Document ID: EPA-HQ-ORD-2006-0187-0082
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-04-05T04:00Z

AMITRAZ:
WOE
Comparison
Of
Human
And
Animal
Studies
For
Single
Chemical
Assessment
John
John
Liccione
Liccione,
Ph.
D.

,
Ph.
D.

U.
S.
EPA
U.
S.
EPA
Office
of
Pesticide
Programs
Office
of
Pesticide
Programs
April
5,
2006
April
5,
2006
2
Amitraz
Amitraz
Uses
Uses

Insecticide/
acaricide

Registered
food/
feed
uses
in
U.
S.

Tick
control
 
dogs

Mite
and
lice
control

Reregistration
Eligibility
Decision
­
1996
3
Human
Intentional
Dosing
Studies
Human
Intentional
Dosing
Studies

Single
Oral
Dose

Acute
Dermal
Dose

Oral
Metabolism
4
Animal
Toxicity
Studies
Animal
Toxicity
Studies

Acute
Oral

Mouse,
cat,
rat,
GP,
rabbit,

dog,
baboon

Repeat
Oral

Subchronic

Chronic
dog,
rat,
mouse

21­
Day
Dermal

Rat

Repeat
Inhalation

Rat

Metabolism

Rat,
mouse,
baboon

Developmental

Rat,
rabbit

Reproduction

Rat
5
Amitraz
Amitraz:
Noncancer
Noncancer
Effects
Effects

Animals

Clinical
signs
°
Excitable,
nervous
&

aggressive
behavior
(
rats)

°
CNS
depression
and
decreased
body
temperature
(
dogs)

°
Dogs
are
most
sensitive

Other
 
Liver,
kidney,
body
weight
loss
(
at
higher
dose
levels)

Humans

Clinical
signs
°
Dry
mouth
°
Slight
pale
appearance
°
Drowsiness,
light
headedness,
disorientation,

Slurred
speech
°
Decreased
body
temperature
°
Bradycardia
6
Human
Study
Details
Human
Study
Details
A
total
of
six
male
volunteers
completed
the
study.
Each
individual
received
all
doses
as
noted
above.
The
phases
were
separated
by
a
two­
week
period.
4
2
0
0.125
mg/
kg
0
2
4
0.0625
mg/
kg
2
2
2
Placebo
Phase
3
Phase
2
Phase
1
Treatment
Single
Oral
Dose
 
MRID
43283101
7
Human
Study
Details
Human
Study
Details

Single
Oral
Dose
°
Double
Blind
°
Encapsulated
in
lactose
°
Frequent
monitoring:
pulse,
respiration
rate,
blood
pressure,
temperature,
ECGs,

psychomotor
performance.
Physical
exams
included
°
Test
material
characterized
(
statistics
included)
8
Human
Study
Details
Human
Study
Details

Effects
in
the
Single
Oral
Dose
Study
°
No
treatment­
related
effects
°
NOAEL
=
0.125
mg/
kg

Strengths
°
Double
blind
°
Adequate
monitoring
for
potential
neurotoxicity

Weaknesses
°
Only
males
studied;
Limited
number
of
subjects
°
No
observed
effects
9
24
P
16
8
8
24
16
P
8
7
P
24
16
8
6
24
16
8
P
5
P
24
16
8
4
24
P
16
8
3
24
16
P
8
2
24
16
8
Placebo
(
P)

1
Phase
IV
Phase
III
Phase
II
Phase
I
Dermal
Dose
of
Amitraz
(
mg/
kg)

Individual
Acute
Dermal
Human
Study
10
Human
Study
Details
Human
Study
Details

Acute
Dermal
Study
°
Double
blind,
sequential
dosing
°
0,
8,
16
or
24
mg/
kg
applied
as
4
equal
doses
of
0,
2,
4
or
6
mg/
g
in
aqueous
1:
1
slurry
every
2.5
hrs
over
10
hrs
according
to
random
schedule
°
Vital
signs,
ECG,
psychomotor
measurements
hematology,
clinical
chemistry,
urinalysis
monitored
°
Test
material
characterized;
statistics
11
Human
Study
Details
Human
Study
Details

Effects
in
the
Dermal
Study
°
No
effects
observed
°
NOAEL
=
24
mg/
kg

Strengths
°
Double
blind
°
Adequate
monitoring
for
potential
Neurotoxicity

Weaknesses
°
Limited
number
of
subjects
°
Only
males
studied
°
No
observed
effects
12
Human
Study
Details
Human
Study
Details
*
Number
of
animals
varied
by
dose
group
and
experiment
(
2
different
experiments
were
run
in
mice
and
rats).
Also,
the
separate
mouse
experiment
that
was
pre­
treated
is
not
reported
here.
2M
0.25
Human
1M,
1F
10
Baboon
0­
4M,
1­
4F
1,
10,
100
Mouse
(
naïve
only)*
2­
3M,
1­
3F
1,
10,
100
Rat
Number/
Gender
Dose
of
Labeled
Amitraz
(
mg/
kg)

Species*
Comparative
Metabolism
Study
13
Human
Study
Details
Human
Study
Details

Metabolism
Study
°
Two
healthy
human
subjects
received
single
dose
(
0.25
mg/
kg)
of
14C­
amitraz
(>
95%
purity
)
by
capsule
°
No
control
group
°
No
statistical
analysis
14
Human
Study
Details
Human
Study
Details

Effects
in
Metabolism
Study
°
First
subject:
dry
mouth,
drowsiness,
disorientation,

slight
paleness
(
90
min
after
Dx).
Fell
asleep
10
min.

later
but
easily
awakened
and
lucid.
After
220
min.,

asleep
but
easily
awakened.
Nausea
and
recurrent
and
vivid
dreams
°
Second
subject:
dry
mouth,
light
headedness,
slurred
speech
(
160
min.
after
Dx).
Decreased
pulse
rate
and
blood
pressure
°
Bradycardia
for
both
subjects
persisted
for
approx.
12
hrs
after
dosing
15
Human
Study
Details
Human
Study
Details

Strength
of
Metabolism
Study
°
Consistent
effects
in
both
subjects
°
Effects
consistent
with
animal
observations

Weakness
of
Metabolism
Study
°
Only
2
male
subjects
°
No
control
group
°
Potential
confounders
not
discussed
16
Neurotoxicity
Neurotoxicity
­
Conclusion
Conclusion

Animal
studies
°
Strong
evidence
°
Most
sensitive
endpoint
°
Not
cumulative

Human
data
°
Clear
signs
of
neurotoxicity
°
Consistent
with
animal
observations
°
Most
sensitive
species
17
Amitraz
Amitraz
Risk
Assessment
And
Use
Of
Risk
Assessment
And
Use
Of
Human
Studies
Human
Studies

Humans
(
most
sensitive
species)

°
Single
dose
oral
study:
NOAEL
=
0.125
mg/
kg
°
Metabolism
study:
LOAEL
=
0.25
mg/
kg

Non­
cancer
Values
°
Acute
RfD:
NOAEL
of
0.125
mg/
kg;
UF
=
100
(
10
for
intraspecies
variation;
10
for
datagaps)

°
Short­
term
oral
and
inhalation:
same
as
acute
RfD
18

Chronic
RfD
and
Long­
term
Inhalation
°
Neurotoxicity
not
cumulative
°
Same
value
as
acute
RfD

Dermal
(
all
durations)

°
Dermal
study
NOAEL
of
24
mg/
kg/
day
°
UF
of
100
(
10
for
intrapecies
variation
and
10
for
datagaps)

Amitraz
Amitraz
Risk
Assessment
And
Use
Of
Risk
Assessment
And
Use
Of
Human
Studies
Human
Studies
19
Amitraz
Amitraz
Charge
To
The
HSRB
Charge
To
The
HSRB

Comment
on
the
scientific
evidence
that
supports
the
conclusion
to
use
the
human
studies
for
identifying
a
point
of
departure
for
acute
and
chronic
dietary
risks,
short­
term
oral
exposure,
and
inhalation
and
dermal
exposures
of
various
durations.