TXR
NO.
0052425
DATE:
March
17,
2004
MEMORANDUM
SUBJECT:
AMITRAZ
­
1st
Report
of
the
Hazard
Identification
Assessment
Review
Committee.

FROM:
Pamela
M.
Hurley
Reregistration
Branch
3
Health
Effects
Division
(
7509C)

THROUGH:
Jess
Rowland,
Co­
Chair
and
Karen
Whitby,
Co­
Chair
Hazard
Identification
Assessment
Review
Committee
Health
Effects
Division
(
7509C)

TO:
Jose
Morales,
Risk
Assessor
Reregistration
Branch
3
Health
Effects
Division
(
7509C)

PC
Code:
106201
On
February
3,
2004,
the
Health
Effects
Division
(
HED)
Hazard
Identification
Assessment
Review
Committee
(
HIARC)
reviewed
the
recommendations
of
the
toxicology
reviewer
for
Amitraz
with
regard
to
the
acute
and
chronic
Reference
Doses
(
RfDs)
and
the
toxicological
endpoint
selection
for
use
as
appropriate
in
occupational/
residential
exposure
risk
assessments.
The
potential
for
increased
susceptibility
of
infants
and
children
from
exposure
to
Amitraz
was
also
evaluated
as
required
by
the
Food
Quality
Protection
Act
(
FQPA)
of
1996
in
accordance
with
the
2002
OPP
10X
guidance
document.
The
conclusions
drawn
at
this
meeting
are
presented
in
this
report.
2
Committee
Members
in
Attendance
Members
present
were:
Jess
Rowland,
Brenda
Tarplee,
Jessica
Kidwell,
Susan
Makris,
William
Burnam,
William
Dykstra,
John
Liccione,
P.
V.
Shah,
Ray
Kent,
Pamela
Hurley
Member(
s)
in
absentia:
Karen
Whitby,
Paula
Deschamp,
Ayaad
Assaad,
Jonathan
Chen,
Elizabeth
Mendez
Data
evaluation
prepared
by:
Pamela
Hurley,
Reregistration
Branch
3
Also
in
attendance
were:
Catherine
Eiden,
Chief,
Reregistration
Branch
3
Data
Evaluation
/
Report
Presentation
Pamela
M.
Hurley
Toxicologist
3
INTRODUCTION
On
February
3,
2004,
the
Health
Effects
Division
(
HED)
Hazard
Identification
Assessment
Review
Committee
(
HIARC)
reviewed
the
recommendations
of
the
toxicology
reviewer
for
Amitraz
with
regard
to
the
acute
and
chronic
Reference
Doses
(
RfDs)
and
the
toxicological
endpoint
selection
for
use
as
appropriate
in
occupational/
residential
exposure
risk
assessments.
The
potential
for
increased
susceptibility
of
infants
and
children
from
exposure
to
Amitraz
was
also
evaluated
as
required
by
the
Food
Quality
Protection
Act
(
FQPA)
of
1996
in
accordance
with
the
2002
OPP
10X
guidance
document.

I.
FQPA
HAZARD
CONSIDERATIONS
1.
Adequacy
of
the
Toxicity
Data
Base
The
HIARC
concluded
that
the
toxicology
database
for
Amitraz
is
not
complete.

2.
Evidence
of
Neurotoxicity
The
HIARC
concluded
that
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.
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
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.
These
signs
could
be
evidence
of
neurotoxicity.

3.
Developmental
Toxicity
Study
Conclusions
a.
In
a
developmental
toxicity
study
(
MRID
44265902)
Amitraz
(
99.7%
a.
i.,
batch/
lot
#
CR
20575/
3)
was
administered
to
three
groups
of
24
mated
female
Sprague
Dawley
Crl:
CD(
SD)
BR
rats/
dose
in
1%
w/
v
methyl
cellulose
in
distilled
water
by
gavage
at
dose
levels
of
0,
7.5,
15,
or
30
mg/
kg
bw/
day
in
10
mL/
kg
bw
from
days
6
through
15
of
gestation.
The
control
group
was
given
the
vehicle
(
1%
w/
v
methylcellulose
in
distilled
water)
only.

Maternal
toxicity
was
manifested
in
the
mid­
and
high­
dose
groups
by
decreases
in
body
weight
(
5%
and
8%,
respectively),
body
weight
gain
(
11%
and
21%,
respectively;
uterine
weights
not
taken
into
account)
and
food
consumption
(
high
dose
only,
16%
less
than
controls).
At
15
mg/
kg/
day,
the
decreases
in
body
weight
and
body
weight
gain
were
borderline
but
were
enough
to
consider
15
mg/
kg/
day
as
a
LOAEL.
The
maternal
LOAEL
is
15.0
mg/
kg
bw/
day,
based
on
decreases
in
body
weight
and
body
weight
gain.
The
maternal
NOAEL
is
7.5
mg/
kg
bw/
day.

Dilated
ureters
and
renal
pelvic
cavitation
were
observed
in
all
groups,
including
controls.
On
a
fetal
basis,
an
increase
in
the
incidence
of
dilated
ureters
was
observed
at
30
mg/
kg/
day
(
65%
compared
to
46.4%
in
the
control
group,
p<
0.01).
However,
these
were
observed
in
23
litters
4
versus
21
litters
in
the
control
group
and
are
thus
not
considered
to
be
toxicologically
significant.
Again,
on
a
fetal
basis,
increases
in
bilateral
renal
pelvic
cavitation
at
both
15
and
30
mg/
kg/
day
(
2.9%
in
controls
versus
5.7%
and
7.1%
at
15
and
30
mg/
kg/
day,
respectively)
were
observed.
In
this
case,
6
litters
were
affected
in
the
control
group
versus
10
and
11
litters
affected
at
15
and
30
mg/
kg/
day,
respectively.
These
incidences
were
not
statistically
significant,
although
were
likely
close
to
an
effect
level.
When
dilated
ureters
and
renal
pelvic
cavitation
grouped
together,
the
incidences
are
similar
to
those
observed
for
dilated
ureters
alone.
If
the
rats
had
been
treated
at
higher
dose
levels,
it
is
likely
that
a
clear
effect
level
would
have
been
observed.

The
developmental
LOAEL
is
greater
than
30
mg/
kg/
day.
The
developmental
NOAEL
is
30
mg/
kg/
day.

The
developmental
toxicity
study
in
the
rat
is
classified
acceptable­
guideline
and
satisfies
the
guideline
requirements
for
a
developmental
toxicity
study
(
OPPTS
870.3700;
§
83­
3a)
in
the
rat.

b.
In
a
developmental
toxicity
study
(
MRID
00029959)
amitraz
(%
a.
i
and,
batch/
lot
#
not
provided)
was
administered
to
11­
13
Boots­
Wistar
rats/
dose
by
gavage
(
assumed)
in
0.4%
cellulose
at
dose
levels
of
0,
1,
3,
or
12
mg/
kg
bw/
day
from
days
8
through
20
of
gestation.

No
treatment
related
maternal
effects
were
observed;
however,
in
a
1­
generation
reproduction
study
where
rats
(
same
strain,
laboratory
and
year)
were
administered
the
test
material
by
gavage
from
gestation
day
1
through
lactation
day
21,
dams
receiving
12
mg/
kg/
day
gained
20%
less
weight
than
the
control
group
during
gestation.
Utilizing
data
from
that
study
(
MRID
00029960),
the
maternal
LOAEL
is
12
mg/
kg
bw/
day,
based
on
decrease
in
body
weight
gain
.
The
maternal
NOAEL
is
3
mg/
kg
bw/
day.

The
developmental
LOAEL
is
undetermined.
The
developmental
NOAEL
is
12
mg/
kg
bw/
day
(
HDT).

The
developmental
toxicity
study
in
the
rat
is
classified
unacceptable
guideline;
and
does
not
satisfy
the
guideline
requirement
for
a
developmental
toxicity
study
(
OPPTS
870.3700;
OECD
414)
in
the
rat.
Very
limited
data
were
provided,
the
purity
of
the
test
substance
was
not
provided
and
the
dosage
period
was
from
gestation
days
8­
20
which
excludes
some
important
gestation
days.

c.
In
a
developmental
toxicity
study
(
MRID
00029961)
amitraz
(%
a.
i
and,
batch/
lot
#
not
provided)
was
administered
to
8­
10
New
Zealand
White
rabbits/
dose
by
gavage
(
assumed)
in
0.4%
cellulose
at
dose
levels
of
0,
1,
5,
or
25
mg/
kg
bw/
day
from
days
6
through
18
of
gestation.

No
treatment­
related
maternal
effects
were
observed
at
either
1
or
5
mg/
kg/
day.
At
25
mg/
kg/
day,
the
does
gained
less
weight
than
the
control
group
and
4
does
aborted.
The
maternal
LOAEL
is
25
mg/
kg
bw/
day,
based
on
decrease
in
body
weight
gain
and
abortions.
The
maternal
NOAEL
is
5
mg/
kg
bw/
day.

No
treatment­
related
developmental
effects
were
observed
at
either
1
or
5
mg/
kg/
day.
At
25
mg/
kg/
day,
decreased
litter
size,
decreased
implantations,
increased
postimplantation
loss
and
decreased
mean
fetal
body
weight
were
observed.
The
developmental
LOAEL
is
25
mg/
kg
5
bw/
day,
based
on
decreased
litter
size,
decreased
implantations,
increased
postimplantation
loss
and
decreased
mean
fetal
body
weight.
The
developmental
NOAEL
is
5
mg/
kg
bw/
day.

The
developmental
toxicity
study
in
the
rabbit
is
classified
unacceptable
guideline;
and
does
not
satisfy
the
guideline
requirement
for
a
developmental
toxicity
study
(
OPPTS
870.3700;
OECD
414)
in
the
rat.
Very
limited
data
were
provided,
there
is
no
indication
that
gavage
dosing
was
used
(
it
is
assumed),
there
was
a
limited
number
of
litters
available
for
analysis
(
too
few
does)
and
the
purity
of
the
test
substance
was
not
provided.

d.
In
a
developmental
toxicity
study
(
MRID
44265901)
Amitraz
(
99.7%
a.
i.,
batch/
lot
#
CR
20575/
3)
was
administered
to
three
groups
of
16
mated
female
New
Zealand
White
rabbits/
dose
in
1%
w/
v
methyl
cellulose
in
distilled
water
by
gavage
at
dose
levels
of
0,
3,
6,
or
12
mg/
kg
bw/
day
in
2
mL/
kg
bw
from
days
7
through
19
of
gestation.
The
control
group
was
given
the
vehicle
(
1%
w/
v
methylcellulose
in
distilled
water)
only.

At
12
mg/
kg/
day,
mortality
was
increased,
with
two
does
sacrificed
moribund
after
they
aborted
their
litters.
The
does
lost
a
mean
body
weight
of
0.06
kg
or
2%
of
the
mean
body
weight
early
in
the
dosing
period
(
between
days
7
and
13)
during
which
the
control
group
gained
140
grams
(
4%
of
the
mean
body
weight).
Later
in
the
dosing
period
(
between
days
13
and
19,
the
12
mg/
kg/
day
group
gained
140
grams
(
4%
of
the
mean
body
weight).
Although
these
values
are
small
when
compared
to
the
overall
mean
weight
of
the
does
and
no
statistical
analyses
were
conducted,
it
appears
that
the
high
dose
induces
a
mild
treatment­
related
effect,
especially
since
there
is
a
rebound
effect
following
the
dosing
period.
Food
consumption
during
the
treatment
period
was
decreased
26%
when
compared
to
controls.
Clinical
signs
included
post­
dosing
langor
(
100%
of
the
animals
in
this
group
displayed
this
finding),
polypnea
(
94%)
and
squinting
(
75%).
Three
of
the
does
totally
resorbed
their
litters.
No
doe
in
any
other
group
displayed
a
total
litter
resorption.
At
6
mg/
kg/
day,
post­
dosing
langor
(
94%),
polypnea
(
75%)
and
squinting
(
25%)
were
observed.
At
3
mg/
kg/
day,
the
same
clinical
signs
were
observed:
post­
dosing
languor
(
75%),
polypnea
(
25%)
and
squinting
(
13%).
These
clinical
signs
were
not
observed
in
the
control
group.

Deaths
were
observed
in
all
groups,
including
controls.
There
was
considerable
gavage
error.
Unfortunately,
maternal
toxicity
was
confounded
by
indications
that
the
animals
were
likely
suffering
from
a
respiratory
illness
throughout
the
study.
The
animals
appear
to
have
been
ill
from
the
start,
even
in
the
control
group.
There
was
a
high
incidence
of
rhinorrhea
and
fur
staining
of
the
paws.
Necropsy
results
revealed
a
high
incidence
of
abnormal
contents
in
the
thoracic
cavity
and
lungs
(
colored
fluid,
white
semi­
solid
foci
on
pleura,
other
changes)
in
all
groups,
including
controls.
Some
of
the
results
from
these
animals
may
be
attributable
to
gavage
administration.

The
maternal
LOAEL
is
3.0
mg/
kg
bw/
day,
based
on
clinical
signs
in
all
treated
groups.
Decreases
in
body
weight
gain
and
food
consumption
were
observed
at
the
highest
dose
level
(
12
mg/
kg/
day).
The
maternal
NOAEL
is
not
established.

There
were
no
indications
of
developmental
toxicity;
however,
in
two
of
the
treated
groups,
there
were
a
limited
number
of
litters
available
for
an
adequate
analysis.
The
number
of
available
litters
ranged
from
9
to
14
for
each
treated
and
control
group.
An
apparent
increase
in
early
resorptions
and
percent
postimplantation
loss
was
seen
at
12
mg/
kg/
day;
however,
these
increases
were
due
6
to
the
fact
that
three
does
at
this
dose
totally
resorbed
their
litters
(
88%
of
the
early
resorptions
at
12
mg/
kg/
day
were
found
in
the
three
does
which
displayed
total
litter
resorptions).
Examination
of
body
weight
gain
and
food
consumption
in
the
animals
displaying
total
litter
resorptions
indicates
that
the
total
litter
resorptions
were
likely
due
to
maternal
toxicity
rather
than
a
direct
effect
on
the
embryo/
fetus.

The
developmental
LOAEL
is
greater
than
12
mg/
kg
bw/
day,
the
highest
dose
tested.
The
developmental
NOAEL
is
12
mg/
kg
bw/
day.

The
developmental
toxicity
study
in
the
rabbit
is
classified
unacceptable
guideline
and
does
not
satisfy
the
guideline
requirement
for
a
developmental
toxicity
study
(
OPPTS
870.3700;
OECD
414)
in
nonrodents.
Deficiencies
include:
too
few
litters
in
two
of
the
treated
groups
and
preexisting
maternal
illness
which
may
have
confounded
the
results.

4.
Reproductive
Toxicity
Study
Conclusions
a.
In
a
1­
generation
reproduction
study
(
MRID
00029960)
BTS
27419
(
Amitraz
(
purity
and
batch
number
not
provided)
was
administered
to
13
Boots­
Wistar
rats/
sex/
dose
(
14
in
the
high
dose)
by
gavage
(
assumed)
at
dose
levels
of
0,1,
3
or
12
mg/
kg
bw/
day
in
a
volume
of
1
ml/
100
g
body
weight
from
gestation
days
1
through
lactation
day
21.

At
12
mg/
kg/
day,
the
dams
gained
a
mean
of
20%
(
p<
0.001)
less
weight
than
the
control
group.
No
maternal
effects
were
observed
in
any
other
treated
group.
No
information
was
provided
on
males.
The
maternal
systemic
LOAEL
is
12
mg/
kg
bw/
day,
based
on
decrease
in
body
weight
gain.
The
maternal
systemic
NOAEL
is
3
mg/
kg
bw/
day.

At
12
mg/
kg/
day,
there
was
a
slightly
lower
mean
litter
size
at
birth
and
on
lactation
day
4
(
p
<
0.01).
By
lactation
day
21,
mean
litter
size
was
comparable
to
the
control
group.
The
offspring
LOAEL
is
12
mg/
kg
bw/
day.
The
offspring
NOAEL
is
3
mg/
kg
bw/
day.
Note:
The
NOAEL
is
lower
than
the
original
DER
because
the
slightly
lower
mean
litter
sizes
support
the
NOAEL,
LOAEL
and
effects
observed
in
the
multi­
generation
reproduction
study
(
MRID
00029962).

No
reproductive
effects
were
observed.

This
study
is
unacceptable,
non­
guideline
and
does
not
satisfy
the
guideline
requirement
for
a
multi­
generation
reproduction
study
(
OPPTS
870.3800;
OECD
416)
in
the
rat.
It
is
only
one
generation,
only
provides
limited
information
and
does
not
provide
the
purity
of
the
test
compound.

b.
In
a
3­
generation
reproduction
study
(
MRID
00029962)
BTS
27
419
(
Amitraz
(
purity
not
provided,
batch/
lot
#
2099DR)
was
administered
to
10
male
and
20
female
Boots­
Wistar
rats/
dose
in
the
diet
at
dose
levels
of
0,
15,
50,
or
200
ppm
(
equivalent
to
0,
1.29,
4.36,
or
16.41
mg/
kg
bw/
day
for
males
and
1.58,
5.09
or
20.05
mg/
kg
bw
for
females).
One
litter
was
produced
per
generation.

At
16.41/
20.05
mg/
kg/
day,
the
F0
parents
gained
less
mean
body
weight
than
the
control
group
7
during
the
premating
period
(
7%
in
males,
14%
in
females;
statistically
significant
in
females).
Body
weights
were
not
reported
during
either
the
gestation
or
lactation
periods.
Body
weight
values
were
not
measured
at
this
dose
level
in
succeeding
generations
because
of
a
nearly
complete
loss
of
the
high
dose
group
during
the
F1
generation.
No
other
parental
effects
were
observed
in
any
of
the
treated
groups.

The
parental
systemic
LOAEL
is
200
ppm
(
16.41
mg/
kg
bw/
day
in
males,
20.05
mg/
kg
bw/
day
in
females),
based
on
decreased
body
weight
gain
during
the
F0
premating
period.
The
parental
systemic
NOAEL
is
50
ppm
(
4.36
mg/
kg
bw/
day
in
males,
5.09
mg/
kg
bw/
day
in
females).

At
16.41/
20.05
mg/
kg/
day,
there
was
an
almost
complete
loss
of
pups
in
the
F1
generation
during
the
lactation
period
(
5
remaining
pups
versus
115
remaining
pups
in
the
control
group).
In
addition,
there
was
a
reduction
in
mean
litter
size
on
day
1
(
6.7
pups/
litter
versus
7.9
pups/
litter
in
the
control
group).
At
4.36/
5.09
mg/
kg/
day,
in
each
generation,
there
was
a
higher
number
of
pup
deaths
than
in
the
control
group.
By
day
21,
the
mean
litter
size
was
smaller
but
was
not
statistically
significantly
smaller
until
the
final
generation
(
p
<
0.05).

The
offspring
LOAEL
is
50
ppm
(
4.36/
5.09
mg/
kg
bw/
day),
based
on
decreased
survival
and
mean
litter
size
during
lactation.
The
offspring
NOAEL
is
15
ppm
(
1.29/
1.58
mg/
kg
bw/
day).

This
study
is
unacceptable
guideline
and
does
not
satisfy
the
guideline
requirement
for
a
[
3]­
generation
reproductive
study
(
OPPTS
870.3800);
OECD
416
in
the
rat.
The
percent
active
ingredient
of
the
test
substance
was
not
reported,
very
limited
data
were
provided,
mating
was
not
1
male
to
1
female
(
only
10
males
used/
dose
group/
generation),
no
data
on
reproductive
organs
were
provided,
litter
data
were
only
provided
for
a
few
time
points,
and
histopathology
data
were
not
provided.

5.
Additional
Information
from
Literature
Sources
No
additional
information
on
developmental/
reproductive
toxicity
and
neurotoxicity
were
found
in
the
literature.

6.
Pre­
and/
or
Postnatal
Toxicity
The
HIARC
cannot
conclude
whether
or
not
there
is
any
concern
for
pre­
and/
or
postnatal
toxicity
resulting
from
exposure
to
Amitraz
because
neither
the
rabbit
developmental
nor
the
rat
reproduction
studies
are
acceptable
and
they
have
too
many
deficiencies.
8
A.
Determination
of
Susceptibility
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
or
following
pre
and/
or
postnatal
exposure
to
rats
could
not
be
ascertained
due
to
many
deficiencies
in
study
designs
and/
or
study
reports.

B.
Degree
of
Concern
Analysis
and
Residual
Uncertainties
There
are
no
concerns
for
residual
uncertainty
for
pre­
natal
toxicity
in
the
available
developmental
toxicity
study
in
rats.

The
HIARC
determined
that
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
following
considerations:

°
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.

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

°
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).

°
Application
of
the
10X
UF
DB
to
the
NOAEL
(
0.25
mg/
kg/
day)
selected
for
the
overall
risk
assessments
yields
a
dose
of
0.025
mg/
kg/
day
which
is
approximately
200­
fold
lower
than
the
lowest
developmental
NOAEL
(
5.0
mg/
kg/
day)
in
the
unacceptable
rabbit
studies
and
50­
fold
lower
than
the
offspring
NOAEL
in
the
unacceptable
three­
generation
reproduction
study.

C.
Special
FQPA
Safety
Factor(
s):

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.

The
Special
FQPA
Safety
Factor
recommended
by
the
HIARC
assumes
that
the
exposure
databases
(
dietary
food,
drinking
water,
and
residential)
are
complete
and
that
the
risk
assessment
for
each
potential
exposure
scenario
includes
all
metabolites
and/
or
degradates
of
concern
and
does
not
underestimate
the
potential
risk
for
infants
and
children
9
7.
Recommendation
for
a
Developmental
Neurotoxicity
Study
The
HIARC
concluded
that
there
is
concern
for
developmental
neurotoxicity
resulting
from
exposure
to
Amitraz.

A.
Evidence
that
suggest
requiring
a
Developmental
Neurotoxicity
study:

°
The
available
toxicity
database
indicates
that
clinical
signs
of
CNS
toxicity
are
observed
in
rats,
dogs
and
possibly
rabbits.

B.
Evidence
that
do
not
support
a
need
for
a
Developmental
Neurotoxicity
study:

°
None
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.

II.
HAZARD
IDENTIFICATION
1.
Acute
Reference
Dose
(
aRfD)
­
General
Population,
including
Infants
and
Children
Study
Selected:
Chronic
Dog
Study
§
870.4100
MRID
No.:
00044586
Executive
Summary:
In
a
chronic
toxicity
study
(
MRID
00044586)
Amitraz
(%
a.
i.
and
batch/
lot
#
not
provided)
was
administered
to
4
beagle
dogs/
sex/
dose
in
gelatin
capsules
at
dose
levels
of
0,
0.1,
0.25,
or
1.0
mg/
kg
bw/
day)
for
2
years.
Clinical
signs
were
monitored;
body
weight
and
temperature,
hematology,
clinical
chemistry,
urinalysis
and
organ
weight
parameters
were
measured;
and
gross
and
microscopic
examinations
were
conducted.
10
At
1.0
mg/
kg/
day,
all
8
dogs
had
CNS
depression
on
the
first
two
days
of
dosing;
however,
the
data
on
clinical
signs
were
not
submitted.
There
was
a
dose­
related
decrease
in
body
temperature
after
dosing
that
lasted
approximately
6
hours;
however,
body
temperatures
essentially
remained
in
the
normal
range.
The
LOAEL
is
1.0
mg/
kg/
day,
based
on
CNS
depression
during
the
first
two
days
of
dosing.
The
NOAEL
is
0.25
mg/
kg/
day.

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

Dose
and
Endpoint
for
Establishing
aRfD:
NOAEL
of
0.25
mg/
kg/
day
based
on
CNS
depression
during
the
first
two
days
of
dosing
at
the
LOAEL
of
1.0
mg/
kg/
day.

Uncertainty
Factor
(
UF):
1000
(
10x
for
interspecies
extrapolation,
10x
for
intraspecies
variations
and
10x
for
data
gaps.)

Comments
about
Study/
Endpoint/
Uncertainty
Factor:
This
study
is
appropriate
for
an
acute
dietary
endpoint
because
CNS
effects
were
observed
three
hours
after
administration
of
a
single
dose.
This
endpoint
is
supported
by
similar
clinical
signs
observed
in
humans
following
an
acute
exposure
(
TXR
No.
011110)
.

2.
Chronic
Reference
Dose
(
cRfD)

Study
Selected:
Chronic
Dog
Study
§
870.4100
MRID
No.:
00044586
Executive
Summary:
See
Section
II.
1.
Acute
Reference
Dose
(
aRfD)

Dose
and
Endpoint
for
Establishing
cRfD:
NOAEL
of
0.25
mg/
kg/
day
based
on
CNS
depression
during
the
first
two
days
of
dosing
at
the
LOAEL
of
1.0
mg/
kg/
day.

Uncertainty
Factor(
s):
1000
(
10x
for
interspecies
extrapolation,
10x
for
intraspecies
variations
and
10x
for
data
gaps.)

Comments
about
Study/
Endpoint/
Uncertainty
Factor:
Although
effects
were
observed
early
on
in
the
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.
Acute
RfD
=
0.25
(
NOAEL
)
mg/
kg/
day
=
0.00025
mg/
kg/
day
1000
(
UF
)
11
3.
Incidental
Oral
Exposure:
All
Durations
(
1
­
30
days
and
1­
6
Months)

Study
Selected:
Chronic
Dog
Study
§
870.4100
MRID
No.:
00044586
Executive
Summary:
See
Section
II.
1.
Acute
Reference
Dose
(
aRfD)

Dose
and
Endpoint
for
Risk
Assessment:
NOAEL
of
0.25
mg/
kg/
day
based
on
CNS
depression
during
the
first
two
days
of
dosing
at
the
LOAEL
of
1.0
mg/
kg/
day.

Comments
about
Study/
Endpoint:
This
study
is
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.

4.
Dermal
Absorption
Dermal
Absorption
Factor:
8%

Ten
male
rats
were
dosed
via
the
dermal
route
with
the
M82
formulation
of
amitraz
diluted
in
water
at
a
dose
of
91
micrograms/
cm2
a.
i.
(
MRID
42133501).
The
application
site
was
shaved
and
washed
with
acetone
24
hours
before
dosing.
After
dosing
the
site
was
protected
with
a
nonocclusive
device
and
the
animals
were
placed
individually
in
metabolism
cages
for
collection
of
total
urine
and
feces.
After
ten
hours
of
exposure,
the
application
site
of
each
animal
was
washed
quantitatively
with
soap
and
water
and
the
animals
were
returned
to
metabolism
cages.
At
24
hours
post
dosing,
5
animals
were
euthanized
and
the
application
site
skin,
digestive
tract
and
the
remaining
carcass
were
collected
for
analysis.
The
remaining
five
animals
were
carried
for
five
days
postdosing,
with
total
urine
and
fecal
samples
for
each
24
hour
period,
and
then
terminated
as
above.
The
mean
percent
of
dose
available
for
risk
assessment
purposes
is
shown
in
the
following
table.

Dermal
Absorption
Study
in
Rats:
Mean
Percent
of
Dose
Available
for
Risk
Assessment
24
Hours
(%)
120
Hours
(%)

Treatment
Site
2.98
1.41
Total
Absorbed
3.69
6.56
Total
6.67
7.79
Chronic
RfD
=
0.25
(
NOAEL
)
mg/
kg/
day
=
0.00025
mg/
kg/
day
1000
(
UF
)
12
5.
Dermal
Exposure:
All
Durations
(
1
­
30
days,
1­
6
Months
and
>
6
Months)

Study
Selected:
Chronic
Dog
Study
§
870.4100
MRID
No.:
00044586
Executive
Summary:
See
Section
II.
1.
Acute
Reference
Dose
(
aRfD)

Dose
and
Endpoint
for
Risk
Assessment:
NOAEL
of
0.25
mg/
kg/
day
based
on
CNS
depression
during
the
first
two
days
of
dosing
at
the
LOAEL
of
1.0
mg/
kg/
day.

Comments
about
Study/
Endpoint:
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
for
risk
assessments
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
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.

6.
Inhalation
Exposure:
All
Durations
(
1
­
30
days,
1­
6
Months
and
>
6
Months)

Study
Selected:
Chronic
Dog
Study
§
870.4100
MRID
No.:
00044586
Executive
Summary:
See
Section
II.
1.
Acute
Reference
Dose
(
aRfD)

Dose/
Endpoint
for
Risk
Assessment:
NOAEL
of
0.25
mg/
kg/
day
based
on
CNS
depression
during
the
first
two
days
of
dosing
at
the
LOAEL
of
1.0
mg/
kg/
day.

Comments
about
Study/
Endpoint:
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
dermal
risk
assessments.
Although
the
endpoint
of
concern
(
CNS
depression)
was
seen
after
a
few
exposures,
it
is
appropriate
for
all
13
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.

7.
Margins
of
Exposure
Summary
of
target
Margins
of
Exposure
(
MOEs)
for
risk
assessment.

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

Occupational
(
Worker)
Exposure
Dermal
100
100
100
Inhalation
100
100
100
Residential
(
Non­
Dietary)
Exposure
Oral
1000
1000
N/
A
Dermal
1000
1000
1000
Inhalation
1000
1000
1000
For
Occupational
exposure:
This
is
based
on
the
conventional
uncertainty
factor
of
100X
(
10X
for
intraspecies
extrapolation
and
10X
for
interspecies
variation)

For
Residential
exposure:
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.

8.
Recommendation
for
Aggregate
Exposure
Risk
Assessments
As
per
FQPA,
1996,
when
there
are
potential
residential
exposures
to
the
pesticide,
aggregate
risk
assessment
must
consider
exposures
from
three
major
sources:
oral,
dermal
and
inhalation
exposures.
The
toxicity
endpoints
selected
for
these
routes
of
exposure
may
be
aggregated
as
follows:
for
short­,
intermediate­
and
long­
term
aggregate
exposure
risk
assessments,
the
oral,
dermal
and
inhalation
routes
can
be
combined
because
of
the
common
study
endpoint
used
for
these
routes
(
i.
e.,
oral
equivalent
doses
were
selected
for
the
dermal
and
inhalation
routes).
14
III.
CLASSIFICATION
OF
CARCINOGENIC
POTENTIAL
1.
Combined
Chronic
Toxicity/
Carcinogenicity
Study
in
Rats
MRID
No.
00044585
Executive
Summary:
In
a
combined
chronic
/
carcinogenicity
study
(
MRID
00044585)
BTS
27
419
(
97.8­
99.8
%
a.
i,
batch/
lot
#'
s
2093DH,
2099DH)
was
administered
to
40
Ash­
Wistar
SPF
rats/
sex/
dose
in
the
diet
at
dose
levels
of
0,
15,
50,
or
200
ppm
(
equivalent
to
0,
0.77/
0.97,
2.5/
3.13
or
10.18/
12.59
mg/
kg
bw/
day,
males/
females,
respectively)
for
2
years.

There
was
no
treatment­
related
effect
on
survival.
The
number
of
rats
reported
as
excitable,
nervous
or
aggressive
was
increased
in
the
50
(
females)
and
200
ppm
groups
(
males
and
females);
the
females
were
more
frequently
affected.
Body
weight
gain
was
decreased
in
the
200
ppm
group
at
weeks
0­
12
for
both
males
and
females,
weeks
12­
24
for
females,
and
weeks
24­
36
and
0­
104
for
males.
Food
consumption
was
reduced
in
both
the
males
and
females
in
the
200
ppm
group
at
the
beginning
of
treatment
but
then
was
comparable
to
the
control
group.
There
were
no
treatment­
related
effects
on
clinical
pathology
parameters
or
necropsy
findings.
The
incidence
of
tumors
was
comparable
between
the
treated
and
control
groups.
The
LOAEL
is
200
ppm
(
males,
10.18
mg/
kg/
day
based
on
clinical
signs
and
decreased
body
weight
gain)
and
50
ppm
(
females,
3.13
mg/
kg/
day
based
on
clinical
signs).
The
NOAEL
is
50
ppm
(
males,
2.5
mg/
kg/
day)
and
15
ppm
(
females,
0.97
mg/
kg/
day).

At
the
doses
tested,
there
were
no
treatment­
related
increases
in
tumor
incidence
when
compared
to
controls.
Dosing
was
considered
adequate
based
on
clinical
signs
and
decreased
body
weight
gain.

This
chronic/
carcinogenicity
study
in
the
rat
is
acceptable
guideline
and
satisfies
the
guideline
requirement
for
a
chronic/
carcinogenicity
study
OPPTS
870.4300);
OECD
453]
in
the
rat.

Discussion
of
Tumor
Data:
At
the
doses
tested,
there
were
no
treatment­
related
increases
in
tumor
incidence
when
compared
to
controls.

Adequacy
of
the
Dose
Levels
Tested:
Dosing
was
considered
adequate
based
on
clinical
signs
of
neurotoxicity
and
decreased
body
weight
gain.

2.
Carcinogenicity
Study
in
Mice
MRID
No.
00139552
Executive
Summary:
In
a
carcinogenicity
study
(
MRID
00139552)
Amitraz
(
88.2­
100.8%
a.
i.,
batch
#'
s
34732Y,
52221,
56105)
was
administered
to
100
control
and
75
treated
B6C3F1
mice/
sex/
dose
in
the
diet
at
dose
levels
of
0,
25,
100
or
400
ppm
(
equivalent
to
0,
2.31/
2.63,
9.61/
10.77,
or
44.65/
50.13
mg/
kg
bw/
day)
for
104
weeks.
15
At
2.31/
2.63
mg/
kg/
day
and
above,
a
dose­
related
increase
in
the
incidence
of
hyperplastic
nodules,
basophilic
and
telangiectatic
foci
was
observed
in
the
liver
of
females,
accompanied
by
an
increased
incidence
of
stomach
hyperkeratosis
and
spleen
hematopoiesis
in
males.

At
9.61/
10.77
mg/
kg/
day
and
above,
hyperactivity
and
aggressive
behavior
were
observed
in
males
during
the
first
12
weeks
of
the
study.
Cutaneous
lesions,
as
evidence
of
fighting
were
also
observed.
By
week
52,
mean
body
weight
gain
was
reduced
by
29%
in
males
and
32%
in
females
(
p<
0.01).
A
6%
decrease
in
food
consumption
was
observed
in
males
during
weeks
1­
12
at
both
the
mid­
and
high
dose
levels
(
p<
0.05)
and
during
weeks
13­
25
at
the
mid­
dose
level
(
p<
0.01).
An
increase
in
food
consumption
was
recorded
at
the
high­
dose
level
in
males
during
weeks
26­
104
(
9­
13%).
In
females,
5­
11%
decreases
in
food
consumption
were
observed
during
weeks
1­
19
(
p<
0.05),
followed
by
increases
in
food
consumption
during
weeks
31­
58
and
93­
104.
The
bone
marrow
myeloid/
erythroid
ratio
was
significantly
reduced
(
p<
0.001)
in
females
(
22%
and
26%
at
the
mid­
and
high­
dose
levels,
respectively).

At
44.65/
50.13
mg/
kg/
day,
piloerection
and
hunched
posture
were
observed
in
males
during
weeks
2­
4.
Food
utilization
was
lower
for
both
sexes
during
the
first
24
weeks
of
the
study
(
approximately
35%­
42%
lower).
Mean
body
weight
gain
was
reduced
by
week
52
in
males
and
females
(
29%
and
32%,
respectively,
p<
0.01).
The
bone
marrow
myeloid/
erythroid
ratio
was
significantly
reduced
(
p<
0.001)
in
males
(
24%).

Males
had
a
significant
positive
trend
in
mortality
with
incremental
doses
of
amitraz.

The
LOAEL
is
2.31/
2.63
mg/
kg/
day,
based
on
a
dose­
related
increase
in
the
incidence
of
hyperplastic
nodules,
basophilic
and
telangiectatic
foci
in
the
liver
of
females,
accompanied
by
an
increased
incidence
of
stomach
hyperkeratosis
and
spleen
hematopoiesis
in
males.
The
NOAEL
is
less
than
2.31/
2.63
mg/
kg/
day.

In
females
there
were
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.
Males
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.
Reduction
in
body
weight
gain
and
a
significant
positive
trend
in
mortality
in
male
mice
suggest
that
the
highest
dose
tested
was
excessive.
In
females,
however,
the
highest
dose
was
high
but
not
excessive
since
it
was
not
life­
threatening.

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

Discussion
of
Tumor
Data:
In
females
there
were
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.
Males
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.
16
Adequacy
of
the
Dose
Levels
Tested
Reduction
in
body
weight
gain
and
a
significant
positive
trend
in
mortality
in
male
mice
suggest
that
the
highest
dose
tested
was
excessive.
In
females,
however,
the
highest
dose
was
high
but
not
excessive
since
it
was
not
life­
threatening.

3.
Classification
of
Carcinogenic
Potential:

The
HED
Cancer
Peer
Review
Committee
met
on
October
31,
1990
and
determined
that
Amitraz
should
be
classified
as
a
Group
C,
possible
human
carcinogen.
The
Q
1*
was
calculated
to
be
5.0
x
10­
2,
based
upon
the
combined
hepatocellular
adenomas
and
carcinomas
in
female
mice.
A
2/
3'
s/
day
cross
species
scaling
factor
was
utilized
for
the
calculation.
On
February
11,
2004,
a
revised
Q
1*
of
2.83
x
10­
2
in
human
equivalents
was
estimated
using
the
3/
4'
s
scaling
factor,
reflecting
the
change
in
Agency
policy
in1994.

IV.
MUTAGENICITY
The
HIARC
concluded
that
there
is
not
a
concern
for
mutagenicity
resulting
from
exposure
to
Amitraz.

Amitraz:
Results
of
Mutagenicity
Studies
Study
Type
Results
Salmonella
reverse
gene
mutation
(
Ames)
Negative
up
to
10
mg/
plate,
w/
wo
metabolic
activation.
MRID
00161009
Forward
Gene
Mutation
Assay
(
mouse
L5178Y
lymphoma
cells)
Negative
at
0.06­
20

g/
ml
w/
wo
activation.
HDT
is
highest
non­
cytotoxic
dose.
MRID
00161008
In
vitro
Structural
Chromosome
Aberration
Assay
(
human
lymphocytes)
Negative
up
to
cytotoxic
and/
or
insoluble
concentrations.
MRID
41795101
Unscheduled
DNA
Synthesis
(
human
embryonic
lung
fibroblast)
Negative
up
to
cytotoxic
concentrations,
w/
wo
activation.
MRID
00161011
Morphological
Transformation
(
C3H/
10T1/
2
cells
derived
from
mouse
embyro
fibroblast)
Negative
up
to
cytotoxic
concentrations,
w/
wo
activation.
MRID
00161010
V.
HAZARD
CHARACTERIZATION
Amitraz
has
a
low
acute
toxicity
by
the
oral,
dermal
and
inhalation
routes
in
a
wide
number
of
species.
It
has
been
tested
in
mice,
rats,
guinea
pigs,
rabbits,
dogs,
baboons
and
domestic
pigs
by
the
oral,
dermal
and
inhalation
routes
of
exposure.
In
the
Registration
Standard
(
TXR
005633),
a
pharmacotoxic
profile
suggests
a
depression
of
hypothalmic
function.
Clinical
signs
of
toxicity
include
central
nervous
system
17
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
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.

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.

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.

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,
niether
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
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
18
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.

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
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.
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.
Amitraz
has
not
been
shown
to
induce
gene
mutations
in
either
bacterial
or
mammalian
cells,
is
not
clastogenic,
either
in
vivo
or
in
vitro,
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.

VI.
DATA
GAPS
/
REQUIREMENTS
°
Prenatal
developmental
toxicity
study
in
rabbits
(
870.3700)

°
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.

°
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
nondietary
(
incidental
oral,
dermal
and
inhalation)
risk
assessments
because
the
required
studies
may
provide
endpoints
applicable
for
risk
assessments.

°
A
28­
day
inhalation
study
which
should
follow
the
OPPTS
Guidance
870.3465,
with
cessation
of
exposure
at
28
days.
19
VII.
ACUTE
TOXICITY
Acute
Toxicity
of
Amitraz
Guideline
No.
Study
Type
MRID
#(
s)
Results
Toxicity
Category
81­
1
Acute
Oral
00041539
LD
50:
531
mg/
kg
(
M)
515
mg/
kg
(
F)
III
81­
2
Acute
Dermal
00040862
LD
50:
>
200
mg/
kg
II
81­
3
Acute
Inhalation
00029963
LC
50:
2.4
mg/
L
III
81­
4
Primary
Eye
Irritation
00040861
Non­
irritating
IV
81­
5
Primary
Skin
Irritation
00040862
Non­
irritating
IV
81­
6
Dermal
Sensitization
­
G.
Pigs
00029965
Not
a
sensitizer
under
conditions
of
study
N/
A
20
VIII.
SUMMARY
OF
TOXICOLOGY
ENDPOINT
SELECTION
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.

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
21
NOTE:
The
Special
FQPA
Safety
Factor
recommended
by
the
HIARC
assumes
that
the
exposure
databases
(
dietary
food,
drinking
water,
and
residential)
are
complete
and
that
the
risk
assessment
for
each
potential
exposure
scenario
includes
all
metabolites
and/
or
degradates
of
concern
and
does
not
underestimate
the
potential
risk
for
infants
and
children.
