Document ID: EPA-HQ-ORD-2006-0187-0017
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-03-23T05:00Z

DATA
EVALUATION
RECORD
AMITRAZ/
106201
NONGUIDELINE
STUDY
TYPE:
HUMAN
TOLERANCE
­
ORAL
MRID:
43283101
Prepared
for
Health
Effects
Division
Office
of
Pesticide
Programs
U.
S.
Environmental
Protection
Agency
1801
Bell
Street
Arlington,
VA
22202
Prepared
by
Toxicology
and
Hazard
Assessment
Group
Life
Sciences
Division
Oak
Ridge
National
Laboratory
Oak
Ridge,
TN
37831
Task
Order
No.
61­
2004
Primary
Reviewer:
Clint
Skinner,
Ph.
D.,
D.
A.
B.
T.
Signature:
Date:
Secondary
Reviewers:
H.
Tim
Borges,
Ph.
D.,
D.
A.
B.
T.
Signature:
Date:
Robert
H.
Ross,
M.
S.,
Group
Leader
Signature:
Quality
Assurance:
Date:
Lee
Ann
Wilson,
M.
A.
Signature:
Date:
Disclaimer
This
review
may
have
been
altered
subsequent
to
the
contractor=
s
signatures
above.

Oak
Ridge
National
Laboratory
managed
and
operated
by
UT­
Battelle,
LLC.,
for
the
U.
S.
Department
of
Energy
under
Contract
No.
DE­
AC05­
00OR22725.
EPA
Reviewer:
Pamela
M.
Hurley,
Ph.
D.
Signature:
Reregistration
Action
Branch
3,
Health
Effects
Division
(
7509C)
Date
EPA
Work
Assignment
Manager:
Ghazi
Dannan,
Ph.
D.
Signature:
Registration
Action
Branch
3,
Health
Effects
Division
(
7509C)
Date
TXR#:
0052737
Supplemental
DATA
EVALUATION
RECORD
Root
TXR:
0011110
STUDY
TYPE:
Double
Blind
Tolerance
Study
in
Humans­
Oral
Non­
Guideline.

PC
CODE:
106201
DP
BARCODE:
N/
A
SUBMISSION
NO.:
N/
A
TEST
MATERIAL
(
PURITY):
Amitraz
technical,
(
98.2%
a.
i.)

SYNONYMS:
1,5­
Di(
2,4­
dimethylphenyl)­
3­
methyl­
1,3,5­
triazapenta­
1,4­
diene;
Baam;
Formamidine
NBmethyl­
N'­
2,4­
xylyl­
N­(
N­
2,4­
xylylformimidoyl)­;
Methyl­
bis(
2,4­
xylyliminomethyl
amine;
Mitac;
Ovasyn;
Taktic;
Triazid;

CITATION:
Cass,
L.
(
1992).
T­
344,
Amitraz:
Report
of
a
double
blind
tolerance
study
of
amitraz
in
six
adult
healthy
volunteers.
Simbec
Research
Ltd.,
Merthyr
Tydfil,
Mid
Glamorgan
CF48
4DR,
South
Wales,
United
Kingdom.
Laboratory
Project
RD
197/
20170.
June
8,
1992.
MRID
43283101.
Unpublished.

SPONSOR:
NOR­
AM
Chemical
Co.,
Little
Falls
Centre
One,
2711
Centerville
Road,
Wilmington,
DE
19808
EXECUTIVE
SUMMARY:
In
a
double­
blind
sequential
dosing
oral
human
tolerance
study
of
Amitraz,
(
Lot
No.
not
reported,
purity
98.2%),
7
adult
male
volunteers
were
given
encapsulated
0,
0.0625,
or
0.125
mg/
kg
in
lactose
over
three
14­
day
periods.
One
volunteer
was
withdrawn
from
the
study
following
development
of
a
rash
unrelated
to
treatment.
The
study
subjects
were
28.17
"
3.54
years
in
age
and
weighed
67.15
"
3.15
kg.
The
study
was
approved
by
the
Simbec
Independent
Ethics
Committee
and
done
according
to
the
Helsinki
and
Hong
Kong
revisions
Human
Tolerance
­
Oral
(
1992)
Page
3
of
6
AMITRAZ/
106201
Nonguideline
(
l989).
Each
dose
was
administered
30
minutes
after
breakfast
with
150
ml
water.
Vital
signs
including:
pulse,
respiration
rate,
blood,
pressure
and
temperature
were
taken
at
B1,
­
0.5,
1,
3,
6,
12,
24,
and
36
hours
after
dosing.
ECGs
were
performed
at
B1,
1,
3,
6,
12,
24,
and
36
hours
after
dosing
and
pupil
responsiveness
and
psychomotor
performance
were
evaluated
pre­
dose
and
at
2.5
and
8
hours
after
dosing.
Urine
was
collected
at
0­
36
hours
and
36­
60
hours
after
treatment
and
blood
for
clinical
chemistry
and
hematology
was
collected
prior
to
the
start
of
the
study
and
36
hours
after
each
phase
of
the
study.

Two
subjects
reported
tiredness,
pre­
dose
(
0.125
mg/
kg)
for
9
and
8h
respectively,
but
this
was
determined
to
be
unrelated
to
treatment.
Vital
signs
and
ECG
parameters
were
within
normal
limits.
No
clinically
significant
changes
were
seen
in
pupil
response.
Psychomotor
performance
results
showed
no
significant
differences
between
pre­
and
post­
treatment.
One
subject
had
a
slightly
elevated
total
bilirubin
at
the
post­
study
screen
but
it
returned
to
normal
limits
within
three
weeks
completion
of
the
study.
No
treatment­
related
effects
were
found
on
hematology
or
urinalysis
parameters.
This
oral
toxicity
study
in
humans
is
Acceptable/
Nonguideline
and
satisfies
the
intent
of
the
study.

COMPLIANCE:
Signed
and
dated
GLP,
Quality
Assurance,
and
Data
Confidentiality
statements
were
provided.

I.
MATERIALS
AND
METHODS:

A.
MATERIALS:

1.
Test
material:
Amitraz
Description:
white
crystalline
powder
Lot/
Batch
#:
not
reported
Purity:
98.2%

Compound
Stability:
one
year
CAS
No.
of
TGAI:
33089­
61­
1
Structure:

2.
Vehicle
and/
or
positive
control:
Lactose
3.
Subjects:

Age:
28.17
"
3.54
years
Sex:
male
Human
Tolerance
­
Oral
(
1992)
Page
4
of
6
AMITRAZ/
106201
Nonguideline
Weight:
67.15
"
3.15
kg
Height:
1.71
"
0.05
m
Blood
Pressure
(
Systolic)
118.33
"
7.53
Blood
Pressure
(
Diastolic)
73.33
"
10.33
Pulse:
75
"
6
Respirations:
17
"
1
Temperature:
36.33
"
0.29
ECG:
Normal
B.
STUDY
DESIGN:

1.
In
life
dates:
Start:
January
21,
1992;
End:
March
4,
1992
2.
Dose
Selection:
Previous
studies
had
demonstrated
no
effect
at
0.03
mg/
kg
and
sedation
at
0.25
mg/
kg
Amitraz
and
it
was
estimated
that
the
maximum
NOAEL
was
between
0.06
and
0.25
mg/
kg
in
humans.
The
present
randomized
double­
blind
study
was
designed
to
identify
the
tolerance
of
male
volunteers
to
two
single
doses
of
Amitraz
spaced
2­
3
weeks
apart
and
determine
the
NOAEL.
The
study
was
approved
by
the
Simbec
Independent
Ethics
Committee
(
20
th
Nov.
91)
and
performed
according
to
the
Helsinki
and
Hong
Kong
revisions
(
l989).

3.
Dosing:
The
study
subjects
were
admitted
to
the
clinical
pharmacology
unit
the
evening
before
dosing
and
remained
fasting
until
the
next
morning.
They
remained
in
the
unit
until
36
hours
after
each
dosing
phase.
No
concomitant
medication,
alcohol,
or
drugs
of
abuse
were
allowed
during
the
study.
Each
study
subject
received
sequential
single
oral
doses
of
Amitraz
(
encapsulated
0.0625
or
0.125
mg/
kg
in
lactose)
with
a
placebo
(
lactose)
control.
Each
dose
was
given
30
minutes
after
breakfast
with
150
mL
of
water.
In
Phase
1
of
the
study,
4
subjects
received
placebo
and
2
received
0.0625
mg/
kg
Amitraz.
During
Phase
2
conducted
14
days
after
Phase
1,
two
subjects
received
placebo,
two
subjects
received
the
low
dose,
and
two
subjects
received
the
high
dose.
In
Phase
3
(
14
days
after
Phase
2)
three
subjects
received
placebo
and
four
subjects
received
the
high
dose.
The
research
was
designed
so
all
subjects
received
placebo,
low­
dose,
and
highdose
during
the
course
of
the
study.

4.
Observations:
On
the
morning
of
dosing
during
each
phase
of
the
study,
the
pulse,
respiration
rate,
blood
pressure,
and
temperature
of
each
subject
were
recorded
at
­
1,
­
0.5,
1,
3,
6,
12,
24,
and
36
hours.
ECGs
were
done
one
hour
before
dosing
and
at
1,
3,
6,
12,
24,
and
36
hours.
Psychomotor
performance
and
pupil
responsiveness
were
measured
pre­
dose
and
at
2.5
and
8
hours
after
dosing.

5.
Hematology
and
clinical
chemistry:
Blood
was
collected
pre­
study,
and
at
36
hours
after
each
phase
of
the
study.
The
CHECKED
(
X)
parameters
were
examined.

a.
Hematology:

X
Hematocrit
(
HCT)
X
Leukocyte
Differential
Count
X
Hemoglobin
(
HGB)
X
Mean
corpuscular
HGB
(
MCH)

X
Leukocyte
count
(
WBC)
X
Mean
corpusc.
HGB
conc.(
MCHC)

X
Erythrocyte
count
(
RBC)
X
Mean
corpusc.
volume
(
MCV)

X
Platelet
count
b.
Clinical
chemistry:
Human
Tolerance
­
Oral
(
1992)
Page
5
of
6
AMITRAZ/
106201
Nonguideline
X
Sodium
X
Creatinine
X
Potassium
X
Urea
nitrogen
X
Bicarbonate
X
Glucose
X
Alanine
aminotransferase
(
also
SGPT)
X
Total
bilirubin
X
Aspartate
aminotransferase
(
also
SGOT)
X
Total
protein
(
TP)

X
Gamma
glutamyl
transferase
(
GGT)
X
Albumin
6.
Urinalysis:
Urine
was
collected
pre­
dose
and
0­
36,
and
36­
60
hours
after
application
for
the
first
phase.
The
CHECKED
(
X)
parameters
were
examined.

X
Specific
gravity/
osmolality
X
Glucose
X
pH
X
Ketones
X
Protein
X
Bilirubin
X
Blood/
blood
cells
X
Urobilinogen
7.
Statistics:
Kruskal
Wallis
one­
way
analysis
of
variance
was
used
for
temporally
related
changes
and
Wilcoxon
Rank
Sum
was
used
to
determine
changes
between
phases.
Critical
data
evaluated
included
blood
pressure,
pulse,
temperature,
respiration
rate
and
ECG.
Human
Tolerance
­
Oral
(
1992)
Page
6
of
6
AMITRAZ/
106201
Nonguideline
II.
RESULTS:

A.
OBSERVATIONS:

3.
Adverse
Events
and
Clinical
Signs:
Two
subjects
reported
tiredness,
predose
(
0.125
mg/
kg)
for
9
and
8h
respectively.
This
was
determined
to
be
unrelated
to
treatment.
One
subject
was
dismissed
from
the
study
because
of
an
unrelated
skin
rash
and
was
replaced.
All
other
subjects
were
reported
well
following
the
study.

4.
Physiological
Measurements:
Vital
signs
and
ECG
parameters
were
normal.
No
clinically
significant
changes
were
seen
in
pupil
response.
Psychomotor
performance
results
showed
no
significant
differences
between
pre­
and
post­
treatment.

5.
Serum
Clinical
Chemistry:
One
subject
had
a
slightly
elevated
total
bilirubin
at
the
post­
study
screen.
By
three
weeks
after
the
end
of
the
study,
the
total
bilirubin
had
returned
to
within
normal
limits.
No
other
effects
of
clinical
chemistry
parameters
were
found.

6.
Hematology:
No
treatment­
related
effects
were
found.

7.
Urinalysis:
No
treatment­
related
effects
were
found.

8.
Drugs
of
Abuse.
No
drugs
of
abuse
were
detected.

III.
DISCUSSION
AND
CONCLUSIONS:

A.
INVESTIGATORS
=

CONCLUSIONS:
The
investigators
concluded
that
Amitraz
at
doses
of
0.0625
mg/
kg
and
0.125
mg/
kg
was
well
tolerated
with
no
clinical
signs
of
toxicity
including
hematology,
clinical
chemistry,
pupil
responsiveness,
eye,
and
psychomotor
evaluations.
The
NOAEL
was
0.125
mg/
kg.

B.
REVIEWER
COMMENTS:
This
report
has
individual
data
for
all
endpoints
and
no
discrepancies
with
investigators
=

conclusions
were
found.
The
highest
dose
(
0.125
mg/
kg)
may
be
considered
a
NOAEL
based
on
the
parameters
investigated.
Previous
studies
had
demonstrated
a
no
effect
level
at
0.03
mg/
kg
and
sedation
at
0.25
mg/
kg
Amitraz
and
it
was
estimated
that
the
maximum
NOAEL
was
between
0.06
and
0.25
mg/
kg
in
humans.
Literature
reported
clinical
signs
and
symptoms
after
human
exposure
to
Amitraz
include
drowsiness,
loss
of
consciousness,
confused
mental
state,
agitation,
weakness,
headache,
vomiting,
and
malaise
(
Ellenhorn,
M.
J.
et
al
1997).
In
a
14
C
Human
Amitraz
study,
many
of
these
symptoms
were
seen
at
0.25
mg/
kg
in
two
human
subjects.
In
this
study
no
complaints
or
adverse
effects
were
seen
at
roughly
half
the
dose
that
had
sedated
subjects
and
caused
nausea
in
previous
studies.
The
psychomotor
performance
and
perhaps
pupil
responsiveness
evaluated
should
be
sensitive
enough
to
detect
CNS
depression
and
respiratory
depression.
Bradycardia
would
have
been
detected
with
the
ECG,
blood
pressure,
heart
rate
and
respiration
evaluations.
Due
to
human
variation,
this
may
prove
to
be
a
tight
bracketing
of
the
no
effect
level.

C.
STUDY
DEFICIENCIES:
There
are
standards
for
human
studies
and
endpoints
are
chosen,
as
with
animal
studies,
to
cover
most
organ
systems
plus
any
known
endpoints
associated
with
the
chemical.
In
the
case
of
Amitraz,
most
of
the
known
human
effects
were
covered
by
these
investigations
and
doses
were
carefully
chosen.
More
discussion
of
known
human
effects,
rationale
for
choosing
parameters
for
evaluation
and
any
known
additivity
of
doses
and
serious
effects
at
higher
doses
or
longer
exposure
would
be
helpful.
Human
Tolerance
­
Oral
(
1992)
Page
7
of
6
AMITRAZ/
106201
Nonguideline
References:

Ellenhorn,
M.
S.
Schonwald,
G.
Ordog,
J.
Wasserberger.
Ellenhorn's
Medical
Toxicology:
Diagnosis
and
Treatment
of
Human
Poisoning.
2nd
ed.
Baltimore,
MD:
Williams
and
Wilkins,
1997.
pg.
1730
as
Cited
in
HSDB
2004.