Document ID: EPA-HQ-OPP-2004-0048-0004
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
TXR
No.
0052456
MEMORANDUM
DATE:
04/
01/
2004
SUBJECT:
106201.
Toxicology
Disciplinary
Chapter
for
the
Reregistration
Eligibility
Decision
Document
(
Tolerance
Reassessment
(
TRED))

PC
Code:
106201
DP
Barcode:
D300298
TO:
John
W.
Pates,
Jr.
Chemical
Review
Manager
#
51
Reregistration
Branch
1
Special
Review
and
Reregistration
Division
(
7508C)

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

THRU:
Catherine
Eiden,
Chief
Reregistration
Branch
3
Health
Effects
Division
(
7509C)

Background
and
Summary:

The
Health
Effects
Division
was
asked
to
review
and/
or
update
all
the
major
toxicology
studies
conducted
with
Amitraz
for
a
tolerance
reassessment
(
TRED)
and
prepare
the
toxicology
chapter.
The
toxicology
chapter
is
attached
to
this
memorandum.
2
AMITRAZ
PC
Code:
106201
Toxicology
Disciplinary
Chapter
for
the
Reregistration
Eligibility
Decision
Document
Date
completed:
April
1,
2004
Prepared
by:
Pamela
M.
Hurley
form:
FINAL
June
21,
2000
3
TABLE
OF
CONTENTS
1.0
HAZARD
CHARACTERIZATION
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4
2.0
REQUIREMENTS
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6
3.0
DATA
GAP(
S)
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7
4.0
HAZARD
ASSESSMENT
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8
4.1
Acute
Toxicity
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8
4.2
Subchronic
Toxicity
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8
4.3
Prenatal
Developmental
Toxicity
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12
4.4
Reproductive
Toxicity
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16
4.5
Chronic
Toxicity
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18
4.6
Carcinogenicity
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19
4.7
Mutagenicity
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20
4.8
Neurotoxicity
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21
4.9
Metabolism
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22
5.0
TOXICITY
ENDPOINT
SELECTION
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24
5.1
See
Section
9.2
for
Endpoint
Selection
Table.
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24
5.2
Dermal
Absorption
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24
5.3
Classification
of
Carcinogenic
Potential
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24
6.0
FQPA
CONSIDERATIONS
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25
6.1
Special
Sensitivity
to
Infants
and
Children
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25
6.2
Recommendation
for
a
Developmental
Neurotoxicity
Study
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26
7.0
OTHER
ISSUES
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26
8.0
REFERENCES
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27
9.0
APPENDICES
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30
9.1
Toxicity
Profile
Summary
Tables
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31
9.1.1
Acute
Toxicity
Table
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31
9.1.2
Subchronic,
Chronic
and
Other
Toxicity
Tables
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31
9.2
Summary
of
Toxicological
Dose
and
Endpoints
for
Amitraz
for
Use
in
Human
Risk
Assessment
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36
AMITRAZ/
MARCH/
2004
RED
Toxicology
Chapter
4
1.0
HAZARD
CHARACTERIZATION
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
multi­
generation
reproduction
study.
There
is
also
concern
for
neurotoxicity
and
developmental
neurotoxicity.
No
studies
are
available
which
access
potential
neurotoxicity.
Therefore,
in
order
to
fulfill
the
requirements
for
a
new
multi­
generation
reproduction
study,
developmental
neurotoxicity
study
and
a
mammalian
neurotoxicity
screening
battery,
a
2­
generation
reproduction
study
with
additional
components
is
required.
To
address
the
instability
of
the
test
material
in
the
diet,
this
study
is
to
be
conducted
by
gavage,
including
the
pups.
The
study
will
include
an
assessment
for
potential
developmental
neurotoxicity
and
for
potential
adult
neurotoxicity.
The
adult
neurotoxicity
section
will
include
assessment
protocols
from
the
mammalian
subchronic
neurotoxicity
protocol.
In
addition
to
the
studies
required
for
FQPA,
a
requirement
for
a
28­
day
inhalation
study
has
been
placed
on
reserve
pending
future
uses
for
amitraz.

Amitraz
has
a
low
acute
toxicity
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
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.
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.
AMITRAZ/
MARCH/
2004
RED
Toxicology
Chapter
5
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
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
AMITRAZ/
MARCH/
2004
RED
Toxicology
Chapter
6
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
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.

2.0
REQUIREMENTS
The
requirements
(
CFR
158.340)
for
Food
Uses
for
Amitraz
are
in
Table
1.
Use
of
the
new
guideline
numbers
does
not
imply
that
the
new
(
1998)
guideline
protocols
were
used.
Table
1.

Test
Technical
Required
Satisfied
870.1100
Acute
Oral
Toxicity
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.1200
Acute
Dermal
Toxicity
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.1300
Acute
Inhalation
Toxicity
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.2400
Primary
Eye
Irritation
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.2500
Primary
Dermal
Irritation
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.2600
Dermal
Sensitization
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
870.3100
Oral
Subchronic
(
rodent)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.3150
Oral
Subchronic
(
nonrodent)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.3200
21­
Day
Dermal
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.3250
90­
Day
Dermal
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
No
#
28­
Day
Inhalation
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.3465
90­
Day
Inhalation
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
yes
yes
yes
no
reserve4
no
yes1
yes2
no3
n/
a
no
n/
a
870.3700a
Developmental
Toxicity
(
rodent)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.3700b
Developmental
Toxicity
(
nonrodent)
.
.
.
.
.
.
.
.
.
.
.
.
870.3800
Reproduction
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
yes
yes
yes
yes
no3
no3
870.4100a
Chronic
Toxicity
(
rodent)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.4100b
Chronic
Toxicity
(
nonrodent)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.4200a
Oncogenicity
(
rat)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.4200b
Oncogenicity
(
mouse)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.4300
Chronic/
Oncogenicity
(
rat)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
yes
yes
yes
yes
yes
yes1
yes
yes1
yes
yes
870.5100
Mutagenicity
C
Gene
Mutation
­
bacterial
.
.
.
.
.
.
.
.
.
870.5300
Mutagenicity
C
Gene
Mutation
­
mammalian
.
.
.
.
.
.
870.5375
Mutagenicity
C
Structural
Chromosomal
Aberrations
870.5550
Mutagenicity
C
Other
Genotoxic
Effects
.
.
.
.
.
.
.
.
.
.
yes
yes
yes
no
yes
yes
yes
yes
870.6100a
Acute
Delayed
Neurotox.
(
hen)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.6100b
90­
Day
Neurotoxicity
(
hen)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.6200a
Acute
Neurotox.
Screening
Battery
(
rat)
.
.
.
.
.
.
.
.
.
870.6200b
90
Day
Neuro.
Screening
Battery
(
rat)
.
.
.
.
.
.
.
.
.
.
.
870.6300
Develop.
Neuro
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
no
no
no
yes
yes
­­

no
no
no
870.7485
General
Metabolism
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.7600
Dermal
Penetration
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
yes
no
yes
yes
AMITRAZ/
MARCH/
2004
RED
Toxicology
Chapter
Test
Technical
Required
Satisfied
7
Special
Studies
for
Ocular
Effects
Acute
Oral
(
rat)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
Subchronic
Oral
(
rat)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
Six­
month
Oral
(
dog)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
no
no
no
n/
a
n/
a
n/
a
1
Satisfied
by
an
acceptable
combined
chronic/
oncogenicity
study
in
the
rat
2
Satisfied
by
an
acceptable
chronic
study
in
the
dog
3
Available
21­
day
dermal
and
developmental
studies
in
the
rabbit
and
reproduction
study
in
the
rat
unacceptable
4
The
requirement
for
a
28­
day
inhalation
study
has
been
placed
on
reserve
pending
future
uses
for
amitraz
3.0
DATA
GAP(
S)

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

°
Reserved
pending
future
uses
for
amitraz:
a
28­
day
inhalation
study
which
should
follow
the
OPPTS
Guidance
870.3465,
with
cessation
of
exposure
at
28
days.
AMITRAZ/
MARCH/
2004
RED
Toxicology
Chapter
8
4.0
HAZARD
ASSESSMENT
4.1
Acute
Toxicity
Adequacy
of
data
base
for
acute
toxicity:
The
data
base
for
acute
toxicity
is
considered
complete.
No
additional
studies
are
required
at
this
time.
Amitraz
is
not
severely
acutely
toxic
by
the
oral,
dermal
and
inhalation
routes.
The
Toxicity
Category
for
the
dermal
route
is
low
(
Category
II)
because
it
was
not
tested
higher
than
200
mg/
kg.
Clinical
signs
of
toxicity
include
central
nervous
system
depression,
ataxia,
ptosis,
emesis,
labored
respiration,
muscular
weakness,
tremors,
hypothermia
and
bradycardia.

The
standard
acute
toxicity
data
on
Amitraz
Technical
are
summarized
below
in
Table
2.

Table
2.
Acute
Toxicity
Data
on
AMITRAZ
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
4.2
Subchronic
Toxicity
Adequacy
of
data
base
for
subchronic
toxicity:
The
data
base
for
subchronic
toxicity
is
considered
incomplete.
A
new
28­
day
inhalation
study
is
required.
Available
subchronic
studies
include
90­
day
feeding
studies
in
rats
and
dogs,
a
21­
dermal
study
in
rabbits
and
a
21­
day
inhalation
study
in
rats.
None
of
the
subchronic
studies
are
considered
to
be
acceptable;
however
the
data
requirement
for
subchronic
oral
studies
in
rodents
and
nonrodents
is
satisfied
by
the
acceptable
chronic
studies
in
dogs
and
rats.
The
studies
are
not
acceptable
for
one
or
more
of
the
following
reasons:
lack
of
individual
animal
data,
no
information
provided
on
the
test
material,
AMITRAZ/
MARCH/
2004
RED
Toxicology
Chapter
9
including
concentration
analyses,
too
few
animals
tested
per
dose
group,
concurrent
infections
and
limited
microscopic
examinations.

870.3100
90­
Day
Oral
Toxicity
­
Rat
In
a
90­
day
oral
toxicity
study
(
MRID
00051784)
Amitraz
(%
a.
i.
and
batch/
lot
#
not
provided)
was
administered
to
21
Ash­
Wistar
rats/
sex/
dose
(
42
controls/
sex)
by
gavage
in
a
dose
volume
of
0.5
ml/
kg
0.4%
Cellosize
solution
at
dose
levels
of
0,
3,
12,
50
and
200
mg/
kg
bw/
day.
The
50
mg/
kg/
day
group
received
50
mg/
kg/
day
for
7
days,
followed
by
11
weeks
untreated
and
then
50
mg/
kg/
day
for
7
days.
The
200
mg/
kg/
day
group
only
received
200
mg/
kg/
day
for
7
days.
The
remaining
groups
were
treated
for
90
days.
Body
weights,
hematological
and
clinical
chemistry
values
and
organ
weights
were
measured
and
microscopic
examinations
were
conducted.

Animals
in
the
200
mg/
kg
group
were
euthanized
after
seven
days
of
dosing
due
to
their
poor
condition.
They
were
observed
to
be
irritable
and
shed
red
tears
immediately
after
dosing
and
were
also
hunched,
lethargic,
weak,
emaciated
and
squealed
when
handled.
Treatment
for
the
50
mg/
kg
group
was
discontinued
after
7
days
due
to
similar
signs
of
toxicity
.
These
animals
recovered
within
7
days.
When
dosing
was
re­
instituted
on
week
13
of
the
study,
the
signs
recurred;
one
male
and
one
female
died.
Occasional
irritability
and
excitability
were
reported
in
the
12
mg/
kg/
group.
There
were
no
clinical
signs
of
toxicity
in
the
3
mg/
kg/
group.

Body
weight
and
body
weight
gain
were
confounded
by
the
deaths
of
the
animals
in
the
200
mg/
kg/
day
group
and
the
discontinuation
of
treatment
in
the
50
mg/
kg
group.
Overall
body
weight
gain
was
significantly
reduced
in
the
12
mg/
kg/
day
group
males.
The
absolute
weight
of
the
majority
of
the
organs
from
the
50
mg/
kg
group
were
decreased,
most
likely
due
to
the
decrease
in
body
weight;
however,
there
were
changes
in
some
of
the
relative
organ
weights,
especially
at
50
mg/
kg/
day.
No
data
were
provided
for
the
200
mg/
kg
group.
Microscopic
examination
indicated
the
following:
at
50
mg/
kg/
day,
swollen
acinar
cells
or
loss
of
acinar
cells
in
the
salivary
gland
were
increased.
After
a
3­
week
recovery
period,
swollen
acini
in
the
salivary
gland
remained
and
congestion
of
the
spleen
and
early
involution
of
the
thymus
were
increased.
At
50
mg/
kg/
day
and
above,
congestion
of
the
spleen,
heart
and
pituitary;
early
thymic
involution
and
vacuolation
of
the
liver.
At
200
mg/
kg/
day,
fatty
infiltration
of
the
adrenals
and
epithelial
degeneration
and
eosinophilia
in
the
epithelium
of
the
trachea
were
observed.
The
LOAEL
is
12
mg/
kg/
day,
based
on
irritability
and
excitability
and
reduced
overall
body
weight
gain.
The
NOAEL
is
3
mg/
kg/
day.

This
90­
day
oral
toxicity
study
in
the
rat
is
unacceptable
guideline
does
not
satisfy
the
guideline
requirement
for
a
90­
day
oral
toxicity
study
(
OPPTS
870.3100;
OECD
408)
in
the
rat.
It
is
not
upgradable.
No
individual
animal
data
were
submitted
for
either
the
clinical
signs
or
the
gross
necropsy
examinations
and
no
information
was
provided
on
the
test
material.
AMITRAZ/
MARCH/
2004
RED
Toxicology
Chapter
10
870.3150
90­
Day
Oral
Toxicity
­
Dog
In
a
90­
day
oral
toxicity
study
(
MRID
00040345)
Amitraz
(%
a.
i.
and
batch/
lot
#
not
provided)
was
administered
to
2
beagle
dogs/
sex/
dose
in
capsules
at
dose
levels
of
0,
0.25,
1.0,
or
4.0
mg/
kg
bw/
day
for
90
days.
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.

At
1.0
mg/
kg/
day
and
above,
transient
central
nervous
system
depression,
decrease
in
pulse
rate,
increase
in
glucose
in
the
urine,
neutrophilia
of
the
bone
marrow,
hypothermia,
increases
in
absolute
and
relative
liver
weights
and
an
increase
in
the
extent
of
liver
lesions
were
noted.
At
4.0
mg/
kg/
day,
ataxia,
emesis
and
catarrhal
conjunctivitis
were
also
observed.
The
LOAEL
is
1.0
mg/
kg/
day,
based
on
CNS
depression,
decrease
in
pulse
rate,
increase
in
glucose
in
the
urine,
hypothermia,
neutrophilia
of
the
bone
marrow
and
increased
liver
weights
and
extent
of
liver
lesions.
The
NOAEL
is
0.25
mg/
kg/
day.

This
90­
day
oral
toxicity
study
in
the
dog
is
unacceptable
guideline
and
does
not
satisfy
the
guideline
requirement
for
a
90­
day
oral
toxicity
study
(
OPPTS
870.3150;
OECD
409)
in
a
nonrodent
species.
The
study
is
unacceptable
because
only
2
dogs/
sex/
dose
were
tested.
It
is
not
upgradable.

870.3200
21/
28­
Day
Dermal
Toxicity
B
Rabbit
In
a
21­
day
dermal
toxicity
study
(
MRID
00029972),
BTS
27
419
(
Amitraz
in
acetone:
%
a.
i.
and
batch/
lot
#
not
provided)
was
applied
to
the
shaved
skin
of
4
New
Zealand
White
rabbits/
sex/
dose
at
dose
levels
of
0,
50
or
200
mg/
kg
bw/
day,
6
hours/
day
for
5
days/
week
during
a
21­
day
period.

At
200
mg/
kg,
sedation
was
observed
in
both
sexes,
starting
after
the
second
or
third
dose.
In
males,
a
slight
to
moderate
erythematous
reaction
that
persisted
throughout
the
study
was
observed
only
in
males
and
was
accompanied
by
desquamation
of
the
skin
and
subcutaneous
hemorrhage
in
one
male.
This
male
died
on
the
last
day
of
treatment.
The
3
surviving
males
steadily
lost
weight
throughout
the
study.
Three
out
of
4
of
both
sexes
had
decreased
food
consumption,
beginning
in
either
the
first
or
second
week
and
continuing
until
either
death
or
study
termination.
Three
females
died
on
days
15,
17
and
20.
Decreased
testicular
weights
were
observed.
This
decrease
corresponded
with
tubular
degeneration
observed
in
the
microscopic
examinations.

At
50
mg/
kg/
day,
the
males
were
sedated,
starting
after
the
3rd
or
4th
dose.
Slight
to
moderate
erythematous
reactions
were
observed
in
the
treated
area
of
the
skin.
One
male
had
some
desquamation
and
subcutaneous
hemorrhage
during
the
final
week
of
treatment.
One
male
stopped
eating
shortly
after
the
treatment
commenced
and
was
found
dead
on
day
6.
One
of
the
3
AMITRAZ/
MARCH/
2004
RED
Toxicology
Chapter
11
surviving
males
lost
weight
while
the
other
two
showed
little
change
in
weight,
even
with
decreased
food
consumption
in
the
second
and
third
weeks
of
dosing.

There
were
indications
of
infection
(
bacterial
and/
or
parasitic)
in
a
few
animals
in
all
groups.
It
is
not
known
how
this
may
have
affected
the
outcome
of
the
study.

The
LOAEL
is
50
mg/
kg/
day,
based
on
clinical
signs
and
a
decrease
in
food
consumption
in
males.
The
NOAEL
cannot
be
determined.

The
dermal
irritation
LOAEL
is
50
mg/
kg/
day
based
on
slight
to
moderate
erythematous
reactions
in
the
treated
area
of
the
skin
in
3
out
of
4
males
accompanied
by
some
desquamation
and
subcutaneous
hemorrhage
in
1
of
the
3
males.
The
dermal
irritation
NOAEL
cannot
be
determined.

This
21­
day
dermal
toxicity
study
in
the
rabbit
is
unacceptable
guideline
and
does
not
satisfy
the
guideline
requirement
for
a
21­
day
dermal
toxicity
study
(
OPPTS
870.3200
;
OECD
410)
in
the
rabbit.
It
is
not
upgradable.
Too
few
animals
were
tested
per
dose
group,
there
were
concurrent
infections
and
a
lack
of
information
on
the
substance
tested
and
limited
histopathological
investigations
were
conducted.

870.3465
21­
Day
Inhalation
B
Rat
In
a
subchronic
inhalation
toxicity
study
(
MRID
00029964)
[
Amitraz,
(%
a.
i.,
batch/
lot
#
not
provided)]
was
administered
to
6
CFHB
rats/
sex/
concentration
by
dynamic
whole
body
exposure
at
nominal
concentrations
of
0,
0.01,
0.1
or
1.0
mg
dust/
L
for
6
hours
per
day
for
14
days
over
a
period
of
3
weeks.
Analytical
concentrations
were
not
measured.

No
treatment­
related
effects
were
observed
at
0.01
mg/
L.
A
decrease
in
body
weight
gain
was
observed
in
females
(
66%
of
the
control
group).
No
statistical
data
or
standard
deviations
were
provided.
An
examination
of
the
individual
animal
data
do
not
indicate
any
significant
outliers;
however,
the
mean
body
weight
was
94%
of
the
control
group
and
no
other
parameters
indicated
any
effects
at
this
concentration
level.

At
0.1
mg/
L
and
above,
the
animals
showed
signs
of
mild
dyspnea
with
occasional
sneezing;
intermittent
blinking
and
licking
of
lips;
hyposensitivity
to
noise;
hypersensitivity
to
touch
and
aggressive
behavior.
Decreases
in
body
weight
gain
were
observed
in
both
sexes
(
54
and
49%
of
control
for
males
and
females,
respectively).

At
1.0
mg/
L,
dyspnea
and
eye
irritation
were
more
severe.
Labored
movements,
increased
nasal
secretion
and
polyuria
with
brown
discoloration
of
the
urine
were
noted
during
exposures.
In
several
rats,
slight
coma
and
body
tremors
were
observed
following
exposure.
Decreases
in
body
weight
and
body
weight
gain
were
observed
in
both
sexes
when
compared
to
the
control
group.
AMITRAZ/
MARCH/
2004
RED
Toxicology
Chapter
12
The
rats
lost
weight
at
this
dose
level.
There
was
a
significant
reduction
of
packed
cell
volume
(
hematocrit),
hemoglobin
and
erythrocyte
count
and
an
increase
in
the
number
of
neutrophils
in
both
sexes.
A
low
mean
corpuscular
hemoglobin
content
and
decrease
in
the
number
of
lymphocytes
was
found
in
the
blood
of
male
rats.
There
was
also
a
significant
reduction
in
total
protein
levels
in
both
sexes.
In
males,
a
low
albumin
concentration
and
a
decreased
albumin/
globulin
ratio
were
observed.
In
females,
a
low
urea
level
and
a
fall
in
the
alpha
and
beta
fractions
of
globulins
were
noted.

No
treatment­
related
macroscopic
or
microscopic
lesions
were
observed
at
any
concentration
level.

The
LOAEL
is
0.1
mg/
L/
day,
based
on
clinical
signs
of
toxicity
(
irritation
and
neurological
signs)
and
decreases
in
body
weight
and
body
weight
gain.
The
NOAEL
is
0.01
mg/
L/
day.

This
subchronic
inhalation
toxicity
study
in
the
rat
is
unacceptable
non­
guideline
and
does
not
satisfy
the
guideline
requirement
for
a
subchronic
inhalation
study
OPPTS
870.3465;
OECD
413
in
the
rat.
It
is
not
upgradable.
Since
analytical
concentrations
were
not
measured
and
the
purity
of
the
test
material
was
not
reported,
the
actual
concentration
of
the
test
material
is
unknown.

4.3
Prenatal
Developmental
Toxicity
Adequacy
of
data
base
for
Prenatal
Developmental
Toxicity:
Although
two
rat
and
two
rabbit
studies
have
been
conducted,
the
data
base
for
prenatal
developmental
toxicity
is
incomplete.
A
new
developmental
study
in
the
rabbit
is
required.
Both
the
developmental
toxicity
studies
in
rabbits
are
unacceptable.
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
were
observed.
This
study
had
too
few
litters,
limited
data
and
an
unclear
method
of
dosing.
No
developmental
toxicity
in
rabbits
was
observed
in
the
repeat
study;
however,
this
study
was
not
tested
at
as
high
a
dose
as
the
first
study.
It
might
be
possible
that
developmental
toxicity
would
be
observed
at
a
higher
dose.
This
study
is
classified
as
unacceptable
because
of
underlying
respiratory
disease
in
the
does
and
because
of
too
few
litters
in
two
of
the
treated
groups.

No
developmental
toxicity
was
observed
in
either
of
the
two
rat
studies.
The
first
study
was
classified
as
unacceptable
because
there
was
very
limited
data
and
the
dosage
period
was
from
gestation
days
8­
20
which
excludes
some
important
gestation
days.
AMITRAZ/
MARCH/
2004
RED
Toxicology
Chapter
13
870.3700a
Prenatal
Developmental
Toxicity
Study
­
Rat
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.

870.3700a
Prenatal
Developmental
Toxicity
Study
­
Rat
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
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
AMITRAZ/
MARCH/
2004
RED
Toxicology
Chapter
14
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.

870.3700b
Prenatal
Developmental
Toxicity
Study
­
Rabbit
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
bw/
day,
based
on
decreased
litter
size,
decreased
implantations,
increased
postimplantation
loss,
abortions
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.

870.3700b
Prenatal
Developmental
Toxicity
Study
­
Rabbit
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
AMITRAZ/
MARCH/
2004
RED
Toxicology
Chapter
15
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
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.
AMITRAZ/
MARCH/
2004
RED
Toxicology
Chapter
16
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.

4.4
Reproductive
Toxicity
Adequacy
of
data
base
for
Reproductive
Toxicity:
The
data
base
for
reproductive
toxicity
is
considered
incomplete.
Both
1­
generation
and
3­
generation
reproduction
studies
are
available.
The
1­
generation
study
is
unacceptable
because
it
is
not
a
guideline
study,
it
provides
limited
information
and
the
purity
of
the
test
material
is
unknown.
The
3­
generation
study
is
considered
to
be
unacceptable
because
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.

870.3800
Reproduction
and
Fertility
Effects
­
Rat
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.

870.3800
Reproduction
and
Fertility
Effects
­
Rat
AMITRAZ/
MARCH/
2004
RED
Toxicology
Chapter
17
In
a
3­
generation
reproduction
study
(
MRID
00029962)
BTS
27
419
(
Amitraz
(
99.8%
a.
i.,
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
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.
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.
AMITRAZ/
MARCH/
2004
RED
Toxicology
Chapter
18
4.5
Chronic
Toxicity
Adequacy
of
data
base
for
chronic
toxicity:
The
data
base
for
chronic
toxicity
is
considered
complete.
No
additional
studies
are
required
at
this
time.
Clinical
signs,
indicative
of
neurotoxicity
were
observed
in
both
dogs
and
rats.
In
rats,
excitable,
nervous
and
aggressive
behavior
were
observed
but
in
dogs,
signs
of
CNS
depression
and
a
dose­
related
decrease
in
body
temperature
were
observed.
The
dog
appears
to
be
the
most
sensitive
species;
however,
it
should
be
noted
that
dosing
was
provided
via
gelatin
capsules
in
the
dog
whereas
in
the
rat
it
was
through
the
diet.

870.4100a
(
870.4300)
Chronic
Toxicity
B
Rat
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.

870.4100b
Chronic
Toxicity
­
Dog
In
a
chronic
toxicity
study
(
MRID
00044586)
Amitraz
(
97.8­
99.8
%
a.
i.
and
batch/
lot
#'
s
2093DH
and
2099DH)
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
AMITRAZ/
MARCH/
2004
RED
Toxicology
Chapter
19
temperature,
hematology,
clinical
chemistry,
urinalysis
and
organ
weight
parameters
were
measured;
and
gross
and
microscopic
examinations
were
conducted.

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.

4.6
Carcinogenicity
Adequacy
of
data
base
for
Carcinogenicity:
The
data
base
for
carcinogenicity
is
considered
complete.
No
additional
studies
are
required
at
this
time.
Amitraz
is
not
carcinogenic
in
the
rat
under
the
conditions
of
the
study;
however,
it
is
considered
to
be
carcinogenic
in
the
mouse,
inducing
hepatocellular
adenomas,
carcinomas
and
combined
adenomas
and/
or
carcinomas
in
females
and
lung
adenomas
in
males.
Dose
levels
were
considered
to
be
adequate
in
both
studies.

870.4200a
Carcinogenicity
Study
­
rat
See
870.4100a
(
870.4300)
Chronic
Toxicity
B
Rat
870.4200b
Carcinogenicity
(
feeding)
­
Mouse
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.

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
AMITRAZ/
MARCH/
2004
RED
Toxicology
Chapter
20
(
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.

4.7
Mutagenicity
Adequacy
of
data
base
for
Mutagenicity:
The
data
base
for
mutagenicity
is
considered
adequate
based
on
the
1991
mutagenicity
guidelines.
Amitraz
does
not
appear
to
be
mutagenic
under
the
conditions
of
the
assays
in
which
it
was
tested:
reverse
mutation
in
Salmonella
typhimurium
(
Ames),
forward
mutation
in
mouse
lymphoma
cells,
in
vitro
structural
chromosome
aberration
assay
in
human
lymphocytes
and
in
a
cell
transformation
assay
in
C3H/
10T1/
2
cells
derived
from
mouse
embyro
fibroblasts.

Gene
Mutation
AMITRAZ/
MARCH/
2004
RED
Toxicology
Chapter
21
Guideline
#
870.5100,
Salmonella
reverse
gene
mutation
(
Ames)
MRID
00161009
Acceptable
Guideline
Dose
range:
33
­

g/
plate
to
10
mg/
plate
Negative
up
to
10
mg/
plate,
with
or
without
metabolic
activation.

Guideline
#
870.5300,
Forward
Gene
Mutation
Assay
(
mouse
L5178Y
lymphoma
cells)
MRID
00161008
Acceptable
Guideline
Negative
at
0.06­
20

g/
ml
with
and
without
activation.
HDT
is
highest
non­
cytotoxic
dose.

Cytogenetics
Guideline
#
870.5375,
In
vitro
Structural
Chromosome
Aberration
Assay
(
human
lymphocytes)
MRID
41795101
Acceptable
Guideline
Dose
range:
5
­
20

g/
ml
without
metabolic
activation
and
3
­
30

g/
ml
with
activation
Negative
up
to
cytotoxic
and/
or
insoluble
concentrations.

Other
Genotoxicity
Guideline
#
870.5550
UDS
Assay
(
Human
Embryonic
Lung
Fibroblast)
MRID
00161011
Acceptable
Guideline
Dose
range:
20
­
300

g/
ml
Negative
up
to
cytotoxic
concentrations,
with
and
without
metabolic
activation.

Guideline
#
N/
A
Morphological
Transformation
(
C3H/
10T1/
2
cells
derived
from
mouse
embyro
fibroblast)
MRID
00161010
Acceptable
Guideline
Dose
range:
12.5
­
37.5

g/
ml
with
S­
9;
5
­
15

g/
ml
without
S­
9.
Negative
up
to
cytotoxic
concentrations,
with
and
without
activation.
MRID
00161010
4.8
Neurotoxicity
Adequacy
of
data
base
for
Neurotoxicity:
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.
AMITRAZ/
MARCH/
2004
RED
Toxicology
Chapter
22
870.6100
Delayed
Neurotoxicity
Study
­
Hen
A
delayed
neurotoxicity
study
in
the
hen
has
not
been
conducted.
This
study
is
not
currently
required
for
amitraz.

870.6200
Acute
Neurotoxicity
Screening
Battery
An
acute
mammalian
neurotoxicity
study
has
not
been
conducted.

870.6200
Subchronic
Neurotoxicity
Screening
Battery
A
subchronic
mammalian
neurotoxicity
study
has
not
been
conducted.

870.6300
Developmental
Neurotoxicity
Study
A
developmental
neurotoxicity
study
has
not
been
conducted.

4.9
Metabolism
Adequacy
of
data
base
for
metabolism:
The
data
base
for
metabolism
is
considered
to
be
complete.
No
additional
studies
are
required
at
this
time.
Extensive
metabolism
studies
have
been
conducted
with
amitraz
in
several
species,
including
humans,
baboons,
dogs,
rats,
and
mice.
In
all
species,
amitraz
was
rapidly
hydrolyzed
in
the
stomach,
following
oral
administration,
to
form
at
least
six
metabolites.
Metabolites
BTS
27,271
(
N­(
2,4­
dimethylphenyl)­
N­
methylformamidine)
and
27919
(
2,4­
dimethylformanilide),
both
of
which
are
formed
via
hydrolysis
at
the
C­
N
[
Nmethylmethanimidamide
bond)
are
the
primary
metabolites
of
amitraz.
Excretion
of
metabolites
occurred
mainly
in
the
urine
over
48
hours
(
62%­
82%
in
all
species)
and
to
a
lesser
extent
in
feces
(
9%­
39%),
with
no
unchanged
parent
compound
observed
in
urine.
The
proportion
of
various
metabolites
recovered
in
the
urine
of
all
species
was
also
similar.
The
highest
levels
of
14C
tissue
residues
in
animals
were
found
in
the
liver,
bile,
kidney,
adrenal
glands,
and
pigmented
areas
of
the
eye
over
3
to
4
days.
The
executive
summar
of
the
most
representative
metabolism
studies
are
summarized
in
the
following
paragraphs.

870.7485
Metabolism
­
Rat
Two
male
and
two
female
Sprague­
Dawley
rats
(
135­
250g)
per
dose
level
were
administered
a
single
dose
of
radiolabeled
14C­
amitraz
in
corn
oil
by
gavage
1,
10
or
100
mg/
kg
body
weight
(
MRID
00161004).
Twenty­
four
hour
collections
of
urine
samples
were
subjected
to
metabolite
isolation
and
identification.
No
sex
differences
were
apparent
in
the
proportion
of
the
various
metabolites
recovered
in
the
24­
hour
urine
samples.
The
metabolic
process
was
saturated
at
the
100
mg/
kg
level.
The
proportion
of
BTS27271
increased
with
a
corresponding
decrease
in
the
amount
of
polar
material
observed
at
the
100
mg/
kg
level.
At
the
10
mg/
kg
level
and
below,
a
AMITRAZ/
MARCH/
2004
RED
Toxicology
Chapter
23
decrease
in
the
amount
of
BTS27271
and
an
increase
in
the
polar
fraction
was
reported.
No
unchanged
parent
material
(
BTS
27419)
was
found
in
the
urine.
The
major
metabolites
were
N­
(
2,4­
dimethylphenyl)­
N­
methyl
formamidine
(
BTS
27271),
4­
formamido­
3­
methyl
benzoic
acid
(
BTS
39098),
4­
acetamido­
3­
methyl
benzoic
acid
(
FBC
31158)
and
a
polar
fraction.
The
polar
fraction
was
labile
to
acid
hydrolysis,
yielding
conjugates
of
4­
amino­
3­
methylbenzoic
acid
(
BTS
28369),
N­(
2,4­
dimethylphenyl)­
N­
methyl
formamidine
(
BTS
27271),
4­
formamido­
3­
methyl
benzoic
acid
(
BTS
39098)
and
4­
acetamido­
3­
methyl
benzoic
acid
(
BTS
31158).

Amitraz
(
94%),
labeled
(
14C)
in
the
­
2
methyl
position
and
the
metabolite,
BTS
27271,
labeled
(
14C)
in
the
phenyl
ring
were
each
administered
by
gavage
at
a
dose
level
of
5.0
mg/
kg
body
weight
to
two
male
Sprague­
Dawley
rats
(
150­
200g;
Knowles
and
Benezet).
The
rats
were
placed
in
metabolism
cages
for
collection
of
urine
and
feces
at
3,
8,
12,
24,
48
and
96
hours.
Tissue
equivalents
(
ppb)
of
amitraz
and
BTS
27271
were
determined
in
brain,
heart,
intestine,
kidney,
liver,
lung,
spleen
and
blood.
Peak
levels
of
amitraz
elimination
in
the
urine
were
reached
within
8
hours
with
78%
of
the
dose
accounted
for
in
the
urine
and
9%
in
the
feces
by
98
hours.
Peak
levels
of
BTS
27271
in
the
urine
were
reached
within
24
hours
with
89%
accounted
for
in
the
urine
and
4%
in
the
feces
by
96
hours.
The
highest
residues
of
amitraz
and
BTS
27271
were
reported
in
the
liver
at
137.7
and
182.6
ppb,
respectively.
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
it's
metabolite,
BTS
27271
were
similar.

870.7600
Dermal
Absorption
­
Rat
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.
AMITRAZ/
MARCH/
2004
RED
Toxicology
Chapter
24
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
5.0
TOXICITY
ENDPOINT
SELECTION
5.1
See
Section
9.2
for
Endpoint
Selection
Table.

5.2
Dermal
Absorption
Dermal
Absorption
Factor:
8
%
from
a
dermal
absorption
study
the
M82
formulation
of
amitraz
diluted
in
water
at
a
dose
of
91
micrograms/
cm2
a.
i.
in
the
rat
The
dermal
absorption
factor
is
required
for
dermal
risk
assessments
(
all
durations)
since
oral
doses
were
selected
for
these
exposure
periods.

5.3
Classification
of
Carcinogenic
Potential
5.3.1
Amitraz
was
not
found
to
be
a
carcinogen
in
rats
under
the
conditions
of
the
study.
In
female
mice
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.
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.

5.3.2
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.

5.3.3
Quantification
of
Carcinogenic
Potential
The
Q
1*
was
calculated
to
be
2.83
x
10­
2
in
human
equivalents,
based
upon
the
combined
hepatocellular
adenomas
and
carcinomas
in
female
mice.
A
3/
4'
s
cross
species
scaling
factor
was
utilized
for
the
calculation.
AMITRAZ/
MARCH/
2004
RED
Toxicology
Chapter
25
6.0
FQPA
CONSIDERATIONS
6.1
Special
Sensitivity
to
Infants
and
Children
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.

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.

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.

°
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.

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
AMITRAZ/
MARCH/
2004
RED
Toxicology
Chapter
26
6.2
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.

7.0
OTHER
ISSUES
Amitraz
is
not
stable
in
the
diet
(
TXR
Nos.
012646
and
005633).
The
current
endpoints
are
based
on
a
gavage
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
dermal
and
inhalation
endpoints
are
also
based
on
a
gavage
study.
AMITRAZ/
MARCH/
2004
RED
Toxicology
Chapter
27
Since
it
is
possible
that
humans
may
more
likely
be
exposed
to
the
technical
material
via
the
dermal
and
inhalation
routes
because
they
will
be
directly
exposed
without
a
chance
for
significant
degradation,
the
gavage
study
may
be
more
appropriate
as
the
study
of
choice
for
these
routes
(
the
dermal
and
inhalation
studies
are
not
acceptable).

8.0
REFERENCES
00029959
Sutton,
M.
M.
(
19??)
BTS
27
419:
Teratogenicity
in
the
Rat:
Report
No.
TX
73028.
(
Unpublished
study
received
Apr
9,
1980
under
43142­
EX­
1;
submitted
by
Boots
Hercules
Agrochemicals
Co.,
Wilmington,
Del.;
CDL:
099368­
I)

00029960
Sutton,
M.
M.
(
19??)
BTS
27
419:
Effect
on
Pregnancy,
Parturition
and
Care
of
the
Young
in
Rats:
Report
No.
TX
73031.
(
Unpublished
study
received
Apr
9,
1980
under
43142­
EX­
1;
submitted
by
Boots
Hercules
Agrochemicals
Co.,
Wilmington,
Del.;
CDL:
099368­
J)

00029961
Sutton,
M.
M.
(
19??)
BTS
27
419:
Teratogenicity
in
the
Rabbit:
Report
No.
TX
73029.
(
Unpublished
study
received
Apr
9,
1980
under
43142­
EX­
1;
submitted
by
Boots
Hercules
Agrochemicals
Co.,
Wilmington,
Del.;
CDL:
099368­
K)

00029962
Sutton,
M.
M.
(
19??)
BTS
27
419:
Multigeneration
Feeding
Test
in
Rats:
Report
No.
TX
73036.
(
Unpublished
study
received
Apr
9,1980
under
43142­
EX­
1;
submitted
by
Boots
Hercules
Agrochemicals
Co.,
Wilmington,
Del.;
CDL:
099368­
L)

00029963
Berczy,
Z.
S.;
Binns,
R.;
Newman,
A.
J.
(
1972)
Acute
Inhalation
Toxicity
to
the
Rat
of
BTS
27419:
Report
No.
4971/
72/
406.
(
Unpublished
study
received
Apr
9,
1980
under
43142­
EX­
1;
prepared
by
Huntingdon
Research
Centre,
submitted
by
Boots
Hercules
Agrochemicals
Co.,
Wilmington,
Del.;
CDL:
099368­
M)

00029964
Berczy,
Z.
S.;
Binns,
R.;
Street,
A.
E.;
et
al.
(
1973)
Subacute
Inhalation
Toxicity
to
the
Rat
of
BTS
27419:
Report
No.
5454/
72/
850.
(
Unpublished
study
received
Apr
9,
1980
under
43142­
EX­
1;
prepared
by
Huntington
Research
Centre,
submitted
by
Boots
Hercules
Agrochemicals
Co.,
Wilmington,
Del.;
CDL:
099368­
N)

00029965
Sutton,
M.
M.
(
1971)
BTS
27
419:
Contact
Sensitisation
?
sic|
in
the
Guinea
Pig.
(
Unpublished
study
received
Apr
9,
1980
under
43142­
EX­
1;
submitted
by
Boots
Hercules
Agrochemicals
Co.,
Wilmington,
Del.;
CDL:
099368­
O)

00029972
Sutton,
M.
M.
(
1977)
BTS
27
419:
Three
Week
Dermal
Toxicity
to
Rabbits:
Report
No.
TX
73026.
(
Unpublished
study
received
Apr
9,1980
under
43142­
EX­
1;
AMITRAZ/
MARCH/
2004
RED
Toxicology
Chapter
28
submitted
by
Boots
Hercules
Agrochemicals
Co.,
Wilmington,
Del.;
CDL:
099368­
V)

00040345
Patton,
D.
S.
G.;
Williams,
G.
A.
H.
(
1973)
BTS
27
419:
90­
Day
Toxicity
Study
in
Dogs:
P
71547.
(
Unpublished
study
received
Oct
7,
1974
under
5G1558;
submitted
by
Upjohn
Co.,
Kalamazoo,
Mich.;
CDL:
094252­
AN)

00040861
Sutton,
M.
M.;
Metcalf,
W.
(
1972)
BTS
27
419.
Eye
Irritancy
in
the
Rabbit:
TXM72037.
(
Unpublished
study
received
Oct
7,
1974
under
5G1558;
submitted
by
Upjohn
Co.,
Kalamazoo,
Mich.;
CDL:
094254­
H)

00040862
Sutton,
M.
M.;
Williams,
P.
A.
(
1972)
BTS
27
419:
Acute
Dermal
Toxicity
to
Rabbits:
YM72011.
(
Unpublished
study
received
Oct
7,1974
under
5G1558;
submitted
by
Upjohn
Co.,
Kalamazoo,
Mich.;
CDL:
094254­
I)

00041539
Shaw,
J.
W.
(
1973)
BTS
27
419:
Acute
Oral
Toxicity
to
Male
and
Female
Rats:
TXM
73041.
(
Unpublished
study
received
Jun
24,
1976
under
6F1817;
submitted
by
Upjohn
Co.,
Kalamazoo,
Mich.;
CDL:
096419­
AE)

00044585
Sutton,
M.
M.;
Offer,
J.
(
1973)
BTS
27
419:
Carcinogenicity
and
Long­
Term
Toxicity
Study
in
Rats:
Report
TX
73043.
(
Unpublished
study
received
Jun
24,
1976
under
6F1817;
submitted
by
Upjohn
Co.,
Kalamazoo,
Mich.;
CDL:
096417­
A)

00044586
Morgan,
H.
E.;
Patton,
D.
S.
G.;
Turnbull,
G.
J.
(
19??)
BTS
27
419:
Two­
Year
Oral
Toxicity
Study
in
Dogs:
TX
73035.
(
Unpublished
study
received
Jun
24,
1976
under
6F1817;
submitted
by
Upjohn
Co.,
Kalamazoo,
Mich.;
CDL:
096415­
A)

00051784
Sutton,
M.
M.;
Williams,
G.
A.
H.
(
1971)
BTS
27
419:
90­
Day
Toxicity
Study
in
Rats.
(
Unpublished
study
received
Jun
24,
1976
under
6F1817;
submitted
by
Upjohn
Co.,
Kalamazoo,
Mich.;
CDL:
096418­
A)

00139552
Colley,
J.;
Dawe,
S.;
Heywood,
R.;
et
al.
(
1983)
Amitraz:
104
Week
Tumorigenicity
Study
in
Mice:
HRC
Report
No.
BTS
153/
8262/
A;
T233.
Final
report.
(
Unpublished
study
received
Jan
5,
1984
under
1023­
59;
prepared
by
FBC,
Ltd.,
Eng.,
submitted
by
Upjohn
Co.,
Kalamazoo,
MI;
CDL:
252098­
A;
252099;
252100;
252101;
252102)

00161004
Campbell,
J.;
Needham,
D.
(
1984)
The
Metabolism
of
[
Carbon
14]­
Amitraz
by
Male
and
Female
Rats:
Study
No.
3L:
Report
No.
METAB/
84/
2.
Unpublished
study
prepared
by
FBC
Ltd.,
Chesterford
Park
Research
Station.
32
p.
AMITRAZ/
MARCH/
2004
RED
Toxicology
Chapter
29
00161008
McGregor,
D.;
Riach,
C.
(
1983)
Technical
Amitraz:
Mouse
Lymphoma
Mutation
Assay:
IRI
Project
No.
730923:
Report
No.
2669.
Unpublished
FBC
Study
No.
TOX
83016
prepared
by
Inveresk
Research
International.
48
p.

00161009
McGregor,
D.;
Prentice,
R.
(
1983)
Technical
Amitraz:
Ames
Bacterial
Mutagenicity
Test:
IRI
Project
No.
730918:
Report
No.
2590.
Unpublished
FBC
Study
No.
TOX
83015
prepared
by
Inveresk
Research
International.
25
p.

00161010
McGregor,
D.;
Riach,
C.
(
1983)
Technical
Amitraz:
Induction
of
Morphological
Transformation
in
C3H/
10T1/
2
Cells:
IRI
Project
No.
730698:
Report
No.
2625.
Unpublished
FBC
Study
No.
TOX
83001
prepared
by
Inveresk
Research
International.
23
p.

00161011
McGregor,
D.;
Riach,
C.
(
1983)
Technical
Amitraz:
Unscheduled
DNA
Synthesis
in
Human
Embryonic
Cells:
IRI
Project
No.
730703:
Report
No.
2634.
Unpublished
FBC
Study
No.
TOX
83002
prepared
by
Inveresk
Research
International.
19
p.

41795101
Brooker,
P.;
Akhurst,
L.;
Gray,
V.
(
1988)
T300
Technical
Amitraz
Metaphase
Chromosome
Analysis
of
Human
Lymphocytes
Cultured
in
vitro:
Lab
Project
Number:
TOX/
88/
179­
154.
Unpublished
study
prepared
by
Huntingdon
Research
Centre.
23
p.

42133501
Challis,
I.
(
1990)
M82
Amitraz:
Dermal
Absorption
of
Amitraz
in
the
Rat:
Lab
Project
Number:
TOX/
90/
179­
178.
Unpublished
study
prepared
by
Schering
Agrochemicals
Ltd.
41
p.

44265901
McIntyre,
M.
(
1987)
Technical
Amitraz:
Teratogenicity
Study
in
the
Rabbit:
Lab
Project
Number:
5536­
194/
13:
TOX/
86157:
194/
13.
Unpublished
study
prepared
by
Hazleton
UK.
124
p.

44265902
McIntyre,
M.
(
1987)
Technical
Amitraz:
Teratogenicity
Study
in
the
Rat:
Lab
Project
Number:
5562­
194/
11:
TOX/
86156:
T
279.
Unpublished
study
prepared
by
Hazleton
UK.
121
p.

No
MRID
Knowles,
C.
O.
and
H.
J.
Benezet.
(
1981)
Excretion
Balance,
Metabolic
Fate
and
Tissue
Residue
Following
Treatment
of
Rats
with
Amitraz
and
N'­(
2,4­
Dimethylphenyl)­
N­
Methylformanidine
(
BTS
27271).
J.
Environ.
Sci.
Health
B16(
5),
547­
555.
AMITRAZ/
MARCH/
2004
RED
Toxicology
Chapter
30
9.0APPENDICES
Tables
for
Use
in
Risk
Assessment
AMITRAZ/
MARCH/
2004
RED
Toxicology
Chapter
31
9.1
Toxicity
Profile
Summary
Tables
9.1.1
Acute
Toxicity
Table
­
See
Section
4.1
9.1.2
Subchronic,
Chronic
and
Other
Toxicity
Tables
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
870.3100
90­
Day
oral
toxicity
rodents
00051784
(
1971)
Unacceptable
Guideline
0,
3,
12,
50,
200
mg/
kg/
day
by
gavage
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
00040345
(
1973)
Unacceptable
Guideline
0,
0.25,
1.0,
4.0
mg/
kg/
day
(
capsules)
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
00029972
(
1973)
Unacceptable
Guideline
0,
50
200
mg/
kg/
day
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
00029964
(
1973)
Unacceptable
Non­
guideline
0,
0.01,
0.1,
1.0
mg
dust/
L;
6
hrs/
day
for
14
days
over
a
period
of
3
weeks.
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.
AMITRAZ/
MARCH/
2004
RED
Toxicology
Chapter
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
32
870.3700a
Prenatal
developmental
in
rats
00029959
(
1973)
Unacceptable
Guideline
0,
1,
3,
or
12
mg/
kg/
day:
GD
days
8
­
20
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
44265902
(
1987)
Acceptable
Guideline
0,
7.5,
15
or
30
mg/
kg/
day
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].

870.3700b
Prenatal
developmental
in
rabbits
00029961
(
1973)
Unacceptable
Guideline
0,
1,
5,
25
mg/
kg/
day
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
44265901
(
1987)
Unacceptable
Guideline
0,
3,
6,
12
mg/
kg/
day
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.
AMITRAZ/
MARCH/
2004
RED
Toxicology
Chapter
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
33
870.3800
Reproduction
and
fertility
effects
(
1­
generation)
00029960
(
1973)
Unacceptable,
Non­
guideline
0,1,
3
or
12
mg/
kg/
day
from
GD
1
­
lactation
day
21.
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)
00029962
(
1973)
Unacceptable
Guideline
0,
1.29/
1.58,
4.36/
5.09,
16.41/
20.05
mg/
kg/
day
(
M/
F)
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
00044586
(
1973)
Acceptable
Guideline
0,
0.1,
0.25,
1.0
mg/
kg/
day
(
capsule)
NOAEL
=
0.25
mg/
kg/
day
LOAEL
=
1.0
mg/
kg/
day
based
on
CNS
depression
during
first
two
days
of
dosing.

870.4300
Chronic
Toxicity/
Carcinogenicity
rats
00044585
(
1973)
Acceptable
Guideline
0,
0.77/
0.97,
2.5/
3.13,
10.18/
12.59
mg/
kg/
day
(
M/
F)
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.
AMITRAZ/
MARCH/
2004
RED
Toxicology
Chapter
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
34
870.4300
Carcinogenicity
mice
00139552
(
1983)
Acceptable
Guideline
0,
2.31/
2.63,
9.61/
10.77,
44.65/
50.13
mg/
kg/
day
(
M/
F)
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
00161009
(
1983)
Acceptable
Guideline
33,
100
and
333

g/
plate
and
1,
3.3
and
10
mg/
plate
Negative
up
to
10
mg/
plate,
with
and
without
metabolic
activation.

Forward
Gene
Mutation
in
mouse
lymphoma
cells
870.5300
00161008
(
1983)
Acceptable
Guideline
0.06,
0.2,
0.6,
2,
6
or
20

g/
ml
Negative
at
0.06­
20

g/
ml
with
and
without
metabolic
activation.
HDT
is
highest
noncytotoxic
dose.

In
Vitro
Cytogenetics
(
Human
Lymphocytes)
870.5375
41795101
(
1988)
Acceptable
Guideline
5,
10,
20

g/
ml
without
metabolic
activation
and
3,
15,
30

g/
ml
with
activation
Negative
up
to
cytotoxic
and/
or
insoluble
concentrations.

UDS
Assay
(
Human
Embryonic
Lung
Fibroblast)
870.5550
00161011
(
1983)
Acceptable
Guideline
20,
60,
100,
140,
180,
220,
260,
300

g/
ml
Negative
up
to
cytotoxic
concentrations,
with
and
without
metabolic
activation.

Cell
Transformation
(
no
guideline
#)
00161010
(
1983)
Acceptable
Nonguideline
12.5,
25
and
37.5

g/
ml
with
S­
9;
5,
10
and
15

g/
ml
without
S­
9.
Negative
up
to
cytotoxic
concentrations,
with
and
without
metabolic
activation.
AMITRAZ/
MARCH/
2004
RED
Toxicology
Chapter
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
35
870.7485
Metabolism
and
pharmacokinetic
s
MRID
00161004
(
1984)/
Acceptable
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)­
Nmethyl
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.

870.7485
Metabolism
and
pharmacokinetic
s
No
MRID:
Knowles,
C.
O.
and
H.
J.
Benezet.
(
1981)
/
Acceptable
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
MRID
42133501
(
1990)/
Acceptable
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).
AMITRAZ/
MARCH/
2004
RED
Toxicology
Chapter
36
9.2
Summary
of
Toxicological
Dose
and
Endpoints
for
Amitraz
for
Use
in
Human
Risk
Assessment
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.
AMITRAZ/
MARCH/
2004
RED
Toxicology
Chapter
Exposure
Scenario
Dose
Used
in
Risk
Assessment,
UF
Special
FQPA
SF*
and
Level
of
Concern
for
Risk
Assessment
Study
and
Toxicological
Effects
37
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
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.