to
the
amide
class
of
pesticides.
It
controls
weeds
by
preventing
root
cell
elongation,
thus
disrupting
the
growth
process
during
germination.
Napropamide
is
registered
to
control
broadleaf
weeds
and
annual
grasses
on
numerous
food/
feed
and
non­
food/
feed
use
sites,
including
fruits
and
nuts,
vegetables,
ornamentals,
turf/
lawns,
forestry
sites
and
tobacco.

Toxicology
The
available
toxicity
data
on
napropamide
are
adequate
to
assess
the
chemical's
hazard
potential.
Technical
napropamide
has
low
(
category
III/
IV)
acute
toxicity
via
the
oral,
dermal
and
inhalation
routes
of
exposure.
It
is
moderately
irritating
to
the
eye
(
category
II)
but
does
not
cause
skin
irritation
or
dermal
sensitization.
The
most
common
effect
in
animal
studies
(
dogs,
mice
and
rats)
from
long­
term
oral
exposure
was
a
decrease
in
body
weight
or
body
weight
gain,
with
females
being
more
sensitive
than
males
to
effects
on
body
weight.
Microscopic
liver
lesions,
spongiosis
hepatis
and
hepatocyte
fatty
vacuolization
were
also
observed
in
male
rats;
however,
these
effects
were
not
accompanied
by
increased
liver
weight
or
changes
in
clinical
chemistry.

Napropamide
did
not
cause
developmental
toxicity
in
fetuses
from
either
rats
or
rabbits
and
did
not
adversely
affect
reproductive
parameters
in
rats
over
three
generations.
There
is
no
quantitative
or
qualitative
evidence
of
increased
susceptibility
of
rat
or
rabbit
fetuses
after
in
utero
and/
or
postnatal
exposure
to
napropamide
in
the
developmental
and
reproduction
studies.
Doseresponse
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
evidence
of
neurotoxicity
was
observed
in
any
study.
Based
on
the
weight
of
evidence,
a
developmental
neurotoxicity
(
DNT)
study
is
not
required
for
napropamide.

No
evidence
for
carcinogenicity
was
seen
in
mice
or
rats.
The
chemical
was
negative
for
gene
mutation
in
four
studies
(
Bacillus
subtilis,
Salmonella
typhimurium,
mouse
host
mediated,
CHO)
and
did
not
induce
micronucleus
formation
in
the
mouse
or
unscheduled
DNA
synthesis
in
rat
hepatocytes.
Positive
results
for
gene
mutation
were
obtained
in
mouse
lymphoma
cells
with
and
Page
7
of
64
without
metabolic
activation
at
concentrations
that
also
cause
significant
cytotoxicity
and
in
Chinese
hamster
lung
cells
with
activation
in
the
absence
of
cytotoxicity.

A
chronic
reference
dose
(
cRfD)
of
0.12
mg/
kg/
day
was
established
for
napropamide
based
on
the
NOAEL
of
12
mg/
kg/
day
in
the
rat
chronic/
oncogenicity
study
and
an
uncertainty
factor
of
100
(
10x
for
interspecies
extrapolation
and
10x
for
intraspecies
variation).
Decreased
weight
gain
in
females
and
an
increased
incidence
of
liver
lesions
in
males
occurred
in
this
study
at
the
LOAEL
of
48/
55
mg/
kg/
day.
An
acute
reference
dose
(
aRfD)
was
not
established,
since
an
endpoint
attributable
to
a
single
exposure
was
not
identified
from
the
available
database.

Residue
Chemistry
The
available
residue
chemistry
data
are
adequate
to
assess
human
dietary
exposure
to
napropamide
from
the
consumption
of
treated
food
commodities.
The
residue
of
concern
for
tolerance
enforcement
and
risk
assessment
is
napropamide
per
se
for
plant
commodities.
Based
on
the
findings
of
the
livestock
metabolism
studies,
HED
has
determined
that
40
CFR
§
180.6(
a)(
3)
is
applicable
to
napropamide;
there
is
no
reasonable
expectation
of
finite
residues
in
ruminants
or
poultry.

Environmental
Fate
The
available
environmental
fate
data
for
napropamide
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
napropamide
only.

Residential
Exposure
There
is
a
potential
for
exposure
in
residential
settings
during
the
application
process
for
homeowners
who
use
products
containing
napropamide.
There
is
also
a
potential
for
exposure
from
entering
residential
areas
treated
with
napropamide.
In
both
cases,
the
duration
of
exposure
is
expected
to
be
short­
term
only.
As
a
result,
short­
term
risk
assessments
have
been
completed
for
both
residential
handler
and
postapplication
scenarios.
Since
a
dermal
endpoint
of
concern
was
not
identified
for
napropamide,
the
routes
of
exposure
considered
in
the
assessments
included
only
inhalation
(
residential
handler
exposure)
and
oral
(
post­
application
exposure).

Chemical­
specific
exposure
data
are
not
available
for
napropamide.
Residential
handler
exposure
was
assessed
using
the
Pesticide
Handlers
Exposure
Database
(
PHED
ver.
1.1)
and
data
from
the
Outdoor
Residential
Exposure
Task
Force
(
ORETF).
The
residential
handler
and
postapplication
assessments
were
conducted
in
accordance
with
the
EPA's
draft
Standard
Operating
Procedures
for
Residential
Exposure
Assessments
(
R­
SOPs)
adopted
December
18,
1997
and
revised
on
February
22,
2001.
Page
8
of
64
Aggregate
Risk
Short­
and
long­
term
(
chronic)
aggregate
risk
assessments
were
conducted
for
napropamide.
The
short­
term
assessment
considered
both
dietary
(
food
+
water)
and
residential
exposures.
The
long­
term
assessment
considered
dietary
exposure
only,
since
the
current
uses
of
napropamide
are
not
expected
to
result
in
long­
term
residential
exposure.

The
results
of
the
deterministic,
Tier
1chronic
dietary
assessment
indicate
that
the
combined
exposure
to
napropamide
from
food
and
water
is
well
below
HED's
level
of
concern,
with
estimated
exposures
representing
<
2%
of
the
cPAD
for
the
U.
S.
population
and
all
population
subgroups,
including
infants
and
children.
When
the
chronic
dietary
exposure
is
combined
with
short­
term
residential
exposure,
the
resulting
aggregate
risks
for
adults
and
children
are
also
below
HED's
level
of
concern.
The
MOE
of
concern
for
short­
term
aggregate
risk
is
100.
Since
the
estimated
short­
term
aggregate
risk
MOEs
for
adults
and
children
(
toddlers)
are
14,340
and
260,
respectively,
short­
term
aggregate
risk
is
not
considered
to
be
of
concern
for
napropamide.

Occupational
Exposure
Exposure
to
pesticide
handlers
is
likely
during
the
occupational
use
of
napropamide
in
a
variety
of
occupational
environments.
Since
no
chemical­
specific
handler
exposure
data
are
available
for
napropamide,
short­
and
intermediate­
term
inhalation
exposures
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
napropamide.
Using
these
assumptions,
the
calculated
occupational
handler
exposures
for
all
exposure
scenarios
do
not
exceed
HED's
level
of
concern
(
i.
e.,
MOEs
>
100).
Short­
and
intermediateterm
inhalation
MOEs
range
from
200
(
loading
granulars
for
aerial
application
to
cranberry)
to
more
than
33,000
(
Mixing/
loading/
Applying
liquid
for
handgun
application
on
lawns).
Dermal
exposure
was
not
assessed,
since
a
dermal
endpoint
of
concern
has
not
been
identified
for
napropamide.

Conclusions
Napropamide
is
a
relatively
low
toxicity
pesticide
whose
potential
routes
of
exposure
include
food,
drinking
water
and
residential
areas.
Under
the
conditions
of
its
current
use,
human
health
risks
to
workers
handling
the
pesticide
or
to
the
general
population
are
below
HED's
level
of
concern.
Aggregate
risk
MOEs
from
the
consumption
of
food/
drinking
water
and
from
exposure
to
the
pesticide
in
residential
settings
exceed
100
for
all
populations,
including
infants
and
children.
Page
9
of
64
O
CH
3
O
N
CH
3
CH
3
2.0
Ingredient
Profile
Napropamide
[
N,
N­
diethyl­
2­(
1­
naphthalenyloxy)
propionamide]
is
a
selective
preemergence
herbicide
belonging
to
the
amide
class
of
pesticides.
It
controls
weeds
by
preventing
root
cell
elongation,
thus
disrupting
the
growth
process
during
germination.
It
does
not
control
established
weeds.

2.1
Summary
of
Registered/
Proposed
Uses
Napropamide
is
registered
to
control
broadleaf
weeds
and
annual
grasses
on
numerous
food/
feed
and
non­
food/
feed
use
sites.
Food/
feed
uses
include
almond,
apple,
apricot,
artichoke,
asparagus,
avocado,
blackberry,
blueberry,
boysenberry,
broccoli,
Brussels
sprouts,
cabbage,
cauliflower,
cherry,
citrus
fruits
(
grapefruit,
lemon,
orange,
tangelo,
and
tangerine),
cranberry,
currant,
eggplant,
fig,
filbert
(
hazelnut),
grapes,
kiwifruit,
loganberry,
mint,
nectarine,
olive,
peach,
pear,
pecan,
pepper,
persimmon,
pistachio,
plum,
pomegranate,
prune,
raspberry
(
black
and
red),
rhubarb,
strawberry,
sweet
potato,
tomato
and
walnut
(
black
and
English).
Non­
food/
feed
uses
include
ornamentals
(
herbaceous
plants,
ground
covers,
woody
shrubs
and
vines
and
shade
trees),
lawns
and
turf,
potting/
topsoil
and
forestry
uses
(
conifer
release),
as
well
as
tobacco.

Napropamide
products
are
registered
in
the
U.
S.
to
United
Phosphorus,
Inc.
under
the
trade
name
Devrinol.
Currently
registered
end­
use
formulations
include
dry
flowables,
flowables,
emulsifiable
concentrates
and
granular
products
containing
2
to
50%
active
ingredient.
Napropamide
is
applied
at
2
to
6
lbs.
a.
i./
A
on
all
crops/
sites
except
cranberries,
where
applications
at
up
to
15
lbs.
a.
i./
A
are
allowed.
Applications
are
generally
made
using
ground
equipment,
including
ground
boom
and
hand­
held
sprayers,
granular
application
equipment,
and
chemigation
equipment.
Aerial
application
is
permitted
on
cranberries.
The
Restricted
Entry
Interval
(
REI)
is
12
hours
for
all
agricultural
uses
of
napropamide.

2.2
Structure
and
Nomenclature
TABLE
2.2.
Test
Compound
Nomenclature
Chemical
Structure
Empirical
Formula
C17H21NO2
Common
name
Napropamide
TABLE
2.2.
Test
Compound
Nomenclature
Page
10
of
64
IUPAC
name
(
RS)­
N,
N­
diethyl­
2­(
1­
naphthyloxy)
propionamide
CAS
name
N,
N­
diethyl­
2­(
1­
naphthalenyloxy)
propanamide
CAS
Registry
Number
15299­
99­
7
Chemical
Class
Amide
Known
Impurities
of
Concern
None
End­
use
products
(
EPs):

70506­
27
21.8%
EC
2
lb/
gal
EC
Devrinol
2­
E
Selective
Herbicide
70506­
281
21.8%
EC
2
lb/
gal
EC
Devrinol
2­
E
Ornamental
Selective
Herbicide
70506­
31
43.2%
FlC
4
lb/
gal
FlC
Devrinol
4­
F
Selective
Herbicide
­
Flowable
70506­
33
2%
G
Devrinol
2­
G
Ornamental
Selective
Herbicide
70506­
34
10%
G
Devrinol
10­
G
Selective
Herbicide
70506­
36
50%
DF
Devrinol
50­
DF
Selective
Herbicide
70506­
37
43.2%
FlC
4
lb/
gal
FlC
Devrinol
4­
F
Ornamental
Selective
Herbicide
70506­
38
50%
DF
Devrinol
50­
DF
Ornamental
Herbicide
70506­
39
2%
unidentified
formulation
Devrinol
Lawn
and
Ornamental
Selective
Herbicide
70506­
63
24.1%
EC
2
lb/
gal
EC
Devrinol
2­
EC
Ornamental
Selective
Herbicide
70506­
64
24.1%
EC
2
lb/
gal
EC
Devrinol
2­
EC
Selective
HErbicide
34704­
771
4%
G
Napropamide­
Oxadiazon
4­
2
Granules
1Reregistration
of
this
product
is
not
supported.
The
registrant,
United
Phosphorus
Inc.,
has
requested
voluntary
cancellation.

2.3
Physical
and
Chemical
Properties
Napropamide
has
relatively
low
volatility,
indicating
only
a
slight
potential
for
human
exposure
via
the
inhalation
route.

TABLE
2.3.
Physicochemical
Properties
of
Napropamide
Parameter
Value
Reference
Melting
point
68­
70
°
C
MRID
41610201;
D303463;
9/
30/
04
pH
8.9
at
22
°
C
MRID
41610201;
D303463;
9/
30/
04
Density,
bulk
density,
or
specific
gravity
0.584
g/
mL
at
22
°
C
MRID
41610201;
D303463;
9/
30/
04
TABLE
2.3.
Physicochemical
Properties
of
Napropamide
Parameter
Value
Reference
Page
11
of
64
Water
solubility
74
mg/
L
at
25
°
C
MRID
41610201;
D303463;
9/
30/
04
Solvent
solubility
at
20
°
C
Miscible
with
acetone,
chlorobenzene,
ethanol,
and
dichloromethane
4.5
g/
100
mL
in
kerosene
17.7
g/
100
mL
in
n­
octanol
55.5
g/
100
mL
in
xylene
D210989,
7/
27/
95,
K.
Dockter
Vapor
pressure
1.7
x
10­
7
torr
or
2.3
x
10­
5
Pa
at
25
°
C
MRID
41610201;
D303463;
9/
30/
04
Dissociation
constant,
pKa
Not
applicable;
napropamide
is
neither
an
acid
nor
a
base.

Octanol/
water
partition
coefficient
2.1
x
103
(
log
KOW
=
3.3)
MRID
41610201;
D303463;
9/
30/
04
UV/
visible
absorption
spectrum
Neutral
(
201.8
nm):
A
=
1.1144,
0=
58560mol­
1cm
­
1
Acidic
(
215nm):
A
=
1.1198,
0=
58844mol­
1cm
­
1
Basic:
unstable
in
alkaline
solution
MRID
46459102;
D314409
&
D314416,
3/
17/
05,
P.
Horng
3.0
Metabolism
Assessment
3.1
Comparative
Metabolic
Profile
Napropamide
is
rapidly
absorbed,
metabolized,
distributed,
and
excreted
by
the
rat
following
oral
administration.
The
major
metabolic
routes
in
the
rat
are
ring
hydroxylation
and
N­
deethylation
followed
by
conjugation
with
glucuronic
acid
and
sulfate.
The
major
metabolites
identified
were
4­
hydroxy
napropamide,
5­
hydroxy
napropamide,
and
4­
hydroxy[
N­
ethyl­
2­(
1­
naphthoxy)]
propionamide.
Highest
residue
concentrations
were
found
in
blood,
followed
by
liver
and
intestine
96
hours
after
dosing.
No
major
sex
differences
in
residues
or
metabolic
profiles
have
been
observed
after
an
oral
dose.
Following
dermal
application,
total
absorption
increased
with
dose;
however,
the
fraction
that
was
absorbed
was
inversely
related
to
dose.
Excretion
is
almost
exclusively
and
completely
via
the
urine
and
feces
after
both
oral
and
dermal
administration.

The
metabolic
pathway
of
napropamide
in
plants
is
similar
to
its
pathway
in
rats:
desethylation
of
the
parent
compound,
followed
by
further
desethylation
and
hydrolysis
to
yield
naphthoxypropionic
acid
(
which
was
found
as
glycoside
conjugate);
and
hydroxylation
of
the
naphthyl
ring
to
yield
4­
and
5­
hydroxy
metabolites.
Natural
incorporation
of
14C
into
plants
occurs
as
a
result
of
the
degradation
of
napropamide
applied
to
the
soil
to
give
14CO
2
,
which
is
taken
in
by
the
plant
and
incorporated
into
plant
sugars
during
photosynthesis.
Page
12
of
64
The
metabolic
pathway
of
napropamide
in
livestock
also
appears
to
be
similar.
Because
of
the
very
low
TRR
levels
found
in
the
livestock
metabolism
studies,
the
metabolites
were
not
identified/
characterized
in
all
tissues.
However,
the
metabolites
that
were
identified
(
napthoxypropionic
acid,
desethylnapropamide,
and
4­
hydroxydesethyl­
napropamide)
are
similar
to
metabolites
identified
in
plants
and
rats,
suggesting
a
similar
metabolic
pathway.

3.2
Nature
of
the
Residue
in
Foods
3.2.1.
Description
of
Primary
Crop
Metabolism
The
qualitative
nature
of
the
residue
in
plants
is
understood.
Acceptable
metabolism
studies
with
napropamide
have
been
conducted
on
three
dissimilar
crops
(
apple,
cabbage,
and
tomato).
Brief
summaries
of
the
available
plant
metabolism
studies
are
presented
below.

Apple
Ring­
labeled
napropamide
was
applied
to
soil
in
a
4­
sq.
meter
area
around
an
apple
tree.
Two
applications
were
made;
the
first
at
green
cluster
at
a
rate
of
4.11
lb
ai/
A
(
1.03x),
and
the
second
approximately
five
months
later
at
4.04
lb
ai/
A
(
1.01x),
to
give
a
preharvest
interval
(
PHI)
of
35
days.
Application
rate
and
timings
adequately
reflected
label
directions.
The
first
and
second
year
crops
were
harvested
and
analyzed
for
total
radioactive
residues
(
TRR).

In
the
first
year's
crop,
the
fruit
TRR
was
0.0032
ppm.
The
radioactivity
was
fractionated,
and
no
fraction
had
a
residue
level
greater
than
0.002
ppm.
Because
of
the
low
residues
detected,
additional
analysis
was
not
performed.
In
the
second
year's
crop,
the
fruit
TRR
was
0.0098
ppm.
The
radioactivity
was
also
fractionated,
and
no
fraction
had
a
residue
level
greater
than
0.006
ppm.
Because
of
the
low
residues
detected,
additional
analysis
was
not
performed.

Cabbage
Ring­
labeled
napropamide
was
applied
to
soil
in
a
pot
at
a
slightly
exaggerated
rate
of
2.25
lb
ai/
A
(
1.125x).
The
PHI
ranged
from
55
to
63
days.
The
TRR
found
in
the
cabbage
heart
sample
was
0.125
ppm.
Of
this,
94.5%
was
extractable
and
a
total
of
90.7%
of
the
TRR
was
characterized
and
59.9%
of
the
TRR
was
identified.
Natural
incorporation
into
sugars
accounted
for
50.1%
of
the
TRR.
The
major
metabolites
identified
were:
naphthoxypropionic
acid
(
3.0%
TRR);
desethylnapropamide
(
2.5%
TRR);
and
5­
hydroxy­
napropamide
(
1.2%
TRR).
The
parent
compound
accounted
for
0.8%
of
the
TRR.

In
whole
cabbage,
the
TRR
found
was
0.457
ppm.
Of
this
amount,
89.1%
was
extractable
and
a
total
of
77.0%
of
the
TRR
was
characterized
and
35.2%
of
the
TRR
was
identified.
Natural
incorporation
into
sugars
accounted
for
12.6%
of
the
TRR.
The
major
identified
metabolites
were:
5­
hydroxy­
napropamide
(
6.7%
TRR);
1,4­
naphthoquinone
(
4.9%
TRR);
Page
13
of
64
napthoxypropionic
acid
(
2.9%
TRR);
and
desethylnapropamide
(
2.3%
TRR).
The
parent
compound
accounted
for
0.9%
TRR.
Page
14
of
64
Tomato
Ring­
labeled
napropamide
was
applied
to
soil
in
a
pot
at
a
slightly
exaggerated
rate
of
2.25
lb
ai/
A
(
1.125x).
Fruits
were
harvested
when
ripe;
PHI
ranged
from
67
to
122
days.
The
TRR
found
in/
on
tomatoes
was
0.051
ppm.
Of
this
amount,
92.3%
was
extractable,
and
a
total
of
83.7%
of
the
TRR
was
characterized
and
43.9%
of
the
TRR
was
identified.
Natural
incorporation
into
sugars
accounted
for
21.2%
of
the
TRR.
The
major
metabolite
found
was
o­
phthalic
acid
(
6.1%
TRR),
followed
by
5­
hydroxydesethyl­
napropamide
(
4.5%
TRR)
and
5­
hydroxynaphthoxypropionic
acid
(
4.2%
TRR).

3.2.2
Description
of
Livestock
Metabolism
The
qualitative
nature
of
the
residue
in
livestock
is
understood.
HED
has
received
and
reviewed
acceptable
ruminant
and
poultry
metabolism
studies
with
napropamide.
Brief
summaries
of
the
available
animal
metabolism
studies
are
presented
below.

Ruminants
(
MRID
42775801)

Two
lactating
goats
were
orally
dosed
with
[
14C]
napropamide
twice
daily
at
levels
equivalent
to
11.2
ppm
and
8.5
ppm
in
the
diet
(
average
of
9.9
ppm)
for
four
consecutive
days.
During
the
testing
period,
milk
was
collected
twice
daily,
in
the
morning
and
afternoon.
The
goats
were
sacrificed
23­
24
hours
after
the
last
dose,
and
the
following
samples
were
collected:
liver,
kidney,
omental
fat,
subcutaneous
fat,
perirenal
fat,
muscle
from
foreleg
and
rump,
urine
from
bladder,
bile,
and
gastrointestinal
tract.
For
both
goats,
approximately
90%
of
the
total
administered
dose
was
eliminated
in
the
urine
and
feces.
The
mean
excretion
of
radioactivity
in
milk
was
very
small
(
0.084%
of
dose).
The
amount
of
radioactivity
found
in
liver
(
0.170%
of
dose)
and
kidney
(
0.007%
of
dose)
was
also
small.

The
TRR
in
milk
over
each
24­
hour
period
encompassed
in
the
study
ranged
from
0.0068
ppm
to
0.0089
ppm,
and
levels
plateaued
after
24
hours.
The
TRRs
averaged
0.0031
ppm
in
muscle
and
0.0066
ppm
in
fat.
The
identification
and/
or
characterization
of
radioactive
residues
in
milk,
muscle,
and
fat
was
not
necessary
because
TRR
levels
were
less
than
0.010
ppm.

The
TRR
in
liver
of
Goat
2
was
0.165
ppm.
Radioactive
residues
in
liver
were
adequately
identified
and/
or
characterized.
Napropamide
and
desethylnapropamide
were
determined
in
liver
at
0.3%
TRR.
Approximately
40%
of
the
TRR
was
associated
with
trichloroacetic
acid
precipitated
proteins.
Following
extensive
fractionation
of
solubilized
radioactivity
from
liver
debris,
no
components
were
present
at
>
0.010
ppm.

The
TRR
in
the
kidney
of
Goat
2
was
0.034
ppm.
Radioactive
residues
in
kidney
were
adequately
identified
and/
or
characterized.
The
only
identified
metabolite
in
kidney
was
napropamide
at
1.8%
TRR.
TLC
analysis
of
various
kidney
fractions
indicated
the
presence
of
13
Page
15
of
64
unknowns,
the
largest
being
4.7%
TRR.
About
19.0%
of
the
TRR
remained
associated
with
trichloroacetic
acid
precipitated
proteins.

Poultry
Gelatin
capsules
containing
[
14C]
napropamide
were
orally
administered
to
10
laying
hens
once
daily
for
ten
consecutive
days.
Each
bird
received
an
average
of
8.3
ppm
napropamide
in
the
diet
(
range
of
7.4
ppm
to
10.1
ppm).
Eggs
were
collected
twice
daily
from
each
chicken.
The
hens
were
sacrificed
23­
24
hours
after
the
last
dose,
and
the
following
samples
were
collected:
skin
plus
subcutaneous
fat,
peritoneal
fat,
leg
muscle,
breast
muscle,
liver,
kidney,
and
gastrointestinal
tract
and
contents.
Most
of
the
administered
dose
was
found
in
the
excreta
(
average
of
92.1%).
Additionally,
2.51%
of
the
administered
dose
was
found
in
cage
washings.
Liver
and
kidney,
the
tissues
with
the
highest
TRR
levels,
contained
only
0.046%
and
0.006%
of
the
administered
dose,
respectively.

The
TRR
levels
in
all
tissues
were
low.
Liver
and
kidney
were
the
tissue
with
the
highest
TRR
levels,
with
values
of
0.105
ppm
and
0.0455
ppm
respectively.
TRR
levels
in
muscle
were
<
0.0034
ppm,
and
levels
in
skin
and
fat
were
<
0.0078
ppm.
Radioactive
residue
levels
in
the
egg
whites
were
reasonably
constant
over
the
dosing
period,
and
were
always
<
0.010
ppm.
Residue
levels
in
egg
yolks
rose
to
a
plateau
of
between
0.0373
ppm
to
0.0419
ppm
on
days
6­
10
of
the
study.

Radioactive
residues
in
poultry
liver
were
adequately
characterized.
About
29.5%
of
the
TRR
in
liver
was
solvent
extractable.
Napthoxypropionic
acid
accounted
for
a
total
of
13.7%
TRR
and
desethylnapropamide
accounted
for
2.5%
TRR.
Following
extensive
fractionation,
no
other
fractions
had
TRR
levels
>
0.010
ppm.

Radioactive
residues
in
egg
yolk
were
also
adequately
characterized.
About
83.6%
of
the
TRR
was
solvent
extractable.
The
following
components
were
identified:
napthoxypropionic
acid
(
6.1%
TRR),
napropamide
(
5.2%
TRR),
desethylnapropamide
(
4.1%
TRR),
and
4­
hydroxydesethyl­
napropamide
(
3.9%
TRR).
No
other
fractions
had
TRR
levels
>
0.010
ppm.

3.2.3
Description
of
Rotational
Crop
Metabolism,
including
identification
of
major
metabolites
and
specific
routes
of
biotransformation
An
acceptable
confined
rotational
crop
study
with
napropamide
has
been
submitted
and
reviewed.
In
this
study,
wheat,
carrots,
and
lettuce
were
planted
at
intervals
of
60,
180,
and
364
days
in
pots
containing
sandy
clay
loam
soil.
The
soil
was
treated
with
[
14C]
napropamide
at
4.4
lb
ai/
A
(
2.2x
the
maximum
registered
rate
on
annual
crops).
TRR
accumulated
$
0.01
ppm
in/
on
wheat
forage
(
0.08­
0.41
ppm),
wheat
straw
(
0.50­
1.85
ppm),
wheat
grain
(
0.04­
0.11
ppm),
carrot
root
(
0.04­
0.14
ppm),
carrot
tops
(
0.08­
0.16
ppm),
and
lettuce
(
0.04­
0.08
ppm)
at
all
plantback
intervals
(
PBI).
All
samples
of
60­
day
PBI
as
well
as
180­
and
364­
day
PBI
wheat
forage
and
wheat
straw
were
subjected
to
extraction/
characterization
of
residues.
The
metabolites
identified
in
the
Page
16
of
64
various
matrices
of
rotational
crops
corresponded
to
the
metabolites
identified
in
the
plant
metabolism
studies
and
were
found
in
approximately
similar
proportions.
Napropamide
and
desethyl
napropamide
were
found
in
all
crops.

3.3
Environmental
Degradation
The
environmental
fate
data
are
complete
and
indicate
that
napropamide
can
be
persistent
in
the
environment.
Napropamide
is
stable
to
hydrolysis
and
biodegradation.
Major
degradates
(>
10
%
of
applied)
were
not
formed
in
the
metabolism
studies,
although
napththoxy
propionic
acid
was
formed
at
up
to
5.8
%
in
anaerobic
aquatic
metabolism
studies
(
representing
sediment).
Photolysis
is
the
only
relatively
rapid
degradation
process,
with
a
half­
life
of
6.8
minutes
in
water
and
28
days
on
soil.
Two
napropamide
isomers
and
a
dimer
of
one
of
the
isomers
were
identified
in
water
that
had
been
exposed
to
light,
but
no
photolytic
degradates
other
than
CO2
have
been
identified
in
soil
exposed
to
light.

3.4
Toxicity
Profile
of
Major
Metabolites
and
Degradates
1,4­
Naphthoquinone,
a
compound
known
to
cause
severe
eye,
skin
and
upper
respiratory
tract
irritation,
was
identified
in
the
plant
metabolism
studies
(
cabbage
only).
However,
based
on
the
low
levels
seen
in
plants,
it
is
not
of
toxological
concern.
Other
plant
metabolites
were
also
identified
in
rat
metabolism
studies;
therefore,
their
potential
toxic
effects
are
assumed
to
have
been
taken
into
account
in
the
rat
studies
(
Napropamide.
Reregistration
Case
No.
2450.
Outcome
of
the
3/
16/
93
Meeting
of
the
HED
Metabolism
Committee;
Steven
A.
Knizner;
April
7,
1993)
Page
17
of
64
3.5
Summary
of
Residues
for
Tolerance
Expression
and
Risk
Assessment
3.5.1
Tabular
Summary
Table
3.5.
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
Napropamide,
per
se
Napropamide,
per
se
Rotational
Crop
Napropamide,
per
se1
Not
Applicable1
Livestock
Ruminant
Not
Applicable2
Not
Applicable2
Poultry
Not
Applicable2
Not
Applicable2
Drinking
Water
Napropamide,
per
se
Not
Applicable
1Residues
are
not
expected
in
rotational
crops
and
rotational
crop
tolerances
are
not
required,
provided
labels
specify
a
60­
day
Plant
Back
Interval
(
PBI)
for
leafy
vegetables,
a
180­
day
PBI
for
cereal
grains,
and
a
365­
day
PBI
for
all
other
crops.
Any
labels
that
do
not
already
specify
the
appropriate
crop
restrictions
should
be
amended.
Rotational
crops
were
not
included
in
the
risk
assessment.
2
HED
has
determined
that
40
CFR
§
180.6(
a)(
3)
is
applicable
to
napropamide;
there
is
no
reasonable
expectation
of
finite
residues
in
ruminants
or
poultry.

3.5.2
Rationale
for
Inclusion
of
Metabolites
and
Degradates
The
results
of
the
plant
metabolism
studies
were
presented
on
3/
16/
93
to
the
HED
Metabolism
Committee.
The
Metabolism
Committee
concluded
that
the
residue
of
concern
in
plants
is
napropamide,
per
se.
The
Committee's
conclusion
was
based
on
the
following
considerations:
(
1)
the
concentration
of
quinones
detected
in
the
metabolism
studies
was
sufficiently
low
so
as
not
to
be
of
toxicological
concern;
and
(
2)
the
other
plant
metabolites
found
in
these
studies
were
also
seen
in
rat
metabolism
studies.
In
addition,
these
metabolites
were
present
at
low
levels
and
would
not
likely
be
found
if
they
were
included
in
the
plant
analytical
method.

The
metabolites
identified
in
the
various
matrices
of
rotational
crops
corresponded
to
the
metabolites
identified
in
the
plant
metabolism
studies
and
were
found
in
approximately
similar
proportions.
Therefore,
the
residue
of
concern
in
rotational
crops
is
also
napropamide,
per
se.

Based
on
the
findings
from
the
livestock
metabolism
studies,
HED
has
determined
that
40
CFR
§
180.6(
a)(
3)
is
applicable
to
napropamide;
there
is
no
reasonable
expectation
of
finite
residues
in
ruminants
or
poultry.
This
determination
is
based
on
the
low
level
of
residues
observed
in
the
goat
metabolism
study
where
the
test
animals
were
dosed
with
[
14C]
napropamide
at
an
average
Page
18
of
64
level
of
9.9
ppm
in
the
diet
which
is
equivalent
to
120x
the
maximum
dietary
burden
of
0.083
ppm
to
dairy
cattle.
This
determination
is
also
based
on
the
fact
that
there
are
no
poultry
or
swine
feedstuffs
associated
with
the
raw
agricultural
commodities
with
established
tolerances.

No
major
degradates
(>
10%
of
the
applied)
of
napropamide
were
formed
in
any
of
the
environmental
fate
studies.
Based
on
the
results
of
these
studies,
the
residue
of
concern
in
drinking
water
is
napropamide,
per
se.

4.0
Hazard
Characterization/
Assessment
4.1
Hazard
Characterization
Napropamide
has
generally
low
acute
toxicity
with
no
deaths
occurring
at
approximately
the
limit
dose
for
oral,
inhalation
and
dermal
studies
(
Table
4.1a).
Clinical
signs
of
toxicity
suggestive
of
irritation
were
observed
in
animals
treated
orally
or
by
inhalation.
The
chemical
caused
moderate
eye
irritation
which
cleared
after
7
days
but
did
not
cause
skin
irritation
and
is
not
a
sensitizer.

The
most
common
effect
in
animal
studies
from
long­
term
oral
exposure
was
a
decrease
in
body
weight
or
body
weight
gain
(
Table
4.1b).
Females
were
more
sensitive
than
males
to
effects
on
body
weight.
In
chronic
studies
a
decrease
in
body
weight
and
body
weight
gain
by
female
dogs
(
500
mg/
kg/
day)
and
rats
(
55
mg/
kg/
day)
and
male
and
female
mice
(
455
and
568
mg/
kg/
day)
was
the
basis
for
the
study
LOAEL.
The
NOAELs
(
m/
f)
for
chronic
toxicity
in
dogs,
rats
and
mice
were
70/
70,
11/
12
and
55/
70
mg/
kg/
day,
respectively.
Microscopic
lesions
were
observed
in
livers
from
male
rats
fed
48
mg
napropamide/
kg/
day
for
two
years.
These
lesions
in
male
rats,
spongiosis
hepatis
and
hepatocyte
fatty
vacuolization,
were
not
accompanied
by
increased
liver
weight
or
changes
in
clinical
chemistry.

No
evidence
of
neurotoxicity
was
observed
in
any
study.
Daily
dermal
application
to
rats
for
21
days
did
not
cause
any
systemic
or
local
effects
up
to
the
limit
dose
of
1000
mg/
kg/
day.

Decreased
maternal
body
weight
gain
was
also
the
only
endpoint
of
toxicity
observed
in
developmental
toxicity
studies
with
rats
and
rabbits
(
1000
and
300
mg/
kg/
day,
respectively).
No
evidence
of
developmental
toxicity
was
observed
in
fetuses
from
either
species
up
to
and
including
the
limit
dose.

Napropamide
did
not
adversely
affect
reproductive
parameters
in
rats
over
three
generations.
Offspring
body
weight
was
decreased
at
the
highest
dose
(
100
mg/
kg/
day)
beginning
as
early
as
PND
7
and
cumulative
weight
gain
by
the
high­
dose
pups
of
all
three
generations
was
decreased
during
lactation.
Therefore,
both
lactational
effects
prior
to
PND
14
and
systemic
effects
after
the
pups
began
eating
the
treated
diets
probably
contributed
to
reduced
growth.
Lower
preweaning
pup
body
weight
continued
into
the
early
part
of
the
premating
interval
for
parental
animals.
The
NOAEL
for
parental
and
offspring
toxicity
(
decreased
body
weight)
was
30
mg/
kg/
day.
Page
19
of
64
No
evidence
for
carcinogenicity
was
seen
in
mice
or
rats.
Administration
of
napropamide
to
mice
for
18
months
and
to
rats
for
24
months
did
not
result
in
an
increase
in
overall
tumor
incidence
or
an
increase
in
the
incidence
of
any
specific
type
of
tumor.
The
chemical
was
negative
for
gene
mutation
in
four
studies
(
Bacillus
subtilis,
Salmonella
typhimurium,
mouse
host
mediated,
CHO)
and
did
not
induce
micronucleus
formation
in
the
mouse
or
unscheduled
DNA
synthesis
in
rat
hepatocytes.
Positive
results
for
gene
mutation
were
obtained
in
mouse
lymphoma
cells
with
and
without
metabolic
activation
at
concentrations
that
also
cause
significant
cytotoxicity
and
in
Chinese
hamster
lung
cells
with
activation
in
the
absence
of
cytotoxicity.

Napropamide
is
rapidly
absorbed,
metabolized,
distributed
and
excreted
by
the
rat
following
oral
administration.
The
major
metabolic
routes
in
the
rat
are
ring
hydroxylation
and
N­
deethylation
followed
by
conjugation
with
glucuronic
acid
and
sulfate.
No
toxic
metabolites
have
been
identified.
Highest
residue
concentrations
were
found
in
blood,
followed
by
liver
and
intestine
96
hours
after
dosing.
No
major
sex
differences
in
residues
or
metabolic
profiles
have
been
observed
after
an
oral
dose.
Following
dermal
application,
total
absorption
increased
with
dose;
however,
the
fraction
that
was
absorbed
was
inversely
related
to
dose.
Excretion
is
almost
exclusively
and
completely
via
the
urine
and
feces
after
both
oral
and
dermal
administration.

The
toxicity
data
base
for
napropamide
is
complete.
No
data
gaps
have
been
identified.

Table
4.1a
Acute
Toxicity
Profile
­
Napropamide
Guideline
No.
Study
Type
MRID(
s)
Results
Toxicity
Category
870.11
Acute
oral
[
rat]
40362902
LD50
=
>
5000
mg/
kg
IV
870.12
Acute
dermal
[
rabbit]
40362902
LD50
=
>
2000
mg/
kg
III
870.13
Acute
inhalation
[
rat]
42231501
LC50
=
>
4.8
mg/
L
IV
870.24
Acute
eye
irritation
[
rabbit]
40362902
moderate
II
870.25
Acute
dermal
irritation
[
rabbit]
40362902
none
IV
870.26
Skin
sensitization
[
guinea
pig]
40362903
negative
Nonsensitizing
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)
00113809
(
1970)
Unacceptable/
guideline
(
not
upgradable)
M&
F:
0,
13,
25,
50
mg/
kg/
d
NOAEL
=
50
mg/
kg/
day
LOAEL
=
not
identified
animals
could
have
tolerated
a
higher
dose
Table
4.1b
Subchronic,
Chronic
and
Other
Toxicity
Profile
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
Page
20
of
64
870.3150
90­
Day
oral
toxicity
(
dog)
00113810
(
1970)
Unacceptable/
guideline
(
upgradable)
M&
F:
0,
16,
40,
100
mg/
kg/
d
NOAEL
=
>
100
mg/
kg/
day
LOAEL
=
not
identified
(
animals
could
have
tolerated
a
higher
dose;
no
homogeneity,
stability,
and
concentration
data
in
the
dietary
formulations)

870.3200
21/
28­
Day
dermal
toxicity
(
rat)
42006701
(
1991)
Acceptable/
guideline
M&
F:
0,
10,
100,
1000
mg/
kg/
d
NOAEL
=
1000
mg/
kg/
day
LOAEL
=
not
identified
870.3250
90­
Day
dermal
toxicity
(
species)
not
required
870.3465
90­
Day
inhalation
toxicity
(
species)
not
required
870.3700a
Prenatal
developmental
in
(
rat)
128104
(
1982)
Acceptable/
guideline
F:
0,
30,
110,
400
mg/
kg/
d
(
GD
6­
15)
Maternal
NOAEL
=
110
mg/
kg/
day
LOAEL
=
400
mg/
kg/
day
based
on
decreased
body
weight
gain.
Developmental
NOAEL
=
400
mg/
kg/
day
LOAEL
=
not
identified
870.3700a
Prenatal
developmental
in
(
rat)
42006703
(
1990)
Acceptable/
guideline
F:
0,
100,
300,
1000
mg/
kg/
d
(
GD
6­
15)
Maternal
NOAEL
=
300
mg/
kg/
day
LOAEL
=
1000
mg/
kg/
day
based
on
decreased
body
weight
gain.
Developmental
NOAEL
=
1000
mg/
kg/
day
LOAEL
=
not
identified
870.3700b
Prenatal
developmental
in
(
rabbit)
142118
(
1984)
Unacceptable/
guideline
(
not
upgradable)
F:
0,
10,
50,
200
mg/
kg/
d
(
GD
7­
19)
Maternal
NOAEL
$
200
mg/
kg/
day
LOAEL
=
not
determined
Developmental
NOAEL
$
200
mg/
kg/
day
LOAEL
=
not
determined
(
supplementary
data
due
to
lack
of
frank
toxicity)

870.3700b
Prenatal
developmental
in
(
rabbit)
42006704
(
1990)
Acceptable/
guideline
F:
0,
100,
300,
1000
mg/
kg/
d
(
GD
7­
19)
Maternal
NOAEL
=
100
mg/
kg/
day
LOAEL
=
300
mg/
kg/
day
based
on
decreased
body
weight
gain.
Developmental
NOAEL
=
1000
mg/
kg/
day
LOAEL
=
not
identified
870.3800
Reproduction
and
fertility
effects
(
rat)
92125069
Acceptable/
guideline
M:
0,
9.9,
29.6,
98.8
mg/
kg/
d
F:
0,
12.7,
39.4,
130.7
Parental/
Systemic
NOAEL
=
29.6/
39.4
mg/
kg/
day
LOAEL
=
98.8/
130.7
mg/
kg/
day
based
on
decreased
body
weight
in
F1
females
and
F2
males
and
females.
Reproductive
NOAEL
=
98.8/
130.7
mg/
kg/
day
LOAEL
=
not
identified.
Table
4.1b
Subchronic,
Chronic
and
Other
Toxicity
Profile
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
Page
21
of
64
mg/
kg/
d
Offspring
NOAEL
=
29.6/
39.4
mg/
kg/
day
LOAEL
=
98.8/
130.7
mg/
kg/
day
based
on
decreased
pup
body
weights.

870.4100b
Chronic
toxicity
(
dog)
41156602
Acceptable/
guideline
M&
F:
0,
10,
70,
500
mg/
kg/
d
NOAEL
=
70
mg/
kg/
day
LOAEL
=
500
mg/
kg/
day
based
on
decreased
body
weight
and
body
weight
gain
in
females.

870.4200
Carcinogenicity
(
mouse)
00081613
(
1978)
Unacceptable/
guideline
M&
F:
0,
10,
30,
100
mg/
kg/
d
NOAEL
=
30
mg/
kg/
day
LOAEL
=
100
mg/
kg/
day
based
on
decreased
body
weight
in
females
after
week
98.
(
animals
could
have
tolerated
a
higher
dose;
inconsistencies
in
number
of
animals
for
which
pathology
was
reported)
no
evidence
of
carcinogenicity
870.4200
Carcinogenicity
(
mouse)
42189101
(
1992)
Acceptable/
guideline
0,
60,
450,
3500,
7000
ppm
M:
0,
7.4,
55,
455,
931
mg/
kg/
d
F:
0,
9.4,
70,
568,
1216
mg/
kg/
d
NOAEL
=
55/
70
mg/
kg/
day
LOAEL
=
455/
568
mg/
kg/
day
based
on
decreased
body
weight
and
body
weight
gain
in
males
and
females.
no
evidence
of
carcinogenicity
870.4300
Chronic/
Carcinoge
nicity
(
rat)
00081614
(
1978)
Unacceptable/
guideline
M&
F:
0,
10,
30,
100
mg/
kg/
d
NOAEL
=
100
mg/
kg/
day
LOAEL
=
not
identified
animals
could
have
tolerated
a
higher
dose
870.4300
Chronic/
Carcinoge
nicity
(
rat)
42189102
(
1992)
43068801
(
1993)
Acceptable/
guideline
0,
250,
1100,
5000
ppm
M:
0,
11,
48,
221
mg/
kg/
d
F:
0,
12,
55,
261
mg/
kg/
d
NOAEL
=
11/
12
mg/
kg/
day
LOAEL
=
48/
55
mg/
kg/
day
based
on
decreased
weight
gain
in
females
and
slightly
increased
incidence
of
spongiosis
hepatis
in
males.
no
evidence
of
carcinogenicity
Gene
Mutation
870.5100
(
Bacillus
subtilis)
00025880
(
1980)
Acceptable/
guideline
negative
up
to
2000
:
g/
disk
Gene
Mutation
870.5100
(
Salmonella
typhimurium)
00025880
(
1980)
Acceptable/
guideline
negative
up
to
5000
:
g/
disk
with
and
without
metabolic
activation
Table
4.1b
Subchronic,
Chronic
and
Other
Toxicity
Profile
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
Page
22
of
64
Gene
Mutation
870.5100
(
host
mediated;
mice)
00025880
(
1980)
Acceptable/
guideline
negative
after
doses
of
1
or
4
g/
kg
Gene
Mutation
870.5300
(
mouse
lymphoma
cells)
00147490
(
1984)
Acceptable/
guideline
positive
for
forward
mutation
at
0.016­
0.08
mg/
mL
with
and
without
metabolic
activation;
significant
cytotoxicity
Gene
Mutation
870.5300
(
CHO)
00162137
(
1985)
Acceptable/
guideline
negative
for
forward
mutation
up
to
0.45
mg/
mL
with
and
without
metabolic
activation
Gene
Mutation
870.5300
(
Chinese
hamster
lung
cells)
41582201
(
1986)
Acceptable/
guideline
positive
at
10,
50,
100
:
g/
mL
with
metabolic
activation;
negative
without
metabolic
activation;
no
cytotoxicity
Cytogenetics
870.5375
(
human
fibroblasts)
00162135
(
1986)
Unacceptable/
guideline
inconclusive
due
to
study
deficiencies
Micronucleus
870.5395
(
mouse)
00147489
(
1984)
00162136
(
1986)
Acceptable/
guideline
negative
at
doses
of
556,
1667,
5000
mg/
kg
Unscheduled
DNA
Synthesis
870.5550
(
rat
hepatocytes)
41610208
(
1990)
Acceptable/
guideline
(
males
only)
negative
in
cultured
hepatocytes
isolated
from
male
rats
treated
with
a
single
oral
dose
of
up
to
2000
mg/
kg
870.6200a
Acute
neurotoxicity
screening
battery
not
required
870.6200b
Subchronic
neurotoxicity
screening
battery
not
required
870.6300
Developmental
neurotoxicity
not
required
870.7485
Metabolism
and
pharmacokinetics
(
rat)
Acc.
#
091008
Unacceptable/
guideline
30
mg/
kg
rapid
absorption,
metabolism,
distribution,
and
excretion;
major
metabolic
routes
are
ring
hydroxylation
and
Ndeethylation
followed
by
conjugation
with
glucuronic
acid
and
sulfate
(
acceptable
with
42758901,
42758902)
Table
4.1b
Subchronic,
Chronic
and
Other
Toxicity
Profile
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
Page
23
of
64
870.7485
Metabolism
and
pharmacokinetics
(
rat)
42027702
(
1991)
42027703
(
1991)
Unacceptable/
guideline
30,
300
mg/
kg
rapid
absorption
and
extensive
metabolism;
recovered
radioactivity
was
urine
=
feces
>>
tissues;
highest
concentrations
in
blood
followed
by
liver,
spleen,
kidneys;
14
metabolites
identified
(
acceptable
with
42758901,
42758902)

870.7485
Metabolism
and
pharmacokinetics
(
rat)
42758901
(
1990)
42758902
(
1993)
Acceptable/
guideline
30
(
multiple),
300
(
single)
mg/
kg
no
sex
or
dose­
related
differences
in
residues
or
metabolic
profile;
after
96
hr
highest
concentrations
found
in
blood,
abdominal
vein,
liver,
and
intestine;
major
metabolites
were
4­
hydroxy
napropamide,
5­
hydroxy
napropamide,
and
4­
hydroxy[
N­
ethyl­
2­(
1­
naphthoxy)]
propionamide
870.7600
Dermal
penetration
(
rat)
40838601
(
1988)
Acceptable/
guideline
1.13,
2.55,
5.56,
77.9
mg/
rat
total
absorption
increased
with
dose;
fraction
of
given
radioactivity
that
was
absorbed
was
inversely
related
to
dose;
maximum
absorption
26.1%;
urine
and
feces
excretion
roughly
equal
over
96
hours
Special
studies
none
required
4.2
FQPA
Hazard
Considerations
4.2.1
Adequacy
of
the
Toxicity
Data
Base
Data
are
adequate
for
evaluation
of
effects
resulting
from
in
utero
and
post­
natal
exposure.
Acceptable
developmental
toxicity
studies
have
been
conducted
in
rodents
and
non­
rodents
and
a
reproductive
toxicity
study
in
rodents
is
available.

4.2.2
Evidence
of
Neurotoxicity
No
evidence
of
neurotoxicity
was
observed
in
any
study.
No
clinical
signs
of
toxicity
were
noted
in
subchronic
and
chronic
studies
in
dogs,
rats,
or
mice.

4.2.3
Developmental
Toxicity
Studies
Developmental
toxicity
studies
have
been
conducted
with
napropamide
in
the
rat
and
rabbit.
Both
species
were
administered
0,
100,
300
or
1000
mg/
kg/
day
by
oral
gavage.
Rats
were
treated
on
GDs
6­
15
and
rabbits
were
treated
on
GDs
7­
19.
Maternal
toxicity
was
evident
in
both
as
decreased
body
weight
gain
and
food
consumption
during
the
treatment
interval.
In
rats
the
most
pronounced
effects
were
during
GDs
6­
9
in
which
body
weight
gain
was
decreased
by
84%
and
food
consumption
was
decreased
by
21%
in
the
high­
dose
group.
For
rabbits,
the
effects
were
cumulative
for
the
entire
dosing
interval.
Does
administered
300
mg/
kg/
day
had
weight
gain
decreased
by
37%,
while
high­
dose
animals
had
a
mean
weight
loss
for
GDs
7­
19.
It
should
be
noted
that
the
standard
deviation
about
the
mean
for
both
mid­
and
high­
dose
group
weight
gain
Page
24
of
64
values
was
much
greater
than
the
mean
value,
suggesting
that
only
a
few
does
in
each
group
were
affected.
High­
dose
rabbits
also
had
reduced
food
consumption
during
GDs
7­
13.

No
developmental
toxicity
was
observed
in
either
species
up
to
and
including
the
limit
dose.
Fetal
body
weight
was
similar
between
the
treated
and
control
groups
and
no
treatment­
related
external,
visceral,
or
skeletal
abnormalities
were
found.

4.2.4
Reproductive
Toxicity
Study
In
a
three­
generation
reproduction
toxicity
study
napropamide
was
administered
to
male
and
female
rats
at
nominal
dose
levels
of
0,
10,
30,
and
100
mg/
kg
bw/
day.
The
premating
intervals
were
approximately
7
weeks
for
the
F
0
animals
and
approximately
11
weeks
for
the
F
1
and
F
2
animals.
Two
litters
were
produced
in
each
generation.
Reproductive
performance
was
not
affected
in
any
generation.
The
only
evidence
of
parental
toxicity
was
slightly
lower
absolute
body
weight
for
the
high­
dose
F
1
and
F
2
males
and
females
at
the
beginning
of
the
premating
interval.
Weight
gain
during
premating
was
comparable
between
the
treated
and
control
groups
of
all
generations.

Offspring
body
weight
was
decreased
at
the
highest
dose
beginning
as
early
as
PND
7.
At
100
mg/
kg,
decreased
(
94­
11%;
p#
0.05)
body
weights
were
noted
in
the
F
2a
pups
on
PND
7
and
14,
in
the
F
1b
and
F
3a
pups
on
PND
14
and
21,
and
in
the
F
1a
and
F
2a
pups
on
PND
21.
Decreases
in
body
weights
also
were
observed
in
the
100
mg/
kg
F
2b
and
F
3b
pups
(
94­
9%;
not
significant).
Although
the
data
were
not
available
to
evaluate
weight
gain
throughout
lactation,
it
appears
that
cumulative
weight
gain
by
the
high­
dose
pups
of
all
generations
was
decreased.
Therefore,
both
lactational
effects
prior
to
PND
14
and
systemic
effects
after
the
pups
began
eating
the
treated
diets
probably
contributed
to
reduced
growth.
The
lower
body
weight
for
adults
at
the
beginning
of
premating
is
a
continuation
of
the
preweaning
effects.
Recovery
of
body
weight
to
the
control
level
was
apparent
for
both
F
1
and
F
2
adults
during
the
premating
interval.

4.2.5
Additional
Information
from
Literature
Sources
No
additional
information
on
the
toxicity
of
napropamide
was
identified
in
the
open
literature.

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.

4.2.6.2
Degree
of
Concern
Analysis
and
Residual
Uncertainties
for
Pre
and/
or
Post­
natal
Susceptibility
Page
25
of
64
There
is
no
degree
of
concern
and
there
are
no
residual
uncertainties.
No
quantitative
or
qualitative
sensitivity
was
observed
in
the
rat
and
rabbit
developmental
studies
or
in
the
3­
generation
reproduction
study
in
the
rat.
Based
on
the
lack
of
evidence
of
pre­
and/
or
postnatal
susceptibility
resulting
following
exposure
to
napropamide,
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
napropamide.

4.3
Recommendation
for
a
Developmental
Neurotoxicity
Study
4.3.1
Evidence
that
supports
requiring
a
Developmental
Neurotoxicity
study
None
of
the
available
data
support
the
recommendation
for
a
developmental
neurotoxicity
study.

4.3.2
Evidence
that
supports
not
requiring
for
a
Developmental
Neurotoxicity
study
The
available
data
on
the
toxicity
of
napropamide
do
not
support
the
recommendation
for
a
developmental
neurotoxicity
study.

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
An
endpoint
attributable
to
a
single
exposure
was
not
identified
from
the
available
database.

4.4.3
Chronic
Reference
Dose
(
cRfD)

Study
Selected:
chronic/
oncogenicity
rat
OPPTS:
870.4100b
MRID
No.:
42189102
and
43068801
Executive
Summary:
In
a
chronic
toxicity/
carcinogenicity
feeding
study
(
MRIDs
42189102
and
43068801),
napropamide
(
purity
94.1%)
was
fed
to
groups
of
60
(
treated
groups)
or
70
(
controls)
Crl:
CD
(
SD)
BR
rats/
sex/
group
for
104
weeks
(
females)
or
101
weeks
(
males)
at
dose
levels
of
0,
250,
1100,
or
5000
ppm
(
corresponding
to
0,
11,
48,
or
221
mg/
kg/
day
for
males
and
0,
12,
55,
or
261
mg/
kg/
day
for
females).
Of
these,
twenty
controls
and
10
treated
animals/
sex/
dose
group
were
sacrificed
at
52
weeks.
An
additional
satellite
group
of
20
Page
26
of
64
animals/
sex
were
fed
a
diet
containing
10,000
ppm
napropamide
(
corresponding
to
522
and
582
mg/
kg/
day,
respectively,
for
males
and
females)
for
52
weeks.

A
1100
ppm,
statistically
significantly
decreased
weight
gain
was
observed
in
females
(
up
to
19%
less
than
controls
during
the
first
year
of
the
study).
At
5000
ppm,
body
weight
gain
was
also
decreased
in
males
(
up
to
12%
less
than
controls).
Increased
severity
of
chronic
progressive
glomerulonephropathy
and
incidence
of
spongiosa
hepatis
and
hepatocyte
fatty
vacuolization
were
observed
in
males;
in
both
sexes
mild
anemia
and
slight
diuretic
effects
were
also
reported
at
5000
ppm.
Mildly
reduced
food
consumption
was
observed
in
females.
Body
weight
gain
was
markedly
depressed
(
up
to
28%,
males
and
45%,
females).
Males
at
10,000
ppm
had
increased
incidence
and
severity
of
hepatocyte
fatty
vacuolization.
The
LOAEL
for
systemic
toxicity
is
1100
ppm
for
male
and
female
rats
(
48/
55
mg/
kg/
day),
based
on
decreased
weight
gain
in
females
and
slightly
increased
incidence
of
spongiosis
hepatis
in
males.
The
NOAEL
is
250
ppm
(
11/
12
mg/
kg/
day).

Neither
male
nor
female
rats
developed
neoplastic
lesions
that
could
be
attributed
to
treatment
with
napropamide
for
up
to
104
weeks.
Dosing
was
considered
adequate
to
test
for
carcinogenicity
of
napropamide
in
rats.

This
study
is
classified
as
Acceptable/
Guideline
and
satisfies
the
guideline
requirements
for
a
combined
chronic
toxicity/
oncogenicity
rodent
feeding
study
(
83­
5).

Dose
and
Endpoint
for
establishing
cRfD:
Chronic
NOAEL
of
12
mg/
kg/
day
based
on
decreased
weight
gain
in
females
and
increased
incidence
of
liver
lesions
in
males
at
48/
55
mg/
kg/
day.

Uncertainty
Factor
(
UF):
100;
includes
10x
for
interspecies
extrapolation
and
10x
for
intraspecies
extrapolation.

Comments
about
Study/
Endpoint/
UF:
The
duration
of
dosing
and
the
endpoint
are
appropriate
for
this
scenario.

Chronic
RfD
=
12
mg/
kg/
day
=
0.12
mg/
kg/
day
100
4.4.4
Incidental
Oral
Exposure
(
Short
and
Intermediate
Term)

Study
Selected:
multi­
generation
OPPTS:
870.3800
MRID
No.:
92125069
Executive
Summary:
In
a
three­
generation
reproduction
toxicity
study
(
MRID
92125069),
Devrinol
Technical
(
Napropamide;
94.6%
a.
i.;
Lot/
batch
#
4059­
17­
1)
was
administered
to
Charles
River
CD
®
rats
(
15
males/
dose;
30
females/
dose)
at
nominal
dose
levels
of
0,
10,
30,
and
Page
27
of
64
100
mg/
kg
bw/
day
(
equivalent
to
0/
0,
9.9/
12.7,
29.6/
39.4,
and
98.8/
130.7
mg/
kg
bw/
day).
The
P
animals
were
given
test
article
diet
formulations
for
approximately
7
weeks
prior
to
mating,
then
were
mated
(
1
male
with
2
females)
to
produce
the
F
1a
litters.
The
P
females
were
allowed
to
rest
for
10
days
after
weaning
of
the
F
1a
litter,
then
were
mated
with
a
different
P
male
in
the
same
treatment
group
to
produce
the
F
1b
litters.
One
week
after
weaning,
F
1b
animals
(
15
males/
dose;
30
females/
dose)
were
selected
to
become
the
parents
of
the
F
2
generations.
This
process
was
repeated
for
a
total
of
3
generations,
with
2
litters
per
generation
produced.
F
1b
animals
were
given
test
formulations
for
11
weeks
prior
to
mating
to
produce
the
F
2a
litters;
F
2b
animals
were
given
test
formulations
for
11
weeks
prior
to
mating
to
produce
the
F
3a
litters.

No
treatment­
related
findings
were
noted
at
10
ppm
in
the
parents
or
offspring.

At
100
mg/
kg,
pre­
mating
body
weights
were
decreased
(
98­
13%;
p#
0.05)
in
the
F
1
females
at
Week
26,
and
in
the
F
2
males
and
females
at
Week
55.
Body
weights
of
P,
F
1
,
and
F
2
generation
females
were
unaffected
by
treatment
throughout
gestation
and
lactation.
There
were
no
treatment­
related
differences
in
absolute
or
relative
food
consumption
in
either
sex
throughout
the
duration
of
this
study,
and
there
were
no
effects
of
treatment
on
the
duration
of
gestation
or
on
male
and
female
fertility
indices.

The
LOAEL
for
parental
toxicity
is
100
mg/
kg/
day
(
equivalent
to
98.8/
130.7
mg/
kg
bw/
day
[
M/
F]),
based
on
decreased
body
weights
in
the
F1
females
and
F2
males
and
females.
The
NOAEL
is
30
mg/
kg/
day
(
equivalent
to
29.6/
39.4
mg/
kg
bw/
day
[
M/
F]).

At
100
mg/
kg,
decreased(
94­
11%;
p#
0.05)
body
weights
were
noted
in
the
F
2a
pups
on
PND
7
and
14,
in
the
F
1b
and
F
3a
pups
on
PND
14
and
21,
and
in
the
F
1a
and
F
2a
pups
on
PND
21.
Decreases
in
body
weights
also
were
observed
in
the
100
mg/
kg
F
2b
and
F
3b
pups
(
94­
9%;
not
significant).
The
only
decreases
in
the
30
mg/
kg
group
were
noted
in
the
F
3a
males
(
98%;
p#
0.05).

The
LOAEL
for
offspring
toxicity
100
mg/
kg/
day
(
equivalent
to
98.8/
130.7
mg/
kg
bw/
day
[
M/
F]),
based
on
decreased
pup
body
weights.
The
NOAEL
is
30
mg/
kg/
day
(
equivalent
to
29.6/
39.4
mg/
kg
bw/
day
[
M/
F]).

The
LOAEL
for
reproductive
performance
was
not
observed.
The
NOAEL
for
reproductive
performance
is
100
mg/
kg/
day
(
equivalent
to
98.8/
130.7
mg/
kg
bw/
day
[
M/
F]).

This
study
is
classified
as
Acceptable/
guideline
and
satisfies
the
guideline
requirements
(
OPPTS
870.3800;
OECD
416)
for
a
three­
generation
reproduction
study
in
the
rat.

Dose
and
Endpoint:
The
offspring
toxicity
NOAEL
of
30
mg/
kg/
day
based
on
decreased
pup
body
weight
at
100
mg/
kg/
day.

Uncertainty
Factor
(
UF):
NA
Page
28
of
64
Comments
about
Study/
Endpoint/
UF:
Reductions
in
offspring
body
weight
began
as
early
as
PND
7,
and
was
also
affected
late
in
lactation
after
the
pups
started
eating
the
treated
food.
Body
weights
were
decreased
in
parental
F1
and
F2
males
and
females.
This
endpoint
is
appropriate
for
duration
of
exposure
and
applies
to
the
population
of
concern.

4.4.5
Dermal
Absorption
Executive
Summary:
In
a
dermal
absorption
study
(
MRID
40838601),
male
CD
rats
(
28/
dose)
were
administered
a
mixture
of
DEVRINOL
50­
WP
®
(
51.7%
a.
i.(
w/
w)
DEVRINOL;
Lot
#
SFH­
2702),
[
naphthoxy­
1­
14C]
DEVRINOL
(
Lot
#
WRC
10887­
47­
01)
and
50­
WP
carrier
(
Lot
#
WFJ­
2301).
This
was
applied
as
a
1:
100,
1:
50,
1:
25,
or
1:
2
dilution
of
DEVRINOL
50­
WP
(
about
1.31,
2.55,
5.56,
and
77.9
mg
DEVRINOL/
rat,
respectively).
Four
rats/
dose
were
sacrificed
1,
4,
10,
24,
48,
72,
or
96
hours
after
application.
Several
in
vitro
and
in
vivo
pilot
studies
were
conducted
that
indicated
the
experimental
protocol
for
assessing
DEVRINOL
(
1:
100
dilution)
dermal
absorption
was
acceptable.

No
animals
died
as
a
result
of
the
treatment
in
the
main
study.
Dermal
absorption
was
most
rapid
during
the
first
hour,
after
which
absorption
continued
to
increase
for
only
the
three
lower
doses,
slowing
after
24
hours.
The
total
absorbed
radioactivity
after
96
hours
(
sum
of
radioactivity
in
carcass,
skin,
urine,
feces
and
blood)
increased
with
dose
(
350,
380,
840,
and
1370
:

gequivalents
DEVRINOL
for
low
to
high
dose).
However,
the
fraction
of
the
given
radioactivity
that
was
absorbed
was
inversely
related
to
dose
(
26.1%,
15.1%,
14.9%,
and
1.8%
for
the
low
to
high
dose,
respectively).
Excretion
paralleled
absorption,
the
total
excreted
radioactivity
increasing
with
dose,
whereas
the
%
administered
radioactivity
excreted
was
inversely
related
to
dose.
Over
96
hours,
roughly
equal
amounts
of
radioactivity
were
excreted
in
the
urine
and
feces
for
all
doses
(
urine:
12.56%,
7.81%,
5.92%,
and
0.69%
of
given
dose;
feces:
12.27%,
6.45%,
6.61%,
and
0.50%
of
given
dose,
respectively,
for
low
to
high
dose).
The
excreted
radioactivity
accounted
for
97%,
97%,
89%,
and
85%
of
the
radioactivity
that
penetrated
the
skin
after
96
hours
for
the
low
to
high
dose,
respectively.
This
indicated
that
at
the
two
highest
doses
DEVRINOL
entry
into
the
bloodstream
was
greater
than
its
rate
of
excretion,
and
is
consistent
with
the
lack
of
a
decrease
in
blood
radioactivity
at
96
hours
at
these
two
doses.

The
average
recovery
of
administered
radioactivity
was
91­
97%
for
the
4
dose
groups
(
94%
overall),
indicating
acceptable
mass
balance
accounting.
DEVRINOL
tissue
distribution
and
metabolite
characterization
were
not
performed.

This
study
is
classified
as
Acceptable/
Guideline
and
meets
the
requirements
for
a
dermal
absorption
study
in
the
rat.

4.4.6
Dermal
Exposure
(
Short,
Intermediate
and
Long
Term)
Page
29
of
64
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:

Study
Selected:
chronic/
oncogenicity
rat
OPPTS:
870.4100b
MRID
No.:
42189102
and
43068801
Executive
Summary:
In
a
chronic
toxicity/
carcinogenicity
feeding
study
(
MRIDs
42189102
and
43068801),
napropamide
(
purity
94.1%)
was
fed
to
groups
of
60
(
treated
groups)
or
70
(
controls)
Crl:
CD
(
SD)
BR
rats/
sex/
group
for
104
weeks
(
females)
or
101
weeks
(
males)
at
dose
levels
of
0,
250,
1100,
or
5000
ppm
(
corresponding
to
0,
11,
48,
or
221
mg/
kg/
day
for
males
and
0,
12,
55,
or
261
mg/
kg/
day
for
females).
Of
these,
twenty
controls
and
10
treated
animals/
sex/
dose
group
were
sacrificed
at
52
weeks.
An
additional
satellite
group
of
20
animals/
sex
were
fed
a
diet
containing
10,000
ppm
napropamide
(
corresponding
to
522
and
582
mg/
kg/
day,
respectively,
for
males
and
females)
for
52
weeks.

A
1100
ppm,
statistically
significantly
decreased
weight
gain
was
observed
in
females
(
up
to
19%
less
than
controls
during
the
first
year
of
the
study).
At
5000
ppm,
body
weight
gain
was
also
decreased
in
males
(
up
to
12%
less
than
controls).
Increased
severity
of
chronic
progressive
glomerulonephropathy
and
incidence
of
spongiosa
hepatis
and
hepatocyte
fatty
vacuolization
were
observed
in
males;
in
both
sexes
mild
anemia
and
slight
diuretic
effects
were
also
reported
at
5000
ppm.
Mildly
reduced
food
consumption
was
observed
in
females.
Body
weight
gain
was
markedly
depressed
(
up
to
28%,
males
and
45%,
females).
Males
at
10,000
ppm
had
increased
incidence
and
severity
of
hepatocyte
fatty
vacuolization.
The
LOAEL
for
systemic
toxicity
is
1100
ppm
for
male
and
female
rats
(
48/
55
mg/
kg/
day),
based
on
decreased
weight
gain
in
females
and
slightly
increased
incidence
of
spongiosis
hepatis
in
males.
The
NOAEL
is
250
ppm
(
11/
12
mg/
kg/
day).

Neither
male
nor
female
rats
developed
neoplastic
lesions
that
could
be
attributed
to
treatment
with
napropamide
for
up
to
104
weeks.
Dosing
was
considered
adequate
to
test
for
carcinogenicity
of
napropamide
in
rats.

This
study
is
classified
as
Acceptable/
Guideline
and
satisfies
the
guideline
requirements
for
a
combined
chronic
toxicity/
oncogenicity
rodent
feeding
study
(
83­
5).

Dose
and
Endpoint
for
Risk
Assessment:
Chronic
oral
NOAEL
of
12
mg/
kg/
day
based
on
decreased
weight
gain
in
females
and
increased
incidence
of
liver
lesions
in
males
at
48/
55
mg/
kg/
day.
Page
30
of
64
Uncertainty
Factor
(
UF):
100;
includes
10x
for
interspecies
extrapolation
and
10x
for
intraspecies
extrapolation.

Comments
about
Study/
Endpoint/
UF:
Long­
term
oral
exposure
to
rats
resulted
in
decreased
body
weight
and
microscopic
lesions
in
the
liver.
While
liver
toxicity
was
adequately
assessed
in
the
21­
day
dermal
study,
the
consequences
of
longer
term
exposure
are
unknown.
Therefore,
a
NOAEL
of
12
mg/
kg/
day
from
the
chronic
oral
study
in
rats
is
recommended
for
use
in
long­
term
dermal
exposure
scenarios.
A
dermal
absorption
factor
(
i.
e.,
26.1%)
is
used
for
route­
to­
route
extrapolation.

4.4.7
Inhalation
Exposure
(
Short,
Intermediate
and
Long
Term)

Short­
and
Intermediate­
Term
Inhalation
Endpoints:

Study
Selected:
multi­
generation
OPPTS:
870.3800
MRID
No.:
92125069
Executive
Summary:
In
a
three­
generation
reproduction
toxicity
study
(
MRID
92125069),
Devrinol
Technical
(
Napropamide;
94.6%
a.
i.;
Lot/
batch
#
4059­
17­
1)
was
administered
to
Charles
River
CD
®
rats
(
15
males/
dose;
30
females/
dose)
at
nominal
dose
levels
of
0,
10,
30,
and
100
mg/
kg
bw/
day
(
equivalent
to
0/
0,
9.9/
12.7,
29.6/
39.4,
and
98.8/
130.7
mg/
kg
bw/
day).
The
P
animals
were
given
test
article
diet
formulations
for
approximately
7
weeks
prior
to
mating,
then
were
mated
(
1
male
with
2
females)
to
produce
the
F
1a
litters.
The
P
females
were
allowed
to
rest
for
10
days
after
weaning
of
the
F
1a
litter,
then
were
mated
with
a
different
P
male
in
the
same
treatment
group
to
produce
the
F
1b
litters.
One
week
after
weaning,
F
1b
animals
(
15
males/
dose;
30
females/
dose)
were
selected
to
become
the
parents
of
the
F
2
generations.
This
process
was
repeated
for
a
total
of
3
generations,
with
2
litters
per
generation
produced.
F
1b
animals
were
given
test
formulations
for
11
weeks
prior
to
mating
to
produce
the
F
2a
litters;
F
2b
animals
were
given
test
formulations
for
11
weeks
prior
to
mating
to
produce
the
F
3a
litters.

No
treatment­
related
findings
were
noted
at
10
ppm
in
the
parents
or
offspring.

At
100
mg/
kg,
pre­
mating
body
weights
were
decreased
(
98­
13%;
p#
0.05)
in
the
F
1
females
at
Week
26,
and
in
the
F
2
males
and
females
at
Week
55.
Body
weights
of
P,
F
1
,
and
F
2
generation
females
were
unaffected
by
treatment
throughout
gestation
and
lactation.
There
were
no
treatment­
related
differences
in
absolute
or
relative
food
consumption
in
either
sex
throughout
the
duration
of
this
study,
and
there
were
no
effects
of
treatment
on
the
duration
of
gestation
or
on
male
and
female
fertility
indices.

The
LOAEL
for
parental
toxicity
is
100
mg/
kg/
day
(
equivalent
to
98.8/
130.7
mg/
kg
bw/
day
[
M/
F]),
based
on
decreased
body
weights
in
the
F1
females
and
F2
males
and
females.
The
NOAEL
is
30
mg/
kg/
day
(
equivalent
to
29.6/
39.4
mg/
kg
bw/
day
[
M/
F]).
Page
31
of
64
At
100
mg/
kg,
decreased(
94­
11%;
p#
0.05)
body
weights
were
noted
in
the
F
2a
pups
on
PND
7
and
14,
in
the
F
1b
and
F
3a
pups
on
PND
14
and
21,
and
in
the
F
1a
and
F
2a
pups
on
PND
21.
Decreases
in
body
weights
also
were
observed
in
the
100
mg/
kg
F
2b
and
F
3b
pups
(
94­
9%;
not
significant).
The
only
decreases
in
the
30
mg/
kg
group
were
noted
in
the
F
3a
males
(
98%;
p#
0.05).

The
LOAEL
for
offspring
toxicity
100
mg/
kg/
day
(
equivalent
to
98.8/
130.7
mg/
kg
bw/
day
[
M/
F]),
based
on
decreased
pup
body
weights.
The
NOAEL
is
30
mg/
kg/
day
(
equivalent
to
29.6/
39.4
mg/
kg
bw/
day
[
M/
F]).

The
LOAEL
for
reproductive
performance
was
not
observed.
The
NOAEL
for
reproductive
performance
is
100
mg/
kg/
day
(
equivalent
to
98.8/
130.7
mg/
kg
bw/
day
[
M/
F]).

This
study
is
classified
as
Acceptable/
guideline
and
satisfies
the
guideline
requirements
(
OPPTS
870.3800;
OECD
416)
for
a
three­
generation
reproduction
study
in
the
rat.

Dose
and
Endpoint:
The
offspring
toxicity
NOAEL
of
30
mg/
kg/
day
based
on
decreased
pup
body
weight
at
100
mg/
kg/
day.

Uncertainty
Factor
(
UF):
NA
Comments
about
Study/
Endpoint/
UF:
Appropriate
inhalation
toxicity
studies
were
not
available
for
any
exposure
scenario.
In
the
three­
generation
reproduction
study
in
the
rat,
reductions
in
offspring
body
weight
began
as
early
as
PND
7,
and
was
also
affected
late
in
lactation
after
the
pups
started
eating
the
treated
food.
Body
weights
were
decreased
in
parental
F1
and
F2
males
and
females.
This
endpoint
is
appropriate
for
duration
of
exposure
and
applies
to
the
population
of
concern.
For
route­
to­
route
extrapolation,
absorption
via
the
inhalation
route
is
assumed
to
be
equivalent
to
oral
absorption.

Long­
Term
Inhalation
Endpoints:

Study
Selected:
chronic/
oncogenicity
rat
OPPTS:
870.4100b
MRID
No.:
42189102
and
43068801
Executive
Summary:
In
a
chronic
toxicity/
carcinogenicity
feeding
study
(
MRIDs
42189102
and
43068801),
napropamide
(
purity
94.1%)
was
fed
to
groups
of
60
(
treated
groups)
or
70
(
controls)
Crl:
CD
(
SD)
BR
rats/
sex/
group
for
104
weeks
(
females)
or
101
weeks
(
males)
at
dose
levels
of
0,
250,
1100,
or
5000
ppm
(
corresponding
to
0,
11,
48,
or
221
mg/
kg/
day
for
males
and
0,
12,
55,
or
261
mg/
kg/
day
for
females).
Of
these,
twenty
controls
and
10
treated
animals/
sex/
dose
group
were
sacrificed
at
52
weeks.
An
additional
satellite
group
of
20
Page
32
of
64
animals/
sex
were
fed
a
diet
containing
10,000
ppm
napropamide
(
corresponding
to
522
and
582
mg/
kg/
day,
respectively,
for
males
and
females)
for
52
weeks.

A
1100
ppm,
statistically
significantly
decreased
weight
gain
was
observed
in
females
(
up
to
19%
less
than
controls
during
the
first
year
of
the
study).
At
5000
ppm,
body
weight
gain
was
also
decreased
in
males
(
up
to
12%
less
than
controls).
Increased
severity
of
chronic
progressive
glomerulonephropathy
and
incidence
of
spongiosa
hepatis
and
hepatocyte
fatty
vacuolization
were
observed
in
males;
in
both
sexes
mild
anemia
and
slight
diuretic
effects
were
also
reported
at
5000
ppm.
Mildly
reduced
food
consumption
was
observed
in
females.
Body
weight
gain
was
markedly
depressed
(
up
to
28%,
males
and
45%,
females).
Males
at
10,000
ppm
had
increased
incidence
and
severity
of
hepatocyte
fatty
vacuolization.
The
LOAEL
for
systemic
toxicity
is
1100
ppm
for
male
and
female
rats
(
48/
55
mg/
kg/
day),
based
on
decreased
weight
gain
in
females
and
slightly
increased
incidence
of
spongiosis
hepatis
in
males.
The
NOAEL
is
250
ppm
(
11/
12
mg/
kg/
day).

Neither
male
nor
female
rats
developed
neoplastic
lesions
that
could
be
attributed
to
treatment
with
napropamide
for
up
to
104
weeks.
Dosing
was
considered
adequate
to
test
for
carcinogenicity
of
napropamide
in
rats.

This
study
is
classified
as
Acceptable/
Guideline
and
satisfies
the
guideline
requirements
for
a
combined
chronic
toxicity/
oncogenicity
rodent
feeding
study
(
83­
5).

Dose
and
Endpoint
for
establishing
cRfD:
Chronic
oral
NOAEL
of
12
mg/
kg/
day
based
on
decreased
weight
gain
in
females
and
increased
incidence
of
liver
lesions
in
males
at
48/
55
mg/
kg/
day.

Uncertainty
Factor
(
UF):
100;
includes
10x
for
interspecies
extrapolation
and
10x
for
intraspecies
extrapolation.

Comments
about
Study/
Endpoint/
UF:
Appropriate
inhalation
toxicity
studies
were
not
available
for
any
exposure
scenario.
Long­
term
oral
exposure
to
rats
resulted
in
decreased
body
weight
and
microscopic
lesions
in
the
liver.
For
route­
to­
route
extrapolation,
absorption
via
the
inhalation
route
is
assumed
to
be
equivalent
to
oral
absorption.

4.4.8
Margins
of
Exposure
The
following
margins
of
exposure
(
MOEs)
represent
HED's
level
of
concern
for
occupational
and
residential
(
non­
dietary)
exposure
risk
assessments:
Page
33
of
64
Route
of
Exposure
Duration
of
Exposure
Short­
Term
(
1­
30
Days)
Intermediate­
Term
(
1
­
6
Months)
Long­
Term
(>
6
Months)

Occupational
Exposure
Dermal
N/
A
N/
A
100
Inhalation
100
100
100
Residential
(
non­
dietary)
Exposure
Oral
100
100
N/
A
Dermal
N/
A
N/
A
100
Inhalation
100
100
100
For
occupational
exposure
(
all
durations),
inhalation
exposure
risk
assessments,
an
MOE
of
100
is
required.
The
MOE
is
based
on
10x
for
intraspecies
variation,
and
10x
for
interspecies
extrapolation.
For
residential
exposures,
an
MOE
of
100
is
required,
and
is
based
on
10x
for
intraspecies
variation,
10x
for
interspecies
extrapolation
and
a
1x
special
FQPA
factor.

4.4.9
Recommendation
for
Aggregate
Exposure
Risk
Assessments
As
per
FQPA,
1996,
when
there
are
potential
residential
exposures
to
the
pesticide,
aggregate
risk
assessment
must
consider
exposures
from
three
major
sources:
oral,
dermal
and
inhalation
exposures.
The
toxicity
endpoints
selected
for
these
routes
of
exposure
may
be
aggregated
as
follows:
for
short­
and
intermediate­
term
aggregate
exposure
risk
assessments,
the
oral
and
inhalation
routes
can
be
combined
because
of
the
common
toxicity
endpoints
(
decreased
body
weight)
via
these
routes.
No
short­
or
intermediate­
term
dermal
endpoint
has
been
identified
for
napropamide,
and
no
long­
term
residential
exposure
is
expected.

4.4.10
Classification
of
Carcinogenic
Potential
No
evidence
for
carcinogenicity
was
seen
in
mice
or
rats.
Administration
of
napropamide
to
mice
for
18
months
and
to
rats
for
24
months
did
not
result
in
an
increase
in
overall
tumor
incidence
or
increase
the
incidence
of
any
specific
type
of
tumor.
The
chemical
was
negative
for
gene
mutation
in
four
studies
(
Bacillus
subtilis,
Salmonella
typhimurium,
mouse
host
mediated,
CHO)
and
did
not
induce
micronucleus
formation
in
the
mouse
or
unscheduled
DNA
synthesis
in
rat
hepatocytes.
Positive
results
for
gene
mutation
were
obtained
in
mouse
lymphoma
cells
with
and
without
metabolic
activation
at
concentrations
that
also
cause
significant
cytotoxicity
and
in
Chinese
hamster
lung
cells
with
activation
in
the
absence
of
cytotoxicity.
Page
34
of
64
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
=
12
mg/
kg/
day
UF
=
100
Chronic
RfD
=
0.12
mg/
kg/
day
FQPA
SF
=
1X
cPAD
=
chronic
RfD
FQPA
SF
=
0.12
mg/
kg/
day
Chronic/
oncogenicity
­
rat
LOAEL
=
48/
55
mg/
kg/
day
(
m/
f)
based
on
decreased
weight
gain
in
females
and
increased
incidence
of
liver
lesions
in
males
Incidental
Oral
Short­
Term
(
1
­
30
days)
NOAEL
=
30
mg/
kg/
day
Residential
LOC
=
100
Occupational
LOC
=
100
Reproductive
toxicity
­
rat
LOAEL
=
100
mg/
kg/
day
based
on
decreased
pup
body
weight
Incidental
Oral
Intermediate­
Term
(
1
­
6
months)
NOAEL
=
30
mg/
kg/
day
Residential
LOC
=
100
Occupational
LOC
=
100
Reproductive
toxicity
­
rat
LOAEL
=
100
mg/
kg/
day
based
on
decreased
pup
body
weight
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.
Dermal
Intermediate­
Term
(
1
­
6
months)

Dermal
Long­
Term
(>
6
months)
oral
study
NOAEL
=
12
mg/
kg/
day
Residential
LOC
=
100
Occupational
LOC
=
100
Chronic/
oncogenicity
­
rat
LOAEL
=
48/
55
mg/
kg/
day
(
m/
f)
based
on
decreased
weight
gain
in
females
and
increased
incidence
of
liver
lesions
in
males
Inhalation
Short­
Term
(
1
­
30
days)
oral
study
NOAEL
=
30
mg/
kg/
day
(
inhalation
absorption
rate
=
100%)
Residential
LOC
=
100
Occupational
LOC
=
100
Reproductive
toxicity
­
rat
LOAEL
=
100
mg/
kg/
day
based
on
decreased
pup
body
weight
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
Page
35
of
64
Inhalation
Intermediate­
Term
(
1
­
6
months)
oral
study
NOAEL
=
30
mg/
kg/
day
(
inhalation
absorption
rate
=
100%)
Residential
LOC
=
100
Occupational
LOC
=
100
Reproductive
toxicity
­
rat
LOAEL
=
100
mg/
kg/
day
based
on
decreased
pup
body
weight
Inhalation
Long­
Term
(>
6
months)
NOAEL
=
12
mg/
kg/
day
(
inhalation
absorption
rate
=
100%)
Residential
LOC
=
100
Occupational
LOC
=
100
Chronic/
oncogenicity
­
rat
LOAEL
=
48/
55
mg/
kg/
day
(
m/
f)
based
on
decreased
weight
gain
in
females
and
increased
incidence
of
liver
lesion
in
males
Cancer
(
oral,
dermal,
inhalation)
Classification:
no
evidence
of
carcinogenicity
UF
=
uncertainty
factor,
FQPA
SF
=
Special
FQPA
safety
factor,
NOAEL
=
no
observed
adverse
effect
level,
LOAEL
=
lowest
observed
adverse
effect
level,
PAD
=
population
adjusted
dose
(
a
=
acute,
c
=
chronic)
RfD
=
reference
dose,
MOE
=
margin
of
exposure,
LOC
=
level
of
concern,
NA
=
Not
Applicable
*
Refer
to
Section
4.5
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
uncertainties
for
pre­
and/
or
post­
natal
toxicity.

°
The
dietary
food
exposure
assessment
utilizes
tolerance
level
residues
and
100%
crop
treated
(
CT)
information
for
all
commodities.
By
using
these
screening­
level
assumptions,
chronic
exposures/
risks
will
not
be
underestimated.

°
The
dietary
drinking
water
assessment
utilizes
values
generated
by
models
and
associated
modeling
parameters
which
are
designed
to
provide
conservative,
health
protective,
highend
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
Page
36
of
64
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
napropamide,
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,
napropamide
may
be
subjected
to
further
screening
and/
or
testing
to
better
characterize
effects
related
to
endocrine
disruption.

5.0
Public
Health
Data
Reference:
Review
of
Napropamide
Incident
Reports,
DP
Barcode:
D303447,
Jerome
Blondell,
11/
04/
04
5.1
Incident
Reports
Relatively
few
incidents
of
illness
have
been
reported
due
to
napropamide.
However,
it
appears
to
be
irritating
to
eyes
and
skin
and
has
been
associated
with
difficulty
breathing
when
used
in
enclosed
spaces.
This
conclusion
is
based
on
information
from
the
following
data
sources:

I.
OPP
Incident
Data
System
Incident#
7791­
4:
A
pesticide
incident
occurred
in
1998,
when
an
adult
female
splashed
some
of
the
product
in
her
mouth.
Reportedly,
she
had
oral
burns,
laryngeal
swelling,
and
excess
secretions.
It
was
unknown
if
napropamide
was
mixed
with
another
product.
No
further
information
on
the
disposition
of
the
case
was
reported.

Incident#
13857­
17:
A
pesticide
incident
occurred
in
2003,
when
an
adult
female
was
exposed
working
in
a
greenhouse
and
had
difficulty
breathing
and
pain
in
the
chest.
No
further
information
on
the
disposition
of
the
case
was
reported.

II.
Poison
Control
Center
Data
­
1993
through
2001
A
total
of
six
exposures
were
reported
to
Poison
Control
Centers
for
the
nine
year
period
1993­
2001.
Three
of
these
case
reported
minor
symptoms,
primarily
dermal
irritation.
Page
37
of
64
III.
California
Data
­
1982
through
2002
Detailed
descriptions
of
20
cases
submitted
to
the
California
Pesticide
Illness
Surveillance
Program
(
1982­
2002)
were
reviewed.
In
nine
of
these
cases
was
napropamide
determined
to
be
the
primary
cause
of
illness.
The
principle
symptoms
reported
involved
irritation
of
the
eyes
and/
or
skin.

IV.
National
Pesticide
Information
Center
On
the
list
of
the
top
200
chemicals
for
which
NPIC
received
calls
from
1984­
1991,
inclusively,
napropamide
was
not
reported
to
be
involved
in
human
incidents.

V.
NIOSH
SENSOR
Out
of
4,221
reported
cases
from
1998­
2002,
just
two
involved
napropamide
alone.
In
a
Florida
case
the
worker
splashed
napropamide
on
himself
and
developed
blisters.
A
Texas
case
reported
difficulty
breathing
when
using
a
napropamide
product
in
an
enclosed
area.
Both
cases
were
considered
probable
with
no
more
than
moderate
severity.

VI.
Scientific
Literature
No
scientific
literature
was
located
concerning
acute
poisoning
due
to
exposure
to
napropamide.

5.2
Other
Napropamide
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
Tolerances
are
established
under
40
CFR
§
180.328
(
a)
and
(
b)
for
negligible
residues
(
0.1
ppm)
of
napropamide
per
se
in/
on
various
raw
agricultural
commodities.
No
meat/
milk/
egg/
poultry
tolerances
are
established
for
napropamide
residues.

The
qualitative
nature
of
the
residue
in
plants
is
understood.
Acceptable
metabolism
studies
with
napropamide
have
been
conducted
on
three
dissimilar
crops
(
apple,
cabbage,
and
tomato).
The
results
of
these
studies
were
presented
on
3/
16/
93
to
the
HED
Metabolism
Assessment
Review
Committee
(
MARC).
The
HED
MARC
concluded
that
the
residue
of
concern
in
plants
is
Page
38
of
64
napropamide
per
se
and
that
the
current
tolerance
expression
is
adequate;
the
tolerance
is
expressed
in
terms
of
residues
of
the
parent
compound
only.

The
qualitative
nature
of
the
residue
in
livestock
is
understood.
HED
has
received
and
reviewed
acceptable
ruminant
and
poultry
metabolism
studies
with
napropamide.
Based
on
the
findings
from
these
studies,
HED
has
determined
that
40
CFR
§
180.6(
a)(
3)
is
applicable
to
napropamide;
there
is
no
reasonable
expectation
of
finite
residues
in
ruminants
or
poultry.
As
a
result
of
this
determination,
HED
has
recommended
that
waivers
be
granted
from
the
requirements
to:
conduct
a
ruminant
and
poultry
feeding
study
(
860.1480),
develop
a
residue
analytical
method
for
meat/
milk/
poultry/
eggs
(
860.1340),
and
conduct
a
storage
stability
study
for
meat/
milk/
poultry/
eggs
(
860.1380).
This
recommendation
is
based
on
the
low
level
of
residues
observed
in
the
goat
metabolism
study
where
the
test
animals
were
dosed
with
[
14C]
napropamide
at
an
average
level
of
9.9
ppm
in
the
diet
which
is
equivalent
to
120x
the
maximum
theoretical
dietary
burden
of
0.083
ppm
to
dairy
cattle
(
74x
the
MTDB
of
beef
cattle).
This
recommendation
is
also
based
on
the
fact
that
there
are
no
poultry
and
swine
feedstuff
associated
with
the
raw
agricultural
commodities
with
established
tolerances.
A
data­
collection
method
and
an
enforcement
method
may
be
required
if
the
registrants
wish
to
register
new
food/
feed
uses
in
the
future
Residue
analytical
methods
for
plant
commodities
are
available
for
the
purposes
of
tolerance
enforcement
and
data
collection.
The
Pesticide
Analytical
Manual,
Volume
I,
indicates
that
napropamide
is
completely
recovered
(>
80%
recovery)
using
Multiresidue
Method
Sections
302
(
Luke
Method;
Protocol
D)
and
401
(
Krause
N­
methyl
carbamate
Method;
Protocol
A).
In
addition,
PAM
Volume
II
lists
a
GLC
method
as
Method
I
(
WRC
71­
35)
for
the
determination
of
napropamide
per
se
in/
on
plant
commodities.

The
current
PAM
Volume
II
method
uses
benzene,
a
hazardous
or
toxic
reagent.
HED
is
recommending
that
the
data­
collection
methods
(
GC/
NPD
methods
with
confirmation
by
GC/
MSD),
which
were
used
in
the
analysis
of
samples
from
the
magnitude
of
the
residue
studies,
be
subjected
to
method
validations
required
for
enforcement
purposes.

There
are
adequate
storage
stability
data
to
support
the
storage
intervals
and
conditions
of
samples
collected
from
the
residue
field
studies.
These
data
indicate
that
napropamide
is
reasonably
stable
under
frozen
storage
conditions
in/
on:
(
i)
alfalfa
hay,
almond
nutmeat,
apple,
and
soybean
seed
for
>
3
years;
(
ii)
wheat
grain
and
straw
for
up
to
2.5
years,
and;
(
iii)
corn
ear,
orange,
and
pepper
for
up
to
­
2
years.
There
are
also
adequate
storage
stability
data
for
representative
processed
commodities.
These
data
indicate
that
residues
of
napropamide
are
reasonably
stable
under
frozen
storage
conditions
in
apple
juice
and
pomace,
orange
juice,
oil,
and
dried
pulp
for
up
to
36­
38
months.

There
are
adequate
magnitude
of
the
residue
data
to
support
the
registered
uses
of
napropamide
on
Brassica
leafy
vegetables
and
fruiting
vegetables
as
well
as
on
the
individual
crops
of
artichokes,
asparagus,
coffee,
mint,
pomegranate,
rhubarb,
sweet
potato,
and
tobacco.
The
Page
39
of
64
available
residue
data
for
the
above
commodities
indicate
that
residues
of
napropamide
are
mostly
nondetectable
(<
0.05
ppm)
following
applications
of
representative
formulations
according
to
the
maximum
registered
use
patterns.
The
registered
uses
on
napropamide
on
pistachio
are
supported
by
residue
data
translated
from
almonds.

There
are
limited
but
adequate
data
to
support
the
reinstatement
of
uses
of
napropamide
on
basil,
marjoram,
rosemary,
and
savory
(
summer
and
winter).
The
product
label
for
the
50%
DF
formulation
(
EPA
Reg.
No.
70506­
36)
should
be
amended
to
reflect
the
parameters
of
the
use
pattern
for
which
residue
data
are
available
for
these
herb
crops.

Additional
magnitude
of
the
residue
data
are
required
for
the
crop
groups
of
citrus
fruits,
pome
fruits,
stone
fruits,
berries,
and
tree
nuts
as
well
as
the
individual
crops
of
avocado,
fig,
grape,
kiwifruit,
olives
and
persimmon.
There
are
presently
no
registered
uses
of
napropamide
on
cucurbit
vegetables.
Unless
the
basic
registrants
of
napropamide
or
other
interested
parties
propose
uses
and
submit
supporting
data,
the
established
tolerance
for
cucurbit
vegetables
should
be
revoked.

Adequate
processing
studies
with
napropamide
have
been
submitted
for
apples,
figs,
grapes,
oranges,
plums,
and
tomatoes.
These
studies
indicate
that
residues
of
napropamide
do
not
concentrate
above
the
analytical
method's
LOQ
of
0.05
ppm
in
the
respective
processed
commodities
of
the
above
crops
except
in
citrus
oil
where
a
processing
factor
of
35x
was
reported.
A
coffee
processing
study
and
a
mint
processing
study
remain
reregistration
requirements.

An
acceptable
confined
rotational
crop
study
has
been
submitted
and
reviewed.
The
metabolites
identified
in
the
various
matrices
of
rotational
crops
corresponded
to
the
metabolites
identified
in
the
plant
metabolism
studies
and
were
found
in
approximately
similar
proportions.
Napropamide
and
desethyl
napropamide
were
found
in
all
crops.
HED
has
determined
that
limited/
extensive
field
rotational
crop
data
(
OPPTS
860.1900)
are
not
required
provided
the
registrants
accept
the
Agency's
recommendation
to
establish
a
60­
day
plantback
interval
(
PBI)
for
leafy
vegetables,
a
180­
day
PBI
for
cereal
grains,
and
a
365­
day
PBI
for
all
other
crops.
Any
labels
that
do
not
already
specify
the
appropriate
crop
restrictions
should
be
amended.

6.1.2
Chronic
Dietary
Exposure
and
Risk
Reference:
Napropamide
Chronic
Dietary
Exposure
Assessment
for
the
Reregistration
Eligibility
Decision,
DP
Barcode:
D305599,
Susan
Stanton,
10/
29/
04
A
chronic
dietary
risk
assessment
was
conducted
using
the
Lifeline
 
Model
Version
2.0
which
uses
food
consumption
data
from
the
United
States
Department
of
Agriculture's
(
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
Page
40
of
64
concern
attributable
to
a
single
dose
was
not
identified
for
napropamide;
therefore,
an
acute
RfD
was
not
established
and
an
acute
dietary
risk
assessment
was
not
conducted.

The
chronic
analysis
assumed
100%
crop
treated
and
tolerance­
level
residues
(
Tier
1)
for
all
commodities.
Processing
factors
were
based
on
the
results
of
processing
studies
for
commodities
where
such
data
were
available
(
apple
juice,
citrus
juice/
oil,
figs,
grape
juice/
raisins,
prunes
and
tomato
juice/
puree/
paste).
For
all
other
commodities,
default
processing
factors
were
used.

Drinking
water
was
incorporated
directly
in
the
dietary
assessment
using
the
Tier
1point
estimate
for
ground
water
generated
by
the
SCI­
GROW
model
(
See
sec.
6.2,
below).

The
resulting
dietary
exposure
estimates
were
less
than
2%
of
the
cPAD
for
the
U.
S.
population
and
all
population
subgroups.
Napropamide
dietary
exposure
(
food
+
water)
was
estimated
at
0.000574
mg/
kg/
day
for
the
U.
S.
population
(<
1%
of
the
cPAD)
and
0.002218
mg/
kg/
day
(
1.8%
of
the
cPAD)
for
the
most
highly
exposed
population
subgroup
(
children,
1­
2
years
old).

Table
6.1:
Summary
of
Chronic
Dietary
Exposure
and
Risk
for
Napropamide
Population
Subgroup
cPAD
(
mg/
kg/
day)
Exposure
(
mg/
kg/
day)
%
cPAD
General
U.
S.
Population
0.12
0.000574
<
1.0
All
Infants
(<
1
year
old)
0.001439
1.2
Children
1­
2
years
olda
0.002218a
1.8a
Children
3­
5
years
old
0.001645
1.4
Children
6­
12
years
old
0.000772
<
1.0
Youth
13­
19
years
old
0.000415
<
1.0
Adults
20­
49
years
old
0.000452
<
1.0
Adults
50+
years
old
0.000464
<
1.0
Females
13­
49
years
old
0.000492
<
1.0
a
The
values
for
the
population
with
the
highest
risk
are
bolded.

6.2
Water
Exposure/
Risk
Pathway
Reference:
Drinking
Water
Assessment
for
Napropamide
for
Terrestrial
Uses;
DP
Barcode:
D305601;
James
Breithaupt;
8/
17/
04;
and
Revised
Drinking
Water
Assessment
for
Napropamide;
DP
Barcode:
D305601;
James
Breithaupt;
11/
12/
04
Napropamide
is
persistent
(
half­
life
of
446
days)
but
not
particularly
mobile
(
median
K
oc
=
577
ml/
g)
and
is
therefore
not
expected
to
pose
a
significant
risk
of
ground
water
contamination.
As
of
2001,
the
USGS
had
not
detected
napropamide
in
ground
water.
Surface
water
contamination
is
possible
through
run­
off
from
treated
fields.
In
its
8/
17/
04
assessment
EFED
provided
Page
41
of
64
estimates
of
napropamide
concentrations
in
drinking
water
using
tier
2
(
PRZM­
EXAMS)
and
tier
1
(
SCI­
GROW)
models
for
surface
and
ground
water,
respectively.
The
modeling
results
are
summarized
below:

Table
6.2.
Summary
of
Estimated
Surface
and
Ground
Water
Concentrations
for
Napropamide.

Exposure
Duration
Napropamide
Surface
Water
Conc.,
ppb
a
Ground
Water
Conc.,
ppb
b
Acute
(
1
in
10
annual
peak
concentration)
112
4.5
Chronic
Non­
Cancer
(
1
in
10
annual
mean
concentration)
0.5
4.5
a
From
the
Tier
II
PRZM­
EXAMS
­
Index
Reservoir
model.
Input
parameters
are
based
on
ground
application
to
Georgia
pecan
at
the
maximum
foliar
application
rate
of
4
lbs.
a.
i./
A,
an
aerobic
soil
metabolic
half­
life
of
1338
days
(
3X
446
day
half­
life
in
MRID
41105901),
a
photolysis
half­
life
of
0.003
days
and
a
K
d
value
of
8
mg/
g.
b
From
the
SCI­
GROW
model
assuming
a
maximum
seasonal
use
rate
of
4
lbs./
A;
a
K
oc
of
577
ml/
g;
and
a
half­
life
of
446
days.
The
following
crop
scenarios
resulted
in
the
highest
estimated
concentration
(
4.5
ppb):
CA
almonds,
FL
citrus,
OR/
PA
apple,
CA
grape
and
GA
pecan).
Estimated
concentrations
for
other
crops
(
OR
berry,
PA
turf,
FL
tomato
and
NC
tobacco)
were
lower.

In
its
11/
12/
04
drinking
water
assessment,
EFED
revised
its
estimates
of
napropamide
concentrations
in
surface
water.
The
revised
acute
and
chronic
estimates
are
258.6
ppb
and
5.1
ppb,
respectively.
Input
parameters
were
the
same
as
in
the
previous
assessment
(
see
footnote
a,
above),
except
for
the
photolysis
half­
life,
which
was
recalculated
to
be
0.018
days.
HED
completed
its
chronic
dietary
and
short­
term
aggregate
risk
assessments
using
the
drinking
water
estimates
provided
in
EFED's
original
assessment,
dated
8/
17/
04.
The
revised
chronic
surface
water
estimate
of
5.1
ppb
is
slightly
higher
than
the
drinking
water
estimate
(
4.5
ppb)
that
was
used
in
HED's
assessments;
however,
because
of
the
minimal
impact
the
revised
estimate
would
be
expected
to
have
on
overall
dietary
or
aggregate
risk,
HED
determined
that
new
dietary/
aggregate
assessments
were
not
warranted.
HED's
rationale
is
explained
in
more
detail
in
section
7.
Page
42
of
64
6.3
Residential
(
Non­
Occupational)
Exposure/
Risk
Pathway
Reference:
Napropamide:
Occupational
and
Residential
Exposure
Assessment
and
Recommendations
for
the
Reregistration
Eligibility
Decision
Document;
DP
Barcode:
D295638;
Seyed
Tadayon;
11/
17/
04
There
is
a
potential
for
exposure
in
residential
settings
during
the
application
process
for
homeowners
who
use
products
containing
napropamide.
There
is
also
a
potential
for
exposure
from
entering
areas
treated
with
napropamide.
As
a
result,
risk
assessments
have
been
completed
for
both
residential
handler
and
postapplication
scenarios.
The
residential
use
of
napropamide
is
limited
to
outdoor
foliar
applications
to
ornamentals
and
turf.

6.3.1
Residential
Handler
Exposures
The
Agency
uses
the
term
"
handlers"
to
describe
those
individuals
who
are
involved
in
the
pesticide
application
process.
The
agency
believes
that
there
are
distinct
tasks
related
to
applications
and
that
exposures
can
vary
depending
on
the
specifics
of
each
task.
Residential
handlers
are
addressed
somewhat
differently
by
the
Agency,
as
homeowners
are
assumed
to
complete
all
elements
of
an
application
with
little
use
of
any
protective
equipment.

6.3.1.1
Handler
Exposure
Scenarios
The
purpose
of
this
section
is
to
describe
how
the
exposure
scenarios
are
defined.
Much
of
the
process
for
residential
uses
is
identical
to
that
considered
for
the
occupational
assessment
with
a
few
notable
exceptions
that
include:

°
Residential
handler
exposure
scenarios
are
only
considered
to
be
short­
term
in
nature
due
to
the
episodic
uses
associated
with
homeowner
products;

°
A
tiered
approach
for
personal
protection
using
increasing
levels
of
PPE
is
not
used
in
residential
handler
risk
assessments.
Homeowner
handler
assessments
are
based
on
the
assumption
that
individuals
are
wearing
shorts,
short­
sleeved
shirts,
socks,
and
shoes.

°
Homeowner
handlers
are
expected
to
complete
all
tasks
associated
with
the
use
of
a
pesticide
product
including
mixing/
loading
if
needed
as
well
as
the
application;

°
Label
use
rates
and
use
information
specific
to
residential
products
serve
as
the
basis
for
the
risk
calculations
as
opposed
to
the
rates
used
in
the
occupational
assessment;
and
°
Area/
volumes
of
spray
or
chemical
used
in
the
risk
assessment
are
based
on
HED
guidance
specific
to
residential
use
patterns.
Page
43
of
64
Exposure
to
pesticide
handlers
is
likely
during
the
residential
use
of
napropamide
in
a
variety
of
environments
including
ornamental
and
turf
uses.
The
anticipated
use
patterns
and
current
labeling
indicate
several
major
residential
exposure
scenarios
based
on
the
types
of
equipment
and
techniques
that
can
potentially
be
used
to
make
napropamide
applications.
The
quantitative
exposure/
risk
assessment
developed
for
residential
handlers
is
based
on
these
scenarios.

Applying
granulars
for
hand
application
Applying
granulars
for
shaker
can
application
Loading/
applying
granulars
for
belly
grinder
application
Loading/
applying
granulars
for
push
type
spreader
application
6.3.1.2
Data
and
Assumptions
For
Handler
Exposure
Scenarios
A
series
of
assumptions
and
exposure
factors
served
as
the
basis
for
completing
the
residential
handler
risk
assessments.
Each
assumption
and
factor
is
detailed
below.
In
addition
to
these
factors,
unit
exposure
values
were
used
to
calculate
risk
estimates.
These
unit
exposure
values
were
taken
from
the
Pesticide
Handlers
Exposure
Database
(
PHED)
or
from
Outdoor
Residential
Exposure
Task
Force
(
ORETF)
data.

The
assumptions
and
factors
used
in
the
risk
calculations
include:

C
Exposure
factors
used
to
calculate
daily
exposures
to
handlers
were
based
on
applicable
data
if
available.
For
lack
of
appropriate
data,
values
from
a
scenario
deemed
similar
enough
by
the
assessor
might
be
used.
In
this
assessment
PHED
mixer/
loader/
applicator
data
for
aerosol
can
application
is
used
to
assess
pumptrigger
sprayer
applications.
The
nature
of
these
application
methods
are
believed
to
be
similar
enough
to
bridge
the
data.

C
The
Agency
always
considers
the
maximum
application
rates
allowed
by
labels
in
its
risk
assessments
to
consider
what
is
legally
possible
based
on
the
label.

C
Residential
risk
assessments
were
not
based
on
what
could
be
applied
in
a
typical
workday
like
with
the
occupational
risk
assessments
presented
above.
Instead,
the
HED
based
calculations
on
what
would
reasonably
be
treated
by
homeowners
such
as
the
size
of
a
lawn,
or
the
size
of
a
garden.
This
information
was
used
by
the
HED
to
define
chemical
use
values
for
handlers
which
in
turn
were
coupled
with
unit
exposure
values
to
calculate
risks.
The
factors
used
for
the
napropamide
assessment
were
those
presented
in
the
Health
Effects
Division
Science
Advisory
Committee
Policy
12:
Recommended
Revisions
To
The
Standard
Operating
Procedures
For
Residential
Exposure
Assessment
which
was
completed
on
February
22,
2001.
The
following
daily
volumes
handled
and
area
treated,
excerpted
from
the
policy
and
used
in
each
residential
scenario,
include:
Page
44
of
64
S
0.023
A/
day
for
hands
and
shaker
cans
S
0.5
A/
day
for
belly
grinder
and
push
type
spreader
Residential
Handler
Exposure
Studies:
The
unit
exposure
values
that
were
used
in
this
assessment
were
based
on
studies
completed
by
the
Pesticide
Handler
Exposure
Database
(
PHED,
Version
1.1
August
1998)
and
the
ORETF.

6.3.1.3
Residential
Handler
Exposure
and
Risk
Estimates
The
residential
handler
exposure
and
risk
estimates
are
presented
in
Table
6.3.1
below.

Table
6.3.1:
Napropamide
Short­
Term
Residential
Handler
Risks
Exposure
Scenario
Crop
or
Target
Application
Ratea
(
lb
ai/
unit)
Amount
Handled
Daily
b
Inhalation
Dose
(
mg/
kg/
day)
Inhalatio
n
MOEc
Mixer/
Loader/
Applicator
Applying
Granulars
for
Hand
application
(
1)
ornamentals
6
0.023
0.0011
28000
Applying
Granulars
for
Shaker
can
application
(
2)
ornamentals
6
0.023
0.0011
28000
Loading/
Applying
Granulars
for
Belly
Grinder
application
(
3)
turf
3
0.5
0.0016
19000
Loading/
Applying
Granulars
for
Push­
type
spreader
application
(
4)
turf
3
0.5
0.00016
190000
Footnotes
a
Application
rates
are
the
maximum
application
rates
determined
from
EPA
registered
labels
for
napropamide.
b
Amount
handled
per
day
values
are
EPA
estimates
of
amount
treated
based
on
revised
Residential
SOPs
(
2/
01).
c
Baseline
inhalation
MOE
=
NOAEL
(
30
mg/
kg/
day)
/
inhalation
daily
dose
(
mg/
kg/
day),
where
inhalation
dose
=
daily
unit
exposure
(
µ
g/
lb
ai)
x
application
rate
x
amount
handled
per
day
x
conversion
factor
(
1mg/
1,000
µ
g
/
body
weight
(
60
kg
adult).

For
residential
handlers,
the
estimated
exposures
for
all
scenarios
do
not
exceed
the
Agency's
level
of
concern
for
risk
assessments
in
non
occupational
settings.

6.3.2
Residential
Postapplication
Exposures
6.3.2.1
Residential
Postapplication
Exposure
Scenarios
There
are
a
number
of
residential
postapplication
exposure
scenarios
for
different
segments
of
the
population
including
toddlers
and
adults.
Risks
were
calculated
for
only
a
few
scenarios,
since
no
dermal
endpoint
of
concern
has
been
identified.
In
general,
postapplication
inhalation
risks
following
outdoor
applications
are
considered
negligible.
Therefore,
at
this
time,
EPA
is
only
assessing
non­
dietary
ingestion
exposures
for
toddlers
(
i.
e.,
soil
ingestion
and
hand­/
object­
tomouth
Page
45
of
64
Residential
postapplication
exposures
will
most
likely
occur
for
short­
term
durations
only.
Intermediate­
term
exposures
are
not
likely
because
of
the
intermittent
nature
of
applications
by
homeowners,
and
are
therefore
not
included
in
this
assessment.

The
SOPs
For
Residential
Exposure
Assessment
define
several
scenarios
that
apply
to
uses
specified
in
current
napropamide
labels.
The
Agency
used
this
guidance
to
define
the
toddler
exposure
scenarios
included
in
this
postapplication
exposure
assessment.
The
SOPs
and
the
associated
scenarios
are
presented
below:

C
Dose
from
hand­
to­
mouth
activity
from
treated
turf
calculated
using
SOP
2.3.2:
Postapplication
dose
among
toddlers
from
incidental
non­
dietary
ingestion
of
pesticide
residues
on
treated
turf
from
hand­
to­
mouth
transfer.

°
Dose
from
object­
to­
mouth
activity
from
treated
turf
calculated
using
SOP
2.3.3:
Postapplication
dose
among
toddlers
from
incidental
non­
dietary
ingestion
of
pesticide
residues
on
treated
turf
from
object­
to­
mouth
transfer.

C
Dose
from
soil
ingestion
activity
from
treated
turf
calculated
using
SOP
2.3.4:
Postapplication
dose
among
toddlers
from
incidental
non­
dietary
ingestion
of
pesticide
residues
from
ingesting
soil
in
a
treated
turf
area.

Napropamide
may
be
applied
as
a
granular
product
to
turf,
and
episodic
ingestion
of
these
granules
by
children
may
occur.
An
episodic
granular
ingestion
assessment
for
children
was
not
performed,
however,
since
no
acute
dietary
endpoint
of
concern
was
identified
for
napropamide.

6.3.2.2
Data
&
Assumptions
for
Residential
Postapplication
Exposure
Scenarios
A
series
of
assumptions
and
exposure
factors
served
as
the
basis
for
completing
the
residential
postapplication
risk
assessments.
Each
assumption
and
factor
is
detailed
below.

°
The
Agency
combines
or
aggregates
risks
resulting
from
exposures
to
individual
chemicals
when
it
is
likely
they
can
occur
simultaneously
based
on
the
use
pattern
and
the
behaviours
associated
with
the
exposed
population.
Within
a
residential
assessment,
this
can
take
two
forms.
The
first
is
to
add
together
individual
exposures
from
all
likely
sources
of
exposure
such
as
after
an
application
to
turf
or
inside
a
home.
For
napropamide,
the
Agency
has
added
together
different
kinds
of
exposures
associated
with
the
chemical's
use
on
turf
(
hand­
to­
mouth,
object­
to­
mouth
and
soil
ingestion).
These
represent
the
standard
set
of
exposures
that
are
typically
added
together
when
chemicals
are
used
on
turf
or
inside
a
home,
because
it
is
logical
they
can
co­
occur.
The
second
is
to
add
exposures
from
different
residential
exposure
scenarios
that
can
possibly
co­
occur
such
as
when
a
homeowner
makes
an
application
and
then
checks
their
garden
for
insects
a
few
hours
later
on
the
same
day.
This
type
of
aggregation
is
not
relevant
for
napropamide,
since
a
Page
46
of
64
dermal
endpoint
of
concern
has
not
been
identified
and
other
exposure
scenarios
have
not
been
assessed.

°
Exposures
of
children
playing
on
treated
turf
(
exercising)
have
been
addressed
using
the
latest
Agency
approaches
for
this
scenario
including:

S
5
percent
of
the
application
rate
has
been
used
to
calculate
the
0­
day
residue
levels
used
for
defining
risks
from
hand­
to­
mouth
behaviours.
Measured
TTR
values
 
even
if
available
 
are
not
used
because
of
differences
in
transferability
versus
what
would
be
expected
during
hand­
to­
mouth
behaviours.

S
20
percent
of
the
application
rate
has
been
used
to
calculate
the
0­
day
residue
levels
used
for
defining
risks
from
object­
to­
mouth
behaviours.
Measured
TTR
values
 
even
if
available
 
are
not
used
because
of
differences
in
transferability
versus
what
would
be
expected
during
hand­
to­
mouth
behaviours.
A
higher
percent
transfer
has
been
used
for
object­
to­
mouth
behaviour
because
it
involves
a
teething
action
believed
to
be
more
analogous
to
DFR/
leaf
wash
sample
collection
where
20
percent
is
also
used.

S
3
year
old
toddlers
have
mean
weight
of
15
kg.

S
Short­
term
hand­
to­
mouth
exposures
are
based
on
a
frequency
of
20
events/
hour.
A
surface
area
per
event
of
20
cm2
representing
the
palmar
surfaces
of
three
fingers
is
assumed.

S
Saliva
extraction
efficiency
is
50
percent,
meaning
that
every
time
the
hand
goes
in
the
mouth
approximately
½
of
the
residues
on
the
hand
are
removed.

S
Object­
to­
mouth
exposures
are
based
on
a
25
cm2
surface
area.

S
Exposure
durations
are
expected
to
be
2
hours
based
on
information
in
the
Agency's
Exposure
Factors
Handbook
S
Soil
residues
are
contained
in
the
top
centimetre
and
soil
density
is
0.67
mL/
gram.

S
Hand­,
object­
to­
mouth
and
soil
ingestion
are
added
together
to
represent
an
overall
risk
from
exposure
to
treated
turf.

°
Postapplication
residential
risks
are
based
generally
on
maximum
application
rates
or
values
specified
in
the
SOPs
For
Residential
Exposure
Assessment.

6.3.2.3
Residential
Postapplication
Exposure
and
Risk
Estimates
Non­
dietary
Ingestion
Exposure
From
Treated
Turf:
Non­
dietary
ingestion
exposure
levels
from
treated
turf
were
calculated
using
the
following
equations.
These
values
were
then
used
to
calculate
MOEs.

The
following
illustrates
the
approach
used
to
calculate
the
non­
dietary
ingestion
exposures
that
are
attributable
to
hand­
to­
mouth
behaviour
on
treated
turf
(
SOP
2.3.2):
Page
47
of
64
Oral
Dose
(
mg/
kg/
day)
=

AR
(
lb
ai/
A)
x
CF
x
F
x
SA
(
cm2)
x
EXT
x
FQ(
events/
hr)
x
ET(
hrs/
day)
x
(
0.001mg/
µ
g)
BW
(
kg)

Where:

Dose
=
oral
dose
on
day
of
application
(
mg/
kg/
day)
AR
=
application
rate
(
lb
ai/
A)
CF
=
conversion
factor
(
11.2)
to
convert
lb
ai/
A
to
µ
g/
cm2
(
1
lb
ai/
A
x
4.54E+
8
µ
g/
lb
x
2.47E­
8
A/
cm2
=
11.2
µ
g/
cm2)
F
=
fraction
of
residue
dislodgeable
from
wet
hands
(
unfitness)
SA
=
surface
area
of
1
to
3
fingers
(
cm2)
EXT
=
extraction
rate
by
saliva
(
unfitness)
FQ
=
frequency
of
hand­
to­
mouth
events
(
events/
hour)
ET
=
exposure
duration
(
hours/
day)
BW
=
body
weight
(
kg)

Assumptions:
SA
­
The
surface
area
of
1
to
3
finger
is
20
cm2
FQ
­
The
frequency
of
hand­
to­
mouth
events
is
20
events
per
hour
for
shortterm
F
­
The
fraction
of
residue
dislodge
able
from
wet
hands
is
5%
EXT
­
The
extraction
rate
by
saliva
is
50%.
ET
­
The
time
spent
outdoors
is
2
hours/
day
The
following
illustrates
the
approach
used
to
calculate
exposures
that
are
attributable
to
objectto
mouth
behaviour
on
treated
turf
that
is
represented
by
a
child
mouthing
a
handful
of
turf
(
SOP
2.3.3):

Oral
Dose
(
mg/
kg/
day)
=
AR
(
lb
ai)
x
CF
x
F
x
SA
(
cm2)
x
F.(
events/
hr)
x
(
0.001mg/
µ
g)
BW
(
kg)
Where:

Dose
=
oral
dose
on
day
of
application
(
mg/
kg/
day)
AR
=
application
rate
(
lb
ai/
A)
CF
=
conversion
factor
(
11.2)
to
convert
lb
ai/
A
to
µ
g/
cm2
(
1
lb
ai/
A
x
4.54E+
8
µ
g/
lb
x
2.47E­
8
A/
cm2
=
11.2
µ
g/
cm2)
F
=
fraction
of
residue
dislodge
able
from
wet
hands
(
unfitness)
SA
=
surface
area
of
1
to
3
fingers
(
cm2/
day)
FQ
=
frequency
of
hand­
to­
mouth
events
(
events/
hour)
BW
=
body
weight
(
kg)

Assumptions:
Page
48
of
64
SA
­
The
surface
area
of
1
to
3
finger
is
20
cm2/
day
FQ
­
The
frequency
of
hand­
to­
mouth
events
is
20
events
per
hour
for
shortterm
F
­
The
fraction
of
residue
dislodge
able
from
wet
hands
is
5%
ET
­
The
time
spent
outdoors
is
2
hours/
day
The
following
illustrates
the
basics
of
the
approach
used
to
calculate
exposures
that
are
attributable
to
soil
ingestion
(
SOP
2.3.4):

Oral
Dose
=
AR(
lb
ai/
A)
x
F(
1.0/
cm)
x
IgR(
mg/
day)
x
(
4.54E+
8
µ
g/
lb)
x
(
2.47E­
8
A/
cm2)
x
(
0.67
cm3/
g)
x
(
1E­
6
g/
µ
g)
BW
(
kg)
Where:

Dose
=
oral
dose
on
day
of
application
(
mg/
kg/
day)
AR
=
application
rate
(
lb
ai/
A)
F
=
fraction
or
residue
retained
on
uppermost
1
cm
of
soil
IgR
=
ingestion
rate
of
soil
(
mg/
day)
CF1
=
weight
unit
conversion
factor
to
convert
the
lbs
ai
in
the
application
rate
to
µ
g
for
the
soil
residue
value
(
4.54
x
108
µ
g/
lb)
CF2
=
area
unit
conversion
factor
to
convert
the
surface
area
units
(
ft2)
in
the
application
rate
to
cm2
for
the
SR
value
(
2.47
x
10­
8
acre/
cm2)
CF3
=
volume
to
weight
unit
conversion
factor
to
convert
the
volume
units
(
cm3)
to
weight
units
for
the
soil
residue
value
(
0.67
cm3/
g
soil)
CF4
=
weight
unit
conversion
factor
to
convert
the
µ
g
of
residues
on
the
soil
to
grams
to
provide
units
of
mg/
day
(
1E­
6
g/
µ
g)
BW
=
body
weight
(
kg)

Assumptions:
F
­
The
fraction
or
residue
retained
on
uppermost
1
cm
of
soil
is
100
percent
based
on
soil
incorporation
into
top
1
cm
of
soil
after
application
(
1.0/
cm)
IgR
­
The
ingestion
rate
of
soil
is
100
mg/
day
Residential
Postapplication
Risk
Calculations:
For
postapplication
exposure,
the
margin
of
exposure
(
MOE)
was
calculated
as
follows:

Short­
term
Oral
MOE
=
NOAEL
(
30
mg/
kg/
day)
Oral
Dose
Residential
postapplication
risk
is
summarised
in
Table
6.3.2.
a.
Page
49
of
64
Table
6.3.2a:
Short­
Term
Postapplication
Residential
Risk
Estimates
from
Oral
Exposure
to
Napropamide
Exposure
Scenario
Route
of
Exposure
Population
Application
Ratea
Ave.
Daily
Dose
(
mg/
kg/
day)
MOEb
Hand
to
Mouth
Activity
on
Turfc
Oral
Toddler
6
0.09
335
Object
to
Mouth
Activity
on
Turfd
Oral
Toddler
6
0.0224
1340
Incidental
Soil
Ingestione
Oral
Toddler
6
0.0003
100000
Footnotes:

a
Application
rates
represent
maximum
label
rates
from
current
EPA
registered
labels
.
b
MOEs
calculated
using
residues
which
would
be
found
on
day
of
treatment.
Oral
MOE
=
Oral
NOAEL
(
30
mg/
kg/
day
for
short­
term/
Oral
Dose
(
mg/
kg/
day).
An
MOE
of
100
represents
HED's
level
of
concern.
c
Hand­
to­
mouth
Dose
Calculation:
oral
dose
to
child
(
1­
6
year
old)
on
the
day
of
treatment
(
mg/
kg/
day)
=
[
application
rate
(
lb
ai/
acre)
x
fraction
of
residue
dislodgeable
from
potentially
wet
hands
(
5%)
x
11.2
(
conversion
factor
to
convert
lb
ai/
acre
to
µ
g/
cm2)]
x
median
surface
area
for
1­
3
fingers
(
20
cm2/
event)
x
hand­
to­
mouth
rate
(
20
events/
hour)
x
exp.
time
(
2
hr/
day)
x
50%
saliva
extraction
factor
x
0.001
mg/:
g]
/
bw
(
15
kg
child).
d
Object
to
Mouth
Activity
on
­
Turf
Dose
Calculation:
oral
dose
to
child
(
1­
6
year
old)
on
the
day
of
treatment
=
[
application
rate
(
lb
ai/
acre)
x
fraction
of
residue
dislodgeable
(
5%)
x
11.2
(
conversion
factor
to
convert
lb
ai/
acre
to
µ
g/
cm2)]
x
median
surface
area
for
1­
3
fingers
(
25
cm2/
event)
x
hand­
to­
mouth
rate
(
20
events/
hour)
x
0.001
mg/:
g]]
/
bw
(
15
kg
child).
e
Incidental
Soil
ingestion
­
Dose
Calculation:
oral
dose
to
child
(
1­
6
year
old)
on
the
day
of
treatment
(
mg/
kg/
day)
=
[(
application
rate
(
lb
ai/
acre)
x
fraction
of
residue
retained
on
uppermost
1
cm
of
soil
(
100%
or
1.0/
cm)
x
4.54E+
08
µ
g/
lb
conversion
factor
x
2.47E­
08
acre/
cm2
conversion
factor
x
0.67
cm3/
g
soil
conversion
factor)
x
100
mg/
day
ingestion
rate
x
1.0E­
06
g/
µ
g
conversion
factor]
/
bw
(
15
kg).
Note:
Assumptions
used
in
dose
calculations
(
e.
g.,
transfer
coefficients)
are
from
Residential
SOPs
(
revised
2/
01).

Residential
Post­
Application
Risk
Summary:

The
Agency
considered
a
number
of
residential
postapplication
exposure
scenarios
for
different
segments
of
the
population
including
toddlers
and
adults.
Short­
term,
non­
dietary
ingestion
risks
were
estimated
for
toddlers'
activities
on
turf.
Intermediate­
term
risk
was
not
estimated,
since
toddler
postapplication
exposures
will
most
likely
occur
for
short­
term
durations
only.
Risk
estimates
for
short­
term
and
intermediate­
term
dermal
exposures
were
not
calculated
for
adults
or
children
because
no
short­
or
intermediate­
term
dermal
endpoint
of
concern
was
identified
in
the
toxicity
database.
Also,
an
episodic
granular
ingestion
assessment
for
children
was
not
performed,
since
no
acute
dietary
end
point
was
identified
for
napropamide.

The
Agency
aggregates
risk
values
resulting
from
separate
postapplication
exposure
scenarios
when
it
is
likely
they
can
occur
simultaneously
based
on
the
use
pattern
and
the
behaviour
associated
with
the
exposed
population.
For
napropamide,
the
Agency
aggregated
risk
values
(
i.
e.,
MOEs)
for
postapplication
exposures
of
toddlers
associated
with
turf
applications
by
combining
risks
from
all
oral
exposures
via
transfer
of
residues
from
turf
to
hands
to
mouth.
Page
50
of
64
Table
6.3.2.
b:
Short­
term
(
aggregate)
Napropamide
Residential
Scenarios
for
Postapplication
Risk
Estimates
Exposure
Scenario
Margins
of
Exposure
(
MOEs)
(
UF=
100)
Dermal
Oral
(
Non­
Dietary)
Total
Non­
Dietary
Riska
Short­
term
Exposures
Toddler
Turf:
6
lb
ai/
A
Hand
to
Mouth
N/
A
335
265
Object
to
Mouth
N/
A
1340
Incidental
Soil
Ingestion
N/
A
10000
a
The
following
formula
is
used
to
calculate
total
MOE
values
by
combining
the
route­
specific
MOEs:
MOE
total
=
1/((
1/
MOE
a)
+
(
1/
MOE
b)
+....
(
1/
MOE
n)).
Where:
MOE
a,
MOE
b,
and
MOE
n
represent
MOEs
for
each
exposure
route
of
concern.

The
aggregated
residential
risk
MOE
is
>
100
and
is,
therefore,
not
of
concern.

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,
spray
drift
could
also
be
a
potential
source
of
exposure
with
ground
application
methods.
Napropamide
may
be
applied
using
ground
equipment
on
a
variety
of
agricultural
crops
(
fruits,
nuts,
vegetables,
forestry
sites
and
tobacco)
and
may
be
applied
aerially
on
cranberries.
As
indicated
in
this
assessment,
applications
of
napropamide
directly
to
residential
turf
do
not
result
in
exposures
of
concern.
Based
on
this
assessment,
HED
believes
it
is
unlikely
that
there
is
a
higher
potential
for
risk
from
exposure
to
spray
drift
from
agricultural
uses
of
this
chemical.

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
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
has
historically
calculated
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
were
then
compared
to
the
EDWCs
provided
by
EFED
to
determine
if
a
potential
concern
existed
for
dietary
exposure
to
residues
in
drinking
water.

In
order
to
fully
implement
the
requirements
of
FQPA,
HED
and
EFED
have
been
working
toward
refining
the
screening­
level
DWLOC
approach
to
conducting
aggregate
risk
assessments
that
combine
exposures
across
all
pathways.
As
part
of
this
process,
EFED
and
HED
have
Page
51
of
64
agreed
that
chronic
and
cancer
EDWCs
can
be
used
directly
in
chronic/
cancer
dietary
exposure
assessments
to
calculate
aggregate
dietary
(
food
+
water)
risk.
This
is
done
by
using
the
relevant
model
value
as
a
residue
for
drinking
water
(
all
sources)
in
the
dietary
exposure
assessment.
The
principal
advantage
of
this
approach
is
that
the
actual
individual
body
weight
and
water
consumption
data
from
the
CSFII
are
used,
rather
than
assumed
weights
and
consumption
for
broad
age
groups.
This
refinement
has
been
used
in
estimating
the
dietary
exposure
component
in
the
napropamide
aggregate
risk
assessments.

7.1
Acute
Aggregate
Risk
A
toxicological
endpoint
of
concern
attributable
to
a
single
dose
has
not
been
identified
for
napropamide.
Therefore,
an
acute
aggregate
risk
assessment
has
not
been
conducted.

7.2
Short­
Term
Aggregate
Risk
Short­
term
aggregate
exposure
takes
into
account
residential
exposure
plus
average
exposure
levels
from
residues
of
napropamide
in
food
and
water
(
considered
to
be
a
background
exposure
level).
The
registered
residential
uses
of
napropamide
constitute
short­
term
exposure
scenarios,
and
endpoints
have
been
selected
for
short­
term
incidental
oral
and
inhalation
exposures.
The
acceptable
MOE
for
short­
term
exposure
is
100
for
both
routes
of
exposure.
The
oral
and
inhalation
routes
may
be
combined
because
of
the
common
toxicity
endpoints
(
decreased
body
weight)
via
these
routes.

Table
7.2.
Short­
Term
Aggregate
Risk
Population
Short
­
Term
Scenario
NOAEL
mg/
kg/
day
Level
of
Concern1
Max
Exposure2
mg/
kg/
day
Average
Food
+
Water
Exposure
mg/
kg/
day
Residential
Exposure3
mg/
kg/
day
Aggregate
MOE
(
food
and
residential)
4
Adult
Female5
30
MOE
#
100
0.3
0.0005
0.0016
14340
Children,
1­
2
yrs.
old6
30
MOE
#
100
0.3
0.00222
0.113
260
1Level
of
Concern
(
MOE)
based
on
10x
for
interspecies
variation
and
10x
for
intraspecies
variation.
2
Maximum
Exposure
(
mg/
kg/
day)
=
NOAEL/
Level
of
Concern
(
MOE)
=
30
mg/
kg/
day/
100
=
0.3
mg/
kg/
day
3
Residential
Exposure
=
Oral
exposure
(
toddler
postapplication
scenarios)
or
Inhalation
exposure
(
adult
residential
handler
scenarios).
There
is
no
dermal
endpoint
of
concern
for
napropamide.
4
Aggregate
MOE
=
[
NOAEL
÷
(
Avg
Food
and
Water
Exposure
+
Residential
Exposure)]
Page
52
of
64
5Adult
population
subgroup
with
highest
dietary
(
food
+
water)
exposure
and
highest
residential
handler
exposure.
Dietary
exposure
from
Table
6.1;
Residential
exposure
from
Table
6.3.1
(
highest
exposure
scenario
­
loading/
applying
granulars
for
belly
grinder
application)
6Population
subgroup
with
highest
dietary
(
food
+
water)
exposure
and
only
subgroup
with
anticipated
post­
application
residential
exposure.
Dietary
exposure
from
Table
6.1;
Residential
exposure
=
sum
of
ave.
daily
doses
from
all
3
toddler
exposure
scenarios
in
Table
6.3.2a
(
0.09mg/
kg/
day
+
0.0224
mg/
kg/
day
+
0.0003
mg/
kg/
day
=
0.113
mg/
kg/
day)

The
estimated
short­
term
aggregate
MOEs
for
adults
and
children
are
greater
than
100
and,
therefore,
do
not
exceed
HED's
level
of
concern.

7.3
Intermediate­
Term
Aggregate
Risk
There
are
no
intermediate­
term
exposure
scenarios
for
napropamide,
based
on
its
current
use
patterns.

7.4
Long­
Term
Aggregate
Risk
The
chronic
aggregate
risk
assessment
considered
exposures
from
food
and
water
only,
because
there
are
no
residential
uses
expected
to
contribute
to
chronic
exposures
for
this
chemical.
Since
water
exposure
was
incorporated
directly
into
the
Lifeline
dietary
exposure
analysis,
the
dietary
risk
estimates
reported
in
section
6.1
represent
the
total
chronic
aggregate
risk
for
napropamide.
The
chronic
aggregate
risk
estimates
for
the
U.
S.
population
and
all
subgroups
are
<
2%
of
the
cPAD
and,
therefore,
below
HED's
level
of
concern.

7.5
Cancer
Risk
A
cancer
aggregate
risk
assessment
is
not
required,
since
there
was
no
evidence
of
carcinogenicity
in
the
toxicology
studies
submitted
for
napropamide.

Note
Regarding
EFED's
Revised
Drinking
Water
Estimates
and
Their
Impact
on
HED's
Dietary
and
Aggregate
Risk
Assessments:

The
drinking
water
value
used
in
HED's
LifeLine
chronic
dietary
exposure
and
aggregate
risk
assessments
was
taken
from
EFED's
August
17,
2004
drinking
water
memo.
In
that
memo,
EFED
provided
drinking
water
estimates
for
surface
water
(
chronic,
non­
cancer)
and
ground
water
of
0.5
ppb
and
4.5
ppb,
respectively.
HED
incorporated
the
higher
of
the
two
values,
4.5
ppb,
directly
in
the
LifeLine
model,
rather
than
comparing
it
to
a
calculated
DWLOC
for
napropamide.
The
resulting
dietary
(
food
+
water)
exposure
estimates
represent
less
than
2
%
of
the
cPAD
for
all
population
subgroups,
including
infants
and
children.

On
November
12,
2004
EFED
provided
HED
with
a
revised
drinking
water
assessment
for
napropamide.
Although
the
estimated
ground
water
concentration
remains
at
4.5
ppb,
the
estimated
surface
water
concentrations
have
been
revised
upward,
with
the
non­
cancer
chronic
concentration
now
estimated
at
5.1
Page
53
of
64
ppb.
The
revised
surface
water
estimate
is
slightly
higher
than
the
4.5
ppb
value
used
in
HED's
dietary
assessment.

Since
the
difference
between
the
revised
estimated
surface
water
concentration
and
the
drinking
water
value
used
in
the
dietary
assessment
is
slight
(
0.6
ppb
or
0.0006
ppm
=
0.0006
mg/
l)
and
the
overall
dietary
risk
is
low,
HED
has
determined
that
a
new
dietary/
aggregate
assessment
is
not
warranted.
This
conclusion
is
based
on
preliminary
calculations
showing
that
the
additional
exposure
would
not
significantly
increase
dietary
or
aggregate
risk
for
napropamide.

Effect
on
Dietary
Risk:
Dietary
exposure
from
food
and
water
is
estimated
to
be
0.00222
mg/
kg/
day,
equivalent
to
1.85%
of
the
cPAD,
for
children
(
the
most
highly
exposed
subgroup).
The
increase
in
exposure
and
risk
from
an
additional
0.0006
ppm
in
drinking
water
would
not
be
significant
for
children,
as
shown
below:

Increase
in
Exposure
=
0.0006
mg
x
1
liter
x
1
child
=
0.00006
mg/
kg/
day
liter
child/
day
10
kg
Increase
as
%
of
cPAD
=
0.00006
mg/
kg/
day
x
100
=
0.05%
of
the
cPAD
0.12
mg/
kg/
day
Effect
on
Aggregate
Risk:
The
short­
term
aggregate
MOE
for
children
from
dietary
(
food
+
water)
and
residential
exposure
is
estimated
to
be
260.
The
MOE
is
calculated
based
on
the
NOAEL
of
30
mg/
kg/
day
from
the
rat
reproduction
study.
Residential
exposure
is
by
far
the
biggest
contributor
to
the
estimated
aggregate
risk
for
napropamide.
The
estimated
MOE
from
residential
exposure
alone
is
265.
The
estimated
MOE
from
food
+
water
(
using
the
estimate
of
4.5
ppb
for
drinking
water)
is
13,514
(
30
mg/
kg/
day
÷
0.00222
mg/
kg/
day).
The
incremental
risk
from
slightly
higher
drinking
water
exposure
would
not
significantly
alter
the
estimated
aggregate
risk:

Dietary
Risk
=
30
mg/
kg/
day
=
13,158
(
0.00222
mg/
kg/
day
+
0.00006
mg/
kg/
day)

Short­
term
Aggregate
Risk
=
1
=
260
(
unchanged)
(
1/
265)
+
(
1/
13,158)

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
napropamide
and
any
other
substances
and
napropamide
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
napropamide
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
Page
54
of
64
procedures
for
cumulating
effects
from
substances
found
to
have
a
common
mechanism
on
EPA's
website
at
http://
www.
epa.
gov/
pesticides/
cumulative/.

9.0
Occupational
Exposure/
Risk
Pathway
Reference:
Napropamide:
Occupational
and
Residential
Exposure
Assessment
and
Recommendations
for
the
Reregistration
Eligibility
Decision
Document;
DP
Barcode:
D295638;
Seyed
Tadayon;
11/
17/
04
9.1
Short/
Intermediate/
Long­
Term
Handler
Risk
Napropamide
Handler
Exposure
Scenarios:
Exposure
to
pesticide
handlers
is
likely
during
the
occupational
use
of
napropamide
in
a
variety
of
occupational
environments.
The
anticipated
use
patterns
and
current
labeling
indicate
several
occupational
exposure
scenarios
based
on
the
types
of
equipment
and
techniques
that
can
potentially
be
used
for
napropamide
applications.
The
quantitative
exposure/
risk
assessment
developed
for
occupational
handlers
is
based
on
the
following
scenarios.

Mixer/
Loaders:

Dry
Flowables
for
Groundboom
application
Loading
Granulars
for
Tractor­
Drawn
Spreaders
application
Dry
Flowables
for
Chemigation
application
Loading
Granulars
for
Tractor­
Drawn
Spreaders
application
Loading
Granulars
for
Aerial
application
Dry
Flowables
for
Chemigation
application
Mixing/
Loading
Liquids
for
Chemigation
application
Mixing/
Loading
Liquids
for
Groundboom
application
Mixing/
Loading
Liquids
for
High­
Pressure
HandWand
application
Applicators:

Sprays
for
Groundboom
application
Applying
Granulars
for
Tractor­
Drawn
Spreaders
application
Applying
Granulars
for
Aerial
application
Sprays
for
Groundboom
application
Sprays
for
High­
Pressure
HandWand
application
Mixer/
Loader/
Applicators:

Loading/
Applying
Granulars
for
Belly
Grinder
application
Loading/
Applying
Granulars
for
Push­
type
spreader
application
Mixing/
loading/
Applying
liquid
for
handgun
(
lawn)
Page
55
of
64
Flaggers:

Flagging
for
Granulars
application
Data
and
Assumptions
For
Handler
Exposure
Scenarios:
A
series
of
assumptions
and
exposure
factors
served
as
the
basis
for
completing
the
occupational
handler
risk
assessments.
Each
assumption
and
factor
is
detailed
below
on
an
individual
basis.
The
assumptions
and
factors
used
in
the
risk
calculations
include:

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

C
No
short­
or
intermediate­
term
dermal
endpoint
of
concern
was
identified
for
napropamide,
and
no
long­
term
handler
exposure
is
expected
based
on
the
current
use
patterns.
Therefore,
only
short­
and
intermediate­
term
inhalation
exposures
were
assessed.

C
The
short­
term
and
intermediate­
term
inhalation
endpoints
are
based
on
an
study
where
the
adverse
effects
were
observed
in
both
males
and
females;
therefore,
to
be
protective
of
the
female
population
an
average
adult
body
weight
of
60
kg
was
used
to
complete
the
risk
assessment.

C
HED
assumed
the
maximum
application
rates
allowed
by
labels
in
its
risk
assessments.

C
The
average
occupational
workday
was
assumed
to
be
8
hours.

C
The
daily
areas
treated
were
defined
for
each
handler
scenario
(
in
appropriate
units)
by
determining
the
amount
that
can
be
reasonably
treated
in
a
single
day
(
e.
g.,
acres,
square
feet,
cubic
feet,
or
gallons
per
day).
When
possible,
the
assumptions
for
daily
areas
treated
were
taken
from
the
Health
Effects
Division
Science
Advisory
Committee
on
Exposure
SOP
#
9:
Standard
Values
for
Daily
Acres
Treated
in
Agriculture,
completed
on
July
5,
2000.

A
summary
of
the
short­
and
intermediate­
term
risks
for
each
exposure
scenario
is
presented
below
in
Table
9.1.
The
short­
and
intermediate­
term
MOEs
are
the
same
because
the
toxicological
endpoints
for
both
exposure
durations
are
the
same
for
napropamide.

Table
9.1:
Summary
of
Short­
and
Intermediate­
Term
Inhalation
Occupational
Risk
for
Napropamide
Exposure
Scenario
(
Scenario
#)
Crop
Inhalation
MOEa
Mixer/
Loader
Table
9.1:
Summary
of
Short­
and
Intermediate­
Term
Inhalation
Occupational
Risk
for
Napropamide
Exposure
Scenario
(
Scenario
#)
Crop
Inhalation
MOEa
Page
56
of
64
Dry
Flowables
for
Groundboom
application
(
1)
almond,
apples,
apricots,
cherries,
nectarines,
peaches,
pears,
plums,
prunes,
grapefruit,
lemon,
oranges,
tangelos,
tangerines,
almonds,
filberts,
pecans,
pistachios,
walnuts,
fig,
artichokes,
avocado,
kiwifruit,
olives,
persimmons,
pomegranates
7300
Loading
Granulars
for
Tractor­
Drawn
Spreaders
application
(
2)
Nurseries
(
apples,
apricots,
cherries,
nectarines,
peaches,
pears,
plums,
prunes,
grapefruit,
lemon,
oranges,
tangelos,
tangerines,
almonds,
filberts,
pecans,
pistachios,
walnuts,
fig,
artichokes,
avocado,
kiwifruit,
olives)
persimmons,
pomegranates
3300
Dry
Flowables
for
Groundboom
application
(
3)
Blueberry,
caneberries
(
boysenberry,
dewberry,
elderberry,
gooseberry,
loganberry,
raspberry),
currant,
grapes,
strawberries,
asparagus,
mint,
rhubarb
7300
Dry
Flowables
for
Chemigation
application
(
4)
Nurseries
(
blueberry,
caneberries
(
boysenberry,
dewberry,
elderberry,
gooseberry,
loganberry,
raspberry),
currant,
grapes,
strawberries,
asparagus,
mint,
rhubarb)
1700
Loading
Granulars
for
Tractor­
Drawn
Spreaders
application
(
5)
Nurseries
(
blueberry,
caneberries
(
boysenberry,
dewberry,
elderberry,
gooseberry,
loganberry,
raspberry),
currant,
grapes,
strawberries,
asparagus,
mint,
rhubarb)
3300
Loading
Granulars
for
Tractor­
Drawn
Spreaders
application
(
6)
Cranberry
880
Loading
Granulars
for
Aerial
application
(
7)
Cranberry
200
Dry
Flowables
for
Chemigation
application
(
8)
Broccoli,
brussels
sprouts,
cabbage,
cauliflower,
eggplant,
peppers,
sweet
potatoes,
tobacco,
tomatoes
3300
Dry
Flowables
for
Groundboom
application
(
9)
Broccoli,
brussels
sprouts,
cabbage,
cauliflower,
eggplant,
peppers,
sweet
potatoes,
tobacco,
tomatoes
15000
Mixing/
Loading
Liquids
for
Chemigation
application
(
10)
Pepper,
tomato,
tobacco,
eggplant
2100
Mixing/
Loading
Liquids
for
Groundboom
application
(
11)
Pepper,
tomato,
tobacco,
eggplant
9400
Mixing/
Loading
Liquids
for
Groundboom
application
(
12)
Postemergence
(
fig,
filberts,
grapefruit,
grape,
lemon,
loganberry,
nectarine,
orange,
peach,
pear,
pecans,
pistachios,
plums,
prunes,
raspberry,
strawberry,
tangerines,
walnuts)
4700
Table
9.1:
Summary
of
Short­
and
Intermediate­
Term
Inhalation
Occupational
Risk
for
Napropamide
Exposure
Scenario
(
Scenario
#)
Crop
Inhalation
MOEa
Page
57
of
64
Mixing/
Loading
Liquids
for
Groundboom
application
(
13)
Ornamentals,
herbaceous
plants,
groundcover,
woody
shrubs
and
vines
3100
Dry
Flowables
for
Groundboom
application
(
14)
Ornamentals,
herbaceous
plants,
groundcover,
woody
shrubs
and
vines
4900
Loading
Granulars
for
Tractor­
Drawn
Spreaders
application
(
15)
Ornamentals,
herbaceous
plants,
groundcover,
woody
shrubs
and
vines
2200
Mixing/
Loading
Liquids
for
High­
Pressure
HandWand
application
(
16)
Ornamentals,
herbaceous
plants,
groundcover,
woody
shrubs
and
vines
30000
Applicator
Sprays
for
Groundboom
application
(
17)
Apples,
apricots,
cherries,
nectarines,
peaches,
pears,
plums,
prunes,
grapefruit,
lemon,
oranges,
tangelos,
tangerines,
almonds,
filberts,
pecans,
pistachios,
walnuts,
fig,
artichokes,
avocado,
kiwifruit,
olives,
persimmons,
pomegranates
7600
Applying
Granulars
for
Tractor­
Drawn
Spreaders
application
(
18)
Nurseries
(
apples,
apricots,
cherries,
nectarines,
peaches,
pears,
plums,
prunes,
grapefruit,
lemon,
oranges,
tangelos,
tangerines,
almonds,
filberts,
pecans,
pistachios,
walnuts,
fig,
artichokes,
avocado,
kiwifruit,
olives)
persimmons,
pomegranates
4700
Sprays
for
Groundboom
application
(
19)
Blueberry,
caneberries
(
boysenberry,
dewberry,
elderberry,
gooseberry,
loganberry,
raspberry),
currant,
grapes,
strawberries,
asparagus,
mint,
rhubarb
7600
Applying
Granulars
for
Tractor­
Drawn
Spreaders
application
(
20)
Nurseries
(
blueberry,
caneberries
(
boysenberry,
dewberry,
elderberry,
gooseberry,
loganberry,
raspberry),
currant,
grapes,
strawberries,
asparagus,
mint,
rhubarb)
4700
Applying
Granulars
for
Aerial
application
(
21)
cranberry
260
(
eng.
control)

Applying
Granulars
for
Tractor­
Drawn
Spreaders
application
(
22)
Cranberry
1300
Sprays
for
Groundboom
application
(
23)
Broccoli,
brussels
sprouts,
cabbage,
cauliflower,
eggplant,
peppers,
sweet
potatoes,
tobacco,
tomatoes
15000
Sprays
for
Groundboom
application
(
24)
Pepper,
tomato,
tobacco,
eggplant
15000
Sprays
for
Groundboom
application
(
25)
Postemergence
(
fig,
filberts,
grapefruit,
grape,
lemon,
loganberry,
nectarine,
orange,
peach,
pear,
pecans,
pistachios,
plums,
prunes,
raspberry,
strawberry,
tangerines,
walnuts)
7600
Table
9.1:
Summary
of
Short­
and
Intermediate­
Term
Inhalation
Occupational
Risk
for
Napropamide
Exposure
Scenario
(
Scenario
#)
Crop
Inhalation
MOEa
Page
58
of
64
Sprays
for
Groundboom
application
(
26)
Ornamentals,
herbaceous
plants,
groundcover,
woody
shrubs
and
vines
5100
Applying
Granulars
for
Tractor­
Drawn
Spreaders
application
(
27)
Ornamentals,
herbaceous
plants,
groundcover,
woody
shrubs
and
vines
3100
Sprays
for
High­
Pressure
HandWand
application
(
28)
Ornamentals,
herbaceous
plants,
groundcover,
woody
shrubs
and
vines
460
Mixer/
Loader/
Applicator
Loading/
Applying
Granulars
for
Belly
Grinder
application
(
29)
Ornamentals,
herbaceous
plants,
groundcover,
woody
shrubs
and
vines
and
turf
4800
Loading/
Applying
Granulars
for
Push­
type
spreader
application
(
31)
Ornamentals,
herbaceous
plants,
groundcover,
woody
shrubs
and
vines
and
turf
9500
Mixing/
loading/
Applying
liquid
for
handgun
(
lawn)
(
31)
Turf
33000
Flagger
Flagging
for
Granulars
application
(
32)
Cranberry
2300
aInhalation
Risk
assumes
no
respirator
used
by
handlers.

HED
believes
that
the
risk
values
presented
in
this
occupational
assessment
represent
the
best
quality
results
that
could
be
produced
given
the
exposure,
use,
and
toxicology
data
that
are
available.
HED
also
believes
that
the
risks
represent
reasonable
worse­
case
estimates
of
exposure
because
maximum
application
rates
are
coupled
with
medium­
to
high­
end
estimates
of
area
treated
daily
to
define
risk
estimates
that
likely
fall
in
the
upper
percentiles
of
the
actual
exposure
distributions.
Using
these
worst­
case
assumptions,
estimated
occupational
handler
MOEs
for
all
exposure
scenarios
are
greater
than
100
and
are,
therefore,
not
of
concern.

9.2
Short/
Intermediate/
Long­
Term
Postapplication
Risk
EPA
did
not
assess
occupational
postapplication
risks
to
agricultural
workers
following
treatments
to
agricultural
crops,
since
no
dermal
endpoint
of
concern
was
identified.
In
lieu
of
a
postapplication
risk
assessment,
a
restricted­
entry
interval
of
12
hours
is
assumed,
unless
the
active
ingredient
and
formulation
meet
all
of
the
criteria
listed
in
PR
Notice
95­
3
for
low
risk
pesticides.

EPA
did
not
specifically
assess
postapplication
exposures
and
risks
following
applications
of
napropamide
to
residential
and
commercial
lawns,
and
in
and
around
industrial,
commercial,
and
residential
premises.
EPA
believes
that
the
residential
postapplication
exposures
and
risk
assessment
is
a
reasonable
surrogate
for
occupational
exposures
at
these
sites.
Page
59
of
64
10.0
Data
Needs
and
Label
Requirements
10.1
Toxicology
­
none
10.2
Residue
and
Product
Chemistry
Deficiencies
°
Label
revisions
are
required
for
the
50%
DF
formulation
(
EPA
Reg.
No.
70506­
36)
if
the
registrant,
United
Phosphorus,
Inc.,
proposes
to
reinstate
uses
of
napropamide
on
basil,
marjoram,
rosemary,
and
savory
(
summer
and
winter).
The
label
should
reflect
the
parameters
of
the
use
pattern
(
application
timing,
rates
and
pre­
harvest
intervals)
for
which
residue
data
are
available
for
these
herb
crops.

°
It
is
recomemnded
that
the
data­
collection
methods,
GC/
NPD
methods
with
confirmation
by
GC/
MSD
(
Method
Nos.
RR
92­
073B,
RR
92­
006B,
RR
92­
072B,
and
RR
91­
101B),
that
were
used
in
the
analysis
of
samples
collected
from
the
magnitude
of
the
residue
studies
be
subjected
to
method
validations
required
for
enforcement
purposes.

°
Additional
magnitude
of
the
residue
data
are
required
for
the
crop
groups
of
citrus
fruits,
pome
fruits,
stone
fruits,
berries,
and
tree
nuts
as
well
as
on
the
individual
crops
of
avocado,
fig,
grape,
kiwifruit,
olives
and
persimmon.

°
A
coffee
processing
study
is
required.
If
coffee
beans
treated
at
exaggerated
rates
equivalent
to
at
least
the
maximum
theoretical
concentration
factor
due
to
processing
do
not
show
measurable
residues,
than
processing
studies
will
not
be
required.

°
A
mint
processing
study
is
required.

°
Labels
should
be
amended
to
include
the
appropriate
preharvest
intervals
(
PHIs).
Not
all
crops
have
PHIs
specified
on
the
label.
Minimum
PHIs
should
reflect
those
used
in
the
crop
field
trials.

°
Additional
product
chemistry
data
are
required
for
the
United
Phosphorous
95.7%
napropamide
T
(
EPA
Reg.
No.
70506­
35)
concerning
product
identity,
materials
used
to
produce
the
product,
the
description
of
the
production
process,
preliminary
analysis,
certified
limits,
enforcement
analytical
method
and
stability
(
OPPTS
830.1550,
1600,
1620,
1700,
1750,
1800,
and
6313).

10.3
Occupational
and
Residential
Exposure
­
none
Page
60
of
64
References:

Napropamide.
Final
Residue
Chemistry
Considerations
for
Reregistration
Eligibility
Decision.
Case
No.
2450.;
D308283;
Danette
Drew;
07/
06/
05
Napropamide
RED
­
Reregistration
Eligibility
Decision.
Final
Product
Chemistry
Considerations.
Case
No.
2450.
D312980;
Danette
Drew;
07/
06/
05
Napropamide.
Reregistration
Case
No.
2450.
Outcome
of
the
3/
16/
93
meeting
of
the
HED
Metabolism
Committee;
Steven
A.
Knizner;
04/
07/
93
Napropamide
Chronic
Dietary
Exposure
Assessment
for
the
Reregistration
Eligibility
Decision,
DP
Barcode:
D305599,
Susan
Stanton,
10/
29/
04
Napropamide:
Occupational
and
Residential
Exposure
Assessment
and
Recommendations
for
the
Reregistration
Eligibility
Decision
Document;
DP
Barcode:
D295638;
Seyed
Tadayon;
11/
17/
04
Review
of
Napropamide
Incident
Reports,
DP
Barcode:
D303447,
Jerome
Blondell,
11/
04/
04
Drinking
Water
Assessment
for
Napropamide
for
Terrestrial
Uses;
DP
Barcode:
D305601;
James
Breithaupt;
8/
17/
04
Revised
Drinking
Water
Assessment
for
Napropamide;
DP
Barcode:
D305601;
James
Breithaupt;
11/
12/
04
Page
61
of
64
Appendices
1.0
TOXICOLOGY
DATA
REQUIREMENTS
The
requirements
(
40
CFR
158.340)
for
food
use
for
napropamide
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
yes1
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
yes2
yes
yes2
yes
yes
870.5100
Mutagenicity 
Gene
Mutation
­
bacterial
.
.
.
.
.
.
.
.
870.5300
Mutagenicity 
Gene
Mutation
­
mammalian
.
.
.
.
.
.
870.5xxx
Mutagenicity 
Structural
Chromosomal
Aberrations
870.5xxx
Mutagenicity 
Other
Genotoxic
Effects
.
.
.
.
.
.
.
.
.
.
yes
yes
yes
no
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
yes
yes
yes
Special
Studies
for
Ocular
Effects
Acute
Oral
(
rat)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
Subchronic
Oral
(
rat)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
Six­
month
Oral
(
dog)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
no
no
no
­
­
­

1Napropamide
is
used
on
tobacco.
If
residue
level
on
cured
tobacco
exceeds
0.1
ppm
level,
a
90­
day
inhalation
study
in
rats
with
tobacco
spiked
with
the
napropamide
residue
may
be
required.
Page
62
of
64
2Satisfied
by
the
combined
chronic/
oncogenicity
study
in
rats.

2.0
NON­
CRITICAL
TOXICOLOGY
STUDIES
Developmental
A
developmental
toxicity
study
(
MRID
42006703)
was
conducted
in
which
Sprague­
Dawley
rats
were
administered
R­
7465
technical
(
94.3%
a.
i.;
Lot
no.
0952­
17)
via
gavage
at
0,
100,
300,
or
1000
mg/
kg/
day
on
gestational
days
(
GDs)
6­
15,
inclusive.
Maternal
toxicity,
observed
at
1000
mg/
kg/
day,
was
manifested
as
decreased
body
weight
gain
during
the
dosing
period.
Based
on
this
finding,
the
maternal
NOAEL
and
LOAEL
were
300
and
1000
mg/
kg/
day,
respectively.

The
NOAEL
for
developmental
toxicity
was
1000
mg/
kg/
day;
the
LOAEL
>
1000
mg/
kg/
day.

This
study
is
classified
as
Acceptable/
guideline
and
satisfies
the
guideline
requirements
(
OPPTS
870.3700a;
OECD
414)
for
a
developmental
toxicity
study
in
the
rat.
Deficiencies
were
not
serious
enough
to
affect
usefulness
of
data.
The
number
of
litters
available
in
the
high­
dose
group
is
adequate
to
make
an
assessment
of
the
developmental
toxicity
of
the
test
material.

A
developmental
toxicity
study
(
MRID
42006704)
was
conducted
in
which
New
Zealand
white
rabbits
were
administered
R­
7465
technical
(
94.3%
a.
i.;
Lot
no.
EHC­
0952­
17)
via
gavage
at
0,
100,
300,
or
1000
mg/
kg/
day
on
gestational
days
(
GDs)
7­
19,
inclusive.
Maternal
toxicity
was
manifested
as
decreased
body
weight
gain
(
at
300
and
1000
mg/
kg/
day)
and
decreased
food
consumption
(
at
1000
mg/
kg/
day)
during
the
dosing
period.
Based
on
these
results,
the
maternal
NOAEL
and
LOAEL
were
100
and
300
mg/
kg/
day,
respectively.

The
NOAEL
for
developmental
toxicity
was
1000
mg/
kg/
day;
the
LOAEL
>
1000
mg/
kg/
day.

This
study
is
classified
as
Acceptable/
guideline
and
satisfies
the
guideline
requirements
(
OPPTS
870.3700b;
OECD
414)
for
a
developmental
toxicity
study
in
the
rabbit.
Deficiencies
were
not
serious
enough
to
affect
usefulness
of
data.
The
number
of
litters
available
in
the
high­
dose
group
is
adequate
to
make
an
assessment
of
the
developmental
toxicity
of
the
test
material.

21­
day
Dermal
Groups
of
5
male
and
5
females
Wistar
rats
were
exposed
dermally
to
0,
10,
100,
or
1000
mg/
kg/
day
of
napropamide
(
95.2%
a.
i.)
for
a
period
of
21
days.
The
systemic
and
local
(
dermal)
NOAEL
is
1000
mg/
kg/
day
(
the
highest
dose
tested).
The
systemic
and
dermal
LOAEL
is
greater
than
1000
mg/
kg/
day.
Page
63
of
64
This
study
is
classified
Acceptable/
guideline
and
does
satisfy
the
requirements
for
a
21­
day
dermal
toxicity
study
in
the
rat.
Not
all
clinical
chemistry
parameters
and
tissue
samples
were
evaluated;
however,
omission
of
these
requirements
does
not
affect
the
validity
of
the
study
because
an
adequate
assessment
of
subchronic
toxicity
could
be
made.

Subchronic
In
a
subchronic
oral
study
(
MRID
00113810),
R­
7465
(
napropamide;
89.1­
100%
a.
i.,
Lot
Nos.:
WRC
569­
38­
1,
WRC
1120­
32­
1,
&
WRC
1182­
16)
was
administered
daily
in
the
diet
to
4
beagle
dogs/
sex/
dose
at
doses
of
0,
16,
40,
or
100
mg/
kg/
day
for
14
weeks.

No
treatment­
related
effects
were
observed
on
mortality,
clinical
signs,
body
weight
and
body
weight
gains,
ophthalmology,
hematology,
urinalysis,
or
gross
and
histological
pathology.
Food
consumption
was
not
reported.
A
treatment­
related
adverse
effect
was
not
observed
at
16
or
40
mg/
kg/
day.

Throughout
the
study,
serum
alkaline
phosphatase
was
increased
(
statistical
analysis
not
performed)
in
both
sexes
at
40
(
87­
50%)
and
100
(
840­
76%)
mg/
kg/
day.
Absolute
and
relative
to
body
liver
weights
increased
(
p<
0.01)
in
100
mg/
kg/
day
males
by
29­
38%.
In
the
absence
of
microscopic
lesions,
these
changes
are
not
considered
biologically
significant.

The
LOAEL
is
not
identified
and
the
NOAEL
is
$
100
mg/
kg/
day.

This
study
is
classified
Unacceptable/
guideline
and
does
not
satisfy
the
requirements
for
a
90­
day
oral
toxicity
study
in
the
dog.
A
LOAEL
was
not
identified
and
the
animals
could
have
tolerated
a
higher
dose.
Homogeneity,
stability,
and
actual
concentration
data
in
the
dietary
formulations
were
not
included.

Chronic
In
a
chronic
toxicity
study
(
MRIDs
41156602
and
41156601),
Devrinol
(
napropamide;
94.7%
purity;
Lot
#:
WRC
4921­
27­
24)
was
administered
daily
for
52
weeks
in
gelatin
capsules
to
5
beagle
dogs/
sex/
dose
at
doses
of
0,
10,
70,
or
500
mg/
kg/
day.

There
were
no
treatment­
related
effects
on
mortality,
clinical
signs,
ophthalmology,
food
consumption,
hematology,
clinical
chemistry,
urinalysis,
or
organ
weights.
Treatment­
related
effects
were
not
observed
at
10
or
70
mg/
kg/
day.

Decreased
body
weight
and
body
weight
gain
were
observed
in
the
500
mg/
kg/
day
females.
Final
body
weight
was
decreased
by
10%.
Body
weight
gain
(
Weeks
0­
13)
was
decreased
by
39%,
and
overall
(
Weeks
0­
52)
body
weight
gain
was
decreased
by
27%.
Page
64
of
64
In
the
500
mg/
kg/
day
males,
there
was
an
increased
incidence
(#
affected/
5)
of
a
raised
area
on
the
spleen
as
follows:
0
(
0),
10
(
0),
70
(
1),
and
500
(
3)
mg/
kg/
day.
An
increase
in
slight
to
moderate
siderotic
nodules
was
observed
in
the
500
mg/
kg/
day
males
(
2/
5
treated
vs
0/
5
controls);
however,
this
effect
may
have
been
incidental
and
unrelated
to
dose.
Slight
to
mild
spleen
congestion
was
observed
in
the
70
and
500
mg/
kg/
day
males
(
2/
5
each
treated
vs
0/
5
controls);
thus,
findings
in
the
spleen
were
not
clearly
dose­
dependent
and
may
have
been
incidental;
otherwise,
the
biological
relevance
is
not
clear.
Therefore,
toxicity
in
the
spleen
was
considered
to
be
equivocal.

The
LOAEL
is
500
mg/
kg/
day,
based
on
decreased
body
weight
and
body
weight
gains
in
females.
The
NOAEL
is
70
mg/
kg/
day.

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

Oncogenicity
R­
7465
was
fed
to
groups
of
50
Crl:
CD­
1
mice/
sex
for
18
months
(
MRID
42189101)
at
dosage
levels
of
0,
60,
450,
3500,
or
7000
ppm
(
for
males:
0,
7.4,
55,
455,
or
931
mg/
kg/
day,
respectively;
for
females:
0,
9.4,
70,
568,
or
1216
mg/
kg/
day,
respectively).
Compound­
related
systemic
toxicity
was
evidenced
as
significantly
decreased
body
weight/
weight
gain
at
7000
and
3500
ppm
for
both
sexes.
Consequently,
the
systemic
NOAEL
and
LOAEL
for
both
sexes
were
450
and
3500
ppm,
respectively.
Administration
of
R­
7465
at
the
stated
doses
did
not
appear
to
be
associated
with
an
increase
in
tumor
incidence
when
the
treated
animals
were
compared
to
the
controls.
The
chemical
appeared
to
have
been
tested
at
adequate
doses
as
seen
by
the
decrease
in
body
weight
gain
in
both
sexes.

This
study
is
classified
Acceptable/
Guideline
and
satisfies
the
guideline
requirement
[
OPPTS
870.4200]
for
a
carcinogenicity
study
mice.
