Document ID: EPA-HQ-OPP-2004-0048-0003
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2004-06-18T04:00Z

UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
OFFICE
OF
PREVENTION,
PESTICIDES
AND
TOXIC
SUBSTANCES
MEMORANDUM
DATE:
4/
29/
2004
SUBJECT:
Amitraz.
Human
Health
Risk
Assessment
PC
Code:
106201
DP
Number:
D300297
REVIEWER:
José
J.
Morales,
Chemist/
Risk
Assessor
Reregistration
Branch
3
Health
Effects
Division
(
7509C)

THROUGH:
Danette
Drew,
Branch
Senior
Scientist
Reregistration
Branch
3
Health
Effects
Division
(
7509C)

TO:
John
Pates,
Chemical
Review
Manager
Reregistration
Branch
1
Special
Review
and
Reregistration
Division
(
7508C)

The
following
human
health
risk
assessment
for
amitraz
has
been
prepared
by
the
Health
Effects
Division
for
Phase
One
of
the
Tolerance
Reassessment
Eligibility
Decision
(
TRED)
process
for
amitraz.
Occupational
risk
assessment
for
amitraz
is
not
addressed
in
this
document.
Aggregate
(
food
/
drinking
water
/
residential)
risk
assessment
is
based
on
the
following
memoranda:

Amitraz:
Report
of
the
Hazard
Identification
Assessment
Review
Committee
(
P.
Hurley
memo,
3/
17/
04)

Amitraz:
Toxicology
Disciplinary
Chapter
for
the
Tolerance
Reassessment
Eligibility
Decision
Document
(
P.
Hurley
memo,
3/
17/
04)

Amitraz.
Product
Chemistry
Chapter
for
the
TRED
Document
(
J.
Morales
memo,
4/
30/
04)

Amitraz:
Residue
Chemistry
Chapter
(
J.
Morales
memo,
4/
30/
04)

Amitraz:
Anticipated
Residues,
Acute,
Chronic,
and
Cancer
Dietary
Exposure
Assessments
for
the
Reregistration
Eligibility
Decision
(
J.
Morales
memo,
4/
30/
04)
Amitraz:
Drinking
Water
Assessment
for
Tolerance
Reassessment
Eligibility
Decision
(
S.
Abel
memo,
2/
11/
04)

Residential
Exposure
Assessment
and
Recommendations
for
the
Tolerance
Reassessment
Evaluation
Decision
(
TRED)
Document
for
Amitraz
(
R.
Travaglini
memo,
4/
30/
04)

Review
of
Incident
Reports
(
J.
Blondell
memo,
In
Preparation)
1.0
Executive
Summary
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4
2.0
Physical/
Chemical
Properties
Characterization
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11
3.0
Hazard
Characterization
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12
3.1
Hazard
Profile
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12
3.2
FQPA
Considerations
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19
3.3
Dose­
Response
Assessment
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21
3.4
Endocrine
Disruption
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23
4.0
Exposure
Assessment
and
Characterization
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24
4.1
Summary
of
Registered
Uses
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24
4.2
Dietary
Exposure/
Risk
Pathway
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25
4.2.1
Residue
Profile
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25
4.2.2
Acute
Dietary
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33
4.2.3
Chronic
and
Cancer
Dietary
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35
4.3
Water
Exposure/
Risk
Pathway
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36
4.4
Residential
Exposure/
Risk
Pathway
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36
4.4.1
Home
Uses
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38
4.4.1.1
Handler
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38
4.4.2
Postapplication
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38
5.0
Aggregate
Risk
Assessments
and
Risk
Characterizations
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42
6.0
Cumulative
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43
7.0
Data
Needs/
Label
Requirements
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43
4
Amitraz
Risk
Assessment
1.0
Executive
Summary
Amitraz
[
N'­(
2,4­
dimethylphenyl)­
N­[[(
2,4­
dimethylphenyl)
imino]
methyl]­
Nmethylmethanimidamide
is
an
insecticide/
acaricide
with
registered
food/
feed
uses
in
the
U.
S.
on
cotton,
pears,
beef
and
dairy
cattle,
and
hogs.
Amitraz
is
currently
registered
for
use
on
cotton
to
control
various
insects
(
bollworm
larvae
and
eggs,
beet
armyworm,
whitefly,
aphids,
and
spider
mites)
as
well
as
on
pears
for
the
control
of
pear
psylla
and
grape
mealybug.
Amitraz
is
also
used
for
tick
control
on
dogs
as
well
as
mite
and
lice
management
on
beef
cattle,
dairy
cattle
and
swine.

Amitraz
can
be
applied
via
dip
or
low
pressure
hand
spray
for
cattle
and
swine
with
up
to
0.2
lb
a.
i./
50
gallons
of
water.
For
the
use
of
Taktic
E.
C.
on
beef
cattle,
dairy
cattle
and
swine,
the
following
application
methods
are
suggested:
1)
cattle
applied
via
spraying
or
by
a
spray
dip
machine,
2)
swine
applied
via
spraying,
and
3)
piglets/
weaners
applied
by
dipping.
However,
Taktic
E.
C.
is
not
to
be
applied
within
three
days
of
slaughter
for
swine,
which
are
not
to
be
treated
more
than
four
times
per
year.
All
of
the
established
tolerances
for
meats,
meat
byproducts
eggs
and
milk
will
be
maintained
to
support
the
animal
health
uses.

In
the
case
of
tick
and
flea
collars
(
Preventic
®
and
Preventic
®
Plus),
application
should
be
made
every
three
months
in
dogs
more
than
12
weeks
of
age.

In
a
recent
letter
to
the
Agency,
Bayer
Crop
Science
(
BCS)
has
decided
to
voluntarily
withdraw
the
registrations
of
Ovaysn
Insecticide/
Miticide
(
EPA
Reg.
No.
264­
625)
and
Mitac
W
Insecticide
(
EPA
Reg.
No.
264­
636).
The
registrant
has
also
requested
to
maintain
the
registration
of
technical
amitraz,
to
revoke
established
tolerances
for
apples,
beeswax,
cotton
(
US
cotton
registration
is
being
volunraily
revoked)
honey,
and
pears
as
well
as
maintain
import
tolerances
for
hops
and
cottonseed
(
Amitraz
Use
Closure
Memo,
10/
22/
03).

Amitraz
is
a
FIFRA
List
A
pesticide
assigned
to
Case
No.
0234
and
was
the
subject
of
a
Reregistration
Standard
Guidance
Document
dated
10/
87.
The
Residue
Chemistry
Chapter
of
the
Amitraz
Reregistration
Standard
Update
was
issued
7/
6/
90.
The
Residue
Chemistry
Chapter
for
the
Amitraz
Reregistration
Eligibility
Decision
document
(
RED)
was
issued
9/
17/
93,
and
the
Amitraz
RED
was
signed
03/
95.

Hazard
Assessment
The
toxicology
database
for
Amitraz
is
incomplete.
There
are
several
major
data
gaps.
The
available
studies
are
not
of
the
most
current
quality;
however,
sufficient
data
may
be
gleaned
from
them
for
use
in
an
assessment
of
risk
to
human
health.
The
toxicity
profile
for
Amitraz
cannot
be
completely
characterized
for
all
effects,
especially
those
relating
to
developmental,
reproductive
and
neurotoxic
effects.
5
Amitraz
has
a
low
acute
toxicity
in
a
wide
number
of
species,
including
mice,
rats,
guinea
pigs,
rabbits,
dogs,
baboons
and
domestic
pigs
by
the
either
the
oral,
dermal
and/
or
inhalation
routes
of
exposure.
A
pharmacotoxic
profile
suggests
that
amitraz
induces
a
depression
of
hypothalmic
function
with
clinical
signs
of
central
nervous
system
depression,
ataxia,
ptosis,
emesis,
labored
respiration,
muscular
weakness,
tremors,
hypothermia
and
bradycardia.
Similar
clinical
signs
are
observed
via
oral,
dermal
or
inhalation
routes
of
exposure.
The
dog
appears
to
be
the
most
sensitive
species
and
there
is
no
indication
of
extra
sensitivity
for
either
sex.
Metabolism
studies
in
humans
indicate
clinical
signs
similar
to
those
observed
in
animals.
Decreased
body
weight
is
the
other
major
effect
following
exposure
to
amitraz
and
there
is
no
concern
for
cumulative
toxicity
(
i.
e.
no
increased
toxicity
with
a
longer
term
of
exposure).

There
is
no
indication
of
developmental
toxicity
in
the
rat
in
either
of
two
available
studies.
Although
two
rabbit
developmental
toxicity
studies
and
two
reproduction
studies
in
the
rat
are
available,
none
are
acceptable
for
regulatory
purposes
due
to
deficiencies
in
either
the
study
designs
and/
or
the
studies
themselves.
Multiple
species
display
evidence
of
neurotoxicity
following
exposure
to
Amitraz.
Signs
of
CNS
depression
were
observed
in
the
dog
and
possibly
the
rabbit.
In
the
rat,
irritability,
nervousness
and/
or
excitability
were
observed.

Amitraz
is
a
carcinogen
in
mice,
inducing
significant
increases
in
hepatocellular
adenomas,
carcinomas
and
combined
adenomas/
carcinomas
in
females
and
lung
adenomas
in
males.
It
is
classified
as
a
Group
C,
possible
human
carcinogen
with
a
Q
1*
of
2.83
x
10­
2.

Amitraz
is
not
stable
in
the
diet
and
the
current
toxicological
endpoints
for
risk
assessment
are
based
on
a
capsule
or
bolus
dose
study.
In
the
dietary
studies,
due
to
significant
degradation,
the
animals
are
likely
more
exposed
to
the
degradation
products
than
to
the
parent.
These
degradation
products
also
happen
to
be
significant
animal
and
plant
metabolites.
Therefore,
in
the
diet,
humans
are
more
likely
to
be
exposed
to
the
degradation
product
than
to
the
parent.
The
capsule
study
protects
for
exposure
to
the
degradates
because
it
has
a
lower
toxicological
endpoint
than
the
long
term
dietary
studies.
The
dermal
and
inhalation
endpoints
are
also
based
on
the
capsule
study.
Humans
are
more
likely
to
be
exposed
to
the
parent
via
the
dermal
and
inhalation
and
non­
dietary
oral
routes
associated
with
livestock
and
pet
uses
being
maintained
by
the
registrant
rather
than
dietary
exposures.
Consequently,
they
will
be
directly
exposed
to
parent,
amitraz,
without
a
chance
for
significant
degradation,
the
capsule
study
may
be
more
appropriate
as
the
study
of
choice
for
these
routes
(
the
dermal
and
inhalation
studies
are
not
acceptable).

FQPA
Decision
On
February
3,
2004,
the
Hazard
Identification
Assessment
Review
Committee
(
HIARC)
determined
that
the
special
FQPA
safety
factor
should
be
reduced
to
1X;
however,
a
10X
database
uncertainty
factor
(
UF
DB)
is
required
due
to
an
incomplete
database
(
i.
e.
lack
of
acceptable
rabbit
developmental
toxicity
and
two­
generation
reproduction
studies).
Despite
the
lack
of
acceptable
rabbit
developmental
and
rat
reproduction
studies,
there
are
no
residual
uncertainties
for
pre­
and/
or
post­
natal
toxicity
based
on
the
the
following
considerations:
6
the
results
of
the
two
unacceptable
rabbit
developmental
studies,
when
taken
together,
show
that
developmental
effects
occurred
at
doses
higher
than
the
doses
that
caused
maternal
toxicity;

a
10X
UF
DB
is
required;

the
endpoint
of
concern
(
neurotoxicity)
for
the
overall
risk
assessment
is
based
on
the
"
apparent"
sensitive
species
(
dogs),

and
the
selected
toxicological
endpoint
for
the
overall
risk
assessment
is
approximately
20­
fold
lower
than
the
lowest
developmental
NOAEL
in
the
unacceptable
rabbit
studies
and
5­
fold
lower
than
the
offspring
NOAEL
in
the
unacceptable
three­
generation
reproduction
study.

Based
on
the
weight
of
evidence
presented,
the
HIARC
is
concerned
about
potential
reproductive
effects
and
neurotoxicity
in
developing
fetuses.
The
HIARC
is
therefore
requiring
a
combined
2­
generation
reproduction
study
in
the
rat
with
components
assessing
for
potential
developmental
and
adult
neurotoxicity.

The
HIARC
determined
that
the
10X
UF
DB
should
be
applied
to
dietary
(
acute
and
chronic)
and
non­
dietary/
residential
(
incidental
oral,
dermal
and
inhalation)
risk
assessments
because
the
required
studies
may
provide
endpoints
applicable
for
risk
assessments.
Therefore,
a
total
UF
of
1000
has
been
applied
to
all
dietary
and
residential
risk
assessments.

Dose
Response
Assessment
The
toxicological
endpoints
for
use
in
human
risk
assessment
for
amitraz
were
selected
from
the
most
sensitive
species
from
the
amitraz
database.
A
NOAEL
of
0.25
mg/
kg/
day
from
a
chronic
oral
(
capsule)
study
in
the
dog
was
selected
for
all
endpoints
for
estimation
of
risk.
The
endpoint
selected
is
based
on
signs
of
neurotoxicity
and
CNS
depression.
This
NOAEL
is
the
lowest
endpoint
in
the
database,
from
the
most
sensitive
species,
and
amitraz
toxic
effects
do
not
cumulate.
Therefore,
both
the
acute
population
adjusted
dose
(
aPAD)
and
the
chronic
population
adjusted
dose
(
cPAD)
=
0.00025
mg/
kg/
day.
Similarly,
the
NOAEL
of
0.25
mg/
kg/
day
was
used
to
estimate
risks
for
dermal,
inhalation,
and
incidental
oral
exposure,
all
durations.
The
dermal
absorption
factor
is
8%
based
on
a
dermal
absorption
study
on
an
amitraz
formulation.
The
target
Margin
of
Exposure
(
MOE)
for
risk
assessment
is
1000
for
all
residential
exposures
via
the
oral,
dermal
and
inhalation
routes.
This
is
based
on
the
conventional
uncertainty
factor
of
100X
(
10X
for
intraspecies
extrapolation
and
10X
for
interspecies
variation)
plus
an
additional
10X
database
uncertainty
factor
for
lack
of
acceptable
developmental
rabbit
and
rat
reproduction
studies.
7
Residue
Chemistry
The
qualitative
nature
of
the
residue
in
plants
and
animals
is
adequately
understood
based
on
plant
metabolism
studies
with
apples,
beans,
lemons,
citrus,
cotton,
and
pears,
and
animal
metabolism
studies
with
cattle
and
swine
(
dermal
application)
and
cattle,
goats
and
hens
(
oral
dosing).
The
terminal
residues
of
concern
for
risk
assessment
and
enforcement
purposes
are
amitraz
and
its
metabolites
containing
the
2,4­
dimethylaniline
(
2,4­
DMA)
moiety
[
BTS­
27919
(
N­(
2,4­
dimethylphenyl)
formamide)
and
BTS­
27271
(
N­(
2,4­
dimethylphenyl)­
Nmethylmethanimidamide
these
are
the
residues
which
are
presently
included
in
the
tolerance
expression.

Dietary
Exposure
and
Risk
Estimates
Refined
probabilistic
acute,
chronic,
and
cancer
dietary
risk
assessments
were
conducted
using
DEEM­
FCID
 
(
Version
1.30)
and
the
Lifeline
 
Model
(
Version
2.0)
which
uses
food
consumption
data
from
the
United
States
Department
of
Agriculture's
(
USDA's).
Continuing
Surveys
of
Food
Intakes
by
Individuals
(
CSFII)
from
1994­
1996
and
1998.
Chronic
and
acute
exposure
estimates
were
based
on
data
from
dermal
metabolism
studies
provided
by
the
registrant
and
percent
crop
treated
provided
by
BEAD.
Conservative
assumptions
were
made
in
the
calculation
of
anticipated
residues
used
in
the
dietary
assessment.

Acute
dietary
risks,
using
Lifeline
 
Model,
are
above
HED's
level
of
concern
for
children
1­
2
yrs
(
186%
of
aPAD,
0.000465
mg/
kg/
day)
and
children
3­
5
years
old
(
170%
of
aPAD,
0.000425
mg/
kg/
day)
at
the
99.9th
percentile
of
exposure.

Acute
dietary
risks,
using
DEEM­
FCID
 
,
are
above
HED's
level
of
concern
for
children
1­
2
yrs
(
140%
of
aPAD,
0.000349
mg/
kg/
day)
at
the
99.9th
percentile
of
exposure.

As
noted
in
this
risk
assessment,
DEEM
 
and
Lifeline
 
provided
different
predicted
exposure
at
the
99.9th
percentiles
for
the
1
to
2
and
3
to
5
year
old
subpopulations
(
both
exceeding
the
aPAD).
The
assessment
accounts
for
exposure
from
the
three
RACs:
beef,
pork
and
milk.
Milk
is
the
primary
RAC
that
drives
exposure
at
the
99.9th
percentile
due
to
the
relatively
high
residues.
Lifeline
had
relatively
higher
predictions
for
both
the
1
to
2
year
old
(
186%
vs
140%
aPAD),
and
3
to
5
year
old
subpopulations
(
170%
vs
94%
aPAD).
The
different
model
predictions
can
be
attributed
to
two
reasons:
(
1)
a
limitation
regarding
the
Lifeline
software,
and
(
2)
modeling
differences
between
DEEM
 
and
Lifeline
 
.
A
complete
explanation
of
how
these
factors
affect
the
model
predictions
will
be
presented
in
a
subsequent
memo.
The
apparent
limitation
in
Lifeline
 
software
is
the
result
of
several
concurrent
factors:
(
i)
milk
is
treated
as
a
food
comprised
of
three
RACS
(
water,
non­
fat
solids,
fat),
(
ii)
the
percent
crop
treated
is
relatively
low
(
0.1%),
and
(
iii)
the
Lifeline
 
Food
Residue
Translator
(
FRT)
approximates
food
(
milk)
residue
percentiles
based
on
a
fixed
number
of
simulations.
The
difference
in
modeling
design
(
frequency
of
using
food
diaries
and
weights
applied)
also
contribute
towards
the
Lifeline
 
model
providing
higher
exposure
estimates
than
DEEM
 
.
This
latter
effect
is
independent
of
the
first
effect,
however,
it
is
also
dependent
upon
the
percent
crop
treated
value
used
for
milk.
8
Given
the
relatively
high
anticipated
residues
for
milk
(
0.03
ppm),
a
moderate
amount
of
milk
consumption
may
provide
exposure
exceeding
the
aPAD.
For
example,
a
20
kg
toddler
(
typical
5
year
old),
consuming
8
ounces
of
milk
(
226
grams
=
8
x
28.3
grams/
oz),
or
equivalently,
11.3
grams/
kg
bwt/
day
(~
226/
20),
would
have
dietary
exposure
of
approximately
0.0003
mg
ai/
kg
bwt/
day
(=
0.03
ppm
x
11.3
gm/
kg
bwt/
day
x
(
1/
1000)),
or
135%
of
the
aPAD
(=
0.00025).
The
average
milk
consumption
for
1­
4
year
olds
is
approximately
337
gm/
day,
with
75%
of
toddlers
(
1to5
year
olds)
consuming
11
grams/
kg
bwt/
day
or
more
of
dairy
products.
Even
though
the
other
two
commodities
(
beef,
pork)
provide
relatively
low
exposure,
milk
continues
to
provide
exposure
at
the
99.9th
percentile
even
with
the
low
percent
crop
treated
due
to
the
application
of
residues
to
the
three
milk
components
(
water,
fat,
non­
fat
solids),
and
the
relatively
high
percent
of
toddlers
that
consume
milk.

Estimated
chronic
dietary
risk
is
below
HED's
level
of
concern
for
all
populations
(<
1%
of
cPAD).
Results
of
the
Lifeline
 
analysis
are
fully
consistent
with
DEEM­
FCID
 
results.
The
estimated
exposure
of
the
general
U.
S.
population
to
amitraz
is
<
0.000001
mg/
kg/
day
for
both
dietary
risk
assessment
models.
Applying
the
Q
1*
of
2.83
x
10­
2
(
mg/
kg/
day)­
1
to
the
exposure
value
results
in
a
cancer
risk
estimate
of
2.8
x
10­
8.
Therefore,
estimated
cancer
dietary
risk
is
below
HED's
level
of
concern.

Surface
and
Drinking
Water
Exposure
Assessment
SRRD
contacted
the
amitraz
registrant
and
received
the
following
information
regarding
the
use
of
amitraz
as
animal
dips/
sprays.
HED
is
awaiting
written
verification
of
this
information.
The
registrant
indicated
that
of
the
product
sold
in
the
US,
25­
30%
is
used
on
swine
operations
in
NC
and
the
Midwest.
They
also
said
that
it
is
almost
never
used
outdoors;
the
bulk
of
the
treatments
are
indoors
directly
to
the
animal
with
10­
20%
of
the
applied
spray
running
off
the
animal
to
inert
(
indoor)
surfaces.
EFED
modeled
amitraz
use
on
swine
based
on
communications
from
the
registrant
regarding
animal
dips/
sprays
and
assumed
that
30%
of
the
product
sold
in
the
US
was
used
in
such
a
manner
that
it
was
available
for
runoff
in
one
watershed
in
NC.
There
is
significant
uncertainty
in
this
assessment
approach
due
to
the
lack
of
concrete
data
on
use
within
a
watershed,
the
vulnerability
of
the
application
site
to
runoff,
the
lack
of
information
on
the
amount
of
product
applied
to
a
hog
that
would
be
available
for
washoff
with
the
first
rainfall
or
subsequent
events,
whether
the
material
available
for
washoff
would
be
amitraz
per
se
or
one
of
its
degradation
products
because
of
its
known
instability,
the
proximity
of
a
surface
water
source
to
the
site
of
application
that
would
be
within
reasonable
proximity
to
a
drinking
water
utility,
and
the
possibility
that
common
drinking
water
treatment
processes
may
affect
the
stability
of
any
remaining
parent
amitraz.

The
following
EECs
were
generated
for
use
in
risk
assessment:

Surface
water
EEC:
Typical
Estimate:
Peak
Concentration
=
0.1
ppb;
Annual
Average
Concentration
=
0.0006
ppb
Groundwater
EEC:
Typical
=
0.000009
ppb
9
Residential
Exposure
Homeowners
can
be
exposed
to
amitraz
via
pet
collars
used
on
dogs.
To
assess
these
potential
exposures,
toxicological
endpoints
were
selected
for
short­
and
intermediate­
term
dermal,
inhalation,
and
incidental
oral
exposures;
no
chronic
exposure
scenarios
are
thought
to
exist
for
amitraz.
In
addition,
amitraz
is
classified
as
a
Group
C
possible
human
carcinogen
and
it
has
a
Q
1*
of
2.83
x
10­
2.
The
target
MOE
for
residential
risk
estimates
is
1000.

HED
considers
this
residential
risk
assessment
to
be
based
on
high­
end
estimates
of
exposure
generated
from
screening­
level
procedures
outlined
in
the
SOPs
for
Residential
Exposure
Assessment
(
U.
S.
EPA,
1997,
1999).
As
such,
the
risk
estimates
associated
with
pet
collars
are
conservative,
largely
driven
by
default
assumptions
and
uncertainties
in
the
toxicity
database.

Although
HED
considers
the
residential
handler
scenario
as
having
some
potential
exposure,
the
most
significant
exposure
of
concern
is
for
post­
application
scenarios
as
these
exposures
are
of
longer
duration
and
may
be
significant
for
children.
Therefore
this
document
primarily
focuses
on
residential
post­
application
exposures
only,
and
does
not
address
residential
handlers.
As
such,
risks
were
estimated
for
post­
application
dermal
exposures
of
adults,
and
dermal
and
incidental
oral
exposures
of
children
for
non­
cancer
effects,
and
cancer
effects
from
dermal
exposures
of
adults,
only.

All
post­
application
scenarios
resulted
in
MOEs
which
exceed
HED's
level
of
concern.
Postapplication
dermal
exposure
estimates
for
toddlers
indicate
MOEs
of
22.
Incidental
oral
postapplication
exposure
to
toddlers
from
amitraz
(
via
hand
to
mouth),
from
such
activities
as
contacting
the
dog
has
an
MOE
of
65.
For
adults,
dermal
post­
application
exposure
estimates
for
amitraz
via
such
an
activity
of
the
hugging
the
dog
indicate
MOEs
of
35.
Post­
application
cancer
risk
estimates
for
adults
range
from
2.8
x
10
­
5
to
5.6
x
10
­
5,
and
exceed
HED's
level
of
concern.
The
8%
dermal
absorption
factor
may
be
considered
conservative
given
the
duration
of
the
study
(
5
days)
compared
to
the
likely
dermal
exposure
of
up
to
24
hours.

Aggregate
Risk
Estimates
Acute
aggregate
risk
estimates
will
not
be
conducted
since
the
dietary
acute
risk
exceed
HEDs
level
of
concern.
Short­
and
Intermediate­
Term
and
cancer
aggregate
risk
estimates
will
not
be
conducted
since
the
post
application
residential
exposure
scenarios
exceed
HED's
level
of
concern.

Chronic
aggregate
risk
estimates
associated
with
exposure
to
amitraz
residues
in
food
and
water
do
not
exceed
HED's
level
of
concern.
Estimates
of
exposure
from
food
were
taken
from
the
dietary
exposure
model
results
described
above
(
Section
4.2.3).
The
chronic
risk
estimates
are
below
the
Agency's
level
of
concern
for
the
general
U.
S.
population
and
all
population
subgroups.

For
considering
exposure
to
residues
of
amitraz
in
drinking
water,
HED
has
calculated
chronic
Drinking
Water
Levels
of
Comparison
(
DWLOCs).
These
values
are
the
maximum
concentration
of
a
chemical
that
can
occur
in
drinking
water
after
taking
into
account
exposures
to
residues
from
other
pathways
and
sources.
The
DWLOCs
are
compared
against
the
modeled
EECs
provided
by
10
the
EFED
(
see
Section
4.3).
DWLOC
values
that
are
greater
than
the
EECs
indicate
that
aggregate
exposures
are
unlikely
to
exceed
HED's
level
of
concern.
HED
calculated
DWLOCs
for
the
following
populations:
general
U.
S.
population
(
DWLOC
=
9
ppb);
females
(
DWLOC
=
8
ppb);
infants
and
children
(
DWLOC
=
2.5
ppb).
The
chronic
DWLOCs
for
the
general
U.
S.
population
and
all
of
the
representative
population
subgroups
modeled
by
LifelineJ
are
greater
than
both
the
surface
water
and
ground
water
chronic
EECs
(
Surface
water
EEC:
Typical
Estimate:
Annual
Average
Concentration
=
0.0006
ppb;
and
Groundwater
EEC:
Typical
=
0.000009
ppb).
Therefore,
chronic
aggregate
risk
estimates
associated
with
exposure
to
amitraz
residues
in
food
and
water
do
not
exceed
HED's
level
of
concern.

Incident
Reports
Animal
incident
reports
for
currently
registered
amitraz
products
from
1992
through
2003
were
reviewed.
In
general,
there
have
been
few
reports
of
amitraz
toxicity
in
recent
years.

The
most
notable
incidents
were
reports
of
dogs
pulling
a
tick
collar
off
another
dog
and
ingesting
the
collar.
This
has
resulted
in
serious
toxicity
including
bradycardia
and
depression,
resulting
in
emergency
veterinary
care.
Yohimbine
is
a
specific
antidote
for
amitraz
toxicity
in
dogs.

There
were
fewer
reports
for
toxicity
in
dogs
while
wearing
tick
collars,
including
weakness,
ataxia,
vomiting,
or
seizures.
These
reports
were
unverified.

There
were
3
reports
of
abortions
or
stillbirths
in
pigs
from
1992
­
1996.
These
reports
were
unverified.
There
were
several
reports
of
misuse
of
cattle/
pig
formulation
on
horses
or
dogs
resulting
in
death.

A
review
of
human
incident
data
is
pending
and
is
not
available
at
this
time.

Data
Gaps
Refer
to
Section
4.2
for
details
of
tolerance
reassessment.
Refer
to
Section
7.0
of
this
document
for
specific
data
gaps.
11
N
N
N
C
H
3
CH
3
C
H
3
CH
3
CH
3
2.0
Physical/
Chemical
Properties
Characterization
The
PC
Code
and
nomenclature
of
amitraz
are
listed
below
in
Table
1.
The
physicochemical
properties
of
amitraz
are
listed
in
Tables
2
and
3.
The
chemical
names
and
structures
of
amitraz
residues
of
concern
are
presented
in
Table
1.

Table
1.
Amitraz
Nomenclature
Chemical
structure
Common
name
Amitraz
Molecular
Formula
C19H23N3
Molecular
Weight
293.42
IUPAC
name
N­
methylbis(
2,4­
xylyliminomethyl)
amine
CAS
name
N'­(
2,4­
dimethylphenyl)­
N­[[(
2,4­
dimethylphenyl)
imino]
methyl]­
Nmethylmethanimidamide
CAS
#
33089­
61­
1
PC
Code
106201
Current
Food/
Feed
Site
Registration
Cotton,
pear,
beef
and
dairy
cattle,
hog,
goats,
horses,
sheep
Table
2.
Physicochemical
Properties
of
Amitraz.

Parameter
Value
Reference
Melting
point/
range
86­
87

C
Amitraz
RED,
03/
95
pH
of
1%
aqueous
suspension
N/
A
(
low
solubility;
decomposes
in
water)
Amitraz
RED,
03/
95
Density
or
specific
gravity
1.128
g/
mL
at
20

C
Amitraz
RED,
03/
95
Water
solubility
<
1
ppm
at
20­
25

C
Amitraz
RED,
03/
95
Solvent
solubility
At
20­
25

C
xylene
66.6
g/
100
mL
acetone
50.0
g/
100
mL
methanol
2.38
g/
100
mL
Amitraz
RED,
03/
95
Vapor
pressure
3.4
x
10­
4
mm
Hg
at
25

C
Amitraz
RED,
03/
95
Octanol/
water
partition
coefficient
(
Kow)
3.0
x
105
at
25

C
(
pH
5.8)
CBRS
No.
3975,
7/
21/
88,
H.
Fonouni.

Amitraz
is
soluble
in
xylene,
acetone,
and
methanol
and
insoluble
in
water.
It
has
a
low
to
moderate
vapor
pressure
and
exposure
to
the
gaseous
state
should
be
negligible.
12
N
N
N
C
H
3
CH
3
C
H
3
CH
3
CH
3
NH
O
H
C
H
3
CH
3
N
NH
C
H
3
CH
3
CH
3
Table
3.
Chemical
Names
and
Structures
of
Amitraz
and
its
Residues
of
Concern.

Company
Name
Chemical
Name
Structure
Amitraz
N'­[
2,4­
dimethylphenyl]­
N­[[(
2,4­
dimethylphenyl)
imino]
methyl]]­
Nmethyl
methanimidamide
BTS­
27919
N­(
2,4­
dimethylphenyl)
formamide
BTS­
27271
N­(
2,4­
dimethylphenyl)­
Nmethylmethanimidamide
3.0
Hazard
Characterization
3.1
Hazard
Profile
General
Toxicity
Profile
The
toxicology
database
for
Amitraz
is
incomplete.
There
are
several
major
data
gaps.
The
available
studies
are
not
of
the
most
current
quality;
however,
sufficient
data
may
be
gleaned
from
them
for
use
in
an
assessment
of
risk
to
human
health.
The
toxicity
profile
for
Amitraz
cannot
be
completely
characterized
for
all
effects,
especially
those
relating
to
developmental,
reproductive
and
neurotoxic
effects.

Acute
Toxicity:
Amitraz
has
a
low
acute
toxicity
in
a
wide
number
of
species.
The
Toxicity
Categories
reflect
low
toxicity
(
Categories
II­
IV;
the
II
was
due
to
the
fact
that
it
was
not
tested
at
sufficiently
high
doses
to
provide
for
a
higher
Category
than
II).
It
has
been
tested
in
mice,
rats,
guinea
pigs,
rabbits,
dogs,
baboons
and
domestic
pigs
by
the
oral,
dermal
and
inhalation
routes
of
exposure.
The
Registration
Standard
(
TXR
005633),
states
that
a
pharmacotoxic
profile
suggests
a
depression
of
hypothalmic
function.
Clinical
signs
of
toxicity
include
central
nervous
system
depression,
ataxia,
ptosis,
emesis,
labored
respiration,
muscular
weakness,
tremors,
hypothermia
and
bradycardia.
These
signs
varied
in
severity
depending
upon
the
species.
The
dog
appears
to
be
the
most
sensitive
species,
with
the
baboon
approximately
2.5
times
less
sensitive,
followed
by
13
the
rat
and
guinea
pig
(
5
times
less
sensitive).
The
mouse
appears
to
be
the
least
sensitive
(
15
times
less
sensitive).
Metabolism
studies
in
humans
indicate
clinical
signs
similar
to
those
observed
in
animals.
These
signs
were
reported
within
90
to
160
minutes
after
ingestion
and
included
sedation,
dry
mouth,
disorientation,
bradycardia,
hypertension
and
hypothermia
persisting
up
to
12
hours
after
dosing..

Table
4.
Acute
Toxicity
Data
on
AMITRAZ
Technical
Guideline
No./
Study
Type
MRID
No.
Results
Toxicity
Category
870.1100
Acute
oral
toxicity
00041539
LD
50:
531
mg/
kg
(
M)
515
mg/
kg
(
F)
III
870.1200
Acute
dermal
toxicity
00040862
LD
50:
>
200
mg/
kg
II
870.1300
Acute
inhalation
toxicity
00029963
LC
50:
2.4
mg/
L
III
870.2400
Acute
eye
irritation
00040861
Non­
irritating
IV
870.2500
Acute
dermal
irritation
00040862
Non­
irritating
IV
870.2600
Skin
sensitization
00029965
Not
a
sensitizer
under
conditions
of
study
N/
A
Target
Tissues
and
Species/
Sex
Sensitivity:
Clinical
signs
of
neurotoxicity
and
decreased
body
weights
appear
to
be
the
major
targets
for
amitraz.
A
comparison
of
the
subchronic
and
chronic
studies
indicates
that
there
does
not
appear
to
be
any
issues
of
cumulative
toxicity
(
i.
e.
no
increased
toxicity
with
a
longer
term
of
exposure).
The
dog
is
the
most
sensitive
species,
although
the
clinical
signs
appear
early
in
the
chronic
study
and
do
not
reappear.
Similar
clinical
signs
are
observed
when
amitraz
is
administered
via
all
three
routes
of
exposure:
oral,
dermal
and
inhalation.
There
does
not
appear
to
be
any
extra
sensitivity
in
any
one
sex.

Developmental/
Reproductive
Effects:
There
is
no
indication
of
developmental
toxicity
in
the
rat
in
either
of
two
available
studies
(
one
unacceptable
study
and
an
acceptable
repeat
study).
Two
studies
are
available
in
the
rabbit;
however,
neither
are
acceptable
due
to
deficiencies
in
either
the
study
designs
and/
or
the
studies
themselves.
In
the
first
rabbit
study,
at
a
dose
level
where
decreased
body
weight
gains
and
abortions
were
observed
in
the
does,
decreased
litter
size,
decreased
implantations,
increased
postimplantation
loss,
abortions
and
decreased
mean
fetal
body
weight
had
been
observed.
However,
the
study
needed
to
be
repeated
because
there
were
too
few
litters
available
for
analysis,
limited
data
available
in
the
report
and
an
unclear
method
of
dosing.
No
developmental
toxicity
was
observed
in
the
second
rabbit
study;
however
this
study
is
not
acceptable
due
to
too
few
available
litters
in
the
two
treated
groups
and
pre­
existing
maternal
respiratory
infections.
In
addition,
this
study
was
not
tested
at
as
high
a
dose
as
in
the
first
study.
In
the
repeat
study,
an
apparent
increase
in
early
resorptions
and
percent
postimplantation
loss
was
14
seen
at
the
highest
dose
tested;
however,
these
increases
were
due
to
the
fact
that
three
does
at
this
dose
totally
resorbed
their
litters
(
88%
of
the
early
resorptions
were
found
in
the
three
does
which
displayed
total
litter
resorptions).
It
might
be
possible
that
developmental
toxicity
could
be
observed
at
a
higher
dose
if
a
new
study
were
conducted.
In
summary,
there
is
no
evidence
(
quantitative
or
qualitative)
of
increased
susceptibility
following
pre­
natal
exposure
to
rats.
However,
evidence
for
susceptibility
following
pre­
natal
exposure
to
rabbits
could
not
be
ascertained
due
to
deficiencies
in
either
the
study
designs
and/
or
study
reports.

Two
reproduction
studies
are
available,
a
1­
generation
and
a
3­
generation
study.
In
the
1­
generation
reproduction
study,
at
the
same
LOAEL,
the
parents
exhibit
a
mean
decrease
in
body
weight
gain
whereas
the
pups
exhibit
a
lower
mean
litter
size
at
birth
and
on
lactation
day
4.
In
the
3­
generation
reproduction
study,
the
parents
exhibit
a
mean
decrease
in
body
weight
gain
during
the
F0
premating
period
at
the
LOAEL.
At
the
parental
NOAEL,
the
pups
exhibit
decreased
survival
and
mean
litter
size
during
lactation.
Unfortunately,
neither
study
is
unacceptable
for
regulatory
purposes.
In
the
1­
generation
study,
the
animals
are
not
tested
over
at
least
two
generations,
only
limited
information
were
provided
and
the
purity
of
the
test
compound
was
not
available.
In
the
3­
generation
reproduction
study,
again,
limited
data
were
provided,
mating
was
not
1
male
to
1
female,
no
data
on
reproductive
organs
were
provided,
litter
data
only
provided
for
a
few
time
points,
and
histopathology
data
were
not
provided.
In
summary,
evidence
for
susceptibility
following
pre
and/
or
postnatal
exposure
to
rats
could
not
be
ascertained
due
to
many
deficiencies
in
study
designs
and/
or
study
reports.

Neurotoxicity:
Multiple
species
display
evidence
of
neurotoxicity
following
exposure
to
Amitraz.
In
both
the
subchronic
and
chronic
oral
studies
in
dogs,
signs
of
CNS
depression
were
observed
and
a
decrease
in
pulse
rate
and
hypothermia
were
noted
in
the
subchronic
study.
In
both
the
subchronic
and
chronic
oral
studies
and
in
the
21­
day
inhalation
study
in
the
rat,
irritability,
nervousness
and/
or
excitability
were
observed.
In
the
rabbit
developmental
toxicity
study,
clinical
signs
that
were
considered
to
be
related
to
treatment
included
langor
and
polypnea.
Sedation
was
also
observed
in
rabbits
in
the
repeated
dose
dermal
study.

Carcinogenicity:
In
rats,
there
is
no
indication
of
potential
carcinogenicity
for
amitraz;
however,
in
female
mice
amitraz
induces
significant
dose­
related
positive
trends
in
hepatocellular
adenomas,
carcinomas
and
in
combined
adenomas/
carcinomas.
Females
also
had
a
significant
increase
in
the
pair­
wise
comparison
of
controls
and
the
highest
dose
group
in
hepatocellular
adenomas,
carcinomas
and
in
combined
adenomas
and/
or
carcinomas.
Male
mice
had
a
significant
doserelated
positive
trend
in
lung
adenomas.
In
addition,
males
had
a
significant
increase
in
the
pairwise
comparison
of
controls
and
the
highest
dose
group
in
lung
adenomas.
Amitraz
is
classified
as
a
Group
C,
possible
human
carcinogen.
The
Q
1*
has
been
calculated
to
be
2.83
x
10­
2
in
human
equivalents
using
the
3/
4'
s
scaling
factor,
reflecting
the
1994
Agency
policy.

Mutagenicity:
Amitraz
has
not
been
shown
to
induce
gene
mutations
in
either
bacterial
or
mammalian
cells,
is
not
clastogenic
in
an
in
vitro
study,
does
not
induce
unscheduled
DNA
synthesis
in
mammalian
cells,
and
does
not
induce
cell
transformations
in
C3H/
10T1/
2
cells
derived
from
mouse
embyro
fibroblasts
under
the
conditions
in
which
the
studies
were
conducted.
15
Metabolism:
Metabolism
studies
have
been
conducted
in
the
mouse,
rat,
cat,
dog,
baboon
and
man.
The
major
metabolites
of
amitraz
include
N­(
2,4­
dimethylphenyl)­
N­
methylformamidine;
2,4­
dimethylformanilide;
2,4­
dimethylaniline;
4­
amino­
3­
methylbenzoic
acid;
4­
formamido­
3­
methyl
benzoic
acid;
4­
acetamido­
3­
methyl
benzoic
acid;
and
N,
N­
bis­
2,4­
dimethylphenylformamidine.
2,4­
dimethylaniline
is
included
in
the
tolerance
expression
along
with
the
parent.

Toxicological
Significance
of
Effects:
The
clinical
signs
of
neurotoxicity
(
i.
e.
CNS
depression
or
irritability
depending
upon
species)
occur
across
species,
sexes
and
routes
of
administration.
These
clinical
signs
do
not
appear
to
be
cumulative
after
multiple
doses.
In
the
dog,
they
appear
to
be
transient.
Insufficient
data
are
available
as
to
whether
or
not
irreversible
effects
may
occur.
16
Table
5.
Toxicity
Profile
of
AMITRAZ
Technical
Guideline
No./
Study
Type
Results
870.3100
90­
Day
oral
toxicity
rats
NOAEL
=
3
mg/
kg/
day
LOAEL
=
12
mg/
kg/
day
based
on
irritability,
excitability
and
reduced
overall
body
weight
gain.
No
individual
animal
data
for
clinical
signs
and
gross
necropsy.

870.3150
90­
Day
oral
toxicity
in
dogs
NOAEL
=
0.25
mg/
kg/
day
LOAEL
=
1.0
mg/
kg/
day
based
on
CNS
depression,
decrease
in
pulse
rate,
increase
in
glucose
in
urine,
hypothermia,
neutrophilia
of
bone
marrow,
increased
liver
weights
and
increased
extent
of
liver
lesions.
Too
few
animals.

870.3200
21/
28­
Day
dermal
toxicity
rabbits
NOAEL
=
Cannot
be
determined
LOAEL
=
50
mg/
kg/
day
based
on
clinical
signs
(
sedation)
and
a
decrease
in
food
consumption
in
males.
Too
few
animals,
concurrent
infections,
lack
of
information
on
the
substance
tested
and
limited
histopathology.

870.3465
90­
Day
inhalation
toxicity
rats
NOAEL
=
0.01
mg/
L/
day
LOAEL
=
0.1
mg/
L/
day
(
nominal)
based
on
clinical
signs
of
toxicity
(
irritation
and
neurological
signs)
and
decreases
in
body
weight
and
body
weight
gain.
Limited
individual
animal
data;
analytical
exposure
concentrations
not
measured;
purity
of
test
material
not
reported
and
reporting
incomplete
in
terms
of
the
study
protocol
and
environmental
conditions.

870.3700a
Prenatal
developmental
in
rats
Maternal
NOAEL
=
3
mg/
kg/
day
LOAEL
=
12
mg/
kg/
day
based
on
decreases
in
body
weight
gain.
Developmental
NOAEL
=
12
mg/
kg/
day
LOAEL
=
>
12
mg/
kg/
day
[
HDT].
Very
limited
data,
dosage
period
was
from
gestation
days
8­
20.

870.3700a
Prenatal
developmental
in
rats
Maternal
NOAEL
=
7.5
mg/
kg/
day
LOAEL
=
15.0
mg/
kg/
day
based
on
decreases
in
body
weight
and
body
weight
gain.
Developmental
NOAEL
=
30
mg/
kg/
day
LOAEL
=
>
30
mg/
kg/
day
[
HDT].
Guideline
No./
Study
Type
Results
17
870.3700b
Prenatal
developmental
in
rabbits
Maternal
NOAEL
=
5
mg/
kg/
day
LOAEL
=
25
mg/
kg/
day
based
on
decrease
in
body
weight
gain
and
abortions
Developmental
NOAEL
=
5
mg/
kg/
day
LOAEL
=
25
mg/
kg/
day
based
on
decreased
litter
size,
decreased
implantations,
increased
postimplantation
loss,
abortions
and
decreased
mean
fetal
body
weight.
Too
few
litters,
limited
data,
unclear
method
of
dosing.

870.3700b
Prenatal
developmental
in
rabbits
Maternal
NOAEL
=
not
established
LOAEL
=
3.0
mg/
kg/
day
based
on
clinical
signs.
Developmental
NOAEL
=
12
mg/
kg/
day
LOAEL
=
>
12
mg/
kg/
day
(
HDT).
Too
few
litters
in
two
treated
groups
and
pre­
existing
maternal
respiratory
infections.

870.3800
Reproduction
and
fertility
effects
(
1­
generation)
rats
Parental/
Systemic
NOAEL
=
3
mg/
kg/
day
LOAEL
=
12
mg/
kg/
day
based
on
decreased
body
weight
gain.
Reproductive
NOAEL
=
12
mg/
kg/
day
LOAEL
>
12
mg/
kg/
day
(
HDT).
Offspring
NOAEL
=
3
mg/
kg/
day
LOAEL
=
12
mg/
kg/
day
based
on
lower
mean
litter
size
at
birth
and
on
lactation
day
4.

870.3800
Reproduction
and
fertility
effects
(
3­
generations)
rats
Parental/
Systemic
NOAEL
=
4.36/
5.09
(
M/
F)
mg/
kg/
day
LOAEL
=
16.41/
20.05
(
M/
F)
mg/
kg/
day
based
on
decreased
body
weight
gain
during
the
F0
premating
period..
Reproductive
NOAEL
=
16.41/
20.05
(
M/
F)
mg/
kg/
day
LOAEL
>
16.41/
20.05
(
M/
F)
mg/
kg/
day
(
HDT).
Offspring
NOAEL
=
1.29/
1.58
(
M/
F)
mg/
kg/
day
LOAEL
=
4.36/
5.09
(
M/
F)
mg/
kg/
day
based
on
decreased
survival
and
mean
litter
size
during
lactation.
Limited
data
provided,
mating
was
not
1
male
to
1
female,
no
data
on
reproductive
organs
provided,
litter
data
only
provided
for
a
few
time
points,
and
histopathology
data
not
provided.

870.4100b
Chronic
toxicity
dogs
NOAEL
=
0.25
mg/
kg/
day
LOAEL
=
1.0
mg/
kg/
day
based
on
CNS
depression
during
first
two
days
of
dosing.
Guideline
No./
Study
Type
Results
18
870.4300
Chronic
Toxicity/
Carcinogenicity
rats
NOAEL
=
2.5/
0.97
(
M/
F)
mg/
kg/
day
LOAEL
=
10.18/
3.13
(
M/
F)
mg/
kg/
day
based
on
clinical
signs
(
M
and
F)
and
decreased
body
weight
gain
(
M).
No
evidence
of
carcinogenicity.

870.4300
Carcinogenicity
mice
NOAEL
=
<
2.31/
2.63
(
M/
F)
mg/
kg/
day
LOAEL
=
2.31/
2.63
(
M/
F)
mg/
kg/
day
based
on
dose­
related
incidence
of
hyperplastic
nodules,
liver
foci,
stomach
hyperkeratosis
and
spleen
hematopoiesis.
Evidence
of
carcinogenicity:
hepatocellular
adenomas,
carcinomas
and
combined;
and
lung
adenomas,
probably
at
dose
levels
above
MTD.

Reverse
Gene
Mutation
in
Salmonella
typhimurium
870.5100
Negative
up
to
10
mg/
plate,
with
and
without
metabolic
activation.

Forward
Gene
Mutation
in
mouse
lymphoma
cells
870.5300
Negative
at
0.06­
20
g/
ml
with
and
without
metabolic
activation.
HDT
is
highest
non­
cytotoxic
dose.

In
Vitro
Cytogenetics
(
Human
Lymphocytes)
870.5375
Negative
up
to
cytotoxic
and/
or
insoluble
concentrations.

UDS
Assay
(
Human
Embryonic
Lung
Fibroblast)
870.5550
Negative
up
to
cytotoxic
concentrations,
with
and
without
metabolic
activation.

Cell
Transformation
(
no
guideline
#)
Negative
up
to
cytotoxic
concentrations,
with
and
without
metabolic
activation.

870.7485
Metabolism
and
pharmacokinetics
rats
No
sex
differences
in
proportion
of
various
metabolites
recovered
in
24­
hour
urine
samples.
Metabolic
process
saturated
at
the
100
mg/
kg
level.
No
unchanged
parent
material
found
in
the
urine.
Major
metabolites:
N­(
2,4­
dimethylphenyl)­
N­
methyl
formamidine,
4­
formamido­
3­
methyl
benzoic
acid,
4­
acetamido­
3­
methyl
benzoic
acid
and
a
polar
fraction.
The
polar
fraction
was
labile
to
acid
hydrolysis,
yielding
conjugates
of
4­
amino­
3­
methylbenzoic
acid,
N­
(
2,4­
dimethylphenyl)­
N­
methyl
formamidine,
4­
formamido­
3­
methyl
benzoic
acid
and
4­
acetamido­
3­
methyl
benzoic
acid.
Guideline
No./
Study
Type
Results
19
870.7485
Metabolism
and
pharmacokinetics
rats
Peak
levels
of
amitraz
reached
in
urine
within
8
hours:
78%
of
the
dose
in
the
urine
and
9%
in
the
feces
by
98
hours.
Peak
levels
of
metabolite
BTS
27271
reached
in
urine
within
24
hours:
89%
of
the
dose
in
the
urine
and
4%
in
the
feces
by
96
hours.
Highest
residues
of
amitraz
and
BTS
27271
reported
in
the
liver.
Blood
residue
levels
were
17.9
ppb
for
amitraz
and
not
detectable
for
BTS
27271.
Kidney
residue
levels
were
comparable
with
18.0
and
24
ppb
for
amitraz
and
BTS
27271,
respectively.
Degradation
products
of
amitraz
and
its
metabolite,
BTS
27271
were
similar.

870.7600
Dermal
penetration
rats
The
mean
percent
of
dose
absorbed:
treatment
site
(
2.98%
at
24
hours,
1.41%
at
120
hours);
total
absorbed
(
3.69%
at
24
hours,
6.56%
at
120
hours);
total
(
6.67%
at
24
hours,
7.79%
at
120
hours).

3.2
FQPA
Considerations
There
is
no
evidence
(
quantitative
or
qualitative)
of
increased
susceptibility
following
pre­
natal
exposure
to
rats.
However,
evidence
for
susceptibility
following
pre­
natal
exposure
to
rabbits
(
devlopmental)
or
following
pre
and/
or
postnatal
exposure
to
rats
(
2­
generation
reproduction)
could
not
be
ascertained
due
to
many
deficiencies
in
study
designs
and/
or
study
reports.
There
is
a
concern
for
neurotoxicity
resulting
from
exposure
to
Amitraz.
No
neurotoxicity
studies
have
been
conducted.
Evidence
of
neurotoxicity
following
exposure
to
Amitraz
is
indicated
in
multiple
studies
across
species
and
across
routes
of
administration,
which
include
signs
of
CNS
depression
in
the
dog;
irritability,
nervousness
and/
or
excitability
in
the
rat
and
langor
and
polypnea
in
the
rabbit.

The
toxicological
database
for
Amitraz
is
inadequate
for
assessment
of
risk
to
infants
and
children.
Significant
data
gaps
exist,
which
include
an
acceptable
developmental
rabbit
study
and
a
multigeneration
reproduction
study.
There
is
also
concern
for
neurotoxicity
and
developmental
neurotoxicity.
No
studies
are
available
which
access
potential
neurotoxicity.

There
are
no
concerns
for
residual
uncertainty
for
pre­
natal
toxicity
in
the
available
developmental
toxicity
study
in
rats.

Despite
the
lack
of
acceptable
rabbit
developmental
and
rat
reproduction
studies,
the
HIARC
determined
that
there
are
no
residual
uncertainties
for
pre­
and/
or
post­
natal
toxicity
based
on
the
following
considerations:
20
°
Although
susceptibility
could
not
be
ascertained
in
rabbits,
the
results
of
the
two
unacceptable
studies
show
that
developmental
effects
occurred
at
doses
higher
than
the
doses
that
caused
maternal
toxicity.

°
A
10X
database
uncertainty
factor
(
UF
DB)
is
required
due
to
an
incomplete
database
(
i.
e.
lack
of
acceptable
rabbit
developmental
toxicity
and
two­
generation
reproduction
studies).

°
At
present,
the
endpoint
of
concern
(
neurotoxicity)
for
the
overall
risk
assessment
is
based
on
the
"
apparent"
sensitive
species
(
dogs).

°
The
dose
(
0.25
mg/
kg/
day)
selected
for
the
overall
risk
assessments
is
approximately
20­
fold
lower
than
the
lowest
developmental
NOAEL
in
the
unacceptable
rabbit
studies
and
5­
fold
lower
than
the
offspring
NOAEL
in
the
unacceptable
three­
generation
reproduction
study.

Based
on
the
above
data,
no
special
FQPA
safety
factor
(
i.
e.
1X)
is
required
since
there
are
no
residual
uncertainties
for
pre­
natal
toxicity
as
discussed
above.
In
addition,
the
drinking
water,
and
residential
exposure
assessments
were
conducted
using
screening­
level
models
and
procedures,
assumptions
and
default
values
that
result
in
high­
end
estimates
that
do
not
underestimate
risk.
Amitraz
metabolites
were
included
in
the
dietary
assessment.
Even
though
the
dietary
assessment
used
percent­
crop­
treated
data
and
anticipated
residues
(
ARs)
these
values
represent
high­
end
residues
from
feeding
studies
and
do
not
underestimate
dietary
exposure
and
risk..

The
HIARC
concluded
that
there
is
concern
for
developmental
neurotoxicity
resulting
from
exposure
to
Amitraz
based
on
the
indications
of
clinical
signs
of
neurotoxicity
across
species,
sexes
and
routes
of
administration.
Based
on
the
weight
of
evidence
presented,
the
HIARC
is
requiring
a
combined
2­
generation
reproduction
study
in
the
rat
with
components
assessing
for
potential
developmental
and
adult
neurotoxicity.
The
HIARC
recommended
that
the
study
design
for
the
required
two­
generation
reproduction
study
should
be
MODIFIED
to
include
the
following:

°
Due
to
the
concern
for
the
lack
of
stability
of
the
test
material
in
the
diet,
treatment
should
be
via
oral
(
gavage)
administration.

°
The
potential
for
neurotoxicity
in
the
developing
fetuses
should
be
evaluated
according
to
the
OPPTS
Guideline
§
870.6300.

°
The
potential
for
neurotoxicity
in
adults
should
be
evaluated
according
to
the
OPPTS
Guideline
§
870.6200.

The
HIARC
determined
that
the
10X
UF
DB
should
be
applied
to
dietary
(
acute
and
chronic)
and
non­
dietary
(
incidental
oral,
dermal
and
inhalation)
risk
assessments
because
the
required
studies
may
provide
endpoints
applicable
for
risk
assessments.

3.3
Dose­
Response
Assessment
21
Discussion
of
Toxicological
Database
for
Risk
Assessment
Purposes:
The
toxicology
database
for
Amitraz
is
incomplete.
There
are
major
data
gaps,
especially
in
the
studies
important
for
a
complete
assessment
under
FQPA.
The
toxicity
profile
for
Amitraz
cannot
be
completely
characterized
for
all
effects,
especially
those
relating
to
developmental,
reproductive
and
neurotoxic
effects.

All
of
the
toxicological
endpoints
for
risk
assessment
are
based
on
the
chronic
dog
study.
This
study
had
a
NOAEL
of
0.25
mg/
kg/
day
based
on
clinical
signs
of
neurotoxicity
(
CNS
depression)
during
the
first
two
days
of
dosing
at
the
LOAEL
of
1.0
mg/
kg/
day.
These
clinical
signs
were
observed
three
hours
after
administration
of
a
single
dose.
This
toxicological
endpoint
is
supported
by
similar
clinical
signs
observed
in
humans
following
an
acute
exposure
(
TXR
No.
011110).

Acute
Dietary
Exposure:
The
endpoint
from
the
dog
study
is
considered
to
be
appropriate
for
acute
dietary
exposure
for
the
general
population,
including
infants
and
children
because
it
is
based
on
clinical
signs
of
neurotoxicity
(
CNS
depression)
which
were
observed
three
hours
after
administration
of
a
single
dose.

Chronic
Dietary
Exposure:
Although
effects
were
observed
early
on
in
the
dog
study
and
were
not
observed
later
in
the
study,
this
study
is
appropriate
for
a
chronic
dietary
endpoint
because
the
dogs
were
exposed
to
the
test
material
for
2
years.
Additionally,
the
dose
(
0.25
mg/
kg/
day)
would
address
the
concerns
for
systemic
effects
seen
in
mice
(
liver,
spleen
and
stomach
lesions)
and
rats
(
clinical
signs
and
decrease
in
body
weight
gain),
following
long
term
oral
administration
at
higher
doses.

Incidental
Oral
Exposure:
All
Durations
(
1
­
30
days
and
1­
6
Months):
The
endpoint
from
the
chronic
dog
study
is
considered
to
be
appropriate
for
the
population
of
concern
(
infants
and
children).
This
dose/
endpoint
is
appropriate
for
both
short­
and
intermediate­
term
exposure
because
the
effects
were
observed
early
in
the
study
(
i.
e.
first
two
days
of
dosing),
dogs
are
the
most
sensitive
species
and
it
would
address
the
concern
for
effects
seen
via
the
oral
route
in
other
species.

Dermal
Exposure:
All
Durations
(
1
­
30
days,
1­
6
Months
and
>
6
Months):
The
HIARC
noted
that
a
21­
day
dermal
toxicity
study
in
rabbits
is
available
and
shows
CNS
depression
at
the
lowest
dose
tested,
50
mg/
kg/
day;
a
NOAEL
was
not
established.
The
Committee
determined
that
this
study
is
not
suitable
for
use
in
risk
assessment
due
to
many
deficiencies
with
the
conduct
of
the
study.
The
deficiencies
noted
were
testing
of
too
few
animals
(
4/
sex/
dose),
concurrent
infections,
lack
of
test
article
characterization
and
limited
histopathological
evaluation
of
the
required
tissues.
Therefore,
an
oral
NOAEL
from
the
chronic
dog
study
was
selected
for
dermal
risk
assessments.
Although
the
endpoint
of
concern
(
CNS
depression)
was
seen
after
a
few
exposures,
it
is
appropriate
for
all
time
periods
(
i.
e.,
short­,
intermediate­
and
long­
term)
since
the
effects
were
seen
in
the
most
sensitive
species
(
dogs)
and
the
selected
dose
(
0.25
mg/
kg/
day)
would
address
the
concerns
of
systemic
toxicity
seen
in
mice
and
rats
following
oral
administration.
Additionally,
the
use
of
an
8%
dermal
absorption
value
with
the
0.25
mg/
kg/
day
oral
dose
yields
a
dermal
equivalent
22
dose
of
3.1
mg/
kg/
day
(
0.25
÷
0.08)
which
is
comparable
to
an
extrapolated
NOAEL
of
5.0
mg/
kg/
day
(
50.0
÷
10
UF
for
use
of
a
LOAEL)
from
the
21­
day
dermal
toxicity
study.

Inhalation
Exposure:
All
Durations
(
1
­
30
days,
1­
6
Months
and
>
6
Months):
The
HIARC
noted
that
a
21­
day
inhalation
toxicity
study
in
rats
is
available
with
a
NOAEL
of
0.42
mg/
kg/
day
and
a
LOAEL
of
4.2
mg/
kg/
day.
These
values
are
based
on
the
conversion
of
nominal
values
and
therefore,
are
considered
to
be
gross
estimates
of
the
actual
values.
The
Committee
determined
that
this
study
is
not
suitable
for
risk
assessments
due
to
many
deficiencies
with
the
conduct
of
the
study.
There
were
limited
individual
animal
data,
analytical
exposure
concentrations
were
not
measured
and
the
study
reports
were
incomplete
in
terms
of
study
protocol
and
environmental
conditions.
Therefore,
an
oral
NOAEL
from
the
chronic
dog
study
was
selected
for
inhalation
risk
assessments.
Although
the
endpoint
of
concern
(
CNS
depression)
was
seen
after
a
few
exposures,
it
is
appropriate
for
all
time
periods
(
i.
e.,
short­,
intermediate­
and
long­
term)
since
the
effects
were
seen
in
the
most
sensitive
species
(
dogs)
and
the
selected
dose
(
0.25
mg/
kg/
day)
would
address
the
concerns
of
systemic
toxicity
seen
in
mice
and
rats
following
oral
administration.

Carcinogenicity:
As
stated
previously,
amitraz
has
been
classified
as
a
Group
C,
possible
human
carcinogen
based
on
an
increased
incidence
of
hepatocellular
adenomas,
carcinomas
and
combined
adenomas/
carcinomas
in
female
mice.
Male
mice
had
a
significant
dose­
related
positive
trend
in
lung
adenomas.
In
addition,
males
had
a
significant
increase
in
the
pair­
wise
comparison
of
controls
and
the
highest
dose
group
in
lung
adenomas.
The
Q
1*
has
been
calculated
to
be
2.83
x
10­
2
in
human
equivalents
using
the
3/
4'
s
scaling
factor,
reflecting
the
1994
Agency
policy.

Toxicology
Endpoint
Selection
Table
Summary
of
Toxicological
Dose
and
Endpoints
for
Amitraz
Exposure
Scenario
Dose
Used
in
Risk
Assessment,
UF
Special
FQPA
SF*
and
Level
of
Concern
for
Risk
Assessment
Study
and
Toxicological
Effects
Acute
Dietary
(
General
population
including
infants
and
children)
NOAEL
=
0.25
mg/
kg/
day
UF
=
1000
Acute
RfD
=
0.00025
mg/
kg/
day
FQPA
SF
=
1
aPAD
=
acute
RfD
FQPA
SF
=
0.00025
mg/
kg/
day
Chronic
oral
study
in
the
dog
(
capsule)
LOAEL
=
1.0
mg/
kg/
day
based
on
CNS
depression
during
the
first
two
days
of
dosing.

Chronic
Dietary
(
All
populations)
NOAEL=
0.25
mg/
kg/
day
UF
=
1000
Chronic
RfD
=
0.00025
mg/
kg/
day
FQPA
SF
=
1
cPAD
=
chronic
RfD
FQPA
SF
=
0.00025
mg/
kg/
day
Chronic
oral
study
in
the
dog
(
capsule)
LOAEL
=
1.0
mg/
kg/
day
based
on
CNS
depression
during
the
first
two
days
of
dosing.
Exposure
Scenario
Dose
Used
in
Risk
Assessment,
UF
Special
FQPA
SF*
and
Level
of
Concern
for
Risk
Assessment
Study
and
Toxicological
Effects
23
Short­
and
Intermediate
­
Term
Incidental
Oral
(
1­
30
days
and
1­
6
months)
NOAEL=
0.25
mg/
kg/
day
Residential
LOC
for
MOE
=
1000
Occupational
=
NA
Chronic
oral
study
in
the
dog
(
capsule)
LOAEL
=
1.0
mg/
kg/
day
based
on
CNS
depression
during
the
first
two
days
of
dosing.

Dermal
(
All
Durations)
Oral
NOAEL=
0.25
mg/
kg/
day
(
dermal
absorption
rate
8%)
Residential
LOC
for
MOE
=
1000
Occupational
LOC
for
MOE
=
100
Chronic
oral
study
in
the
dog
(
capsule)
LOAEL
=
1.0
mg/
kg/
day
based
on
CNS
depression
during
the
first
two
days
of
dosing.

Inhalation
(
All
Durations)
Oral
NOAEL=
0.25
mg/
kg/
day
(
inhalation
absorption
rate
=
100%)
Residential
LOC
for
MOE
=
1000
Occupational
LOC
for
MOE
=
100
Chronic
oral
study
in
the
dog
(
capsule)
LOAEL
=
1.0
mg/
kg/
day
based
on
CNS
depression
during
the
first
two
days
of
dosing.

Cancer
(
oral,
dermal,
inhalation)
Q1*
=
2.83
x
10­
2
Group:
C
Combined
hepatocellular
adenomas
and
carcinomas
in
female
mice.

UF
=
uncertainty
factor,
FQPA
SF
=
Special
FQPA
safety
factor,
NOAEL
=
no
observed
adverse
effect
level,
LOAEL
=
lowest
observed
adverse
effect
level,
PAD
=
population
adjusted
dose
(
a
=
acute,
c
=
chronic)
RfD
=
reference
dose,
MOE
=
margin
of
exposure,
LOC
=
level
of
concern,
NA
=
Not
Applicable
3.4
Endocrine
Disruption
EPA
is
required
under
the
Federal
Food
Drug
and
Cosmetic
Act
(
FFDCA),
as
amended
by
FQPA,
to
develop
a
screening
program
to
determine
whether
certain
substances
(
including
all
pesticide
active
and
other
ingredients)
"
may
have
an
effect
in
humans
that
is
similar
to
an
effect
produced
by
a
naturally
occurring
estrogen,
or
other
such
endocrine
effects
as
the
Administrator
may
designate."
Following
the
recommendations
of
its
Endocrine
Disruptor
Screening
and
Testing
Advisory
Committee
(
EDSTAC),
EPA
determined
that
there
were
scientific
bases
for
including,
as
part
of
the
program,
the
androgen
and
thyroid
hormone
systems,
in
addition
to
the
estrogen
hormone
system.
EPA
also
adopted
EDSTAC's
recommendation
that
the
Program
include
evaluations
of
potential
effects
in
wildlife.
For
pesticide
chemicals,
EPA
will
use
FIFRA
and,
to
the
extent
that
effects
in
wildlife
may
help
determine
whether
a
substance
may
have
an
effect
in
humans,
FFDCA
authority
to
require
the
wildlife
evaluations.
As
the
science
develops
and
24
resources
allow,
screening
of
additional
hormone
systems
may
be
added
to
the
Endocrine
Disruptor
Screening
Program
(
EDSP).

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

4.0
Exposure
Assessment
and
Characterization
4.1
Summary
of
Registered
Uses
Amitraz
[
N'­(
2,4­
dimethylphenyl)­
N­[[(
2,4­
dimethylphenyl)
imino]
methyl]­
Nmethylmethanimidamide
is
an
insecticide/
acaricide
with
registered
food/
feed
uses
in
the
U.
S.
on
cotton,
pears,
beef
and
dairy
cattle,
and
hogs.
Amitraz
is
currently
registered
for
use
on
cotton
to
control
various
insects
(
bollworm
larvae
and
eggs,
beet
armyworm,
whitefly,
aphids,
and
spider
mites)
as
well
as
on
pears
for
the
control
of
pear
psylla
and
grape
mealybug.
Amitraz
can
be
applied
by
airblast
and
concentrate
spray
(
pears)
with
up
to
3.0
lb
a.
i./
acre
applied
during
dormancy
and
throughout
the
growing
season
excluding
prebloom
applications.
It
can
also
be
applied
via
ground
boom
or
aircraft
(
cotton)
with
up
to
1.0
lb
a.
i./
acre
during
the
growing
season
with
a
maximum
of
eight
applications
per
year.
Current
formulations
include:
wettable
powder,
emulsifiable
concentrate,
and
soluble
concentrate/
liquid.
In
addition,
an
import
tolerance
has
been
established
to
support
amitraz
use
on
hops
to
be
imported
into
the
U.
S.
Amitraz
products
with
food/
feed
uses
are
registered
in
the
U.
S.
to
Bayer
CropScience
(
BCS)
LP
and
Intervet,
Inc.
under
the
trade
names
Ovasyn
®
,
Mitac
®
,
and
Taktic
®
.
Currently,
the
1.5
lb/
gal
soluble
concentrate
(
SC),
50%
wettable
powder
(
WP),
and
12.5%
emulsifiable
concentrate
(
EC)
formulations
are
registered
for
use
on
food/
feed
sites.
The
SC
formulation
is
registered
for
use
on
cotton,
and
the
WP
formulation
is
registered
for
use
on
pears.
The
EC
formulation
is
registered
for
use
on
cattle
and
swine
as
dermal
treatments.

Amitraz
is
also
used
for
tick
control
on
dogs
as
well
as
mite
and
lice
management
on
beef
cattle,
dairy
cattle
and
swine.
In
the
case
of
tick
and
flea
collars
(
Preventic
®
and
Preventic
®
Plus),
application
should
be
made
every
three
months
in
dogs
more
than
12
weeks
of
age.
Additionally,
amitraz
can
be
applied
via
dip
or
low
pressure
hand
spray
for
cattle
and
swine
with
up
to
0.2
lb
a.
i./
50
gallons
of
water.
For
the
use
of
Taktic
E.
C.
on
beef
cattle,
dairy
cattle
and
swine,
the
following
application
methods
are
suggestedl:
1)
cattle
applied
via
spraying
or
by
a
spray
dip
machine,
2)
swine
applied
via
spraying,
and
3)
piglets/
weaners
applied
by
dipping.
However,
Taktic
E.
C.
is
not
to
be
applied
within
three
days
of
slaughter
for
swine,
which
are
not
to
be
treated
more
than
four
times
per
year.
All
of
the
established
tolerances
for
meats,
meat
byproducts
and
milk
will
be
maintained
to
support
the
animal
health
uses.

In
a
recent
letter
to
the
Agency,
BCS
has
decided
to
voluntarily
withdraw
the
registrations
of
Ovaysn
Insecticide/
Miticide
(
EPA
Reg.
No.
264­
625)
and
Mitac
W
Insecticide
(
EPA
Reg.
No.
264­
636).
The
registrant
has
also
requested
to
maintain
the
registration
of
technical
amitraz,
to
revoke
established
tolerances
for
apples,
beeswax,
cotton,
honey,
and
pears
as
well
as
maintain
import
tolerances
for
hops
and
cottonseed
(
Amitraz
Use
Closure
Memo,
10/
22/
03).
25
4.2
Dietary
Exposure/
Risk
Pathway
4.2.1
Residue
Profile
Tolerances
for
residues
of
amitraz
in/
on
plant
and
animal
commodities
are
expressed
in
terms
of
the
combined
residues
of
"
amitraz
(
N'­[
2,4­
dimethylphenyl]­
N­[[(
2,4­
dimethylphenyl)
imino]
methyl]]­
N­
methylmethanimidamide)
and
its
metabolites
N­(
2,4­
dimethylphenyl)­
N­
methyl
formamide
and
N­(
2,4­
dimethylphenyl)­
N­
methylmethanimidamide,"
both
calculated
as
the
parent
compound
[
40
CFR
§
180.287].

Tolerances
have
been
established
under
40
CFR
§
180.287
for
the
combined
residues
of
amitraz
and
its
two
metabolites,
N­(
2,4­
dimethylphenyl)
formamide
and
N­(
2,4­
dimethylphenyl)­
Nmethylmethanimidamide
both
calculated
as
the
parent
compound
in/
on
cotton,
undelinted
seed,
at
1
ppm,
honey
at
1
ppm,
honeycomb
at
6
ppm,
dried
hop
cones
at
60
ppm,
and
pear
at
3
ppm,
and
in
animal
commodities
at
levels
ranging
from
0.01
to
0.3
ppm.

The
HED
Chem
SAC
(
3/
31/
04
meeting)
has
recommended
that
the
current
tolerance
expression
for
amitraz
needs
to
be
changed
by
removing
the
reference
to
specific
metabolites.
The
tolerance
expression
should
specify
that
the
terminal
residues
of
concern
for
enforcement
purposes
are
amitraz
and
its
metabolites
containing
the
2,4­
dimethylaniline
moiety.

A
summary
of
the
amitraz
tolerance
reassessments
and
recommended
modifications
in
commodity
definitions
is
presented
in
Table
6.

Nature
of
the
Residue
­
Plants
and
Livestock
The
qualitative
nature
of
the
residue
in
plants
and
animals
is
adequately
understood
based
on
plant
metabolism
studies
with
apples,
beans,
lemons,
citrus,
cotton,
and
pears,
and
animal
metabolism
studies
with
cattle
and
swine
(
dermal
application)
and
cattle,
goats
and
hens
(
oral
dosing).

Residue
analytical
methods
­
Plants
and
Animals
Adequate
tolerance
enforcement
methods
are
listed
in
PAM
Volume
II
for
the
determination
of
amitraz
residues
of
concern
in
plant
and
animal
commodities.

Enforcement
methods:
There
are
two
adequate
methods
listed
in
FDA's
Pesticide
Analytical
Manual
(
PAM
Vol.
II)
for
purposes
of
data
collection
and
enforcement
of
tolerances
for
residues
of
amitraz
and
its
metabolites
containing
the
2,4­
dimethylaniline
moiety.
Methods
I
(
designed
for
animal
tissues
and
milk)
and
II
(
designed
for
plant
commodities)
are
both
GLC
methods
with
electron
capture
detection
(
ECD),
and
involve
conversion
of
residues
of
amitraz
and
its
metabolites
containing
the
2,4­
dimethylaniline
moiety
to
2,4­
DMA
using
acid
and
base
hydrolysis,
respectively.
The
detection
limits
of
the
methods
are
0.01
ppm
for
milk
and
0.05
ppm
for
plant
commodities
and
animal
tissues.
26
The
enforcement
methods
have
not
been
radiovalidated;
however,
the
data
collection
method
for
plant
commodities
(
similar
to
Method
II)
was
successfully
radiovalidated
using
samples
from
the
pear
metabolism
study.
Because
the
extraction
procedure
is
extensive
(
hydrolysis
with
acid
at
reflux),
the
Agency
will
not
require
radiovalidation
data
for
the
enforcement
method
for
animal
commodities.

Data
collection
methods:
A
GC/
ECD
method
was
used
for
the
determination
of
amitraz
residues
of
concern
in
hops.
This
method
differs
from
the
enforcement
method
for
plant
commodities
in
that
residues
are
extracted/
hydrolyzed
using
acid
and
then
basified
to
convert
to
2,4­
dimethylaniline;
2,4­
dimethylaniline
residues
are
then
distilled
into
hexane.
In
Method
II
of
PAM
Vol.
II,
base
hydrolysis
is
used
to
extract
residues
and
convert
them
to
2,4­
dimethylaniline;
these
residues
are
then
partitioned
into
isooctane.
HED
has
recommended
that
this
method
be
forwarded
to
FDA
for
publication
in
PAM
Vol.
II
as
Method
A.

Amitraz
residues
of
concern
in
animal
commodities
were
determined
using
a
GC/
ECD
method
similar
to
the
method
used
for
hops.

Storage
Stability
Adequate
data
are
available
to
support
the
existing
crop
field
trial
and
feeding
studies.

Storage
stability
studies
have
been
conducted
using
fortified
samples
of
citrus
fruits,
cow
tissues
and
milk,
and
cottonseed.
Residues
of
amitraz
are
stable
in
cottonseed
for
13.5
months
of
frozen
storage,
and
residues
of
BTS­
27271
and
BTS­
27919
are
stable
in/
on
citrus
fruits
stored
frozen
(­
20
C)
for
up
to
18
months;
these
data
may
be
translated
to
hops.
Residues
of
amitraz,
BTS­
27271,
and
BTS­
27919
are
stable
in
cow
tissues
and
milk
stored
frozen
(­
20
C)
for
up
to
12­
15
months,
and
in
hog
muscle
and
fat
stored
frozen
(
­
15
C)
for
at
least
12
months.
The
storage
intervals
and
conditions
from
the
magnitude
of
the
residue
studies
in
plants
and
animals
are
adequately
supported
by
storage
stability
data.

Crop
Field
Trials
Since
the
registrant
is
requesting
cancellation
of
all
U.
S.
registrations
on
crops
used
as
foods/
feeds,
residue
data
on
crops
are
not
relevant
to
this
risk
assessment.

Processed
Commodities
The
9/
93
RED
Chapter
concluded
that
the
reregistration
data
requirements
pertaining
to
magnitude
of
the
residues
in
processed
food/
feed
were
fulfilled.
Adequate
cotton
processing
studies
indicate
that
amitraz
residues
of
concern
do
not
concentrate
in
the
hull
meal,
crude
oil,
refined
oil,
and
soapstock
processed
from
cottonseed
following
application
at
exaggerated
rates.

Rotational
Crops
27
The
9/
93
RED
Chapter
concluded
that
additional
data
were
required
to
upgrade
the
available
confined
rotational
crop
study
to
allow
a
conclusion
to
be
made
regarding
the
magnitude
of
residues
in
rotational
crops.
These
data
were
considered
confirmatory
for
the
purposes
of
reregistration.
The
RED
Chapter
also
noted
that
field
rotational
crop
studies
had
been
reviewed
by
EFED
and
deemed
acceptable.

Since
the
9/
93
RED
Chapter,
the
available
field
rotational
crop
studies,
originally
reviewed
by
EFED,
have
been
evaluated
by
HED.
It
was
concluded
that
the
limited
field
rotational
crop
studies
were
adequate
and
that
additional
data
were
no
longer
needed
to
upgrade
the
confined
rotational
crop
study.
The
available
data
support
rotational
crop
restrictions
of
44
days
for
root
and
leafy
vegetables
and
60
days
for
small
grains
and
other
crops,
which
are
the
established
rotational
crop
restrictions
for
use
of
amitraz
on
cotton.
Rotational
crop
tolerances
are
not
needed.

The
registrants
have
stated
that
they
intend
to
cancel
use
of
amitraz
on
cotton,
the
only
annual
crop
with
registered
uses.
Therefore,
no
data
pertaining
to
confined
and
field
accumulation
in
rotational
crops
are
required.

Codex
Harmonization
Several
maximum
residue
limits
(
MRLs)
for
amitraz
have
been
established
by
Codex
in
various
commodities.
The
Codex
MRLs
are
currently
expressed
as
the
sum
of
amitraz
and
N­(
2,4­
dimethylphenyl)­
N'­
methylformamidine
calculated
as
N­(
2,4­
dimethylphenyl)­
N'­
methylformamidine.

The
Codex
tolerance
expression
is
somewhat
different
from
the
U.
S.
tolerance
expression.
The
Codex
expression
is
the
sum
of
amitraz
plus
metabolite
BTS­
27271,
calculated
as
BTS­
27271.
The
U.
S.
expression
is
the
sum
of
amitraz
and
its
metabolites
BTS­
27271
and
BTS­
27919,
both
calculated
as
the
parent
compound.
The
enforcement
methods
for
amitraz
tolerances
in
the
U.
S.
(
Methods
I
and
II
of
PAM
Vol.
II)
consists
of
hydrolysis
of
all
metabolites
containing
the
2,4­
DMA
moiety
to
2,4­
DMA
and
determination
using
gas
chromatography
with
electron
capture
detection.
The
enforcement
method
under
the
Codex
system
involves
treatment
of
the
RAC
with
acidic
methanol
to
convert
the
parent
compound
to
metabolite
BTS­
27271,
followed
by
extraction,
cleanup,
and
determination
of
BTS­
27271
using
gas
liquid
chromatography
with
flame
ionization
detection.
Presently,
compatibility
between
the
Codex
MRL
and
U.
S.
tolerance
cannot
be
achieved
due
to
the
differences
between
the
tolerance
definitions
and
analytical
enforcement
methods.

The
current
U.
S.
tolerances
and
Codex
MRLs
are
identical
in
magnitude
for
cattle
and
pig
meat.
However,
the
reassessed
tolerances
in
the
U.
S.
are
lower
than
Codex
MRLs
with
the
exception
of
milk
which
are
the
same.
There
are
several
Codex
MRLs
for
which
there
are
no
U.
S.
tolerances.

Tolerance
Reassessment
28
The
HED
Chem
SAC
(
3/
31/
04
meeting)
has
recommended
that
the
current
tolerance
expression
for
amitraz
needs
to
be
changed
by
removing
the
reference
to
specific
metabolites.
The
tolerance
expression
should
specify
that
the
terminal
residues
of
concern
for
enforcement
purposes
are
amitraz
and
its
metabolites
containing
the
2,4­
dimethylaniline
moiety.

Adequate
residue
data
have
been
submitted
to
reassess
the
established
tolerances
for
the
following
commodities:
cattle,
fat;
cattle,
meat
byproducts;
cattle,
meat;
hog,
fat;
hog,
kidney;
hog,
liver;
hog,
meat
byproducts;
hog,
meat;
hop,
dried
cones;
milk;
and
milk,
fat.
The
available
data
indicate
that
the
established
tolerances
for
cattle
meat
byproducts,
hog
liver
and
kidney,
and
milk
fat
may
be
reduced.
The
tolerances
for
cattle
fat,
hog
fat,
hog
meat
byproducts,
hog
meat,
hop
dried
cones,
and
milk
are
reassessed
at
the
same
level.
We
note
that
for
dried
hops,
because
the
percent
dry
matter
was
not
known
for
all
samples
submitted
in
support
of
the
tolerance
petition,
HED
recommended
a
tolerance
level
higher
than
the
maximum
observed
residues
to
account
for
the
potential
that
the
samples
had
dry
matter
contents
different
from
the
expected
value
of
approximately
85%.
A
U.
S.
registration/
tolerance
for
hops
was
never
established.

Because
the
tolerance
for
dried
hops
under
40
CFR
§
180.287
is
an
import
tolerance,
the
tolerance
listing
should
be
amended
with
a
footnote
stating
"
No
U.
S.
registrations
as
of
[
date
of
FR
notice]".
The
registrant
has
indicated
that
they
would
like
to
keep
the
cotton
tolerance
as
an
import
tolerance.
HED
notes
that
there
is
a
Codex
MRL
for
cottonseed.
If
a
Codex
MRL
has
been
established,
the
NAFTA
countries
may
conduct
a
more
limited
review
of
the
residue
chemistry
data
under
certain
conditions.
The
NAFTA
countries
are
more
likely
to
adopt
MRLs
similar
to
Codex
MRL
levels
if
MRLs
for
the
pesticide
are
already
established
on
other
commodities
with
a
contemporary
robust
database.
Standard
data
and
review
requirements
would
be
applied
where
exposure
and/
or
risk
to
any
subpopulation
from
the
pesticide
is
high.
An
EPA­
specific
detailed
description
of
how
the
U.
S.
may
consider
Codex
MRLs
as
they
relate
to
data
requirements
can
be
found
in
Unit
VIII
of
the
U.
S.
Import
Tolerances
Guidance
document
(
65
FR
35069).
The
registrant
needs
to
submit
a
formal
request
to
the
Agency
for
establishment
of
the
cottonseed
tolerance
as
an
import
tolerance,
and
information
about
the
use
pattern
in
foreign
countries,
and
residue
data
from
those
countries
to
support
the
request.

All
registered
uses
of
amitraz
in
beehives
have
been
cancelled,
and
the
registrants
intend
to
cancel
use
of
amitraz
on
cotton
and
pears
in
the
U.
S.
Therefore,
the
established
U.
S.
(
Section
3)
tolerances
for
the
following
commodities
should
be
revoked:
cotton,
undelinted
seed;
honey;
honeycomb;
and
pear.
In
addition,
because
there
will
no
longer
be
any
dietary
exposure
of
livestock
to
amitraz,
the
established
tolerances
for
the
following
animal
commodities
should
be
revoked:
egg;
goat,
fat;
goat,
meat
byproducts;
goat,
meat;
poultry
fat/
meat;
poultry
meat
byproducts;
sheep,
fat;
sheep,
meat
byproducts;
and
sheep,
meat.
Tolerances
for
horse
commodities
were
previously
revoked
(
67FR
49606,
7/
31/
02).

Table
6.
Tolerance
Reassessment
Summary
for
Amitraz.

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

Tolerances
Listed
Under
40
CFR
§
180.287:
Table
6.
Tolerance
Reassessment
Summary
for
Amitraz.

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

29
Cattle,
fat
0.1
0.04
Cattle,
meat
byproducts
0.3
0.2
Cattle,
meat
0.05
0.02
Cotton,
undelinted
seed
1
1
The
registrant
intends
to
cancel
use
of
amitraz
on
cotton
in
the
US
and
to
retain
the
tolerance
as
an
import
tolerance
for
cottonseed.
The
following
footnote
should
be
added
to
the
tolerance
listing
for
cottonseed:
"
No
U.
S.
registrations
as
of
[
date
of
FR
notice]."

Egg
0.01
Revoke
When
use
of
amitraz
on
cotton
is
cancelled,
there
will
be
no
need
for
tolerances
for
poultry
commodities.

Goat,
fat
0
Revoke
When
use
of
amitraz
on
cotton
is
cancelled,
there
will
be
no
need
for
tolerances
for
goat
commodities.
Goat,
meat
byproducts
0
Revoke
Goat,
meat
0
Revoke
Hog,
fat
0.1
0.1
Hog,
kidney
0.2
0.1
Hog,
liver
0.2
0.1
Hog,
meat
byproducts
0.3
0.3
Hog,
meat
byproducts,
except
kidney
and
liver
Hog,
meat
0.05
0.05
Honey
1
Revoke
There
are
no
longer
any
registered
uses
of
amitraz
in
beehives.
Honeycomb
6
Revoke
Hop,
dried
cones
60
60
The
registrant
intends
to
retain
the
import
tolerance
on
hops.
The
following
footnote
should
be
added
to
the
tolerance
listing
for
dried
hop
cones:
"
No
U.
S.
registrations
as
of
[
date
of
FR
notice]."

Milk
0.03
0.03
Milk,
fat
0.3
0.2
Pear
3
Revoke
The
registrant
intends
to
cancel
use
of
amitraz
on
pears.

Poultry
fat/
meat
0.01
Revoke
When
use
of
amitraz
on
cotton
is
cancelled,
there
will
be
no
need
for
tolerances
for
poultry
commodities.
Poultry
meat
byproducts
0.05
Revoke
Sheep,
fat
0
Revoke
When
use
of
amitraz
on
cotton
is
cancelled,
there
will
be
no
need
for
tolerances
for
sheep
commodities.
Sheep,
meat
byproducts
0
Revoke
Table
6.
Tolerance
Reassessment
Summary
for
Amitraz.

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

30
Sheep,
meat
0
Revoke
Currently,
there
are
registered
direct
animal
treatments
of
amitraz
to
beef
and
dairy
cattle
and
hogs.
The
only
registered
amitraz
use
with
associated
livestock
feed
items
is
cotton,
which
the
registrants
do
not
intend
to
support.
The
9/
93
RED
Chapter
indicated
that
it
is
highly
unlikely
that
beef
cattle
would
be
exposed
to
amitraz
via
consumption
of
treated
commodities;
dairy
cattle
in
milksheds
in
which
cottonseed
is
readily
available
may
be
exposed
to
amitraz
both
dermally
and
in
the
diet.
Residues
of
amitraz
in
meat,
fat,
and
meat
byproducts
are
likely
to
result
from
dermal
application
only,
while
amitraz
residues
in
milk
may
be
the
result
of
dermal
application
and/
or
consumption
of
the
treated
feed
commodity.
Since
cottonseed
registration
in
the
U.
S.
will
not
be
supported
by
the
registrant,
residues
in
milk
will
only
result
from
dermal
application.

Refined
probabilistic
acute,
chronic,
and
cancer
dietary
risk
assessments
were
conducted
using
DEEM­
FCID
 
(
Version
1.30)
and
the
Lifeline
 
Model
(
Version
2.0)
which
uses
food
consumption
data
from
the
United
States
Department
of
Agriculture's
(
USDA's).
Continuing
Surveys
of
Food
Intakes
by
Individuals
(
CSFII)
from
1994­
1996
and
1998.
Chronic
and
acute
exposure
estimates
were
based
on
data
from
dermal
metabolism
studies
provided
by
the
registrant
and
percent
crop
treated
provided
by
BEAD.
Conservative
assumptions
were
made
in
the
calculation
of
anticipated
residues
used
in
the
dietary
assessment.

Currently,
amitraz
may
be
applied
twice
to
beef
and
dairy
cattle
as
a
0.05%
ai
spray,
with
a
7­
day
retreatment
interval
and
no
pre­
slaughter
interval
(
PSI).
Hogs
may
be
treated
four
times
per
year
with
a
solution
containing
0.36
lb
ai/
100
gal,
or
0.05%.
A
3­
day
PSI
has
been
established.
Although
an
acceptable
dairy
cattle
feeding
study
has
been
submitted,
the
only
magnitude
of
the
residue
data
relevant
to
the
current
use
pattern
are
dermal
application
data.
Cotton
seed
imported
as
a
feed
item
for
poultry
is
insignificant.

Data
have
been
submitted
reflecting
total
amitraz
residues
(
residues
of
amitraz
and
its
metabolites
convertible
to
2,4­
dimethylaniline)
in
cattle
matrices
following
dermal
treatment.
Cattle
were
treated
twice
with
either
a
0.05%
or
0.15%
ai
spray
solution
with
a
7­
day
retreatment
interval
and
then
sacrificed
at
pre­
slaughter
intervals
of
1,
3,
7,
and
14
days.
The
results
of
this
study
are
presented
below.
31
Pre­
slaughter
Interval
(
days)
%
ai
in
Spray
Maximum
Total
Amitraz
Residues
(
ppm)
in
Cattle
Muscle
Liver
Kidney
Fat
1
0.05
(
2
applications)
0.02
0.09
0.13
0.04
3
0.01
0.08
0.08
0.07
7
<
0.01
0.04
0.02
0.02
14
<
0.01
0.02
0.01
0.01
1
0.15
(
2
applications)
0.05
0.24
0.31
0.09
3
0.02
0.15
0.21
0.09
7
<
0.01
0.07
0.07
0.04
14
<
0.01
0.03
0.01
0.02
In
addition,
in
a
study
in
which
lactating
dairy
cattle
were
treated
with
two
sprays
containing
0.025%,
0.05%,
or
0.10%
amitraz,
with
a
10­
day
retreatment
interval,
total
amitraz
residues
in
milk
were
0.003­
0.013
ppm,
0.006­
0.025
ppm,
and
0.012­
0.038
ppm,
respectively.
Residues
were
found
to
concentrate
5x
in
butterfat.

Data
have
been
submitted
reflecting
total
amitraz
residues
in
hog
matrices
following
dermal
treatment.
Hogs
were
sprayed
to
runoff
with
a
solution
containing
0.1%
amitraz.
Two
applications
were
made
seven
days
apart,
and
the
hogs
were
slaughtered
one
day
following
the
second
treatment.
Maximum
combined
residues
of
amitraz
and
its
metabolites
containing
the
2,4­
dimethylaniline
moiety
were
<
0.05
ppm
in
muscle,
0.06
ppm
in
fat,
0.05
ppm
in
liver,
and
0.07
ppm
in
kidney.

A
second
hog
study
reflecting
dermal
application
was
conducted
in
which
hogs
were
treated
with
a
solution
of
2
oz
(
0.05%
amitraz)
or
4
oz
(
0.10
%
amitraz)
of
product
(
Taktic
E.
C.)
in
3
gal
of
water.
A
second
application
was
made
seven
days
after
the
first,
and
hogs
were
slaughtered
1,
3,
7,
and
14
days
following
treatment.
Maximum
combined
residues
of
amitraz
and
its
metabolites
containing
the
2,4­
dimethylaniline
moiety
were
0.006
ppm
in
muscle,
0.017
ppm
in
fat,
0.038
ppm
in
liver,
and
0.039
ppm
in
kidney
from
hogs
slaughtered
3
days
following
treatments
at
2
oz
product/
3
gal
(
approximately
1x).

A
hog
skin
processing
study
has
also
been
submitted.
The
results
of
this
study
indicated
that
residues
in
hog
skin
and
puffed
rind
exceeded
0.2
ppm
and
that
a
0.3­
ppm
tolerance
was
appropriate
for
hog
meat
byproducts.

Based
on
the
above
dermal
studies,
the
following
residue
data
were
used
for
chronic,
acute,
and
cancer
assessments:
32
Table
7.
Residue
Values
for
Amitraz.

Commodity
Residue
Value
Used
for
the
Chronic
and
Cancer
Assessments
(
ppm)
RDFs
Used
in
the
Acute
Assessment
Cattle,
fat
0.04
CattleFat(%
CT=
0.1)
TOTALNZ=
1
TOTALZ=
999
0.04
Cattle,
meat
byproducts
0.2
CattleMbyp(%
CT=
0.1)
TOTALNZ=
1
TOTALZ=
999
0.2
Cattle,
meat
0.02
CattleMeat(%
CT=
0.1)
TOTALNZ=
1
TOTALZ=
999
0.02
Hog,
fat
0.1
PigFat(%
CT=
0.1)
TOTALNZ=
1
TOTALZ=
999
0.1
Hog,
kidney
0.1
Pig
Kidney/
Liver(%
CT=
0.1)
TOTALNZ=
1
TOTALZ=
999
0.1
Hog,
liver
0.1
Pig
Kidney/
Liver(%
CT=
0.1)
TOTALNZ=
1
TOTALZ=
999
0.1
Hog,
meat
byproducts
0.3
PigMbyp(%
CT=
0.1)
TOTALNZ=
1
TOTALZ=
999
0.3
Hog,
meat
0.05
PigMeat(%
CT=
0.1)
TOTALNZ=
1
TOTALZ=
999
0.05
Table
7.
Residue
Values
for
Amitraz.

Commodity
Residue
Value
Used
for
the
Chronic
and
Cancer
Assessments
(
ppm)
RDFs
Used
in
the
Acute
Assessment
33
Milk
0.03
Milk(%
CT=
0.1)
TOTALNZ=
1
TOTALZ=
999
0.03
Milk,
fat
0.2
MilkFat(%
CT=
0.1)
TOTALNZ=
1
TOTALZ=
999
0.2
For
all
commodities,
a
percent
livestock
treated
value
of
0.1%
was
used
(
communication
between
BEAD
and
HED,
2/
23/
04).

4.2.2
Acute
Dietary
The
results
of
the
acute
dietary
exposure
analysis
at
the
95th,
99th,
and
99.9th
percentiles
of
exposure
are
reported
in
Table
8.

Table
8.
Results
of
Acute
Dietary
Exposure
Analysis
Using
both
DEEM­
FCID
 
and
Lifeline
 
Softwares
(
DEEM­
FCID
 
results
on
the
line
below
for
purposes
of
comparison)

Population
Subgroup
aPAD
(
mg/
kg/
day)
95th
Percentile
99th
Percentile
99.9th
Percentile
Exposure
(
mg/
kg/
day)
%
aPAD
Exposure
(
mg/
kg/
day)
%
aPAD
Exposure
(
mg/
kg/
day)
%
aPAD
U.
S.
Population
0.00025
0.000001
<
1
0.000008
3
0.000098
39
0.000001
<
1
0.000020
<
1
0.000063
25
All
Infants
(<
1year
old)
0.00025
0.000001
<
1
0.000008
3
0.000162
65
0.000001
<
1
0.000001
<
1
0.000090
36
Children
1­
2
years
old
0.00025
0.000001
<
1
0.000050
20
0.000465
186
0.000001
<
1
0.000007
3
0.000349
140
Children
3­
5
years
old
0.00025
0.000001
<
1
0.000042
17
0.000425
170
0.000001
<
1
0.000006
2
0.000234
94
Children
6­
12
years
old
0.00025
0.000001
<
1
0.000017
7
0.000168
67
0.000001
<
1
0.000004
2
0.000137
55
Youth
13­
19
years
old
0.00025
0.000001
<
1
0.000008
3
0.0000100
40
Table
8.
Results
of
Acute
Dietary
Exposure
Analysis
Using
both
DEEM­
FCID
 
and
Lifeline
 
Softwares
(
DEEM­
FCID
 
results
on
the
line
below
for
purposes
of
comparison)

Population
Subgroup
aPAD
(
mg/
kg/
day)
95th
Percentile
99th
Percentile
99.9th
Percentile
Exposure
(
mg/
kg/
day)
%
aPAD
Exposure
(
mg/
kg/
day)
%
aPAD
Exposure
(
mg/
kg/
day)
%
aPAD
34
0.000001
<
1
0.000001
<
1
0.000060
24
Adults
20­
49
years
old
0.00025
0.000001
<
1
0.000006
2
0.000062
25
0.000001
<
1
0.000001
<
1
0.000044
18
Adults
50+
years
old
0.00025
0.000001
<
1
0.000006
2
0.000069
28
0.000001
<
1
0.000001
<
1
0.000040
16
Females
13­
49
years
old
0.00025
0.000001
<
1
0.000007
3
0.000072
29
0.000001
<
1
0.000001
<
1
0.000043
17
Acute
dietary
risks,
using
Lifeline
 
Model,
are
above
HED's
level
of
concern
for
children
1­
2
yrs
(
186%
of
aPAD,
0.000465
mg/
kg/
day)
and
children
3­
5
years
old
(
170%
of
aPAD,
0.000425
mg/
kg/
day)
at
the
99.9th
percentile
of
exposure.

Acute
dietary
risks,
using
DEEM­
FCID
 
,
are
above
HED's
level
of
concern
for
children
1­
2
yrs
(
140%
of
aPAD,
0.000349
mg/
kg/
day)
at
the
99.9th
percentile
of
exposure.

As
noted
in
this
risk
assessment,
DEEM
 
and
Lifeline
 
provided
different
predicted
exposure
at
the
99.9th
percentiles
for
the
1
to
2
and
3
to
5
year
old
subpopulations
(
both
exceeding
the
aPAD).
The
assessment
accounts
for
exposure
from
the
three
RACs:
meat,
pork
and
milk.
Milk
is
the
primary
RAC
that
drives
exposure
at
the
99.9th
percentile
due
to
the
relatively
high
residues.
Lifeline
 
had
relatively
higher
predictions
for
both
the
1
to
2
year
old
(
186%
vs
140%
aPAD),
and
3
to
5
year
old
subpopulations
(
170%
vs
94%
aPAD).
The
different
model
predictions
can
be
attributed
to
two
reasons:
(
1)
a
limitation
regarding
the
Lifeline
 
software,
and
(
2)
modeling
differences
between
DEEM
 
and
Lifeline
 
.
A
complete
explanation
of
how
these
factors
affect
the
model
predictions
will
be
presented
in
a
subsequent
memo.
The
apparent
limitation
in
Lifeline
 
software
is
the
result
of
several
concurrent
factors:
(
i)
milk
is
treated
as
a
food
comprised
of
three
RACS
(
water,
non­
fat
solids,
fat),
(
ii)
the
percent
crop
treated
is
relatively
low
(
0.1%),
and
(
iii)
the
Lifeline
 
.
Food
Residue
Translator
(
FRT)
approximates
food
(
milk)
residue
percentiles
based
on
a
fixed
number
of
simulations.
The
difference
in
modeling
design
(
frequency
of
using
food
diaries
and
weights
applied)
also
contribute
towards
the
Lifeline
 
model
providing
higher
exposure
estimates
than
DEEM
 
.
This
latter
effect
is
independent
of
the
first
effect,
however,
it
is
also
dependent
upon
the
percent
crop
treated
value
used
for
milk.

Given
the
relatively
high
anticipated
residues
for
milk
(
0.03
ppm),
a
moderate
amount
of
milk
consumption
may
provide
exposure
exceeding
the
aPAD.
For
example,
a
20
kg
toddler
(
typical
5
year
old),
consuming
8
ounces
of
milk
(
226
grams
=
8
x
28.3
grams/
oz),
or
equivalently,
11.3
35
grams/
kg
bwt/
day
(~
226/
20),
would
have
dietary
exposure
of
approximately
0.0003
mg
ai/
kg
bwt/
day
(=
0.03
ppm
x
11.3
gm/
kg
bwt/
day
x
(
1/
1000)),
or
135%
of
the
aPAD
(=
0.00025).
The
average
milk
consumption
for
1­
4
year
olds
is
approximately
337
gm/
day,
with
75%
of
toddlers
(
1to5
year
olds)
consuming
11
grams/
kg
bwt/
day
or
more
of
dairy
products.
Even
though
the
other
two
commodities
(
beef,
pork)
provide
relatively
low
exposure,
milk
continues
to
provide
exposure
at
the
99.9th
percentile
even
with
the
low
percent
crop
treated
due
to
the
application
of
residues
to
the
three
milk
components
(
water,
fat,
non­
fat
solids),
and
the
relatively
high
percent
of
toddlers
that
consume
milk.

4.2.3
Chronic
and
Cancer
Dietary
The
results
of
the
chronic
dietary
exposure
analysis
are
reported
in
the
summary
table
below.
Results
of
the
Lifeline
 
analysis
are
fully
consistent
with
DEEM­
FCID
 
results.
Estimated
chronic
dietary
risk
is
below
HED's
level
of
concern
for
all
populations
(<
1%
of
cPAD).

The
estimated
exposure
of
the
general
U.
S.
population
to
amitraz
is
<
0.000001
mg/
kg/
day
for
both
dietary
risk
assessment
models.
Applying
the
Q
1*
of
2.83
x
10­
2
(
mg/
kg/
day)­
1
to
the
exposure
value
results
in
a
cancer
risk
estimate
of
2.8
x
10­
8.
Therefore,
estimated
cancer
dietary
risk
is
below
HED's
level
of
concern.
Results
are
shown
in
the
Table
below.

Table
9.
Summary
of
Acute,
Chronic,
and
Cancer
Dietary
Exposure
and
Risk
Estimates
for
Amitraz.

Population
Subgroup
PAD,
mg/
kg/
day
DEEM­
FCID
 
Lifeline
 
Exposure,
mg/
kg/
day
%
PAD
Exposure,
mg/
kg/
day
%
PAD
Acute
Dietary
Estimates
(
99.9th
Percentile
of
Exposure)

U.
S.
Population
0.00025
0.000063
25
0.000098
39
All
infants
(<
1
yr)
0.00025
0.000090
36
0.000162
65
Children
1­
2
yrs
0.00025
0.000349
140
0.000465
186
Children
3­
5
yrs
0.00025
0.000234
94
0.000425
170
Children
6­
12
yrs
0.00025
0.000137
55
0.000168
67
Youth
13­
19
yrs
0.00025
0.000060
24
0.00010
40
Adults
20­
49
yrs
0.00025
0.000044
18
0.000063
25
Adults
50+
yrs
0.00025
0.000040
16
0.000069
28
Females
13­
49
yrs
0.00025
0.000043
17
0.000073
29
Chronic
Dietary
Estimates
U.
S.
Population
0.00025
0.000001
<
1
0.000001
<
1
All
infants
(<
1
yr)
0.00025
0.000001
<
1
0.000001
<
1
Children
1­
2
yrs
0.00025
0.000001
<
1
0.000001
<
1
Children
3­
5
yrs
0.00025
0.000001
<
1
0.000001
<
1
Children
6­
12
yrs
0.00025
0.000001
<
1
0.000001
<
1
Youth
13­
19
yrs
0.00025
0.000001
<
1
0.000001
<
1
Table
9.
Summary
of
Acute,
Chronic,
and
Cancer
Dietary
Exposure
and
Risk
Estimates
for
Amitraz.

Population
Subgroup
PAD,
mg/
kg/
day
DEEM­
FCID
 
Lifeline
 
Exposure,
mg/
kg/
day
%
PAD
Exposure,
mg/
kg/
day
%
PAD
36
Adults
20­
49
yrs
0.00025
0.000001
<
1
0.000001
<
1
Adults
50+
yrs
0.00025
0.000001
<
1
0.000001
<
1
Females
13­
49
yrs
0.00025
0.000001
<
1
0.000001
<
1
Cancer
Dietary
Estimate
U.
S.
Population
0.028
<
0.000001
2.8
x
10­
8
<
0.000001
2.8
x
10­
8
4.3
Water
Exposure/
Risk
Pathway
Application
information
was
insufficient
to
conduct
an
exposure
assessment
that
could
be
referenced
to
a
registrant's
supported
label.
Labels
were
clear
only
on
the
maximum
number
of
applications
that
could
be
applied
to
animals
or
inert
surfaces
in
a
year,
the
intervals
between
application
for
controlling
certain
pests,
and
the
mixing
directions.
Application
quantities
were
in
general
terms
such
as,
"
apply
to
animals
until
runoff".
To
address
the
lack
of
clear
application
rates
per
unit
area,
SRRD
contacted
the
registrant
for
more
information.
As
a
result
EFED
conducted
"
what
if"
scenarios
for
estimating
drinking
water
exposures.
All
of
these
scenarios
assumed
that
the
amitraz
applied
is
applied
within
one
watershed.
HED
and
EFED
understand
that
these
assumptions
may
not
represent
the
typical/
actual
use
of
amitraz
in
animal
facilities
and
they
likely
overestimate
actual
environmental
exposures
(
EECs).
Details
of
the
drinking
water
assessment
can
be
found
in
the
EFED
drinking
water
memo.

SRRD
contacted
the
amitraz
registrant
and
received
the
following
information
regarding
the
use
of
amitraz
as
animal
dips/
sprays.
HED
is
awaiting
written
verification
of
this
information.
The
registrant
indicated
that
of
the
product
sold
in
the
US,
25­
30%
is
used
on
swine
operations
in
NC
and
the
Midwest.
They
also
said
that
it
is
almost
never
used
outdoors;
the
bulk
of
the
treatments
are
indoors
directly
to
the
animal
with
10­
20%
of
the
applied
spray
running
off
the
animal
to
inert
(
indoor)
surfaces.
EFED
modeled
amitraz
use
on
swine
based
on
communications
from
the
registrant
regarding
animal
dips/
sprays
and
assumed
that
30%
of
the
product
sold
in
the
US
was
used
in
such
a
manner
that
it
was
available
for
runoff
in
one
watershed
in
NC.
The
following
EECs
were
generated
for
use
in
risk
assessment:

Surface
water
EEC:
Typical
Estimate:
Peak
Concentration
=
0.1
ppb;
Annual
Average
Concentration
=
0.0006
ppb
Groundwater
EEC:
Typical
=
0.000009
ppb
4.4
Residential
Exposure/
Risk
Pathway
Amitraz
is
registered
as
an
insecticide/
miticide
for
the
control
of
ticks,
mange
mites,
lice
on
domestic
livestock
such
as
dairy
and
beef
cattle
and
swine.
Amitraz
is
also
registered
for
use
in/
on
dog
collars
for
the
control
of
fleas
and
ticks.
For
the
purposes
of
this
Tolerance
Reassessment
37
Eligibility
Decision
(
TRED)
document,
HED
is
concerned
with
use
of
amitraz
on
dog
collars
for
the
control
of
fleas
and
ticks
on
the
dog
only.
EPA
published
a
Registration
Eligibility
Document
(
RED)
for
amitraz
in
March,
1995.
In
the
RED,
EPA
assessed
occupational
applicator
exposure
to
amitraz
for
handlers
and
applicators
as
well
as
post­
application
occupational
exposure
resulting
from
agricultural
uses
registered
for
amitraz
at
that
time.
Residential
uses
were
not
assessed
for
the
RED.

A
regulatory
review
of
residential
exposure
to
amitraz
[
N­
methylbis(
2,4­
xylyliminomethyl)
amine]
was
conducted
for
this
TRED
because
there
is
potential
exposure
to
non­
occupational
(
residential)
handlers
(
applicators)
during
handling
and
application
of
pet
collars
which
have
been
impregnated
with
the
active
ingredient
amitraz
to
dogs
for
the
prevention
of
canine
ticks
and
fleas.
There
is
also
potential
residential
post­
application
exposure
to
amitraz
for
the
duration
of
the
use
of
the
collar
on
the
dog.

As
of
the
date
of
this
document,
pesticide
products
containing
amitraz
are
intended
for
both
occupational
(
i.
e.,
cattle
dipping)
and
residential
uses
(
i.
e.,
dog
collars).
There
are
two
Federally
registered
dog
collar
products
impregnated
with
amitraz,
manufactured
in
France
for
Virbac
of
Fort
Worth,
Texas;
EPA
Reg.
Nos.
2382­
104
and
2382­
170.
Each
of
these
collars
contain
9.0%
amitraz
as
the
active
ingredient.
EPA
Reg.
No.
2382­
170
also
contains
0.5%
Pyripoxyfen
as
an
active
ingredient
and
each
product
label
contains
the
language
"
For
Veterinary
Use
Only".
According
to
product
labeling,
the
collars
kill
ticks,
fleas
and
flea
eggs
on
a
dog
for
three
months.
For
the
purposes
of
this
assessment,
HED
used
EPA
Reg.
No.
2382­
170*
to
estimate
potential
residential
exposure
to
the
insecticide
amitraz
via
it's
use
in
impregnated
pet
collars
on
domestic
dogs
for
the
prevention
of
fleas
and
ticks.

According
to
the
labeling
associated
with
this
active
ingredient,
the
collars
prevent
ticks
for
3
months,
therefore,
the
collars
can
be
applied
4
times
per
year.
Product
labeling
specifies
only
the
use
of
these
collars
on
dogs.

The
March
17th,
2004
report
of
the
Hazard
Identification
Assessment
Review
Committee
(
HIARC)
for
amitraz
identified
toxicological
endpoints
of
concern
for
amitraz.
All
calculations
completed
in
this
document
are
based
on
the
most
current
toxicity
information
available
for
amitraz.
For
short
and
intermediate
term
dermal
and
inhalation
exposures,
and
incidental
exposures
a
NOAEL
of
0.25
mg/
kg/
day
with
a
LOAEL
of
1.0
mg/
kg/
day,
from
a
chronic
oral
study
based
on
CNS
depression
during
the
first
two
days
of
dosing
was
selected.
A
dermal
absorption
factor
of
8.0%
is
applied
for
dermal
exposure
for
route
to
route
extrapolation.

A
Q
1*
based
upon
female
rat
liver
(
carcinoma
and/
or
adenoma)
tumor
rates
was
generated
using
mg/
kg
b.
w.^
2/
3'
s/
day
cross
species
scaling
factor.
The
revised
unit
risk,
Q
1
*
(
mg/
kg/
day)­
1,
of
Amitraz
based
upon
female
mouse
liver
combined
adenoma
and
carcinoma
tumor
rates
is
2.83
x
10­
2
in
human
equivalents
(
converted
from
animals
to
humans
by
use
of
the
3/
4'
s
scaling
factor
­
Tox_
Risk
program,
Version
5.31,
K.
Crump,
2000).
38
The
HIARC
determined
that
a
Margin
Of
Exposure
(
MOE)
of
1000,
based
on
an
uncertainty
factor
of
100X
for
traditional
inter
and
intra
species
variation
and
an
additional
10X
for
lack
of
acceptable
developmental
and
reproductive
data
is
adequate
for
residential
exposures.

One
applicator/
handler
scenario
and
three
post­
application
scenarios
were
identified
and
and
considered
in
this
assessment.
The
scenarios
identified
and
examined
in
this
TRED:

­
Adult
residential
handler
(
applicator),
the
person
unwraps
the
collar
and
places
it
on
the
dog
­
dermal.

­
Toddler
­
dermal
(
post­
application)

­
Toddler
­
incidental
oral
(
post­
application)

­
Adult
­
dermal
(
post­
application)

Intermediate­
term
dermal
and
oral
MOEs
were
calculated
for
this
assessment.
A
target
MOE
of
1000
is
considered
adequate
for
intermediate­
term
residential
exposure
via
dermal
and
oral
routes.

In
this
TRED,
HED
also
estimated
dermal
postapplication
cancer
risks
for
adults.
(
Cancer
risk
estimates
<
1
x
10­
6
are
not
of
concern.)

4.4.1
Home
Uses
4.4.1.1
Handler
Although
HED
considers
the
residential
handler
scenario
as
having
potential
exposure
risk,
the
most
significant
exposure
of
concern
is
for
post­
application
scenarios
as
these
exposures
are
of
longer
duration
and
potentially
affect
more
sensitive
residents
including
infants
and
children.
Therefore
this
document
primarily
focuses
on
residential
post­
application
exposures
only,
and
does
not
address
residential
handlers.

4.4.2
Postapplication
As
stated
above,
HED
considers
post­
application
exposure
to
residents,
including
children,
to
be
the
primary
concern
of
potential
exposure
to
amitraz
via
this
registered
use.
Residents
(
adults
and
children)
can
be
exposed
to
amitraz
via
its
use
in
a
dog
collar.
Once
the
collar
is
applied
the
amitraz
residues
potentially
are
spread
throughout
the
surface
area
of
the
dog
exposing
residents
to
these
residues
by
dermal
contact
with
the
treated
dog.
Therefore,
HED
assessed
residential
postapplication
exposure
to
amitraz
via
its
presence
in
the
collar
on
the
dog
and
thereby
potentially
spreading
throughout
the
fur
of
the
dog.
Identifying
toddlers
as
the
most
sensitive
of
potentially
exposed
residential
populations,
HED
conducted
post­
application,
intermediate­
term
risk
assessments
for
toddlers
and
adults.
For
toddlers,
one
assessment
was
based
on
the
likely
dermal
exposure
of
a
toddler
contacting
(
hugging)
the
dog,
and
a
second
assessment
based
on
incidental
39
oral
ingestion
through
hand­
to­
mouth
actions
after
contacting
(
vigorous
petting)
the
dog.
An
assessment
for
dermal
exposure
of
adults,
based
on
contacting
the
dog
,
was
also
conducted.

Since
the
vapor
pressure
for
amitraz
=
3.4
x
10­
4
mm
Hg,
and
as
such,
is
considered
low
to
moderate,
HED
feels
that
there
is
potential
inhalation
exposure
as
a
certain
amount
of
off­
gassing
is
expected
to
occur.
However,
HED
did
not
address
post­
application
inhalation
exposures
as
the
dermal
exposures
exceeded
HED's
levels
of
concern
and
data
concerning
inhalation
exposures
via
pet
collars
was
not
available.

Residential
risks
attributable
to
non­
dietary
ingestion
and
dermal
exposure
were
assessed
for
toddlers
and
adults
after
contact
with
treated
pets
based
on
the
guidance
provided
in
the
SOPs
for
Residential
Exposure
Assessment
(
U.
S.
EPA,
1997,
1999)
1,
and
also
Exposure
to
Children
and
Adults
to
Transferable
Chlorpyrifos
Residues
from
Dogs
Treated
with
Flea
Control
Collars
(
Boone,
J.
s.
et
al.
2001)
2.
Boone,
J.
et
al.
also
served
as
a
source
of
surrogate
data
for
transferrable
pesticide
residues
from
dog
fur.
(
To
this
date,
HED
has
received
no
chemical
specific
data
concerning
this
use
pattern
from
the
amitraz
registrant(
s).

The
dermal
contact
scenario
is
based
on
the
use
of
the
transferable
residue
data
normalized
by
the
sampling
area
and
by
the
amount
of
active
ingredient
in
the
collar
(
in
units
of

g/
cm2/
gram
ai).
A
linear
relationship
between
the
active
ingredient
and
the
residues
is
assumed.
The
transferable
residues
are
then
extrapolated
to
the
surface
area
of
a
"
hug"
(
i.
e.,
1875
cm2
­
toddlers).
No
data
are
available
to
determine
the
frequency
of
"
hugs".
However,
the
transferability
of
the
residues
from
the
5
minute
vigorous
petting
routine
in
the
study
is
a
reasonable
surrogate
for
the
transferability
of
a
days
worth
of
"
hugs"
of
a
dog
by
a
child.

To
determine
an
"
area"
weighted
mean
of
the
residues
from
the
neck
with
collar,
neck
without
collar,
and
back
of
the
dog
hugged,
a
simplistic
use
of
proportions
(
i.
e.,
thirds)
of
the
three
monitored
areas
of
the
dog
was
used.
That
is,
residues
measured
on
the
neck
of
the
dog
with
collar,
without
collar,
and
the
back
of
the
dog
from
1
to
168
days
after
treatment
(
DAT)
were
weighted
by
1/
3
each,
summed
and
averaged.
The
initial
4
­
hour
measurement
was
not
included
in
the
time­
weighted
average
(
TWA).
The
surrogate
value
to
be
used
as
the
dermal
TWA
transferable
residue
of
amitraz
is
0.29

g/
cm2/
gram
ai
(
or
0.29

g/
cm2/
gram
ai
x
1875
cm2
hug
=
540

g/
gram
ai
for
toddlers
and
0.29

g/
cm2/
gram
ai
x
5625
cm2
hug
=
1630

g/
gram
ai
for
adults).
This
represents
a
unit
daily
exposure
for
an
intermediate
to
chronic
duration.

The
traditional
estimates
of
hand­
to­
mouth
exposure
are
based
on
estimates
of
residues
on
a
child's
hand,
the
frequency
of
which
the
hand
goes
in
the
mouth,
and
the
duration
the
child
is
in
contact
with
the
treated
surface.
While
duration
estimates
are
available
for
a
child
playing
outside
(
e.
g.,
on
lawn),
no
estimates
of
contact
time
are
available
for
pets.
Therefore,
it
is
recommended
for
the
pet
collar
scenario
that
the
oral
hand­
to­
mouth
route
be
based
on
the
amount
of
residue
transferred
from
the
neck
with
the
collar
(
highest
of
the
three
areas
monitored).
The
residues
available
from
the
5
minute
vigorous
petting
routine
is
believed
to
be
a
conservative
estimate
of
the
amount
of
residue
available
for
ingestion
for
a
day.
It
is
believed
to
be
a
conservative
estimate
because
it
represents
7.5
seconds
of
petting
prior
to
each
of
40
hand­
to­
mouth
events
(
i.
e.,
(
5
minutes
sampling
x
60
seconds/
minute)
/
(
2
hours
per
day
x
20
hand­
to­
mouth
events
per
hour)).
40
The
two
hour
duration
is
arbitrary,
only
presented
as
a
point
of
reference.
Furthermore,
the
biological
monitoring
data,
even
though
inconclusive
for
regulatory
decisions,
do
not
indicate
any
dose
levels
higher
than
that
estimated
by
the
residue
method.
However,
more
research
is
needed
in
this
area
of
pet
collar
exposure.

Labels
for
the
impregnated
collars
state
efficacy
for
three
months,
therefore,
the
maximum
application
to
the
dog
would
be
four
times/
year.
The
net
weight
of
the
collar
is
42g
with
9.0%
amitraz
yields
3.8
g
active
ingredient
(
ai)
in
the
collar
(
EPA
Reg.
No.
2382­
170*).

A
series
of
assumptions
and
exposure
factors
served
as
the
basis
for
completing
intermediate­
term
homeowner
non­
cancer,
post­
application
risk
assessments.
Each
assumption
is
detailed
below:

S
The
average
body
weight
of
an
adult
used
in
all
assessments
is
70
kg.
For
toddler
assessments,
15
kg
weight
was
used
as
directed
by
SOPs
for
Residential
Exposure
Assessment.

S
The
amount
of
available
pesticide
on
the
dog's
fur
as
a
result
of
wearing
the
treated
collar
on
a
Time
Weighted
Average
(
TWA)
=
0.29
ug/
cm2
/
g
ai
as
a
transferable
unit
of
residue.
2
$
In
calculating
potential
post­
application
dermal
exposure
for
such
dog
related
activities
as
contacting,
HED
used
the
following
surface
areas
(
the
dermal
contact
area)
of
a
hug
to
a
dog:
toddler
=
1875
cm2;
adults
=
5625
cm2.1
Thus
the
equation
for
Estimated
Absorbed
Dermal
Dose
(
EADD)
exposure
postapplication
for
residents
becomes:

EADD
=
Transferable
residue
x
fraction
transferred
x
application
rate
x
dermal
absorption/
body
weight.

Thus
for
toddlers:

S
EADD
(
mg/
kg/
day)
=
(
0.29
ug/
cm2
/
g
ai)
x
0.001
mg/
ug
x
1875
cm2
x
(
3.8
g
ai
Amitraz
pet
collar)
x
Dermal
Absorption(
DA*)/
15
kg.

And,
the
equation
for
Estimated
Absorbed
Dermal
Dose
(
EADD)
exposure
postapplication
for
adults
becomes:

S
EADD
(
mg/
kg/
day)
=
(
0.29
ug/
cm2
/
g
ai)
x
0.001
mg/
ug
x
5625
cm2
x
(
3.8
g
ai
Amitraz
pet
collar)
x
Dermal
Absorption(
DA*)/
70
kg.

Toddler
Hand­
to­
Mouth
exposure
from
Residential
Exposures
Assessment
SOPs
was
calculated
as
follows:
41
Dose
(
mg/
kg/
day)
=
(
Dog's
neck
with
collar
of
1.5
ug/
cm2
/
gram
ai
x
3.8
gm
ai
Amitraz/
collar
x
0.001mg/
ug
x
0.5
saliva
extraction
efficiency
x
20
cm2
palmar
surface
area
of
fingers
into
mouth)*/
15
kg
body
weight.

Where:
*
Neck
with
collar
of
1.5

g/
cm2/
gram
ai
=
(
TWA
340

g
neck
with
collar/
88
cm2
child's
palm)
/
2.54
gram
ai
in
chlorpyrifos
test
collar.
[
child's
palm
surface
area
is
350
cm2
for
both
hands;
therefore,
175
cm2
represents
one
hand
and
88
cm2
represents
the
palm
of
one
hand].
Using
the
child's
hand
assumes
that
the
sampling
area
of
the
dog
(
258
cm2)
would
yield
the
same
amount
of
transferable
residue
regardless
if
the
hand
used
to
pet
the
dog
was
an
adult's
hand
(
as
monitored
in
the
study)
or
a
smaller
hand
of
a
child.

MOE
=
NOAEL
(
0.25
mg/
kg/
day)/
Estimated
Absorbed
Daily
Dose
(
EADD)

*
Dermal
Absorption
=
8.0%.

Table
10.
represents
the
calculated
residential
MOEs
for
various
activities
as
related
to
amitraz
treated
dog
collars.

Table
10.
Residential
Post­
Application
Intermediate­
Term
Risk
Estimates
Resident
Dog
Related
Activity
EADD
*
(
mg/
kg/
day)
MOE
Toddler
contacting
0.011
22
Toddler
hand
to
mouth
0.0038
65
Adult
contacting
0.007
35
*
EADD
=
Estimated
Absorbed
Dermal
Dose
MOE
=
NOAEL
(
0.25
mg/
kg/
day)/
Estimated
Absorbed
Dermal
Dose
Postapplication
Cancer
Risks
To
assess
carcinogenic
risk
for
amitraz
exposure
through
the
examined
use,
HED
selected
contacting
the
animal
as
the
most
likely
or
common
vector
of
concern
for
the
potential
exposure
over
the
course
of
a
lifetime.
HED
therefore
used
the
same
Estimated
Absorbed
Dermal
Dose
(
EADD)
described
above
in
the
non­
cancer
risk
estimates
and
extrapolated
over
a
70
year
lifetime,
using
high
and
low
end
lifetime
expectations
for
the
dog
(
10
and
20
years)
and
employing
the
following
assumptions:

S
The
dog
will
wear
the
treated
collar
throughout
it's
lifetime
(
estimated
for
10
and
20
years).

S
A
dog
owner
will
hug
his
or
her
dog
once
a
day
over
the
lifetime
of
the
dog.

S
As
in
the
case
of
post­
application
non­
cancer
estimates,
the
Time
Weighted
Average
(
TWA)
of
available
pesticide
on
the
dog's
fur
is
constant.
42
Hence,
the
equation
for
carcinogenic
risk
estimate
over
a
lifetime
for
the
examined
use,
utilizing
Q
1*
method
becomes:

­
LADD
(
Lifetime
Average
Daily
Dose)
=
(
EADD)
x
(
number
hugs/
year)
x
(
number
of
years
of
pet
ownership/
70
year
lifetime).

S
Carcinogenic
Risk
=
(
LADD)
x
(
Q
1*),
where
Q
1*
=
2.83
x
10E­
2
(
mg/
kg/
day
E­
1)
(
Memorandum
February
11,
2004).

The
following
table
represents
the
numerical
risk
estimation
for
carcinogenic
residential
handler
risk
associated
with
application
of
pet
collars
impregnated
with
amitraz.

Table
11:
Residential
Post­
Application
Carcinogenic
Risk
Assessment
Over
a
Lifetime
Estimated
Lifetime
of
Treated
Dog
Estimated
Absorbed
Daily
Dosea
(
mg/
kg/
day)
Amortization
LADDb
(
mg/
kg/
day)
Carcinogenic
Riskc
(
mg/
kg/
day)
#
of
Days
Exposed
/
Year
Years
of
lifetime
(
70
yrs)

10
years
0.007
365
10/
70
0.
001
2.8
x
10
­
5
20
years
0.007
365
20/
70
0.002
5.6
x
10
­
5
a.
Estimated
Absorbed
Daily
Dermal
Dose
is
from
Table
3.
b.
LADD
(
lifetime
average
daily
dose)
=
(
absorbed
dermal
dose)
x
(
number
of
days
exposed/
365days)
x
(
number
of
years
of
pet
ownership/
70
year
lifetime)
c.
Carcinogenic
Risk
=
(
LADD)*(
Q
1
*),
where
the
Q
1
*,
is
2.83
x
10E­
2
(
mg/
kg/
day)­
1
Risk
Characterization
and
Uncertainties
HED
considers
this
residential
risk
assessment
to
be
based
on
high­
end
estimates
of
exposure
generated
from
screening­
level
procedures
outlined
in
the
SOPs
for
Residential
Exposure
Assessment
(
U.
S.
EPA,
1997,
1999).
As
such,
the
risk
estimates
associated
with
pet
collars
are
conservative,
largely
driven
by
default
assumptions
and
uncertainties
in
the
toxicity
database.

5.0
Aggregate
Risk
Assessments
and
Risk
Characterizations
Acute
aggregate
risk
estimates
will
not
be
conducted
since
the
dietary
acute
risk
exceed
HEDs
level
of
concern.
Short­
and
Intermediate­
Term
and
cancer
aggregate
risk
estimates
will
not
be
conducted
since
the
post
application
residential
exposure
scenarios
exceed
HED's
level
of
concern.

Chronic
aggregate
risk
estimates
associated
with
exposure
to
amitraz
residues
in
food
and
water
do
not
exceed
HED's
level
of
concern.
Estimates
of
exposure
from
food
were
taken
from
the
dietary
exposure
model
results
described
above
(
Section
4.2.3).
The
chronic
risk
estimates
are
below
the
Agency's
level
of
concern
for
the
general
U.
S.
population
and
all
population
subgroups.

For
considering
exposure
to
residues
of
amitraz
in
drinking
water,
HED
has
calculated
chronic
Drinking
Water
Levels
of
Comparison
(
DWLOCs).
These
values
are
the
maximum
concentration
43
of
a
chemical
that
can
occur
in
drinking
water
after
taking
into
account
exposures
to
residues
from
other
pathways
and
sources.
The
DWLOCs
are
compared
against
the
modeled
EECs
provided
by
the
EFED
(
see
Section
4.3).
DWLOC
values
that
are
greater
than
the
EECs
indicate
that
aggregate
exposures
are
unlikely
to
exceed
HED's
level
of
concern.
HED
calculated
DWLOCs
for
the
following
populations:
general
U.
S.
population
(
DWLOC
=
9
ppb);
females
(
DWLOC
=
8
ppb);
infants
and
children
(
DWLOC
=
2.5
ppb).
The
chronic
DWLOCs
for
the
general
U.
S.
population
and
all
of
the
representative
population
subgroups
modeled
by
Lifeline
 
are
greater
than
both
the
surface
water
and
ground
water
EECs
(
Surface
water
EEC:
Typical
Estimate:
Annual
Average
Concentration
=
0.0006
ppb;
and
Groundwater
EEC:
Typical
=
0.000009
ppb).
Therefore,
chronic
aggregate
risk
estimates
associated
with
exposure
to
amitraz
residues
in
food
and
water
do
not
exceed
HED's
level
of
concern.

6.0
Cumulative
Section
408(
b)(
2)(
D)(
v)
of
the
FFDCA
requires
that,
when
considering
whether
to
establish,
modify,
or
revoke
a
tolerance,
the
Agency
consider
"
available
information"
concerning
the
cumulative
effects
of
a
particular
pesticide's
residues
and
"
other
substances
that
have
a
common
mechanism
of
toxicity."

Amitraz
is
a
member
of
the
formamidine
class
of
pesticides.
This
class
also
includes
chlordimeform
among
others.
The
formamidine,
as
a
group,
have
been
determined
to
share
a
common
mechanism
of
toxicity
(
July
2001
memo
from
Office
Director
Marcia
Mulkey).
However,
a
cumulative
risk
assessment
has
not
been
performed
as
part
of
this
review
because
the
Agency
is
currently
examining
approaches
for
completing
this
type
of
assessment.
EPA's
Office
of
Research
and
Development
is
currently
investigating
the
pharmacokinetics
and
pharmcodynamics
of
formamidines
which
will
provide
a
more
solid
scientific
foundation
for
the
cumulative
assessment
of
these
pesticides
in
the
future.

7.0
Data
Needs/
Label
Requirements
Toxicology
870.3700:
Prenatal
developmental
toxicity
study
in
rabbits
870.3800:
A
two­
generation
reproduction
study
which
should
be
MODIFIED
to
include
the
following:

°
Due
to
the
concern
for
the
lack
of
stability
of
the
test
material
in
the
diet,
treatment
should
be
via
oral
(
gavage)
administration.

°
The
potential
for
neurotoxicity
in
the
developing
fetuses
should
be
evaluated
according
to
the
OPPTS
Guideline
§
870.6300.
44
°
The
potential
for
neurotoxicity
in
adults
should
be
evaluated
according
to
the
OPPTS
Guideline
§
870.6200.

870.3465:
HED
recommends
reserving
the
requirement
for
a
28­
day
inhalation
study
following
the
OPPTS
Guideline,
with
cessation
of
exposure
at
28
days.

Rationale
for
reserving
28­
day
inhalation
toxicity
study:

HED
is
reserving
the
requirement
for
a
28­
day
inhalation
study
in
rats
pending
future
uses
of
amitraz
based
on
the
following
rationale.
Currently,
amitraz
is
registered
for
residential
use
in
pet
collars
and
for
commercial
use
as
livestock
dips
and
sprays.
Exposure
via
inhalation
from
pet
collars
impregnated
with
amitraz
is
expected
to
be
less
than
dermal
exposures
associated
with
that
use.
HED
has
focused
on
post­
application
dermal
and
incidental
oral
exposures
for
the
registered
residential
uses
of
amitraz.
Estimated
dermal
exposures
alone
result
in
risk
estimates
that
exceed
levels
of
concern.
Regarding
commercial
dips
and
sprays,
the
occupational
risk
assessment
conducted
for
the
1995
Reregistration
Eligibility
Decision
(
RED)
on
amitraz,
states
that
because
of
adequate
ventilation
in
treatment
areas
inhalation
exposure
is
minimal.
The
RED
included
additional
personal
protective
equipment
(
PPE)
to
mitigate
exposures
of
workers
to
amitraz
using
sprays.
In
addition,
the
current
NOAEL
of
0.25
mg/
kg/
day
from
a
dog
study
results
in
MOEs
of
60
­
600
for
combined
dermal
+
inhalation
exposures
for
the
livestock
spray
use,
i.
e.,
approaching
or
greater
than
the
target
MOE
of
100.
The
1995
RED
indicates
that
dermal
exposures
are
approximately
10X
inhalation
exposures.

Although
HED
cannot
waive
the
inhalation
study
because
amitraz
does
not
meet
the
criteria
of
low
toxicity
via
the
inhalation
route,
low
vapor
pressure,
and
inhalation
MOEs
greater
than
1000,
and
the
subchronic
toxicity
database
is
incomplete,
HED
does
not
believe
a
28­
day
inhalation
toxicity
study
is
warranted
at
this
time.
However,
HED
reserves
the
right
to
require
this
study
pending
future
uses
of
amitraz.

Product
Chemistry
All
pertinent
product
chemistry
data
requirements
are
satisfied
for
the
only
registered
manufacturing
use
product,
the
Bayer
CropSciences
97%
T,
except
that
data
are
required
concerning
the
UV/
visible
absorption
of
the
PAI
(
OPPTS
830.7050).
Provided
that
the
registrant
submits
the
data
required
in
the
attached
data
summary
table
for
the
amitraz
technical
product,
and
either
certifies
that
the
suppliers
of
beginning
materials
and
the
manufacturing
process
have
not
changed
since
the
last
comprehensive
product
chemistry
review
or
submits
a
complete
updated
product
chemistry
data
package,
the
Agency
has
no
objections
to
the
reregistration
of
amitraz
with
respect
to
product
chemistry
data
requirements.

Residue
Chemistry
Provided
that
the
registered
uses
on
cotton
and
pears
are
cancelled,
there
are
no
residue
chemistry
deficiencies
pertaining
to
amitraz
reregistration.
However,
the
registrant
has
indicated
that
they
would
like
to
keep
the
cotton
tolerance
as
an
import
tolerance.
HED
notes
that
there
is
a
Codex
45
MRL
for
cottonseed.
If
a
Codex
MRL
has
been
established,
the
NAFTA
countries
may
conduct
a
more
limited
review
of
the
residue
chemistry
data
under
certain
conditions.
The
NAFTA
countries
are
more
likely
to
adopt
MRLs
similar
to
Codex
MRL
levels
if
MRLs
for
the
pesticide
are
already
established
on
other
commodities
with
a
contemporary
robust
database.
Standard
data
and
review
requirements
would
be
applied
where
exposure
and/
or
risk
to
any
subpopulation
from
the
pesticide
is
high.
An
EPA­
specific
detailed
description
of
how
the
U.
S.
may
consider
Codex
MRLs
as
they
relate
to
data
requirements
can
be
found
in
Unit
VIII
of
the
U.
S.
Import
Tolerances
Guidance
document
(
65
FR
35069).
The
registrant
needs
to
submit
a
formal
request
to
the
Agency
for
establishment
of
the
cottonseed
tolerance
as
an
import
tolerance,
and
information
about
the
use
pattern
in
foreign
countries,
and
residue
data
from
those
countries
to
support
the
request.

Non­
Dietary
Exposure
875.2400
Dermal
Exposure
Study
Non­
Guideline
Dog
Fur
Residue
Study