Document ID: EPA-HQ-OPP-2005-0061-0136
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-06-09T04:00Z

Page
1
of
42
UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
OFFICE
OF
PREVENTION,
PESTICIDES
AND
TOXIC
SUBSTANCES
Date:
June
6,
2006
MEMORANDUM
SUBJECT:
Revised
Occupational
Exposure
and
Risk
Assessment
for
Azinphos
Methyl
(
Reflecting
Recommendations
from
the
Human
Studies
Review
Board
(
HSRB)
Meeting
held
April
3­
6,
2006)

FROM:
Steven
Weiss,
Industrial
Hygienist
Seyed
Tadayon,
Chemist
John
Doherty,
Toxicologist
Reregistration
Branch
3
Health
Effects
Division
(
7509P)

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

TO:
Diane
Isbell,
Chemical
Review
Manager
Special
Review
and
Reregistration
Division
(
7508W)

DP
Barcode
:
367772
PC
Codes:
058001
In
this
document,
which
is
for
use
in
EPA's
development
of
the
azinphos
methyl
(
AZM,
O,
O­
Dimethyl
S­[(
4­
oxo­
1,2,3­
benzotriazin­
3(
4H)­
yl)
methyl]
phosphorodithioate)
Re­
evaluation
Decision,
the
Health
Effects
Division
(
HED)
presents
the
results
of
its
revision
of
the
human
health
risk
assessment
for
the
effects
of
occupational
exposures
to
AZM.
This
document
updates
and
supersedes
the
HED's
2001
handler
and
post­
application
assessment
(
DP
Barcodes:
D276108
and
D276109).

Assumptions
and
resulting
risk
estimates
for
dietary
exposures
to
AZM
have
not
changed
from
those
presented
in
the
2/
18/
99
human
health
risk
assessment
(
D252505)
and
reflected
in
the
Interim
Reregistration
Eligibility
Decision
(
IRED)
dated
10/
30/
2001.
There
are
no
residential
uses
of
AZM
Page
2
of
42
Executive
Summary
Changes
Affecting
AZM
This
assessment
provides
the
updated
occupational
exposure
and
risk
estimates
for
AZM.
It
includes
risk
estimates
for
handlers
and
post­
application
workers.
There
have
been
several
changes
since
the
2001
assessments
affecting
this
revision:
 
use
pattern
changes,
 
product
formulation
changes,
 
exposure
and
toxicity
data
submitted,
and
 
a
Human
Studies
Review
Board
(
HSRB)
meeting
regarding
the
use
of
human
toxicity
study
data
in
this
risk
assessment.

The
following
is
a
brief
synopsis
of
these
changes.

Use
Pattern
Changes:

Crops
registered
for
AZM
use
were
divided
into
three
groups.
Group
1
uses
were
cancelled
after
the
IRED
was
issued
(
10/
30/
2001)
and
were
removed
from
product
labels.
Group
1
uses
included:
beans
(
succulent
and
snap),
birdsfoot
trefoil,
broccoli,
cabbage
(
including
Chinese),
cauliflower,
citrus,
celery
clover,
cucumbers,
eggplant,
filberts,
grapes,
melons
(
honeydew,
muskmelon/
cantaloupe,
watermelons,
other
melons)
onions,
green,
onions,
dry
bulb,
pecans,
peppers,
plums
and
dried
plums,
quince,
spinach,
strawberries,
and
tomatoes.

Group
2
uses
are
being
phased
out
as
of
9/
30/
2006.
Group
2
uses
include:
cotton,
cranberries,
nectarines,
peaches,
potatoes,
southern
pine
seed
orchards,
and
caneberries
(
blackberries,
boysenberries,
loganberries,
raspberries
application
to
cane
and
soil
only).

Group
3
uses
are
the
subject
of
this
occupational
risk
assessment
and
include:
almonds,
apples
and
crab
apples,
blueberries
(
low
bush
and
high
bush),
Brussels
sprouts
(
application
to
soil
at
transplant
only),
cherries
(
sweet
and
tart),
nursery
stock,
parsley,
pears,
pistachios,
and
walnuts.
This
assessment
is
based
on
the
AZM
applications
for
the
Group
3
crops/
use
sites
only.

Formulation
Changes:

AZM
is
an
organophosphate
insecticide
that
is
formulated
as
manufacturing
product
(
88.1
percent
active
ingredient),
and
several
wettable
powder
products
(
35
to
50
percent
active
ingredient).
All
wettable
powder
formulations
are
contained
in
watersoluble
packaging.
Registrations
for
all
the
liquid
formulation
products
have
been
voluntarily
cancelled
by
the
registrant.

New
Data:

New
dislodgeable
foliar
residue
(
DFR)
data
for
blueberries,
apples,
sweet
cherries,
and
ornamentals
were
also
submitted.
These
studies
were
required
as
part
of
a
Page
3
of
42
Data
Call­
In
(
DCI)
for
AZM.
Data
from
the
new
exposure
studies
along
with
data
already
reviewed
by
the
Agency
were
included
in
this
assessment.

Since
the
last
version
of
this
occupational
risk
assessment,
the
primary
registrant
for
AZM
has
submitted
additional
exposure
studies
for
handlers
and
post­
application
activities.
The
new
studies
include
one
study
assessing
handler
exposures
and
three
studies
assessing
post­
application
exposures
based
on
biomonitoring.
The
handler
study
was
designed
to
quantify
worker
exposure
to
AZM
during
mixing/
loading/
application
of
GUTHION
®
50
WP
to
orchard
crops
(
i.
e.,
apples
at
29
sites
and
apples
plus
stone
fruit
at
1
site)
by
open
and
closed
cab
airblast
application.
The
post­
application
studies
were
designed
to
quantify
worker
exposure
to
AZM
after
application
of
GUTHION
®
50
WP
resulting
from
manual
harvesting
activities
in
apples,
walnuts,
and
blueberries.
Urine
samples
collected
in
these
studies
were
used
to
estimate
workers'
internal
doses
of
AZM
based
on
measurement
of
the
metabolite
methylsulfonylbenzazimide
(
MSMB)
in
their
urine.
MSMB
serves
as
a
biomarker
for
AZM.
Results
from
a
metabolism
study
with
human
volunteers
were
used
to
estimate
the
percentage
of
AZM
that
is
represented
by
the
biomarker
MSMB
in
urine
(
MRID
44785801).
Blood
samples
were
drawn
from
postapplication
workers
only
and
assayed
for
cholinesterase
activity.
However,
the
design
of
these
biomonitoring
studies
reflects
the
intent
to
quantify
worker
exposure
to
AZM
under
controlled
field
conditions,
not
to
monitor
cholinesterase
activity
as
a
result
of
exposure.

Data
from
these
biomonitoring
studies
and
the
pharmacokinetic
study
were
used
to
refine
the
exposure
estimates
used
in
this
risk
assessment.
Data
from
a
metabolism
study
involving
human
volunteers
were
used
to
estimate
the
internal
dose
of
AZM
in
workers
based
on
the
metabolite
of
AZM,
MSMB,
which
was
measured
in
the
worker's
urine.
The
metabolism
and
biomonitoring
studies
used
in
this
assessment
are
listed
below.
Although
not
subject
to
review
by
the
HSRB
under
EPA
Human
Subjects
Protections
Rule,
40
CFR
Part
26,
these
studies
do
require
a
review
of
their
ethical
conduct.
EPA
is
currently
preparing
these
ethics
reviews
in
accordance
with
EPA
Human
Subjects
Protections
Rule,
40
CFR
Part
26.

MRID
447858­
01.
"
Selim,
S.
Absorption,
Excretion,
Balance
and
Pharmacokinetics
of
14
C
Radioactivity
After
Single
Dose
Dermal
Application
of
Three
Dose
Levels
of
14
C
Labeled
Guthion
to
Healthy
Volunteers."
March
24,
1999.

MRID
463164­
02.
"
Assessment
of
Pharmacokinetic
Data
to
Identify
A
Biomarker
for
the
Biological
Monitoring
of
Azinphos­
Methyl".
This
MRID
contains
a
summary
of
MRID
44785801.

MRID#:
463164­
03,
"
GUTHION
®
50
WP
­
Biological
Monitoring
of
Post­
Application
Workers
During
Manual
Thinning
and
Harvesting
of
Apples:.

MRID#:
463164­
04:
"
GUTHION
®
50
WP
­
Biological
Monitoring
of
Post
Application
Workers
During
Manual
Harvesting
of
Blueberries
MRID#:
463164­
05:
GUTHION
®
50
WP
­
Biological
Monitoring
of
Post­
Application
Workers
During
Manual
Harvesting
of
Walnuts
Page
4
of
42
MRID#:
463164­
06,
"
Azinphos­
methyl
­
Biomonitoring
of
Applicators
Following
Airblast
Treatment
of
Orchard
Crops
using
Open
and
Closed
Cab
Equipment".

HSRB
Recommendations:

This
revision
reflects
the
HSRB
recommendation
against
the
use
of
toxicological
data
from
toxicity
studies
involving
human
volunteers
exposed
to
AZM
for
assessing
occupational
handler
and
post­
application
exposure
and
risk.
The
HSRB
recommendations
are
discussed
in
more
detail
below.
Consequently,
this
occupational
risk
assessment
relies
on
data
from
toxicity
studies
using
animals.
Toxicity
data
from
studies
in
which
adult
human
subjects
were
intentionally
exposed
to
AZM
to
elicit
a
toxic
effect
have
not
been
used
in
this
risk
assessment.

Hazard
Characterization
The
No
Observed
Adverse
Effect
Level
(
NOAEL)
of
0.56
mg/
kg/
day
from
a
rat
dermal
absorption
study
in
which
the
Lowest
Observed
Adverse
Effect
Level
(
LOAEL)
was
5.6
mg/
kg/
day
for
inhibition
of
red
blood
cell
(
RBC)
acetyl
cholinesterase
was
selected
as
the
endpoint
for
estimating
risk
from
short­
term
dermal
exposures.
This
NOAEL
from
a
routespecific
study
is
appropriate
for
estimating
risk
based
on
external,
dermal
exposures
as
collected
through
passive
dosimetry
(
i.
e.,
transfer
coefficients
from
the
Agricultural
Reentry
Task
Force
(
ARTF)
and
unit
exposure
estimates
from
the
Pesticide
Handlers
Exposure
Database
(
PHED)).
It
is
not
appropriate
for
use
with
exposure
estimates
based
on
internal
doses
of
AZM
from
biomonitoring
studies.
As
this
is
a
route­
specific
study,
dermal
risk
assessments
based
on
this
endpoint
do
not
need
modification
by
a
dermal
absorption
factor.

The
NOAEL
from
a
chronic
feeding
study
in
the
dog
of
0.15
mg/
kg/
day
in
which
the
LOAEL
was
0.69
mg/
kg/
day
for
inhibition
of
red
blood
cell
(
RBC)
acetyl
cholinesterase
(
AChE)
was
selected
as
the
endpoint
for
estimating
risk
from
intermediate­
term
dermal
exposures.
This
NOAEL
from
an
oral­
dosing
study
is
appropriate
for
estimating
risk
based
on
either
external,
dermal
exposures
as
collected
through
passive
dosimetry
(
i.
e.,
transfer
coefficients
from
the
Agricultural
Reentry
Task
Force
(
ARTF)
and
unit
exposure
available
in
the
Pesticide
Handlers
Exposure
Database
(
PHED))
and/
or
exposure
estimates
based
on
internal
doses
of
AZM
from
biomonitoring
studies.
Internal
doses
estimated
from
biomonitoring
studies
capture
all
routes
of
exposure
(
dermal,
inhalation,
and
oral).
This
endpoint
should
be
used
to
estimate
risk
from
all
routes
of
exposure
wherever
they
are
based
on
internal
doses
from
biomonitoring
studies,
regardless
of
exposure
duration.

A
dermal
absorption
rate
of
42%
from
a
rat
dermal
absorption
study
was
assumed
for
estimating
exposure
via
the
dermal
route
when
using
conventional
exposure
data
(
from
PHED
and
transfer
coefficients)
in
conjunction
with
an
oral
endpoint.

The
inhalation
toxicity
risk
assessment
endpoint
is
based
on
the
NOAEL
of
0.2
mg/
kg/
day
from
a
90­
day
inhalation
study
that
is
route
specific
for
inhalation
exposures.
It
is
used
when
conventional
exposure
data
(
e.
g.
from
data
collected
through
passive
dosimetry
and
Page
5
of
42
available
in
PHED)
are
used
rather
than
biomonitoring
data.
For
inhalation
risk
assessments,
100%
absorption
of
inhaled
AZM
is
assumed.

Exposure
and
Risk
Estimates
Occupational
risks
have
been
estimated
based
on
short­
term
(
1
to
30
days)
and
intermediate­
term
(
30
to
180
days)
exposures.
Occupational
exposure
for
chronic
durations
(
more
than
6
months)
is
not
expected
based
on
the
registered
use
patterns.
Based
on
an
uncertainty
factor
of
100,
a
Margin
of
Exposure
(
MOE)
that
is
less
than
100
is
a
risk
concern.
The
Agency
used
biomonitoring
data
when
available
to
estimate
risk.
These
data
were
available
for
mixers/
loaders/
applicators
for
airblast
applications
and
for
all
post­
application
risks
except
those
from
activities
involving
parsley.
All
other
risk
estimates
were
estimated
through
the
use
of
PHED
and
ARTF
data.

MOEs
calculated
based
on
the
biomonitoring
study
for
mixer/
loader/
applicators
using
open
and
closed
cab
air
blast
sprayers
for
Group
3
crops
ranged
from
18
to
205,
and
for
some
crops/
activities
resulted
in
risk
estimates
of
concern.

In
addition
to
collecting
urine
to
measure
internal
AZM
dose,
breathing
zone
samples
were
also
taken
for
mixer/
loader/
applicators.
MOEs
based
on
the
breathing
zone
samples
and
the
NOAEL
of
0.2
mg/
kg/
day,
ranged
from
43
to
2390,
are
also
a
risk
concern.
This
indicates
that
AZM
exposures
via
inhalation
and
the
dermal
routes
both
have
risk
concerns.

MOEs
for
short­
term
exposure
based
on
PHED
data
for
mixer/
loaders
and
applicators
for
Group
3
crops
range
from
7
to
623
and
for
some
crop/
activities
resulted
in
risk
estimates
of
concern.
These
MOEs
are
based
on
the
maximum
application
rate
and
assume
area
treated
of
350
acres
for
aerial
application,
80
acres
for
groundboom
application
and
40
acres
for
airblast
application.

MOEs
for
intermediate­
term
exposure
based
on
PHED
data
for
mixer/
loaders/
applicators
for
Group
3
crops
range
from
5
to
400
and
for
most
crops
resulted
in
risk
estimates
of
concern.
These
MOEs
are
based
on
the
maximum
application
rate
and
assume
area
treated
of
350
acres
for
aerial
application,
80
acres
for
groundboom
application
and
40
acres
for
airblast
application.

Bayer
submitted
2003
AZM
biomonitoring
data
for
blueberry,
apple,
and
walnut
postapplication
activities
at
current
restricted
entry
intervals
(
REIs).
Data
from
these
studies
were
analyzed
and
used
to
estimate
risk
for
all
Group
3
uses
except
parsley.
Post­
application
activities
associated
with
parsley
(
hand­
harvesting)
are
very
different
from
the
types
of
harvesting
activities
represented
in
the
submitted
biomonitoring
studies.
MOEs
based
on
internal
doses
from
biomonitoring
studies
were
estimated
using
the
oral
NOAEL
of
0.15
mg/
kg/
day.
Dislodgeable
foliar
residue
(
DFR)
data
for
AZM
were
used
to
extrapolate
exposures
on
postapplication
days
beyond
the
Reentry
Interval
(
REI)
in
cases
where
MOEs
were
less
than
100
at
the
current
REI.
For
parsley,
exposures
were
estimated
using
the
same
dermal
transfer
coefficient
(
TC)
method
that
was
used
in
the
2001
AZM
IRED.
MOEs
for
short­
term
dermal
exposures
from
parsley
were
estimated
using
the
dermal
NOAEL
of
0.56
mg/
kg/
day.
The
MOEs
for
intermediate­
term
dermal
exposures
from
parsley
were
estimated
using
the
oral
NOAEL
of
0.15
mg/
kg/
day
and
a
42%
dermal
absorption
factor.
Page
6
of
42
REIs
are
not
of
concern
when
MOEs
for
post­
application
workers
reach
100.
Walnuts
and
almonds
are
the
only
Group
3
crops
with
MOEs
of
at
least
100
for
current
REIs
(
30
days).
MOEs
on
day
30
for
pistachios
are
greater
than
100;
however,
the
REI
(
and
PHI)
is
21
days.
An
estimate
of
the
day
that
MOEs
would
reach
100
for
pistachios
can
not
be
calculated
based
on
available
data.
The
number
of
days
for
most
of
the
crops
to
reach
100
is
significantly
longer
than
the
current
REIs
specified
on
EPA
labels
(
e.
g.,
the
number
of
days
for
MOEs
to
reach
100
range
from
18
days
for
nursery
crops
to
103
days
for
apples).

Risk
Characterization
HED
believes
these
risk
estimates
for
occupational
activities
are
conservative
and
probably
overestimate
risks.
These
risk
estimates
are
the
result
of
a
comparison
of
estimates
of
exposure
to
an
endpoint
for
toxic
effects,
and
there
are
conservative
assumptions
inherent
in
each
of
these
risk
components.

On
the
exposure
side,
the
handler
exposure
scenarios
for
aerial
and
groundboom
applications
are
based
on
conventional
PHED
data
and
assumptions
likely
to
overestimate
risk,
such
as
maximum
application
rates
and
acreages
treated.
The
airblast
exposure
estimates
have
been
refined
through
the
use
of
biomonitoring
data
and
are
considered
less
conservative.
Available
medical
monitoring
data
(
Washington
State)
support
the
characterization
of
this
risk
assessment
as
conservative
as
it
indicates
that
typical
exposures
of
handlers
to
AZM
may
result
in
detectable
cholinesterase
inhibition,
but
only
in
a
small
number
of
handlers
(
2/
580
in
2004
and
1/
611
in
2005)
or
<
1%
of
the
workers
tested.
The
2
cases
in
2004
and
1
case
in
2005
reported
AZM
use
specifically.
HED
notes
that
the
580
and
611
workers
tested
in
2004
and
2005,
respectively,
were
tested
irrespective
of
the
active
ingredient
handled.
However,
given
that
AZM
is
used
on
73%
of
the
apple
crop,
many
of
the
workers
tested
in
2004
and
2005
likely
applied
AZM.
The
MOEs
on
which
the
REIs
are
based
have
been
refined
through
biomonitoring
data.
REIs
indicate
the
minimum
amount
of
time
between
an
AZM
treatment
and
when
a
worker
can
reenter
the
field.
The
biomonitoring
data
for
post­
application
workers
reflect
reentry
into
a
field
at
the
minimum
time
specified
(
the
REI)
and,
therefore,
worst­
case
exposures.
In
practice,
a
post­
application
worker
may
not
reenter
a
treated
field
until
several
days
after
the
REI
by
which
time
AZM
residues
may
have
dissipated.
Although
representative
of
only
one
day
of
exposure
to
AZM,
available
biomonitoring
data
show
no
firm
evidence
of
cholinesterase
inhibition
in
post­
application
workers.

On
the
hazard
side,
HED
recognizes
that
as
regards
cholinesterase
inhibition,
animals
and
humans
probably
are
similar.
Although
the
NOAELs
for
cholinesterase
(
ChE)
inhibition
across
species
including
humans
are
not
very
different,
since
the
repeat
dose
study
with
humans
is
a
NOAEL­
only
study,
there
is
no
LOAEL
for
ChE
inhibition
in
humans
to
compare
with
animal
LOAELs.
More
importantly,
the
steep
dose­
response
that
occurs
in
going
from
cholinesterase
inhibition
to
more
severe
systemic
effects
is
a
caution
to
eliminating
10­
fold
safety
factor
for
interspecies
differences.
In
particular,
HED
notes
the
progression
from
moderate
ChE
inhibition
to
more
severe
systemic
effects
seen
in
the
rat
reproductive
studies.
In
the
rat
reproduction
study
there
was
25­
47%
RBC
AChE
inhibition
during
lactation
at
0.55
mg/
kg/
day.
Systemic
effects
are
seen
in
pups
(
decrease
in
viability
index
accompanied
by
a
decrease
in
pup
body
weight
during
lactation)
at
the
next
higher
dose
of
1.5
mg/
kg/
day
where
there
is
75
to
83%
inhibition
of
RBC
Page
7
of
42
AChE
during
lactation.
There
is
only
a
2
to
3
fold
difference
between
the
non­
systemic
effect
dose
on
RBC
AChE
inhibition
and
a
systemic
effect
dose
of
AZM.
As
the
dose
level
in
the
rats
is
increased
to
4.8
mg/
kg/
day
and
RBC
AChE
inhibition
reaches
89
to
91%
there
are
convulsions
and
deaths
in
the
dams
further
indicating
the
seriousness
of
the
systemic
toxicity
of
AZM.

Incident
data
indicate
a
50%
decline
in
poisoning
incidents
involving
AZM
over
time.
Medical
monitoring
data
indicating
that
a
small
percentage
of
workers
exhibit
mild
but
detectable
cholinesterase
inhibition
as
a
result
of
AZM
exposure.
Given
this,
HED
believes
that
the
majority
of
the
time
workers
are
using
AZM
safely.
HED
further
believes
the
selection
of
the
dog
oral
endpoint
as
the
lowest
NOAEL
in
the
toxicity
database
on
the
most
sensitive
endpoint
coupled
with
a
100­
fold
safety
factor
is
adequately
protective,
and
results
in
MOEs
that
are
conservative
and
overestimate
risk.
However,
HED
remains
concerned
that
on
occasion
a
worker's
accidental
exposures
to
AZM
at
higher
levels
than
may
be
typical
may
occur
and
result
in
serious
health
consequences
regardless
of
all
safeguards
because
of
the
steep
dose­
response
for
more
serious
effects
seen
in
the
animal
reproduction
studies.

1.0
Hazard
Characterization
and
Summary
AZM
is
an
organophosphate
cholinesterase
inhibitor.
AZM
inhibits
the
enzymes
plasma
cholinesterase
and
red
blood
cell
and
brain
acetylcholinesterase
by
forming
a
covalent
bond
between
the
phosphate
part
of
the
AZM
molecule
and
a
free
hydroxyl
group
of
the
enzyme.
This
bond
renders
the
enzyme
irreversibly
inhibited
and
recovery
of
inhibition
is
slow.
The
toxicity
database
for
AZM
is
robust
and
complete.
It
consists
of
the
standard
guideline
acute,
subchronic,
chronic,
carcinogenicity
studies
using
rats,
dogs,
and
mice,
reproduction
and
developmental
studies
in
rats
and/
or
rabbits,
acute
and
subchronic
neurotoxicity
studies,
a
developmental
neurotoxicity
study,
and
mutagenicity
studies.
In
addition,
there
is
a
special
comparative
cholinesterase
study
in
neonatal
and
adult
rats
and
both
a
single
dose
and
repeat
dose
study
using
human
volunteers.
Inhibition
of
cholinesterase
is
the
basis
for
the
NOAEL
or
LOAEL
for
all
of
these
species.
In
addition,
there
is
a
progression
from
moderate
ChE
inhibition
to
more
severe
systemic
effects
(
decreases
in
pup
viability
and
weight,
and
convulsions
and
death
in
adults)
seen
in
the
rat
reproductive
studies
that
exhibits
a
steep
dose
response.
Clinical
signs
of
toxicity
that
are
considered
related
to
the
effects
of
cholinesterase
inhibition
come
at
doses
higher
than
the
LOAEL
except
for
certain
gastrointestinal
reactions
in
the
dog.
Table
A
in
Appendix
I
gives
the
NOAEL
(
when
it
was
established)
and
the
LOAEL
for
cholinesterase
inhibition.

1.1
Human
Studies
Review
Board
(
HSRB)

HED
presented
an
oral,
repeat
dose
toxicity
study
using
AZM
and
involving
human
volunteers
to
the
HSRB
at
a
meeting
on
April
3­
6,
2006.
The
HSRB
discussed
the
study
during
this
meeting
and
has
prepared
a
draft
written
report
summarizing
its
discussions.
HED
has
reviewed
the
HSRB's
draft
report
of
the
April
2006
meeting.
The
following
reference
is
for
the
oral,
repeat
dose
study
using
AZM
and
human
volunteers
that
was
presented
to
the
HSRB:

MRID
45476101.
McFarlane,
P.
and
Freestone,
S.
"
A
Randomized
Double­
Blind
Placebo
Controlled
Study
with
AZM
to
Determine
the
No
Effect
Level
on
Plasma
and
RBC
Cholinesterase
Activity
After
Repeat
Doses.
13
August,
1999.
Page
8
of
42
With
regards
to
the
single
chemical
occupational
risk
assessment
for
AZM,
it
is
HED's
understanding
based
on
discussions
held
during
the
meeting
that
the
results
of
the
28­
day
repeat
dose
study
using
human
volunteers
should
not
be
used
to
develop
a
point
of
departure
for
extrapolation
of
risk
to
workers
exposed
to
AZM
via
the
dermal
and
inhalation
routes.
HED
understands
that
the
HSRB
had
little
confidence
in
the
study
because
only
one
dose
level
was
used
over
the
28­
day
period,
and
that
dose
level
could
not
be
used
to
establish
an
effect
level
for
cholinesterase
inhibition
in
the
human
subjects.
The
HSRB
expressed
concerns
that
the
laboratory
conducting
the
cholinesterase
assays
may
not
have
been
able
to
detect
cholinesterase
inhibition
at
the
one
dose
tested
in
the
subjects.
The
HSRB's
conclusion
is
consistent
with
the
recommendation
of
the
NAS
committee
(
NAS
2001)
that
the
Agency
should
not
consider
data
from
No
Observed
Effect
Level
(
NOEL­
only)
studies.

In
an
effort
to
respond
to
the
HSRB's
concerns
related
to
the
study,
HED
contacted
the
registrant
and
the
laboratory
in
Scotland
that
conducted
the
assays
on
AZM.
The
registrant
confirmed
that
the
repeat
dose
study
was
only
intended
to
establish
a
NOAEL.
The
laboratory
confirmed
that
the
study
director
and
technicians
were
the
same
for
a
variety
of
chemicals
for
which
changes
in
cholinesterase
activity
were
measurable
and
cholinesterase
inhibition
was
detected.
Although
this
point
was
made
to
the
HSRB
during
the
April
2006
meeting,
there
remain
residual
uncertainties
about
the
assay
used
for
AZM
and
variables
that
may
have
resulted
in
the
negative
result
for
cholinesterase
inhibition
seen
in
the
study.
As
a
result,
HED
returned
to
the
toxicity
database
to
reconsider
both
animal
and
human
data.

On
balance,
HED
finds
the
repeat
dose
study
with
AZM
using
human
volunteers
to
have
been
well­
conducted
and
well­
documented.
The
results
of
this
study
are
well
supported
by
the
animal
studies
indicating
little
species
differences
regarding
plasma
and
RBC
cholinesterase
inhibition.
Although
cholinesterase
inhibition
was
not
detected
at
0.25
mg/
kg/
day
in
this
study,
the
laboratory
conducting
the
assay
has
experience
conducting
assays
for
cholinesterase
inhibition
with
carbamates
and
other
organophosphate
chemicals
in
which
they
have
detected
cholinesterase
inhibition.
While
HED
does
not
completely
agree
with
the
HSRB's
recommendation
against
relying
upon
the
use
of
the
human
study,
it
is
acknowledged
that
there
are
residual
uncertainties
associated
with
the
use
of
a
single
dose
study
in
which
only
a
NOAEL
was
established.
More
importantly,
HED
is
concerned
about
the
steep
dose
response
between
the
dose
level
for
ChE
inhibition
without
systemic
effects
and
systemic
effects
seen
in
pups
(
reduced
viability
and
weight)
and
more
severe
neurotoxic
effects
(
convulsions
and
death)
at
higher
doses
in
adults
as
seen
in
the
rat
reproduction
studies.
Consequently,
HED
selected
endpoints
(
NOAELs
and
LOAELs)
from
animal
studies
based
on
RBC
cholinesterase
inhibition
for
use
in
this
risk
assessment.
Toxicity
studies
involving
human
volunteers
and
exposure
to
AZM
to
elicit
a
toxic
response
have
not
been
used
in
this
risk
assessment.

1.2
Endpoint
Selection
for
Occupational
Risk
Assessments
The
toxicity
database
was
reviewed
and
toxic
endpoints
for
use
in
risk
assessments
for
workers
were
selected.
They
are
as
follows:
Page
9
of
42
Dermal
Risk
Assessments
The
No
Observed
Adverse
Effect
Level
(
NOAEL)
of
0.56
mg/
kg/
day
from
a
rat
dermal
absorption
study
(
MRID
42452701,
1992)
in
which
the
Lowest
Observed
Adverse
Effect
Level
(
LOAEL)
was
5.6
mg/
kg/
day
for
inhibition
of
red
blood
cell
(
RBC)
acetyl
cholinesterase
(
AChE)
was
selected
as
the
endpoint
for
estimating
risk
from
short­
term
dermal
exposures.
This
NOAEL
from
a
route­
specific
study
is
appropriate
for
estimating
risk
based
on
external,
dermal
exposures
as
collected
through
passive
dosimetry
(
i.
e.,
transfer
coefficients
from
ARTF
and
unit
exposures
from
PHED.
It
is
not
appropriate
for
use
with
exposure
estimates
based
on
internal
doses
of
AZM
from
biomonitoring
studies.
As
this
endpoint
is
from
a
route­
specific
dermal
study,
no
absorption
factor
is
required
for
dermal
risk
assessment.

The
study
was
not
designed
to
meet
the
guideline
requirements
for
a
21­
or
90­
day
dermal
toxicity
study,
but
cholinesterase
assessments
were
included
in
a
study
designed
to
meet
the
guidelines
for
a
dermal
absorption
study.
HED
recognizes
the
limitations
of
this
study
in
that
only
a
single
dose
was
applied,
there
were
only
four
males
assessed
and
females
were
not
assessed.
The
extent
of
inhibition
of
RBC
AChE
was
only
about
17%
and
there
were
no
indications
of
recovery
as
would
be
expected
over
the
time
frame
of
the
study.
However,
the
study
demonstrated
depression
of
RBC
AChE
consistent
with
other
studies
and
the
apparent
inhibition
was
statistically
significant
on
two
successive
assessment
times
(
10
and
24
hours
postdosing
The
selection
of
this
study
as
the
endpoint
for
short­
term
occupational
dermal
risk
assessment
is
considered
conservative
because
of
the
relatively
small
effect
on
RBC
AChE
and
the
10­
fold
difference
between
the
NOAEL
and
the
LOAEL.
This
10­
fold
difference
is
considered
protective
for
the
cumulative
effect
of
possible
intermittent
exposure
during
the
shortterm
(
1­
30
days)
exposure
period.

The
NOAEL
from
a
chronic
feeding
study
in
the
dog
(
MRID
41804901,
1990)
of
0.15
mg/
kg/
day
in
which
the
LOAEL
was
0.69
mg/
kg/
day
for
inhibition
of
red
blood
cell
(
RBC)
acetyl
cholinesterase
(
AChE)
was
selected
as
the
endpoint
for
estimating
risk
from
intermediateterm
dermal
exposures.
This
NOAEL
from
an
oral­
dosing
study
is
appropriate
for
estimating
risk
based
on
either
external,
dermal
exposures
as
collected
through
passive
dosimetry
and
available
in
the
Pesticide
Handlers
Exposure
Database
(
PHED)
and/
or
exposure
estimates
based
on
internal
doses
of
AZM
from
biomonitoring
studies.
This
endpoint
should
be
used
to
estimate
risk
from
dermal
exposures
wherever
they
are
based
on
internal
doses
from
biomonitoring
studies,
regardless
of
exposure
duration.
The
NOAEL
of
0.15
mg/
kg/
day
is
the
lowest
and
most
protective
demonstrated
NOAEL
on
the
most
sensitive
endpoint
(
ChE
inhibition)
from
all
of
the
available
animal
studies.

Bench
Mark
Dose
(
BMD)
analysis
of
rat
cholinesterase
data
resulted
in
BMD10
values
(
doses
at
which
cholinesterase
activity
is
inhibited
by
10%)
and
BMDL10
values
(
the
lower
95th
percentile
confidence
limit
on
doses
at
which
cholinesterase
activity
is
inhibited
by
10%)
that
bracket
and
support
the
NOAEL
of
0.15
mg/
kg/
day
(
see
Table
B
in
Appendix
I).
The
BMDL10
value
for
RBC
AChE
inhibition
in
adult,
male
rats
from
a
repeat
dose
comparative
cholinesterase
study
was
0.16
mg/
kg/
day.
Other
BMD10
and
BMDL10
values
for
adults
were
in
the
range
of
the
0.15
mg/
kg/
day
dose
selected
based
on
the
dog
study.
Page
10
of
42
In
the
chronic
study
in
the
dog,
there
was
20
to
43%
inhibition
of
RBC
AChE
at
0.69
mg/
kg/
day
(
the
LOAEL)
and
66
to
92
%
inhibition
at
3.8
mg/
kg/
day,
the
next
higher
dose.
Results
from
two
reproduction
studies
in
the
rat
show
systemic
effects,
such
as
reduced
pup
viability
and
body
weights
at
doses
approximating
1.7
mg/
kg/
day,
and
more
severe
effects
including
clinical
signs
of
neurotoxicity
(
convulsions
and
death)
in
adult
female
rats
at
doses
approximating
4.8
mg/
kg/
day.
The
dose­
response
curve
in
going
from
ChE
inhibition
to
systemic
effects
to
the
more
severe
effects
of
convulsions
and
death
is
considered
to
be
steep
seen
in
the
rat
reproduction
studies,
as
there
is
only
a
2
to
3
fold
increase
in
dose
between
these
effects.

The
dog
chronic
study
also
demonstrated
a
possible
effect
on
the
gastro­
intestinal
system
in
the
dogs
at
the
LOAEL.
There
was
increased
incidence
of
dogs
in
both
sexes
with
mucus
containing
feces
at
the
LOAEL
but
the
incidence
was
lower
(
rather
than
higher)
at
the
next
higher
dose.
Dogs
are
prone
to
gastro­
intestinal
disturbance
and
the
significance
of
this
relative
to
humans
is
uncertain.
A
factor
that
was
considered
in
selecting
this
study
for
intermediate
term
dermal
risk
assessment
is
that
the
dermal
absorption
study
selected
for
the
short
term
scenarios
is
based
on
a
single
dose
and
cumulative
effects
of
the
intermittent
exposure
that
may
occur
for
exposure
durations
of
one
to
six
months
may
begin
to
be
contribute
to
depression
of
ChE
and
this
could
be
underestimated
by
the
use
of
this
study
for
longer
term
exposures.

Overall,
as
the
lowest
NOAEL
in
the
database
on
the
most
sensitive
endpoint,
HED
believes
the
0.15
mg/
kg/
day
is
protective
of
all
effects
seen
in
the
database.

Inhalation
Risk
Assessments
The
inhalation
toxicity
risk
assessment
endpoint
was
based
on
the
NOAEL
and
LOAEL
for
the
90­
day
inhalation
study
(
MRID
00155011,
1976)
and
is
route
specific
for
risk
assessments
based
on
inhalation
exposures.
The
NOAEL
of
0.0012
mg/
L
was
converted
to
mg/
kg/
day
by
making
slightly
different
assumptions
concerning
body
weight
and
mean
daily
intake
than
was
used
in
the
previous
risk
assessment
(
July
10,
2001).
(
See
Appendix
I
for
assumptions
and
calculations.)
Thus,
a
dose
of
0.2
mg/
kg/
day,
rather
than
0.32
mg/
kg/
day,
was
used
for
this
revised
risk
assessment.
Inhalation
exposure
appears
to
be
significant
in
a
number
of
scenarios.
For
inhalation
risk
assessments,
100%
absorption
of
inhaled
AZM
is
assumed.

Dermal
Absorption
A
dermal
absorption
factor
of
42%
was
determined
based
on
a
weight­
of­
the­
evidence
from
both
dermal
absorption
studies
with
human
volunteers
(
1999,
MRID
No.:
44785801)
and
in
rats
(
1992,
MRID
No.:
42452701).
Although
the
study
with
human
subjects
was
classified
as
unacceptable
because
only
percentage
data
were
provided
in
the
report,
HED
determined
that
the
results
can
be
included
in
the
WOE
analysis
to
select
the
dermal
absorption
factor
for
AZM.
In
the
study
with
humans,
three
groups
of
six
male
subjects
were
dosed
for
8
hours
on
a
4
x
6
cm
area
of
their
forearms
with
14C
radiolabeled
AZM
at
doses
of
0.79,
3,
or
1.49
gm/
kg.
Urinary
recovery
following
5
to
8
days
of
collection,
the
key
index
of
absorption,
indicated
a
wide
variety
for
the
individual
subjects
with
the
range
for
the
low
dose
being
12.7
to
45.18%,
for
the
mid
dose
group
being
10.2
to
39.44%
and
to
be
9.91
to
34.56%
for
the
high
dose
group.
The
ranges
(
rather
than
the
means)
for
the
percent
radioactivity
in
the
urine
values
from
this
study
Page
11
of
42
indicate
that
humans
can
vary
widely
in
their
ability
to
absorb
AZM.
As
much
as
45.18%
was
demonstrated
to
be
absorbed.

In
the
dermal
absorption
study
(
with
rats,
14C
labeled
AZM
in
GUTHION
35WP
was
applied
at
doses
of
0.056,
0.56
or
5.6
mg/
kg
for
a
period
of
10
hours.
The
rats
were
sacrificed
at
1,
4,
10,
24,
72
and
168
hours
post­
dosing.
Total
recovery
was
from
70.45
to
103%
with
the
low
dose
group
demonstrating
the
best
recovery
(
96.8
to
103.21%).
The
mean
total
absorption
(
blood,
urine,
feces,
carcass
and
cage
wash
was
41.65%,
21.86%
and
18.34%
for
the
0.056,
0.56
and
5.6
mg/
kg
dose
groups,
respectively.
Most
of
the
radioactivity
was
in
the
urine
(
10.14
to
26.24%).
Significant
amounts
remained
on
the
skin
after
washing
and
this
appears
to
be
able
to
be
absorbed
after
washing
as
indicated
by
the
slow
decline
from
10
to
168
hours
and
increases
in
radioactivity
in
the
urine
for
that
same
period.
A
dermal
absorption
factor
of
42%
based
on
total
absorption
is
supported
by
this
study
when
the
percent
absorption
for
the
lowest
test
dose
is
considered.
This
factor
was
retained
from
the
previous
risk
assessment
document
and
was
recommended
by
the
HIARC
(
April
20,
1998,
HED
Document
No.:
012591).
Thus,
since
similar
values
in
the
range
of
40%
were
obtained
in
the
rat
and
human
studies,
the
42%
dermal
absorption
factor
is
considered
appropriate.

The
dermal
absorption
factor
of
42%
is
used
to
modify
the
oral
endpoint
when
it
is
used
in
conjunction
with
conventional
exposure
data
from
PHED
and
other
HED
occupational
exposure
databases
for
dermal
risk
assessment.
It
is
not
used
in
conjunction
with
the
oral
endpoint
and
internal
doses
from
biomonitoring
studies.

Metabolism
Results
from
a
study
designed
to
determine
the
absorption,
excretion,
balance,
and
pharmacokinetics
of
radio­
labelled
AZM
in
humans
after
a
single
dermal
dose
was
used
to
estimate
internal
doses
of
AZM
in
workers
(
MRID
447858­
01).
The
volunteers
received
topical
doses
of
AZM
at
either
0.79
ug/
kg
or
3.0
ug/
kg
in
isopropyl
alcohol,
or
1.49
ug/
kg
as
the
25%
a.
i.
wettable
powder
formulation.
The
distribution
of
the
radioactivity
was
followed
in
all
3
dose
groups
for
120
hours
after
which
83.6%
of
the
absorbed
dose
is
excreted
in
the
urine
for
the
1.49
ug/
kg
dose
of
the
25%
active
ingredient
(
a.
i.)
wettable
powder
(
WP)
formulation.
There
was
little
difference
between
dose
groups.
Based
on
an
analysis
of
pooled
urine,
MSMB
was
determined
to
represent
9.2%
of
the
activity
in
the
urine
in
the
0
to
120
hour
pooled
sample.
Based
on
MSMB
accounting
for
9.2%
of
the
urine
activity
and
urine
activity
accounting
for
83.6%
of
the
absorbed
dose,
MSMB
represents
7.7%
of
the
absorbed
dermal
dose
of
AZM.

Safety
Factors
The
following
safety
factors
have
been
applied
to
all
the
occupational
risk
assessments
for
workers:
a
10X
for
interspecies
variations
and
a
10X
for
intraspecies
variations.
A
total
uncertainty
factor
of
100X
has
been
applied
to
all
risk
assessments.

Table
1
summarizes
toxicological
endpoints
of
concern
that
were
used
to
estimate
shortand
intermediate­
term
risks
for
workers.
Occupational
exposure
for
chronic
durations
(
more
than
6
months)
is
not
expected
based
on
the
registered
use
patterns.
Page
12
of
42
Table
1.
Toxicity
Endpoints
Selected
for
Occupational
Risk
Assessments
for
AZM
Exposure
Route/
Scenario
Study
NOAEL
Effect
UF
Short­
Term
Dermal
Dermal
absorption
in
rat
0.56
mg/
kg/
day
RBC
ACHE
100
Intermediate­
Term
Dermal*
1­
year
oral
dog
feeding
study
0.15
mg/
kg/
day
RBC
ACHE
100
Inhalation**
90­
day
subchronic
rat
study
0.2
mg/
kg/
day
RBC
ACHE
100
All
exposure
scenarios
based
on
Internal
AZM
Dose
(
i.
e.
all
exposure
routes)
from
Biomonitoring
Data
1­
year
oral
dog
feeding
study
0.15
mg/
kg/
day
RBC
ACHE
100
*
Dermal
absorption
rate
was
assumed
to
be
42%
**
Inhalation
absorption
rate
assumed
to
be
100%

Table
2
summarizes
the
acute
toxicity
categories
for
AZM
Table
2.
Acute
Toxicity
Categories
for
AZM
Guideline
No.
Study
Type
MRID
#(
S).
Results
Toxicity
Category
81­
1
Acute
Oral
(
Rat)
00155002
LD50
=
4.6
mg/
kg_
4.4
mg/
kg_
I
81­
2
Acute
Dermal
(
Rabbit)
40280102
LD50
=>
2000
mg/
kg
III
81­
2
Acute
Dermal
(
Rat)
00155003
LD50
=
200­
250
mg/
kg_
155
mg/
kg_
I
81­
3
Acute
Inhalation
(
Rat)
40280103
LC50
=
>
0.21mg/
L
II
81­
4
Primary
Eye
Irritation
(
Rabbit)
43337501
No
ocular
effects
at
48
hrs.
III
81­
5
Primary
Skin
Irritation
(
Rabbit)
43337101
Non­
irritating
IV
81­
6
Dermal
Sensitization
(
Guinea
Pig)
41064401
Sensitizer
N/
A
2.0
Summary
of
Use
Patterns
and
Formulations
Page
13
of
42
AZM
is
formulated
as
a
manufacturing
product
(
88.1
percent
active
ingredient),
and
several
wettable
powder
(
35.0
to
50.0
percent
active
ingredient).
All
wettable
powder
formulations
are
contained
in
water­
soluble
packaging.
All
liquid
formulations
have
been
cancelled.

Information
regarding
registered
use
sites,
application
rates
and
frequency
of
application
in
this
assessment
was
based
on
the
Benefits
and
Economic
Analysis
Division
(
BEAD's)
3/
25/
05
use
summary
tables
and
was
confirmed
by
SRRD.

Table
3
presents
a
summary
of
the
Group
3
uses
based
on
the
crop
grouping
system
developed
by
Markle,
et.
al.
The
grouping
is
based
on
cultural
practices,
leaf
size,
leaf
shape
and
type
of
pests
attracted
to
the
plants.
AZM
can
be
applied
to
agricultural
crops
from
early
season
up
to
harvest
time.
This
assessment
covers
the
maximum
application
rates
and
typical
equipment
used
to
apply
AZM.

Table
3.
Use
Paztterns
and
Application
Rate
for
AZM
Crop
Grouping
Specific
Crop
Application
rate
lb
a.
i./
A
Pome
Fruits
Apple,
Pear,
Crabapple
1.5
Stone
Fruits
Cherry
0.75
Berries
Blueberry
0.75
Tree
Nuts
Almond,
Walnut,
pistachio
2.0
Brassica
Leafy
Vegetables
Brussels
Sprouts
0.75
Leafy
Vegetables
Parsley
0.5
Ornamental
Plants
Nursery
Stock
1.0
The
following
use
patterns
are
associated
with
the
application
equipment:

 
Aerial
(
spray)
Equipment:
foliar
applications
to
fruit/
nut
trees.
 
Chemigation
Equipment:
The
exposure
to
the
handlers
using
chemigation
equipment
is
represented
by
the
mixer/
loader
and
the
amount
handled
is
assumed
to
be
equivalent
to
that
of
the
aerial
applicators.
 
Groundboom
Equipment:
fruit/
nut
orchard
floors
and
vegetable
crops.
 
Airblast
Equipment:
fruit/
nut/
ornamental
tree
foliage.
The
use
of
hand
held
equipment
voluntarily
cancelled
by
the
registrants.

3.0
Handler
Exposure
and
Risk
3.1
Exposure
Scenarios
HED
has
determined
that
there
are
potential
exposures
to
mixers,
loaders,
applicators,
and
other
handlers
during
usual
use­
patterns
associated
with
AZM.
Based
on
the
use
patterns
and
potential
exposures
described
above,
7
major
agricultural
exposure
scenarios
are
identified
in
this
Page
14
of
42
document
to
represent
the
extent
of
AZM
uses.
The
use
of
hand­
held
equipment
has
been
voluntarily
cancelled
by
the
registrants.

 
Mixing/
loading
wettable
powders
for
aerial
application/
chemigation
irrigation;
 
Mixing/
loading
wettable
powders
for
groundboom
application;
 
Applying
sprays
with
fixed­
wing
aircraft;
 
Aapplying
sprays
using
a
groundboom
sprayer;
 
Applying
sprays
using
an
airblast
sprayer;
 
Flagging
during
aerial
application
(
sprays).
 
Mixing/
loading/
applying
wettable
powders
for
airblast
sprayer
application;

For
the
occupational
RED
chapter
process,
HED
has
adopted
a
methodology
to
present
the
risks
separately
for
some
scenarios
and
combine
others.
For
equipment
such
as
fixed­
wingaircraft
and
groundboom
tractors,
the
applicators
are
assessed
separately
from
the
individuals
who
mix
and
load
the
formulated
product.
HED
assumes
that
the
pilots
are
rarely
involved
in
the
mixing/
loading.
By
separating
the
two
job
functions,
HED
can
determine
the
most
appropriate
PPE
or
engineering
control
without
requiring
the
handler
to
wear
PPE
throughout
the
entire
workday
or
engineering
controls
that
are
not
needed.
The
biomonitoring
airblast
study
submitted
by
the
registrant
monitored
exposures
during
combined
mixing,
loading,
and
application
activities;
no
separate
measurement
for
exposures
from
specific,
individual
activities
was
made.

Typically,
handler
exposure
assessments
are
completed
by
HED
using
a
baseline
exposure
scenario
and,
if
required,
increasing
levels
of
risk
mitigation
(
through
PPE
and
up
to
engineering
controls)
to
achieve
an
acceptable
margin
of
exposure
(
depending
on
the
selected
safety
factor)
for
dermal
and
inhalation
exposure.
Products
containing
AZM
are
only
marketed
as
wettable
powder
formulation
and
packaged
in
water­
soluble
bags.
Water­
soluble
bags
are
considered
to
be
a
form
of
engineering
control.
Therefore,
increasing
the
level
of
risk
mitigation
for
mixer/
loaders
from
baseline
is
not
considered
to
be
applicable.
The
risk
mitigation
for
the
applicators
is
presented
for
both
open
and
closed
cab
equipment.

Table
4
presents
the
exposure
scenarios,
application
rates,
and
area
(
i.
e.,
acres)
potentially
treated
that
have
been
used
in
the
exposure
calculations.
AZM
labels
include
a
multitude
of
uses
and
a
wide
range
of
application
rates.
Therefore,
the
rates
presented
in
Table
4
are
the
maximum
used
to
evaluate
exposure
associated
with
each
scenario.
Page
15
of
42
T
able
4.
Exposure
Variables
for
Agricultural
Uses
of
AZM
Exposure
Scenario
Crop
Group
Crop
Application
Rates
(
lb
ai/
acre)
Daily
Acres
Treated
Mixer/
Loader
Exposure
(
source
PHED)

Pome
Fruits
Apple,
Pear,
Crabapple
(
SLN)
1.5
Mixing/
loading
wettable
powders
for
aerial
application/
chemigation
irrigation
Berries
Blueberry
0.75
350
Berries
Blueberry
0.75
80
Brassica
Leafy
Vegetables
Brussels
Sprouts
0.75
Leafy
Vegetables
Parsley
0.5
80
Mixing/
loading
wettable
powders
for
groundboom
application
Ornamental
Plants
Nursery
Stock
1.0
40
Applicator
Exposure
(
Source
PHED)

Pome
Fruits
Apple,
Pear,
Crabapple
(
SLN)
1.5
Applying
Sprays
with
fixed
wing
aircraft
Berries
Blueberry
0.75
350
Berries
Blueberry
0.75
80
Brassica
Leafy
Vegetables
Brussels
Sprouts
0.75
Leafy
Vegetables
Parsley
0.5
Applying
sprays
using
a
groundboom
sprayer
Ornamental
Plants
Nursery
Stock
1.0
80
Flagger
(
Source
PHED)

Berries
Blueberry
0.75
Flagging
during
aerial
application
(
sprays).

Pome
Fruits
Apple,
Pear,
Crabapple
(
SLN)
1.5
350
Mixing/
loading/
Applying
with
Airblast
(
open
and
Closed)
using
biomomitoring
study
(
source
MRID
#
46316406)

Pome
Fruits
Apple,
Pear,
Crabapple
1.5
Stone
Fruits
Cherry
0.75
Tree
Nuts
Almond,
Pistachio,
Walnut
2.0
Mixing/
loading/
Applying
wettable
powders
for
airblast
sprayer
application
Ornamental
Plants
Nursery
Stock
1.0
40
3.2
Handler
Exposure
Data
3.2.1
Biomonitoring
Data
A
study
titled
"
AZM
­
Biomonitoring
of
Applicators
Following
Airblast
Treatment
of
Orchard
Crops
using
Open
and
Closed
Cab
Equipment"
(
MRID#:
463164­
06)
was
submitted
to
the
Agency
for
the
purpose
of
assessing
handler
risk
associated
with
orchard
crops.
Page
16
of
42
The
purpose
of
this
study
was
to
quantify
potential
exposure
from
the
use
of
AZM
in
the
wettable
powder
formulation,
while
applying
it
to
orchard
crops
(
primarily
apple)
using
an
open
cab
and
closed
cap
airblast
application
equipment.
The
facilities
for
open
cab
trials
were
located
in
PA,
MD
and
WA
and
for
closed
cab
trials
were
located
in
NY,
PA
and
WA.
Guthion
®

wettable
powder
Insecticide
was
applied
using
open
and
closed
cab
airblast
sprayer.

Fifteen
experienced
volunteer
applicators
for
open
cab
and
fifteen
for
closed
cab
were
monitored
via
urinary
and
inhalation
analyses.
AZM
exposure
was
quantified
by
measuring
total
MSMB
in
urine
samples.
Total
24
hour
urine
output
was
collected
from
each
worker
performing
mixer/
loader/
applicator
activities
for
the
time
period
including
the
day
before
mixer/
loader/
applicator
activities
until
4
days
after
mixer/
loader/
applicator
activities.
Potential
inhalation
exposure
was
also
measured
using
OVS
tubes
and
a
personal
air­
sampling
pump
with
the
inlet
positioned
near
the
face
of
the
worker.
HED
included
the
collection
of
this
additional
information
on
the
inhalation
route
of
exposure,
alone,
to
determine
the
significance
of
inhalation
as
a
route
of
exposure.
The
air
sampling
pumps
were
calibrated
prior
to
use
and
the
flow
rate
was
approximately
2
L/
min.
The
workers
were
sequestered
in
a
hotel
during
the
test
period,
leaving
only
to
perform
application
activities.
Test
subjects
wore
the
following
personal
protective
equipment
(
PPE)
during
the
application,
as
prescribed
on
the
product
label:
longsleeved
shirt
and
long
pants
underneath
coveralls;
waterproof
gloves;
chemical­
resistant
footwear
plus
socks;
protective
eye
wear;
chemical­
headgear
for
overhead
exposure;
and
dust/
mist
filtering
respirator
(
MSHA/
NIOSH
approval
number
prefix
TC­
21C).
The
raw
data
were
corrected
for
a
field
recovery.

The
average
AZM
doses
for
open
cab
and
closed
cab
field
trials,
without
background
correction,
are
0.0035
and
0.00080mg/
kg
body
weight,
respectively.
The
total
average
AZM
doses
for
open
cab
and
closed
cab
field
trials,
with
background
correction,
are
0.0027
and
0.00057mg/
kg
body
weight,
respectively.
AZM
doses
for
open
and
closed
cab
field
trials,
based
on
pounds
active
ingredient
handled,
are
0.013
and
0.0023
mg/
lb
ai
handled
(
without
background
correction)
and
0.0095
and
0.0017
mg/
lb
ai
handled
(
with
background
correction).
Average
potential
inhalation
exposures
for
open
cab
trials
were
calculated
to
be
166.8
µ
g
or
4.0
µ
g/
lb
ai
handled
and
average
exposures
for
enclosed
cab
trials
were
calculated
to
be
14.7
µ
g
or
0.2
µ
g/
lb
ai
handled.

The
study
was
in
compliance
with
OPPTS
Series
875
Occupational
and
Residential
Exposure
Test
Guidelines
and
is
considered
to
be
of
sufficient
scientific
quality
to
be
used
in
determining
handler
exposure
to
AZM.

The
AZM
dose
in
the
urine
(
mg/
kg
body
weight)
and
the
air
concentration
(
mg/
m3)
were
then
analyzed
to
determine
the
data
distribution
type
(
i.
e.,
normal,
lognormal,
or
other),
using
the
XLSTAT
program
in
Excel.
This
program
uses
the
Kolmogorov­
Smirnov
test
and
the
Chisquare
Goodness
of
Fit
test
to
determine
if
the
sample
distribution
is
significantly
different
from
a
normal
distribution.
For
the
urine
data
sets
and
air
concentration
data
sets,
the
distributions
were
not
found
to
be
significantly
different
from
a
normal
distribution.
Therefore,
arithmetic
mean
values
have
been
used
for
all
calculations.
Page
17
of
42
Risk
estimates
for
handlers
based
on
internal
doses
from
biomonitoring
studies
are
calculated
with
a
NOAEL
of
0.15
mg/
kg/
day,
regardless
of
exposure
duration
or
route;
no
dermal
absorption
factor
is
required.

3.2.2
PHED
Data
PHED
data
were
used
to
estimate
dermal
and
inhalation
exposures
for
all
handler
scenarios,
except
the
scenarios
involving
airblast
applications
to
orchard
crops
(
i.
e.,
apple,
pear,
crabapple,
cherry,
walnut,
pistachio,
almond,
and
nursery
stock).

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

Users
select
criteria
to
subset
the
PHED
database
to
reflect
the
exposure
scenario
being
evaluated.
The
sub­
setting
algorithms
in
PHED
are
based
on
the
central
assumption
that
the
magnitude
of
handler
exposures
to
pesticides
is
primarily
a
function
of
activity
(
e.
g.,
mixing/
loading,
applying),
formulation
type
(
e.
g.,
wettable
powders),
application
method
(
e.
g.,
aerial,
groundboom),
and
clothing
scenarios
(
e.
g.,
gloves,
double
layer
clothing).
Once
the
data
for
a
given
exposure
scenario
have
been
selected,
the
data
are
normalized
(
i.
e.,
divided
by)
for
the
amount
of
pesticide
handled,
resulting
in
standard
unit
exposures
(
milligrams
of
exposure
per
pound
of
active
ingredient
handled).
Following
normalization,
the
data
are
statistically
summarized.
The
distribution
of
exposure
values
for
each
body
part
(
e.
g.,
chest,
upper
arm)
is
categorized
as
normal,
lognormal,
or
"
other"
(
i.
e.,
neither
normal
nor
lognormal).
A
central
tendency
value
is
then
selected
from
the
distribution
of
the
exposure
values
for
each
body
part.
These
values
are
the
arithmetic
mean
for
normal
distributions,
the
geometric
mean
for
lognormal
distributions,
and
the
median
for
all
"
other"
distributions.
Once
selected,
the
central
tendency
values
for
each
body
part
are
composited
into
a
"
best
fit"
exposure
value
representing
the
entire
body.

The
data
presented
in
this
assessment
are
found
in
both
the
summary
tables
and
the
appendix
tables.
The
summary
tables
provide
total
MOEs
for
baseline
attire
and
engineering
control
at
short
and
intermediate­
term
duration.

For
short­
term
dermal
exposures,
risk
estimates
for
handlers
based
on
PHED
data
are
calculated
with
a
NOAEL
of
0.56
mg/
kg/
day;
no
dermal
absorption
factor
is
required
because
this
endpoint
comes
from
a
route­
specific
dermal
study.
For
intermediate­
term
dermal
exposures,
risk
estimates
for
handlers
based
on
PHED
data
are
calculated
with
a
NOAEL
of
and
0.15
mg/
kg/
day
and
a
dermal
absorption
factor
of
42%
is
applied.
For
inhalation
exposures
of
any
duration,
risk
estimates
for
handlers
based
on
PHED
data
are
calculated
with
a
NOAEL
of
0.2
mg/
kg/
day.
Since
the
inhalation
endpoint
is
from
a
route­
specific
study,
100%
absorption
is
assumed.
Page
18
of
42
3.3
Summary
of
Uncertainties
The
handler
exposure
assessments
encompass
all
of
the
major
uses
of
AZM
throughout
the
country.
It
is
difficult
to
assess
all
of
the
"
typical"
agricultural
uses
(
i.
e.,
actual
or
predominant
application
rates
and
farm
sizes),
and,
therefore,
an
assessment
has
been
developed
that
is
believed
to
be
realistic
and
yet
provides
a
reasonable
certainty
that
the
exposures
are
not
underestimated.
The
assumptions
and
uncertainties
are
identified
below
to
be
used
in
risk
management
decisions:

 
Application
Rates:
The
application
rates
are
the
maximum
allowable
that
were
identified
on
the
available
product
labels.
 
Amount
Handled:
The
daily
acres
treated
are
HED
standard
values
(
see
Table
4).
 
Unit
Exposures:
The
unit
exposure
values
calculated
by
PHED
generally
range
from
the
geometric
mean
to
the
median
of
the
selected
data
set.
To
add
consistency
and
quality
control
to
the
values
produced
from
this
system,
the
PHED
Task
Force
has
evaluated
all
data
within
the
system
and
has
developed
a
set
of
grading
criteria
to
characterize
the
quality
of
the
original
study
data.
While
data
from
PHED
provide
the
best
available
information
on
handler
exposures,
it
should
be
noted
that
some
aspects
of
the
included
studies
(
e.
g.,
duration,
acres
treated,
pounds
of
active
ingredient
handled)
may
not
accurately
represent
labeled
uses
in
all
cases.

3.4
Exposure
and
Risk
Calculations
Potential
daily
dermal
exposure
is
calculated
using
the
following
formula:

Potential
daily
inhalation
exposure
is
calculated
using
the
following
formula:

Using
the
daily
dermal
exposure
scenarios
identified
in
the
exposure
section,
EPA
calculated
the
potential
risk
to
persons
from
handler
exposures
to
AZM.

The
inhalation
and
dermal
daily
doses
were
calculated
using
the
following
formulas:
 
 

 
 

 
 

 
 

  
 

  
 

 
 

 
 

 
 

 
 

  
 

  
 
 
 

 
 

 
 

 
 

day
A
Treated
Acres
Daily
x
A
ai
lb
Rate
Use
x
g
1,000
1mg
Factor
Conversion
x
ai
lb
ai
g
Exposure
Unit
=
day
ai
mg
Exposure
Inhalation
Daily
µ
µ
 
 

 
 

 
 

 
 
 

  

 

  
 
 

  

 

  
 

 
 

 
 

 
 

 
 

Day
Acres
Treated
Area
.
Acre
ai
lb
Rate
Appl.
.
ai
lb
ai
mg
Exposure
Unit
Dermal
=
Day
ai
mg
Exposure
Dermal
Daily
Max
Max
Page
19
of
42
The
MOEs
were
calculated
using
the
following
formulas:

The
MOE's
derived
for
dermal
and
inhalation
exposures
may
be
combined
to
obtain
a
total
MOE
since
a
common
toxicological
endpoint
(
i.
e.,
cholinesterase
inhibition)
was
observed
in
dermal
and
inhalation
toxicity
studies/
routes.

Total
MOE
=
1/
((
1/
Dermal
MOE)
+
(
1/
Inhalation
MOE)).

3.5
Risk
From
Handler
Exposures
(
based
on
biomonitoring
and
PHED
data)

Typically,
handler
exposure
assessments
are
completed
by
EPA
using
a
baseline
exposure
scenario
and,
if
required,
increasing
levels
of
risk
mitigation
(
through
PPE
and
up
to
engineering
controls)
to
achieve
an
acceptable
margin
of
exposure
(
depending
on
the
selected
safety
factor)
for
dermal
and
inhalation
exposure.
Products
containing
AZM
are
only
marketed
as
wettable
powder
formulations
and
packaged
in
water
soluble
bags.
Water
soluble
bags
are
considered
to
be
a
form
of
engineering
control.
Therefore,
increasing
level
of
risk
mitigation
for
mixer/
loaders
from
baseline
is
not
considered
to
be
applicable.
The
risk
mitigation
for
the
applicators
is
presented
for
both
open
and
closed
cab
equipment.
The
total
short­
term
and
intermediate
term
MOE
calculations
for
baseline
exposure
and
engineering
controls
using
biomonitoring
and
surrogate
data
from
PHED
for
the
agricultural
uses
of
AZM
are
presented
in
Appendix
II.

HED
calculated
the
total
baseline
MOE
(
short­
term
and
intermediate­
term)
for
each
of
the
exposure
scenarios
using
the
following
baseline
PPE
assumptions:
(
100%)
1
*
(
kg)
Weight
Body
1
x
day
ai
mg
Exposure
Inhalation
Daily
=
kg/
day
ai
mg
Dose
Inhalation
Daily
 
 

 
 

 
 

 
 

 
 

 
 

 
 

 
 

 
 

 
 

 
 

 
 

%)
(
1
*
(
kg)
Weight
Body
1
x
day
ai
mg
Exposure
Dermal
Daily
=
kg/
day
ai
mg
Dose
Dermal
Daily
42
 
 

 
 

 
 

 
 

 
 

 
 

 
 

 
 

 
 

 
 

 
 

 
 

 

  
 

 

  
 
 

  
 

 

  
 

kg/
day
mg
Dose
Daily
Dermal
kg/
day
mg
NOAEL
=
MOE
 

  
 

 

  
 
 

  
 

 

  
 

kg/
day
mg
Dose
Daily
Inhlation
kg/
day
mg
NOAEL
=
MOE
Page
20
of
42
 
all
occupational
handlers
are
wearing
footwear
(
socks
plus
shoes
or
boots).

 
Occupational
mixers
and
loaders
using
open
mixing
techniques
are
wearing
longsleeved
shirts,
long
pants,
and
no
gloves.

 
Occupational
applicators
who
use
open
cab
airblast
or
tractor­
driven
application
equipment
and
handlers
flagging
for
aerial
applications
are
wearing
long­
sleeved
shirts,
long
pants,
and
no
gloves.

HED
calculated
the
engineering­
control
total
short­
term
or
intermediate­
term
MOE
for
each
occupational
exposure
scenario
using
the
following
engineering
control
assumptions:

 
all
occupational
handlers
are
wearing
footwear
(
socks
plus
shoes
or
boots).

 
Occupational
mixers
and
loaders
handling
wettable
powders
using
a
closed
system
(
water­
soluble
packages)
are
wearing
long­
sleeved
shirts
and
long
pants,
and
chemical­
resistant
gloves.

 
Occupational
applicators
who
use
aerial,
airblast,
or
tractor­
driven
application
equipment
and
handlers
flagging
for
aerial
applications
are
located
in
enclosed
cabs
or
cockpits
and
are
wearing
long­
sleeved
shirts
and
long
pants,
and
no
gloves
(
gloved
value
used
for
airblast).

Tables
5
and
6
summarize
the
MOE
values
for
the
total
short­
term
and
intermediate­
term
exposure
durations.
The
comprehensive
table
of
MOE
values
is
presented
in
Appendix
II.

Assessment
of
short­
term
and
intermediate­
term
handler
exposure
for
orchard
crops
using
an
open
or
closed
cab
airblast
sprayer
and
data
from
biomonitoring
studies
resulted
in
MOEs
ranging
from
18
to
205.
MOEs
for
mixer/
loader/
applicators
using
open
cab
airblast
exceed
EPA's
level
of
concern.
For
mixer/
loader/
applicators
using
closed
cab
airblast
equipment,
MOEs
(
with
the
exception
of
apple,
pear,
crabapple,
nursery
stock
and
cherry)
are
also
less
than100
and
exceed
EPA's
level
of
concern.

In
addition
to
collecting
urine
to
measure
internal
AZM
dose,
breathing
zone
samples
were
also
taken
for
mixer/
loader/
applicators.
MOEs
based
on
the
breathing
zone
samples
and
the
NOAEL
of
0.2
mg/
kg/
day,
ranged
from
43
to
2390,
are
also
a
risk
concern.
This
indicates
that
AZM
exposures
via
inhalation
and
the
dermal
routes
both
have
risk
concerns.
Page
21
of
42
The
results
of
the
total
short­
term
handler
assessments
using
PHED
data
for
remaining
crops
in
Group
3
indicate
that
all
potential
exposure
scenarios
provide
a
total
MOE(
s)
less
than
or
equal
to
100
(
except
ground
application
of
blueberry,
Brussels
sprouts
and
parsley).
Table
5:
Summary
of
Short
­
term
Risk
for
Agricultural
Handlers
of
AZM:
Group
3
Crops
Exposure
Scenario
(
Scenario
#)
Crop
Application
Rate
lb
ai/
A
Daily
Area
Treated
A/
Day
Total
Baseline
MOE
Total
Eng.
Control
MOE
Mixer/
Loader
(
Source
PHED)

Wettable
Powders
for
Aerial
application
Apple,
Pear,
Crabapple
1.50
350
<
1
7
Wettable
Powders
for
Aerial
application
Blueberry
0.75
350
<
1
14
Wettable
Powders
for
Groundboom
application
Blueberry
0.75
80
<
1
62
Wettable
Powders
for
Groundboom
application
Brussels
Sprouts
0.75
80
<
1
62
Wettable
Powders
for
Groundboom
application
Parsley
0.50
80
<
1
93
Wettable
Powders
for
Groundboom
application
Nursery
stock
1
80
<
1
46
Applicator
(
Source
PHED)

Sprays
for
Aerial
application
Apple,
Pear,
Crabapple
1.50
350
No
Data
14
Sprays
for
Aerial
application
Blueberry
0.75
350
No
Data
26
Sprays
for
Groundboom
application
Blueberry
0.75
80
40
127
Sprays
for
Groundboom
application
Brussels
Sprouts
0.75
80
40
127
Sprays
for
Groundboom
application
Parsley
0.50
80
60
191
Sprays
for
Groundboom
application
Nursery
stock
1
80
30
95
Flagger
(
Source
PHED)

Flagging
for
Sprays
application
Apple,
Pear,
Crabapple
1.50
350
6
311
Flagging
for
Sprays
application
Blueberry
0.75
350
12
623
Mixer/
Loader/
Applicator
(
Source
bimonitoring
study
MRID
#
46316406)

Open
Cab
Closed
Cab
Mixing/
Loading/
Applying
for
Airblast
Apple,
Pear,
Crabapple
1.5
40
18
102
Mixing/
Loading/
Applying
for
Airblast
Cherry
0.75
40
36
205
Mixing/
Loading/
Applying
for
Airblast
Almond,
pistachio,
walnut
2.0
40
14
80
Mixing/
Loading/
Applying
for
Airblast
Nursery
stock
1.0
40
28
155
Page
22
of
42
Table
6.
Summary
of
Intermediate­
term
Risk
for
Agricultural
Handlers
of
AZM:
Group
3
Crops
Exposure
Scenario
(
Scenario
#)
Crop
Application
Rate
lb
ai/
A
Daily
Area
Treated
A/
Day
Total
Baseline
MOE
Total
Eng.
Control
MOE
Mixer/
Loader
(
Source
PHED)

Wettable
Powders
for
Aerial
application
Apple,
Pear,
Crabapple
1.50
350
<
1
5
Wettable
Powders
for
Aerial
application
Blueberry
0.75
350
<
1
9
Wettable
Powders
for
Groundboom
application
Blueberry
0.75
80
<
1
40
Wettable
Powders
for
Groundboom
application
Brussels
Sprouts
0.75
80
<
1
40
Wettable
Powders
for
Groundboom
application
Parsley
0.50
80
<
1
60
Wettable
Powders
for
Groundboom
application
Nursery
stock
1
80
<
1
30
Applicator
(
Source
PHED)

Sprys
for
Aerial
application
Apple,
Pear,
Crabapple
1.50
350
No
Data
10
Sprays
for
Aerial
application
Blueberry
0.75
350
No
Data
18
Sprays
for
Groundboom
application
Blueberry
0.75
80
25
80
Sprays
for
Groundboom
application
Brussels
Sprouts
0.75
80
25
80
Sprays
for
Groundboom
application
Parsley
0.50
80
40
122
Sprays
for
Groundboom
application
Nursery
stock
1
80
20
60
Flagger
(
Source
PHED)

Flagging
for
Sprays
application
Apple,
Pear,
Crabapple
1.50
350
25
200
Flagging
for
Sprays
application
Blueberry
0.75
350
8
400
Mixer/
Loader/
Applicator
(
Source
bimonitoring
study
MRID
#
46316406)

Open
Cab
Closed
Cab
Mixing/
Loading/
Applying
for
Airblast
Apple,
Pear,
Crabapple
1.5
40
18
102
Mixing/
Loading/
Applying
for
Airblast
Cherry
0.75
40
36
205
Mixing/
Loading/
Applying
for
Airblast
Almond,
pistachio,
walnut
2.0
40
14
80
Mixing/
Loading/
Applying
for
Airblast
nursery
stock
1.0
40
28
155
The
results
of
the
total
intermediate­
term
handler
assessments
using
PHED
data
for
remaining
crops
in
Group
3
indicate
that
all
potential
exposure
scenarios
provide
a
total
MOE(
s)
less
than
or
equal
to
100
(
except
parsley).

4.0
Post­
application
Exposure
and
Risk
Bayer
submitted
2003
AZM
biomonitoring
data
for
blueberry,
apple,
and
walnut
postapplication
activities
at
current
restricted
entry
intervals
(
REIs).
The
biomonitoring
studies
were
required
as
part
of
the
2001
Data
Call­
In
(
DCI)
for
AZM.
Data
from
these
studies
were
analyzed
and
used
to
estimate
risk
for
all
Group
3
uses
except
parsley.
(
As
mentioned
previously,
harvesting
activities
for
parsley
are
very
different
from
those
used
in
the
biomonitoring
studies
on
other
crops,
i.
e.,
blueberries,
apples,
and
walnuts).
MOEs
based
on
internal
doses
from
biomonitoring
studies
were
estimated
using
the
oral
NOAEL
of
0.15
mg/
kg/
day
for
both
short­
and
intermediate­
term
exposures.
Dislodgeable
foliar
residue
(
DFR)
Page
23
of
42
data
for
AZM
were
used
to
extrapolate
exposures
on
post­
application
days
beyond
the
REI
in
cases
where
MOEs
were
less
than
100
at
the
REI.

The
data
from
the
three
biomonitoring
studies
were
not
appropriate
for
estimating
high
contact
post­
application
activities
associated
with
parsley
(
e.
g.
hand
harvesting
at
30­
day
REI).
For
parsley,
exposures
were
estimated
using
the
same
dermal
transfer
coefficient
(
TC)
method
that
was
used
in
the
2001
AZM
IRED.
MOEs
for
short­
term
dermal
exposures
from
parsley
were
estimated
using
the
dermal
NOAEL
of
0.56
mg/
kg/
day.
The
MOEs
for
intermediate­
term
dermal
exposures
from
parsley
were
estimated
using
the
oral
NOAEL
of
0.15
mg/
kg/
day
and
a
42%
dermal
absorption
factor.

Inhalation
exposures
are
not
anticipated
for
post­
application
workers
and
typically
are
not
assessed.

HED
considers
the
updated
post­
application
exposure
estimates
based
on
biomonitoring
data
to
be
more
accurate
than
those
based
on
TCs
and
DFR
data
only.

4.1
Biomonitoring
Data
Study
protocols
for
the
blueberry,
apple,
and
walnut
biomonitoring
studies
were
submitted
to
the
Agency
and
reviewed
by
HED
in
2003
(
see
5/
13/
03
HED
memo
from
S.
Weiss/
HED
to
V.
LaCapra/
SRRD,
Review
of
DRAFT
Protocols
and
Urinary
Biomarker
Data
for
AZM
Occupational
Exposure
Studies,
D288496).

MRID#:
463164­
03,
GUTHION
®
50
WP
­
Biological
Monitoring
of
Postapplication
Workers
During
Manual
Thinning
and
Harvesting
of
Apples
(
A
review
of
this
study
is
included
in
HED
memo
D307558)

This
study
measured
worker
exposure
to
AZM
following
thinning
and
harvesting
of
apples.
Harvesting
activity
exposures
took
place
at
a
New
York
test
site
14
days
following
the
last
of
6
airblast
applications.
Exposure
of
harvesters
was
also
studied
in
Oregon
for
workers
reentering
fields
14
days
following
the
last
of
3
applications.
Exposures
of
workers
thinning
apple
orchards
14
days
following
the
first
application
at
the
Oregon
test
site
were
also
studied.
The
application
rates
used
in
the
trials
were
0.275
lb
ai/
A/
application
in
New
York,
and
0.47
lb
ai/
A/
application
in
Oregon
(
based
on
the
tree
row
volume
concept).

The
Study
Report
stated
that
the
workers
wore
clothing
typical
of
what
they
would
normally
wear
when
performing
agricultural
work.
The
workers
clothing
is
listed
in
Tables
10,
11
and
12
of
the
Study
Report,
and
typically
included
long
sleeve
shirts
and
long
pants.
Three
workers
wore
short
sleeve
or
sleeveless
shirts
and
seven
workers
wore
a
t­
shirt
underneath
their
long
sleeve
shirt.
Each
worker
wore
a
painter's
hat
provided
by
the
Principle
Field
Investigator.
No
personal
protective
equipment,
including
gloves,
was
worn
by
the
workers
during
any
of
the
reentry
activities.

MRID#:
463164­
04,
GUTHION
®
50
WP
­
Biological
Monitoring
of
Post­
Application
Workers
During
Manual
Harvesting
of
Blueberries
(
A
review
of
this
study
is
included
in
HED
memo
D307560)
Page
24
of
42
This
study
measured
worker
exposure
to
AZM
following
harvesting
of
high
bush
blueberries,
which
had
received
two
airblast
applications
of
0.749
lb
ai/
A.
Reentry
activity
was
monitored
in
10
male
and
5
female
workers
at
one
Michigan
field
location.
Harvesting
activities
took
place
7
days
following
the
final
application.

The
Study
Report
stated
that
the
workers
wore
clothing
typical
of
what
they
would
normally
wear
when
performing
agricultural
work.
The
workers'
clothing
was
listed
in
Table
6
of
the
Study
Report,
and
typically
included
long
sleeve
shirts
or
sweatshirts
and
jeans,
sweatpants,
or
long
work
pants.
Each
worker
wore
a
painter
hat,
supplied
by
the
Principle
Field
Investigator.

MRID#:
463164­
05,
GUTHION
®
50
WP
 
Biological
Monitoring
of
Post­
Application
Workers
During
Manual
Harvesting
of
Walnuts
(
A
review
of
this
study
is
included
in
HED
memo
D307561)

This
study
measured
worker
exposure
to
AZM
following
harvesting
of
walnuts,
which
had
received
one
application
by
airblast
at
2.01
lb
ai/
A.
The
reentry
harvesting
activities
took
place
30
days
after
the
pesticide
application.
In
this
study,
15
male
workers
were
monitored,
including
2
shakers,
2
sweepers,
and
11
rakers.
The
shakers
operated
a
shaker
machine
within
an
enclosed
cab,
the
sweepers
operated
a
sweeper
machine
with
an
open
cab,
and
the
rakers
used
rakes
and
their
hands
to
move
walnuts
and
small
tree
limbs.

The
Study
Report
states
that
the
workers
wore
clothing
typical
of
what
they
would
normally
wear
when
performing
agricultural
work.
The
workers
clothing
was
listed
in
Table
6
of
the
Study
Report,
and
typically
included
long
sleeve
shirts
and
long
work
pants.
One
worker
wore
a
short
sleeve
shirt
and
two
workers
wore
a
short
sleeve
shirt
underneath
a
long
sleeve
shirt.
Each
worker
wore
a
hat,
plastic
hair
cover,
or
bandana
on
the
head,
except
for
one
worker
who
did
not
wear
any
head
protection.
Type
N95
dust
masks
were
made
available
to
each
worker
just
prior
to
beginning
harvest
and
each
worker
was
allowed
to
make
their
own
decision
regarding
the
use
of
a
mask.
All
workers
wore
a
dust
mask;
however,
the
mask
was
not
necessarily
worn
for
the
entire
exposure
period.

4.2
Sampling
Media
Urine,
blood,
and
breathing
zone
air
sampling
data
were
collected
in
each
of
the
three
studies.

Urine
Samples
(
MSMB
as
a
urinary
biomarker
for
AZM)

Total
urine
output
was
collected
from
each
worker
during
each
24­
hour
period
starting
1
day
prior
to
reentry
through
4
days
after
reentry.
Day
­
1
samples
were
those
collected
starting
after
the
first
void
of
the
bladder
in
the
morning
on
the
day
prior
to
reentry
and
ending
after
the
first
void
on
the
day
of
reentry.
Day
0
samples
were
those
collected
during
the
24­
hour
period
starting
when
the
workers
began
the
reentry
activities.
Re­
entry
activities
occurred
for
1
day
only
(
Day
0).
No
AZM
exposure
occurred
during
Day
1,
2,
3
and
4.
Page
25
of
42
Data
from
a
metabolism
study
in
humans
(
MRID
447858­
01)
were
used
to
estimate
internal
doses
of
AZM
in
workers.
Using
the
raw
data
provided
in
the
Study
Reports,
AZM
internal
dose
estimates
in
mg/
kg
body
weight
were
calculated
for
each
worker
and
each
worker
type
by
sampling
interval
and
as
a
cumulative
total
over
the
4
sampling
days
(
120
hours).
The
results
were
corrected
for
background
(
day
­
1)
residue.
The
measured
residues
were
corrected
to
100%
recovery
based
on
recoveries
of
the
associated
field
fortification
samples.
Residues
<
LOD
were
set
to
1/
2
LOD
for
all
calculations.
The
measured
residues
were
adjusted
for
the
volume
of
urine
collected
and
the
internal
dose
was
calculated
by
adjusting
the
MSMB
excreted
during
each
sampling
interval
for
the
cumulative
percent
of
the
absorbed
dose
excreted
120
hours
after
exposure
(
as
determined
from
a
previous
study
 
83.6%)
and
the
percent
of
the
urine
activity
attributed
to
MSMB
(
determined
from
a
previous
study
­­
9.2%).

MSMB
residue
levels
are
presented
in
this
report
as
µ
g
equivalents
of
parent
AZM.
Equivalents
were
calculated
using
a
molecular
weight
conversion
factor
of
1.328.
The
total
MSMB
excreted
by
each
worker
over
the
120­
hour
sampling
period
following
exposure
was
used
to
arrive
at
an
estimated
internal
dose
of
AZM
for
each
worker.
(
See
equation
below.)

Risk
estimates
included
this
risk
assessment
are
based
on
the
estimated
AZM
internal
doses
from
these
three
biomonitoring
studies.
Internal
dose
estimates
reflect
exposure
via
all
routes
(
dermal,
inhalation,
and
oral).
The
following
equation
was
used
to
estimate
AZM
internal
doses:

Mean
AZM
Equivalent
Dose
(
mg/
kg/
day)
=
[
Total
MSMB
excreted
in
urine
(
mg)
*
83.6%
of
abs
dose
excreted
after
120
hrs/
100
*
9.2%
of
total
AZM
dose
represented
by
MSMB/
100]
/
Body
Weight
(
kg)

Blood
Samples
Plasma
and
red
blood
cell
cholinesterase
levels
were
measured
in
the
workers
to
determine
changes
in
cholinesterase
activity
prior
to
exposure
in
the
field,
on
their
first
day
in
the
field,
and
on
their
2nd
day
in
the
field,
which
was
4
days
after
their
first
exposure.
These
measurements
were
compared
to
estimate
the
percentage
of
change
in
ChE
activity
as
a
result
of
single
day
exposures
4
days
apart.

For
the
three
studies,
the
percent
change
of
plasma
and
RBC
ChE
inhibition
compared
to
pre­
exposure
measurements
of
cholinesterase
activity
ranged
from
­
7
to
19%
and
­
10
to
20%,
respectively,
as
a
result
of
one
day
of
exposure.
The
average
percent
change
of
plasma
and
RBC
ChE
inhibition
after
one
day
of
exposure
for
the
three
studies
was
6.3%
and
1.7%,
respectively.

For
the
three
studies,
the
percent
change
of
plasma
and
RBC
ChE
inhibition
compared
to
pre­
exposure
measurements
ranged
from
­
12
to
28%
and
­
9
to
18%,
respectively,
as
a
result
of
a
2
single
days
of
exposure
that
were
4
days
apart.
The
average
percent
change
of
plasma
and
RBC
ChE
inhibition
on
day
4
for
the
three
studies
was
­
1.7%
and
1.5%,
respectively.

Based
on
these
data,
there
is
no
firm
evidence
of
ChE
inhibition.
The
data
on
plasma
ChE
and
RBC
AChE
activity
are
considered
variable
as
would
be
expected
from
assessing
human
plasma
and
RBC
AChE
under
field
conditions.
Values
for
apparent
decreases
in
ChE
activity
are
nearly
as
much
as
the
values
obtained
for
apparent
increase
in
activity.
A
few
subjects
may
Page
26
of
42
appear
to
be
showing
some
slight
inhibition,
but
this
is
not
considered
to
be
within
the
resolving
power
of
the
assay
defining
inhibition.

Breathing
Zone
Air
Samples
Although
inhalation
exposures
are
reflected
in
the
internal
doses
estimated
from
MSMB
in
the
workers'
urine
samples,
HED
included
the
collection
of
separate
inhalation
exposure
data
to
determine
the
significance
of
inhalation
exposures.
Breathing
zone
air
samples
were
taken
using
OVS
tubes,
containing
XAD­
2
sorbent,
and
a
personal
air­
sampling
pump
attached
to
the
worker's
belt.
The
data
were
used
to
estimate
risk
for
AZM
exposure
via
the
inhalation
route
for
post
application
activities
monitored
in
the
blueberry,
walnut,
and
apple
studies.

Dermal
exposure
is
expected
to
be
the
major
route
of
concern
for
the
postapplication
activities
monitored
in
the
three
studies.
Inhalation
doses
(
mg/
kg/
day)
were
calculated
based
on
the
air
concentrations
(
ug/
m3)
measured
in
the
breathing
zones
of
the
workers.
A
minute
volume
of
16.7
liters
per
minute,
representing
light
activity
was
assumed
(
based
on
the
1997
EPA
Exposure
Factors
Handbook
Volume
III).
Exposures
were
assumed
to
occur
for
8
hours
per
day.

Inhalation
MOEs
for
post­
application
workers
were
based
on
an
inhalation
NOAEL
of
0.2
mg/
kg/
day
and
uncertainty
factor
(
UF)
of
100).
Estimated
inhalation
MOEs
(
ranged
from
100
to
790)
are
not
a
risk
concern.

4.3
Exposure
and
Risk
Estimates
for
AZM's
Group
3
Uses
Postapplication
exposures
for
all
Group
3
crops,
except
parsley,
were
based
on
internal
AZM
doses
from
biomonitoring
studies
conducted
for
apples,
blueberries,
walnuts.
Biomonitoring
data
from
blueberry
postapplication
activities
were
used
as
a
surrogate
for
nursery
stock
activities.
Biomonitoring
data
for
apples
were
used
for
crabapples,
pears,
and
cherries.
Biomonitoring
data
for
walnuts
were
used
for
almonds
and
pistachios.
It
is
assumed
that
the
activities
monitored
in
these
biomonitoring
studies
are
representative
of
high­
end
postapplication
exposures
for
which
there
are
no
biomonitoring
data:
crabapples,
cherries,
and
pears,
almonds
and
pistacios,
and
nursery
stock.
Risk
for
contact
with
treated
foliage
of
Brussels
sprouts
was
not
evaluated
since
applications
are
soil
directed
at
transplant
only.
All
exposure
estimates
were
calculated
at
maximum
label
rates
provided
by
SRRD.

Walnuts
and
almonds
are
the
only
Group
3
crops
with
MOEs
of
at
least
100
for
current
REI
(
30
days).
MOEs
on
day
30
for
pistachios
are
greater
than
100;
however,
the
REI
(
and
PHI)
is
21
days.
An
estimate
of
the
day
that
MOEs
would
reach
100
for
pistachios
can
not
be
calculated
based
on
available
data.

DFR
data
for
blueberries,
nursery
stock,
apples,
and
cherries
were
used
to
extrapolate
the
number
of
days
for
MOEs
to
reach
100.
This
extrapolation
is
considered
to
be
a
conservative
estimate
of
the
DFR
for
crops
for
which
we
have
no
data.
To
determine
the
absorbed
dose
representing
reentry
on
subsequent
days,
the
initial
dose
was
adjusted
for
the
decline
of
DFR
using
predicted
DFR
values
calculated
from
a
linear
regression
analysis
of
DFR
data.
Page
27
of
42
AZM
internal
dose
"
x"
DAT
=
AZM
internal
dose
Initial
DAT
*
(
DFR
"
x"
DAT
/
DFR
Initial
DAT)

Where:
AZM
internal
dose
"
x"
DAT
=
AZM
internal
dose
received
from
exposure
to
a
pesticide
in
a
given
scenario
for
"
x"
days
after
treatment
(
mg
pesticide
active
ingredient/
kg
body
weight/
exposure)
AZM
internal
dose
Initial
DAT
=
AZM
internal
dose
received
from
exposure
to
a
pesticide
in
a
given
scenario
on
the
initial
day
which
the
postapplication
activity
was
conducted
in
the
biomonitoring
study,
adjusted
for
application
rate
(
mg/
kg/
exposure)
DFR
"
x"
DAT
=
DFR
value
in
a
given
scenario
for
"
x"
days
after
treatment
(
ug/
cm2),
adjusted
for
application
rate
DFR
Initial
DAT
=
Predicted
DFR
value
from
DFR
study
on
the
initial
day
which
the
postapplication
activity
was
conducted
in
the
biomonitoring
study
(
ug/
cm2),
adjusted
for
application
rate
MOE
=
oral
NOAEL
/
AZM
internal
dose
"
x"
DAT
For
both
DFR
and
biomonitoring
data,
HED
assumed
a
linear
relationship
with
application
rate.
This
assumption
regarding
a
linear
relationship
between
rate
and
DFR
and
biomonitoring
data
is
considered
to
be
conservative.

For
parsley,
transfer
coefficients
were
based
on
HED's
Science
Advisory
Council
for
Exposure,
Policy
Memo
#
003.1
'
Agricultural
Transfer
Coefficients',
August
17,
2000.
Exposures
for
postapplication
activities
associated
with
parsley
(
vegetable
"
leafy"
transfer
coefficient
group)
were
estimated
for:

*
high
exposure:
hand
harvesting,
pruning,
thinning
mature
plants
(
500
cm2/
hr)
*
medium
exposure:
irrigation,
scouting
of
mature
plants
(
1500
cm2/
hr).
*
low
exposure:
irrigation,
scouting,
thinning,
weeding
of
immature
plants
(
2500
cm2/
hr).

Table
7
contains
a
summary
of
the
exposure
and
risk
for
post­
application
activities
associated
with
for
all
Group
3
uses.
The
number
of
days
for
most
of
the
crops
to
reach
a
MOE
of
100
is
significantly
longer
than
the
current
REIs
specified
on
EPA
labels.
Page
28
of
42
Table
7.
Summary
of
Risks
for
Short­
term
and
Intermediate­
term
Exposures
(
Group
3)
Postapplication
Activities
DFR
Data
Biomonitoring
Data
Crop
Max
Application
Rate
(
lb
ai/
A)
Crop/
Location
MRID#
Dissipation
Inputs
Location
Reentry
Activity
MOE
at
current
REI
(
Day
where
MOE
is
>
100)
REI
on
label
Blueberries,
Low
Bush
0.75
MI
MOE
=
30
at
7
days
(
MOE
=
100
at
42
days)
10
days
for
low
bush,

7
for
high
bush
Nursery
Stock
1.0
Blueberry/

ME,
MI
4637602
Slope:
­
0.0345
Initial:
1.82
ug/
cm2
Study
Rate:
0.75
lb
ai/
A
MI
High
Bush
Blueberry
Harvesting
MOE
=
23
at
day
7
(
MOE
=
102
at
18
days)
4
days
Apple/
CA
44685303
Avg
for
CA
Initial
%:
22.7
dissipation
per
day
%:
3
Apple
Harvesting
MOE
=
7
at
day
14
(
MOE=
100
at
103
days)

Apple/
OR,

WA
44694901
44685301
46317601
Avg
for
OR
and
WA
Initial
%:
19.3
dissipation
per
day
%:
4.5
Apple
Harvesting
MOE
=
7
at
day
14
(
MOE=
101
at
73
days)

Apples
1.5
Apple/
NY
44685303
46317601
Avg
for
NY
Initial
%:
15.7
dissipation
per
day
%:
8.7
NY,
OR
Apple
Harvesting
MOE
=
7
at
day
14
(
MOE=
102
at
44
days)
14
days
NY,
OR
Apple
Harvesting
MOE
=
7
at
14
days
(
MOE=
104
at
64
days)
14
days
Apples,
Crabapples,

Pears
1.5
OR
Apple
Thinning
MOE=
24
at
14
days
(
MOE=
102
at
41
days)
14
days
Cherries
0.75
Apple/

CA,
OR,
NY,

WA
44685303
44685301
44694901
46317601
Avg
for
CA,
OR,
NY,
WA
Initial
%:
19.2
dissipation
per
day
%:
5.3
NY,
OR
Apple
Harvesting
MOE
=
14
at
14
days
(
MOE
=
103
at
49
days)
15
days
NA
NA
NA
Walnut
Shakers
MOE
=
790
at
day
30
NA
NA
NA
Walnut
Sweepers
MOE=
440
at
day
30
Walnuts,
Almonds,

Pistachios
2.0
NA
NA
NA
CA
Walnut
Rakers
MOE=
170
at
day
30
30
days
for
walnuts
and
almonds,

21
days
for
pistachios
Parsley
0.5
Potato
40899801
Slope:
­
0.0833
Initial:
1.03
ug/
cm2
Study
Rate:
0.75
lb
ai/
A
no
data
no
data
Short­
term
MOE
=
100
at
day
44
Intermediate­
term
MOE
=

100
at
day
49
(
with
potatoes
DFR
and
ARTF
TCs)
30
days
Page
29
of
42
Incident
Reports
Historically,
AZM
has
ranked
as
one
of
the
top
organophosphate
pesticides
associated
with
worker
exposure
incidents.
The
incident
summary
in
the
2/
18/
99
IRED
for
AZM
(
D252505)
ranked
AZM
as
6th
among
the
28
chemicals
on
which
the
Poison
Control
Center
(
PCC)
collects
data
(
J.
Blondell,
1994).
This
ranking
considered
data
from
the
PCC
and
the
State
of
California.
An
updated
summary
of
incident
data
for
AZM
covering
PCC
data
up
through
1996
did
not
indicate
much
change
in
incidents
reported
as
to
number
or
severity
(
J.
Blondell,
1999
via
email
communication
with
M.
Rice).
Past
incidents
have
been
associated
with
re­
entry
violations,
spray
drift,
and
tree
crop
use.
The
majority
of
the
incidents
reported
resulted
in
systemic
illnesses
defined
as
a
poisoning
case
including
eye,
skin,
or
respiratory
effects.
The
data
summaries
indicate
relatively
few
hospitalizations
have
been
associated
with
workers'
exposure
to
AZM.
The
most
recent
data
indicate
that
there
has
been
a
decline
in
poisoning
incidents
with
AZM.
Overall,
PCC
data
indicate
that
over
the
10
year
period
1993­
2003
there
has
been
a
54%
decline
in
exposures
reported
and
a
47%
decline
in
poisoning
incidents
reported
(
personal
communication
J.
Blondell
2005).
Some
of
this
decline
may
be
because
of
improved
reporting
requirements
for
workers
in
California,
safer
work
practices,
and
mitigation
measures
implemented
since
the
2001
IRED,
such
as
lengthened
REIs
and
formulation
changes
to
place
wettable
powders
in
water­
soluble
bags,
and
voluntary
cancellation
of
the
liquid
products
by
the
registrant.

In
addition
to
the
summary
incident
data,
Washington
State
is
conducting
medical
monitoring
of
pesticide
handlers.
The
program
monitors
mixing,
loading,
and
application
activities
associated
with
handlers
only;
post­
application
workers
are
not
being
monitored.
Under
the
program,
the
workers
are
monitored
for
cholinesterase
activity
changes
as
a
result
of
exposure
to
multiple
pesticides.
The
study
represents
workers'
exposures
under
uncontrolled
field
conditions,
working
at
least
8
hours
per
day,
in
some
cases
wearing
no
protective
clothing,
using
open
mixing
and
open
cabs,
and
treating
large
acreages.
In
2004,
2
out
of
580
workers
tested
were
reported
with
AZM
exposures,
but
no
information
was
given
regarding
their
exposures'
impact
on
cholinesterase
activity.
In
2005,
1
worker
out
of
611
tested
was
reported
to
have
had
cholinesterase
depression
of
RBC
AChE
from
8
to
21%
over
a
3
month
period
as
a
result
of
exposure
to
AZM.

Although
the
biomonitoring
studies
supplied
by
the
registrant
were
not
designed
as
medical
monitoring
studies,
cholinesterase
activity
was
monitored
for
the
post­
application
workers.
However,
the
field
conditions
in
these
biomonitoring
studies
were
much
more
controlled
than
those
in
the
WA
State
medical
monitoring
program.
Workers
were
exposed
for
1
day
and
then
removed
from
the
field
for
urine
collection
over
the
next
4
days,
and
they
were
exposed
to
AZM
only.
The
data
were
variable
and
there
was
no
firm
evidence
of
ChE
inhibition.

Conclusions
and
Risk
Characterization
In
summary,
the
majority
of
the
handler
MOEs
are
less
than
100.
Handlers
and
mixer/
loaders
involved
in
activities
to
support
aerial
applications
of
AZM
have
the
lowest
MOEs
and
are
of
the
most
concern.
In
the
case
of
activities
that
support
airblast
applications,
biomonitoring
data
and
engineering
controls
(
closed
cabs)
result
in
MOEs
of
102
for
apples,
pear
Page
30
of
42
and
crabapples
and
80
for
nuts.
MOEs
for
activities
that
support
groundboom
applications
vary
depending
the
type
of
handler
activity
(
mixer/
loader
versus
applicator),
but
most
are
less
than
100
with
engineering
controls.
For
post­
application
activities,
the
number
of
days
for
most
of
the
crops
to
reach
a
MOE
of
100
is
significantly
longer
that
the
current
REIs
specified
on
EPA
labels.

HED
believes
these
risk
estimates
for
occupation
activities
are
conservative
and
probably
overestimate
risks.
These
risk
estimates
are
the
result
of
a
comparison
of
estimates
of
exposure
to
an
endpoint
for
toxic
effects.

On
the
exposure
side,
the
handler
exposure
scenarios
for
aerial
and
groundboom
applications
are
based
on
conventional
PHED
data
and
assumptions
likely
to
overestimate
risk,
such
as
maximum
application
rates
and
acreages
treated.
The
airblast
exposure
estimates
have
been
refined
through
the
use
of
biomonitoring
data
and
are
less
conservative.
Available
medical
monitoring
data
(
Washington
State)
support
the
characterization
of
this
risk
assessment
as
conservative
as
it
indicates
that
typical
exposures
of
handlers
to
AZM
may
result
in
detectable
cholinesterase
inhibition,
but
only
in
a
small
number
of
handlers
(
2/
580
in
2004
and
1/
611
in
2005)
or
<
1%
of
the
workers
tested.
The
2
cases
in
2004
and
1
case
in
2005
reported
AZM
use
specifically.
HED
notes
that
the
580
and
611
workers
tested
in
2004
and
2005,
respectively,
were
tested
irrespective
of
the
active
ingredient
handled.
However,
given
that
AZM
is
used
on
73%
of
the
apple
crop,
many
of
the
workers
tested
in
2004
and
2005
likely
applied
AZM.
The
MOEs
on
which
the
REIs
are
based
have
been
refined
through
biomonitoring
data.
REIs
indicate
the
minimum
amount
time
between
an
AZM
treatment
and
when
a
worker
can
reenter
the
field.
The
biomonitoring
data
for
post­
application
workers
reflect
reentry
into
a
field
at
the
minimum
of
time
specified
(
the
REI)
and,
therefore,
worst­
case
exposures.
In
practice,
a
post­
application
worker
may
not
reenter
a
treated
field
until
several
days
after
the
REI
by
which
time
AZM
residues
may
have
dissipated.
Although
representative
of
only
one
day
of
exposure
to
AZM,
available
biomonitoring
data
show
no
firm
evidence
of
cholinesterase
inhibition
in
postapplication
workers.

On
the
hazard
side,
HED
recognizes
that
as
regards
cholinesterase
inhibition,
animals
and
humans
probably
are
similar.
Although
the
NOAELs
for
ChE
inhibition
across
species
including
humans
are
not
very
different,
since
the
repeat
dose
study
with
humans
is
a
NOAEL­
only
study,
there
is
no
LOAEL
for
ChE
inhibition
in
humans
to
compare
with
animal
LOAELs.
More
importantly,
the
steep
dose­
response
that
occurs
in
going
from
cholinesterase
inhibition
to
more
severe
systemic
effects
is
a
caution
to
eliminating
10­
fold
safety
factor
for
interspecies
differences.
In
particular,
HED
notes
the
progression
from
moderate
ChE
inhibition
to
more
severe
systemic
effects
seen
in
the
rat
reproductive
studies.
In
the
rat
reproduction
study
there
was
25­
47%
RBC
AChE
inhibition
during
lactation
at
0.55
mg/
kg/
day.
Systemic
effects
are
seen
in
pups
(
decrease
in
viability
index
accompanied
by
a
decrease
in
pup
body
weight
during
lactation)
at
the
next
higher
dose
of
1.5
mg/
kg/
day
where
there
is
75
to
83%
inhibition
of
RBC
AChE
during
lactation.
There
is
only
a
2
to
3
fold
difference
between
the
non­
systemic
effect
dose
on
RBC
AChE
inhibition
and
a
systemic
effect
dose
of
AZM.
As
the
dose
level
in
the
rats
is
increased
to
4.8
mg/
kg/
day
and
RBC
AChE
inhibition
reaches
89
to
91%
there
are
convulsions
and
deaths
in
the
dams
further
indicating
the
seriousness
of
the
systemic
toxicity
of
AZM.
Page
31
of
42
Incident
data
indicate
a
50%
decline
in
poisoning
incidents
involving
AZM
over
time.
Medical
monitoring
data
indicating
that
a
small
percentage
of
workers
exhibit
mild
but
detectable
cholinesterase
inhibition
as
a
result
of
AZM
exposure.
Given
this,
HED
believes
that
the
majority
of
the
time
workers
are
using
AZM
safely.
HED
further
believes
the
selection
of
the
dog
oral
endpoint
as
the
lowest
NOAEL
in
the
toxicity
database
on
the
most
sensitive
endpoint
coupled
with
a
100­
fold
safety
factor
is
adequately
protective,
and
results
in
MOEs
that
are
conservative
and
overestimate
risk.
However,
HED
remains
concerned
that
on
occasion
a
worker's
accidental
exposures
to
AZM
at
higher
levels
than
may
be
typical
may
occur
and
result
in
serious
health
consequences
regardless
of
all
safeguards
because
of
the
steep
dose­
response
for
more
serious
effects
seen
in
the
animal
reproduction
studies.
Page
32
of
42
APPENDICES
Page
33
of
42
APPENDIX
I
ADDITIONAL
TOXICITY
TABLES
Page
34
of
42
Table
A.
Comparison
of
NOAELs
and
LOAELs
for
ChE
inhibition
across
animal
species
Species
Type
MRID
NOAEL
(
mg/
kg/
day)
LOAEL
­
effects
(
mg/
kg/
day)

Single
Dose
Studies
Rat
CC
Pups
46162101
0.49
1
­
plasma,
RBC
and
brain
Rat
CC
Adults
46162101
0.6
1.1
­
plasma,
RBC
or
brain
(
not
always)

Rat
ANT
43360301
Not
established
1
plasma,
RBC
and
brain
and
clinical
signs.

Repeat
Dose
Studies
Rat
(
2
years)
Chronic
feeding/
carcinogenicity
41119901
0.25
@
0.75
plasma,
RBC
and
brain
inhibited
Rat
(~
10
days)
Prenatal
developmental
toxicity
40464801
*
0.5
@
1.0
brain
inhibited
Rat
(
11
days)
Comparative
Cholinesterase
Assay
46239001
<
0.24
@
0.24
RBC
AChE
inhibited
(
Pups)

Rat
(
11
days)
Comparative
Cholinesterase
Assay
46239001
0.54
1
plasma,
RBC
or
brain
(
Adults)

Rat
(
continuous)
Multi
generation
reproduction
41916801
<
0.4
@
0.4
inhibition
of
RBC
Dog
(
1
year)
Chronic
feeding
41804801
0.15
@
0.69
RBC
inhibition
Rabbit
(~
13
days)
Prenatal
developmental
toxicity
40713901
*
1
@
2.5
plasma
and
RBC
inhibition
Mouse
(
1
year)
Chronic
feeding/
carcinogenicity
46009101
<
0.71
@
0.71
RBC
and
brain
inhibition
Rat
­
90
day
Inhalation
00155011
0.20
@
0.78
plasma
and
RBC
inhibition
Rat
­
single
dose
Dermal
absorption
42452701
0.56
@
5.6
plasma
inhibition
Page
35
of
42
Table
B.
Bench
Mark
Dose
(
BMD)
Analyses
for
AZM
RBC
AChE
­
Adults
Only
Chronic
Feeding
(
MRID
No.:
41119901)
Interval
Males
Females
BMD
BMDL
BMD
BMDL
30­
days
0.4241*
0.3656*
0.6486*
0.6876
0.4997*
0.5032
90­
days
0.5679*
0.4764*
0.866
0.6625
0.7974
0.5151
180­
days
0.7042*
0.5641*
0.5613*
0.4881*
360­
days
0.3514*
0.3042*
0.4375*
0.3959*
540­
days
0.4204*
0.3688*
0.4369*
0.4065*
720­
days
0.377*
0.2427
0.3278*
0.2083
0.5544*
0.4992*

*
High
value
dropped
and
based
on
3
doses
included
the
control.
Subchronic
Neurotoxicity
(
MRID
No.:
43826601)
­
W.
Sletzer
25
0.2205
0.1857
0.1627*
0.1316
0.1504*
0.1132
88
0.1451
0.1047
0.219
0.1499
Single
Dose
Comparative
ChE
(
MRID
No.:
46162101)­
P.
Villaneuva
1
0.23
0.17
0.37
0.26
Repeat
Dose
Comparative
ChE
(
MRID
No.:
46239001)­
P.
Villaneuva
11
0.21
0.16
0.09
0.08
Brain
AChE
Adults
and
Pups
Single
Dose
ChE
(
MRID
No.:
46162101)
Comparative
ChE
WS
Adult
11­
day
old
1.14
0.252
1.04
0.0936
PV
Adult
11­
day
old
0.88
0.63
0.70
0.43
1.84
0.44
1.10
0.35
Repeat
dose
(
MRID
No.:
46239001)
Comparative
ChE
PV
Adult
11­
day
old
13.85
0.19
1.40
0.16
1.90
0.13
1.14
0.12
Plasma
and
RBC
ChE
­
Adults
and
Pups
Single
Dose
Comparative
ChE
(
MRID
No.:
46162101)
Plasma
­
PV
Adult
11­
day
old
6.51
0.64
0.60
0.40
1.20
0.47
0.59
0.35
RBC
­
PV
Adult
11­
day
old
0.23
0.26
0.17
0.19
0.37
0.25
0.26
0.19
Repeat
Dose
Comparative
ChE
(
MRID
No.:
46239001)­
P.
Villaneuva
Plasma
­
PV
Adult
11­
day
old
0.37
0.16
0.28
0.14
0.39
0.20
0.25
0.17
RBC
­
PV
Adult
11­
day
old
0.21
0.06
0.16
0.05
0.09
0.07
0.08
0.06
Page
36
of
42
AZM­
Conversion
of
Inhalation
Dose
in
mg/
L
to
mg/
kg/
day
Basis
Equation:

Mg/
L
x
RVa
(
in
hours)
x
hours
of
exposure
x
study
days/
week
=
mg/
kg/
day
Wa
x
7
days/
week
Where
RVa
(
in
hours)
=
respiratory
volume
in
liters
is
fixed
for
rat
strain
and
sex.
For
the
Wistar
strain
rat,
the
RVa
is
15.4
and
10.8
L/
hr
for
males
and
females
respectively.

Wa
=
Mean
body
weight
for
a
rat
for
a
typical
inhalation
study.
For
the
Wistar
strain
rat,
these
are
0.4
Kg
and
0.25
kg
for
males
and
females
respectively.

Note:
The
original
equation
did
not
specifically
include
the
number
of
hours
per
day
that
the
animals
breathed
the
test
atmosphere.

Specifics
for
the
AZM
study
(
1976,
MRID
No.:
00155011).

For
the
90
day
study
with
AZM,
the
Wistar
strain
rat
was
used
and
exposure
was
for
6
hours
per
day,
five
days
per
week
for
a
total
of
90
days
(~
13
weeks)
so
it
is
assumed
that
there
were
65
exposure
days.
The
NOAEL
was
determined
to
be
0.0012
mg/
L.

Applying
the
Equation:

(
0.0012
mg/
L)
X
(
15.4
L/
hr)
X
(
6
hr/
day)
X
(
5
days/
week)
=
0.198
mg/
kg/
day
(
0.4
Kg)
X
(
7
days/
week)
(
For
males)

Similarly,
the
dose
for
females
would
be
0.222
mg/
kg/
day.
Page
37
of
42
APPENDIX
II
TOTAL
SHORT­
TERM
AND
INTERMEDIATE­
TERM
HANDLER
EXPOSURE
RISK
Page
38
of
42
Table
A1
Intermediate­
Term
Baseline
Risk
for
Agricultural
Uses
of
AZM
Exposure
Scenario
(
Scenario
#)
Dermal
Unit
Exposure
(
mg/
lb
ai)
1
Inhalation
Unit
Exposure
(
Ug/
lb
ai)
2
Crop3
Applicati
on
Rate4
lb
ai/
A
Daily
Area
Treated5
A/
day
Dermal
Dose
(
mg/
kg/
day)
6
Dermal
MOE
7
Inhalation
Dose
(
mg/
kg/
day)
8
Inhalation
MOE9
Total
MOE10
Mixer/
Loader
Wettable
Powders
for
Aerial
application)
3.7
43
Apple,
Pear,
Crabapple
1.50
350
12
<
1
0.32
<
1
<
1
Wettable
Powders
for
Aerial
application
3.7
43
Blueberry
0.75
350
5.8
<
1
0.16
<
1
<
1
Wettable
Powders
for
Groundboom
application
3.7
43
Blueberry
0.75
80
1.3
<
1
0.037
5
<
1
Wettable
Powders
for
Groundboom
application
3.7
43
Brussels
Sprouts
0.75
80
1.3
<
1
0.037
5
<
1
Wettable
Powders
for
Groundboom
application
3.7
43
Parsley
0.50
80
0.89
<
1
0.025
6
<
1
Wettable
Powders
for
Groundboom
application
3.7
43
Nursery
stock
1
80
1.8
<
1
0.049
3
<
1
Applicator
Sprays
for
Aerial
application
No
Data
No
Data
Apple,
Pear,
Crabapple
1.50
350
No
Data
No
Data
No
Data
No
Data
No
Data
Sprays
for
Aerial
application
No
Data
No
Data
Blueberry
0.75
350
No
Data
No
Data
No
Data
No
Data
No
Data
Sprays
for
Groundboom
application
0.014
0.74
Blueberry
0.75
80
0.0050
30
0.00063
240
25
Sprays
for
Groundboom
application
0.014
0.74
Brussels
Sprouts
0.75
80
0.0050
30
0.00063
240
25
Sprays
for
Groundboom
application
0.014
0.74
Parsley
0.50
80
0.0034
45
0.00042
360
40
Sprays
for
Groundboom
application
0.014
0.74
Nursery
stock
1
80
0.0067
23
0.00085
175
20
Flagger
Flagging
for
Sprays
application
0.011
0.35
Apple,
Pear,
Crabapple
1.50
350
0.035
42
0.0026
60
25
Flagging
for
Sprays
application
0.011
0.35
Blueberry
0.75
350
0.017
8
0.0013
115
8
1Baseline
dermal
unit
exposures
represent
long
pants,
long
sleeved
shirts,
shoes,
and
socks.
Values
are
reported
in
the
PHED
Surrogate
Exposure
Guide
dated
August
1998
2Baseline
inhalation
unit
exposures
represent
no
respirator.
Values
are
reported
in
the
PHED
Surrogate
Exposure
Guide
dated
August
1998
3Crops
and
use
patterns
are
from
AZM
crops
in
groups
3
4Application
rates
are
based
on
maximum
values
found
in
various
sources
including
LUIS
and
labels.

5Amount
treated
is
based
on
the
area
that
can
be
reasonably
applied
in
a
single
day
for
each
exposure
scenario
of
concern
based
on
the
application
method
and
formulation/
packaging
type.
(
Standard
EPA/
OPP/
HED
values).

6Dermal
dose
(
mg/
kg/
day)
=
[
unit
exposure
(
mg/
lb
ai)
*
Dermal
absorption
(
42%)
*
Application
rate
(
lb
ai/
acre
or
lb
ai/
gallon)
*
Daily
area
treated
(
acres)]
/
Body
weight
(
70
kg).

7Dermal
MOE
=
NOAEL
(
0.15
mg/
kg/
day)
/
Daily
Dermal
Dose.
Target
Dermal
MOE
is
100.

8Inhalation
dose
(
mg/
kg/
day)
=
[
unit
exposure
(
ug/
lb
ai)
*
0.001
mg/
g
unit
conversion
*
Inhalation
absorption
(
100%)
*
Application
rate
(
lb
ai/
acre)
*
Daily
area
treated
(
acres)]
/
Body
weight
(
70
kg).

9Inhalation
MOE
=
NOAEL
(
0.2
mg/
kg/
day)
/
Daily
Inhalation
Dose.
Target
Inhalation
MOE
is
100.
Page
39
of
42
Table
A2:
Intermediate­
Term
Engineering
Control
Risk
for
Agricultural
Uses
of
AZM
Exposure
Scenario
(
Scenario
#)
Dermal
Unit
Exposure
(
mg/
lb
ai)
1
Inhalation
Unit
Exposure
(
Ug/
lb
ai)
2
Crop3
Applicat
ion
Rate4
Daily
Area
Treated5
Dermal
Dose
(
mg/
kg/
day)
6
Dermal
MOE
7
Inhalation
Dose
(
mg/
kg/
day)
8
Inhalation
MOE9
Total
MOE10
Mixer/
Loader
Wettable
Powders
for
Aerial
application
0.0098
0.24
Apple,
Pear,
Crabapple
1.50
350
0.031
5
0.0018
110
5
Wettable
Powders
for
Aerial
application
0.0098
0.24
Blueberry
0.75
350
0.015
10
0.0009
165
9
Wettable
Powders
for
Groundboom
application
0.0098
0.24
Blueberry
0.75
80
0.0035
42
0.00021
715
40
Wettable
Powders
for
Groundboom
application
0.0098
0.24
Brussels
Sprouts
0.75
80
0.0035
42
0.00021
715
40
Wettable
Powders
for
Groundboom
application
0.0098
0.24
Parsley
0.50
80
0.0024
63
0.00014
1070
60
Wettable
Powders
for
Groundboom
application
0.0098
0.24
Nursery
stock
1
80
0.0047
32
0.00027
555
30
Applicator
Sprays
for
Aerial
application
0.005
0.068
Apple,
Pear,
Crabapple
1.50
350
0.016
10
0.00051
295
10
Sprays
for
Aerial
application
0.005
0.068
Blueberry
0.75
350
0.0079
20
0.00026
575
18
Sprays
for
Groundboom
application
0.005
0.043
Blueberry
0.75
80
0.0018
85
0.000037
4055
80
Sprays
for
Groundboom
application
0.005
0.043
Brussels
Sprouts
0.75
80
0.0018
85
0.000037
4055
80
Sprays
for
Groundboom
application
0.005
0.043
Parsley
0.50
80
0.0012
125
0.000025
6000
122
Sprays
for
Groundboom
application
0.005
0.043
Nursery
stock
1
80
0.0024
63
0.000049
3060
60
Flagger
Flagging
for
Sprays
application
0.00022
0.007
Apple,
Pear,
Crabapple
1.50
350
0.00069
217
0.000053
2830
200
Flagging
for
Sprays
application
0.00022
0.007
Blueberry
0.75
350
0.00035
430
0.000026
5770
400
1Engineering
controls
dermal
unit
exposures
represent
long
pants
and
long
sleeved
shirts.
For
mixers
and
loaders,
chemical­
resistant
gloves
are
also
included.
Values
are
reported
in
the
PHED
Surrogate
Exposure
Guide
dated
August
1998.

2Engineering
controls
inhalation
unit
exposures
represent
no
respirator.
Values
are
reported
in
the
PHED
Surrogate
Exposure
Guide
dated
August
1998
3Crops
and
use
patterns
are
from
AZM
crops
in
Group
3
4Application
rates
are
based
on
maximum
values
found
in
various
sources
including
LUIS
and
labels.

5Amount
treated
is
based
on
the
area
that
can
be
reasonably
applied
in
a
single
day
for
each
exposure
scenario
of
concern
based
on
the
application
method
and
formulation/
packaging
type.
(
Standard
EPA/
OPP/
HED
values).

6Dermal
dose
(
mg/
kg/
day)
=
[
unit
exposure
(
mg/
lb
ai)
*
Dermal
absorption
(
42%)
*
Application
rate
(
lb
ai/
acre)
*
Daily
area
treated
(
acres]
/
Body
weight
(
70
kg).

7Dermal
MOE
=
NOAEL
(
0.15
mg/
kg/
day)
/
Daily
Dermal
Dose.
Target
Dermal
MOE
is
100.

8Inhalation
dose
(
mg/
kg/
day)
=
[
unit
exposure
(
ug/
lb
ai)
*
0.001
mg/
g
unit
conversion
*
Inhalation
absorption
(
100%)
*
Application
rate
(
lb
ai/
acre)
*
Daily
area
treated
(
acres
)]
/
Body
weight
(
70
kg).

9Inhalation
MOE
=
NOAEL
(
0.2
mg/
kg/
day)
/
Daily
Inhalation
Dose.
Target
Inhalation
MOE
is
100.

Table
A3
Short­
Term
Baseline
Risk
for
Agricultural
Uses
of
AZM
Page
40
of
42
Exposure
Scenario
(
Scenario
#)
Dermal
Unit
Exposure
(
mg/
lb
ai)
1
Inhalation
Unit
Exposure
(
Ug/
lb
ai)
2
Crop3
Applicatio
n
Rate4
lb
ai/
A
Daily
Area
Treated5
A/
day
Dermal
Dose
(
mg/
kg/
day)
6
Dermal
MOE
7
Inhalation
Dose
(
mg/
kg/
day)
8
Inhalation
MOE9
Total
MOE10
Mixer/
Loader
Wettable
Powders
for
Aerial
application)
3.7
43
Apple,
Pear,
Crabapple
1.50
350
27.750
<
1
0.3225
<
1
<
1
Wettable
Powders
for
Aerial
application
3.7
43
Blueberry
0.75
350
13.875
<
1
0.1612
1
<
1
Wettable
Powders
for
Groundboom
application
3.7
43
Blueberry
0.75
80
3.171
<
1
0.0368
5
<
1
Wettable
Powders
for
Groundboom
application
3.7
43
Brussels
Sprouts
0.75
80
3.171
<
1
0.0368
5
<
1
Wettable
Powders
for
Groundboom
application
3.7
43
Parsley
0.50
80
2.114
<
1
0.0246
8
<
1
Wettable
Powders
for
Groundboom
application
3.7
43
Nursery
stock
1
80
4.228
<
1
0.0491
4
<
1
Applicator
Sprays
for
Aerial
application
No
Data
No
Data
Apple,
Pear,
Crabapple
1.50
350
No
Data
No
Data
No
Data
No
Data
No
Data
Sprays
for
Aerial
application
No
Data
No
Data
Blueberry
0.75
350
No
Data
No
Data
No
Data
No
Data
No
Data
Sprays
for
Groundboom
application
0.014
0.74
Blueberry
0.75
80
0.012
46
0.000634
315
40
Sprays
for
Groundboom
application
0.014
0.74
Brussels
Sprouts
0.75
80
0.012
46
0.000634
315
40
Sprays
for
Groundboom
application
0.014
0.74
Parsley
0.50
80
0.008
70
0.000422
472
60
Sprays
for
Groundboom
application
0.014
0.74
Nursery
stock
1
80
0.016
35
0.000846
236
30
Flagger
Flagging
for
Sprays
application
0.011
0.35
Apple,
Pear,
Crabapple
1.50
350
0.0825
7
0.002625
76
6
Flagging
for
Sprays
application
0.011
0.35
Blueberry
0.75
350
0.0412
13
0.00131
152
12
1Baseline
dermal
unit
exposures
represent
long
pants,
long
sleeved
shirts,
shoes,
and
socks.
Values
are
reported
in
the
PHED
Surrogate
Exposure
Guide
dated
August
1998
2Baseline
inhalation
unit
exposures
represent
no
respirator.
Values
are
reported
in
the
PHED
Surrogate
Exposure
Guide
dated
August
1998
3Crops
and
use
patterns
are
from
AZM
crops
in
groups
3
4Application
rates
are
based
on
maximum
values
found
in
various
sources
including
LUIS
and
labels.

5Amount
treated
is
based
on
the
area
that
can
be
reasonably
applied
in
a
single
day
for
each
exposure
scenario
of
concern
based
on
the
application
method
and
formulation/
packaging
type.
(
Standard
EPA/
OPP/
HED
values).

6Dermal
dose
(
mg/
kg/
day)
=
[
unit
exposure
(
mg/
lb
ai)
*
Application
rate
(
lb
ai/
acre
or
lb
ai/
gallon)
*
Daily
area
treated
(
acres
)]
/
Body
weight
(
70
kg).

7Dermal
MOE
=
NOAEL
(
0.56
mg/
kg/
day)
/
Daily
Dermal
Dose.
Target
Dermal
MOE
is
100.

8Inhalation
dose
(
mg/
kg/
day)
=
[
unit
exposure
(
ug/
lb
ai)
*
0.001
mg/
g
unit
conversion
*
Inhalation
absorption
(
100%)
*
Application
rate
(
lb
ai/
acre)
*
Daily
area
treated
(
acres)]
/
Body
weight
(
70
kg).

9Inhalation
MOE
=
NOAEL
(
0.2
mg/
kg/
day)
/
Daily
Inhalation
Dose.
Target
Inhalation
MOE
is
100.
Page
41
of
42
Table
A4:
Short
­
Term
Engineering
Control
Risk
for
Agricultural
Uses
of
AZM
Exposure
Scenario
(
Scenario
#)
Dermal
Unit
Exposure
(
mg/
lb
ai)
1
Inhalation
Unit
Exposure
(
Ug/
lb
ai)
2
Crop3
Applicat
ion
Rate4
Daily
Area
Treated5
Dermal
Dose
(
mg/
kg/
day)
6
Dermal
MOE
7
Inhalation
Dose
(
mg/
kg/
day)
8
Inhalation
MOE9
Total
MOE10
Mixer/
Loader
Wettable
Powders
for
Aerial
application
0.0098
0.24
Apple,
Pear,
Crabapple
1.50
350
0.0735
7
0.0018
111
7
Wettable
Powders
for
Aerial
application
0.0098
0.24
Blueberry
0.75
350
0.03675
15
0.0009
222
14
Wettable
Powders
for
Groundboom
application
0.0098
0.24
Blueberry
0.75
80
0.0084
66
0.000206
972
62
Wettable
Powders
for
Groundboom
application
0.0098
0.24
Brussels
Sprouts
0.75
80
0.0084
66
0.000206
972
62
Wettable
Powders
for
Groundboom
application
0.0098
0.24
Parsley
0.50
80
0.0056
100
0.000137
1458
93
Wettable
Powders
for
Groundboom
application
0.0098
0.24
Nursery
stock
1
80
0.0112
50
0.000274
730
46
Applicator
Sprays
for
Aerial
application
0.005
0.068
Apple,
Pear,
Crabapple
1.50
350
0.0375
15
0.00051
392
14
Sprays
for
Aerial
application
0.005
0.068
Blueberry
0.75
350
0.02036
27
0.000277
722
26
Sprays
for
Groundboom
application
0.005
0.043
Blueberry
0.75
80
0.00429
130
0.0000368
5426
127
Sprays
for
Groundboom
application
0.005
0.043
Brussels
Sprouts
0.75
80
0.00429
130
0.0000368
5426
127
Sprays
for
Groundboom
application
0.005
0.043
Parsley
0.50
80
0.00286
196
0.0000246
8139
191
Sprays
for
Groundboom
application
0.005
0.043
Nursery
stock
1
80
0.00571
98
0.0000492
4069
95
Flagger
Flagging
for
Sprays
application
0.00022
0.007
Apple,
Pear,
Crabapple
1.50
350
0.00165
340
0.0000525
3809
311
Flagging
for
Sprays
application
0.00022
0.007
Blueberry
0.75
350
0.000825
680
0.00002625
7619
623
1Engineering
controls
dermal
unit
exposures
represent
long
pants
and
long
sleeved
shirts.
For
mixers
and
loaders,
chemical­
resistant
gloves
are
also
included.
Values
are
reported
in
the
PHED
Surrogate
Exposure
Guide
dated
August
1998.

2Engineering
controls
inhalation
unit
exposures
represent
no
respirator.
Values
are
reported
in
the
PHED
Surrogate
Exposure
Guide
dated
August
1998
3Crops
and
use
patterns
are
from
AZM
crops
in
Group
3
4Application
rates
are
based
on
maximum
values
found
in
various
sources
including
LUIS
and
labels.

5Amount
treated
is
based
on
the
area
that
can
be
reasonably
applied
in
a
single
day
for
each
exposure
scenario
of
concern
based
on
the
application
method
and
formulation/
packaging
type.
(
Standard
EPA/
OPP/
HED
values).

6Dermal
dose
(
mg/
kg/
day)
=
[
unit
exposure
(
mg/
lb
ai)
*
Application
rate
(
lb
ai/
acre
)
*
Daily
area
treated
(
acres
]
/
Body
weight
(
70
kg).

7Dermal
MOE
=
NOAEL
(
0.56
mg/
kg/
day)
/
Daily
Dermal
Dose.
Target
Dermal
MOE
is
100.

8Inhalation
dose
(
mg/
kg/
day)
=
[
unit
exposure
(
ug/
lb
ai)
*
0.001
mg/
g
unit
conversion
*
Inhalation
absorption
(
100%)
*
Application
rate
(
lb
ai/
acre)
*
Daily
area
treated
(
acres
)]
/

Body
weight
(
70
kg).

9Inhalation
MOE
=
NOAEL
(
0.2
mg/
kg/
day)
/
Daily
Inhalation
Dose.
Target
Inhalation
MOE
is
100.
Page
42
of
42
Table
A5:
Short
and
Intermediate­
Term
Risk
for
Agricultural
Uses
of
AZM
(
Biomonitoring
Study)

Exposure
Scenario
(
Scenario
#)
Internal
Unit
Exposure
(
mg/
lb
ai)
1
Crop2
Application
Rate3
lb
ai/
A
Daily
Area
reated4
A/
day
Total
Dose
(
mg/
kg/
day)
5
Total
MOE
6
Mixer/
Loader/
applicator
for
Open
Cab
Airblast
(
Data
Source
biomonitoring
study
46316406)

Mixing/
Loading/
Applying
for
Airblast
0.0095
Apple,
Pear,
Crabapple
1.5
40
0.00814
18
Mixing/
Loading/
Applying
for
Airblast
0.0095
Cherry
0.75
40
0.00417
36
Mixing/
Loading/
Applying
for
Airblast
0.0095
Almond,
pistachio,
walnut
2.0
40
0.0109
14
Mixing/
Loading/
Applying
for
Airblast
0.0095
Nursery
stock
1.0
40
0.00542
28
Mixer/
Loader/
applicator
for
Closed
Cab
Airblast
(
Data
Source
biomonitoring
study
46316406)

Mixing/
Loading/
Applying
for
Airblast
0.0017
Apple,
Pear,
Crabapple
1.5
40
0.00146
102
Mixing/
Loading/
Applying
for
Airblast
0.0017
Cherry
0.75
40
0.00073
205
Mixing/
Loading/
Applying
for
Airblast
0.0017
Almond,
pistachio,
walnut
2.0
40
0.00194
80
Mixing/
Loading/
Applying
for
Airblast
0.0017
Nursery
stock
1.0
40
0.00097
155
1
Values
are
reported
in
the
Biomonitoring
study
with
MRID
#
46316406
2.
Crops
and
use
patterns
are
from
AZM
Group
3
3
Application
rates
are
based
on
maximum
values
found
in
various
sources
including
LUIS
and
labels
4.
Amount
treated
is
based
on
the
area
that
can
be
reasonably
applied
in
a
single
day
for
each
exposure
scenario
of
concern
based
on
the
application
method
and
formulation/
packaging
type.
(
Standard
EPA/
OPP/
HED
values)

5Internal
dose
(
mg/
kg/
day)
=
[
unit
exposure
(
mg/
lb
ai)
*
Gut
absorption
(
100%)
*
Application
rate
(
lb
ai/
acre)
*
Daily
area
treated
(
acres]
/
Body
weight
(
70
kg).

6
Total
MOE
=
NOAEL
(
0.15
mg/
kg/
day)
/
Internal
Dose.
Target
MOE
is
100.